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Deep convolutional neural network-based automated segmentation of the maxillofacial complex from cone-beam computed tomography:A validation study. The present study investigated the accuracy, consistency, and time-efficiency of a novel deep convolutional neural network (CNN) based model for the automated maxillofacial bone segmentation from cone beam computed tomography (CBCT) images. A dataset of 144 scans was acquired from two CBCT devices and randomly divided into three subsets: training set (n = 110), validation set (n = 10) and testing set (n = 24). A three-dimensional (3D) U-Net (CNN) model was developed, and the achieved automated segmentation was compared with a manual approach. The average time required for automated segmentation was 39.1 s with a 204-fold decrease in time consumption compared to manual segmentation (132.7 min). The model was highly accurate for identification of the bony structures of the anatomical region of interest with a dice similarity coefficient (DSC) of 92.6%. Additionally, the fully deterministic nature of the CNN model was able to provide 100% consistency without any variability. The inter-observer consistency for expert-based minor correction of the automated segmentation observed an excellent DSC of 99.7%. The proposed CNN model provided a time-efficient, accurate, and consistent CBCT-based automated segmentation of the maxillofacial complex. Automated segmentation of the maxillofacial complex could act as an alternative to the conventional segmentation techniques for improving the efficiency of the digital workflows. This approach could deliver accurate and ready-to-print3D models, essential to patient-specific digital treatment planning for orthodontics, maxillofacial surgery, and implant dentistry.

The accuracy and learning curve of active and passive dynamic navigation-guided dental implant surgery: An in vitro study. Infrared dynamic navigation systems can be categorized into active and passive based on whether the surgical instruments can emit or only reflect light. This in vitro study aimed to compare the accuracy of implant placement and the learning curve of both active and passive dynamic navigation systems, using different registration methods. Implants (n = 704) were placed in 64 sets of models and divided into active (Yizhime, DCARER, Suzhou, China) and passive (Iris-Clinic, EPED, Kaohsiung, China) dynamic navigation groups. Both marker point-based registration (M-PBR) and feature point-based registration (F-PBR) were employed for the two groups. Based on preoperative and postoperative cone-beam computed tomography imaging, the coronal, midpoint, apical, and angular deviations were analyzed from 2D and 3D views. The operation time was recorded for each group. The active dynamic navigation group exhibited significantly higher accuracy than the passive dynamic navigation group (angular deviation, 4.13 ± 2.39° versus 4.62 ± 3.32°; coronal global deviation, 1.48 ± 0.60 versus 1.86 ± 1.12 mm; apical global deviation, 1.75 ± 0.81 versus 2.20 ± 1.68 mm, respectively). Significant interaction effects were observed for both registration methods and four quadrants with different dynamic navigation systems. Learning curves for the two dynamic navigation groups approached each other after 12 procedures, and finally converged after 27 procedures. The accuracy of active dynamic navigation system was superior to that of passive dynamic navigation system. Different combinations of dynamic navigation systems, registration methods, and implanted quadrants displayed various interactions. Our findings could provide guidance for surgeons in choosing an appropriate navigation system in various implant surgeries. Furthermore, the time required by surgeons to master the technique was calculated. Nevertheless, there are certain limitations in this in vitro study, and therefore further research is required.

The effects of Aroclor 1254 alone and in combination with X-rays on the male mice germ cells quantity and quality. The effects of chemical and physical environmental factors are concerned as the main reason of diminished male fertility. The aim of the study was the investigation of the effects of low doses of Aroclor 1254 or combined exposure to low doses of Aroclor 1254 and low doses of ionizing radiation on the sperm quantity and quality of male germ cells including damage to genetic material of adult male mice. Mice were exposed for 2 weeks, 3 times per week by intraperitoneal injection with Aroclor 1254 diluted in corn oil at doses of 1, 2 and 4 mg/kg bw or to whole body X-rays irradiation at doses 0.05 Gy, 0.10 Gy and 0.15 Gy or to combination of X-rays and Aroclor 1254 at following doses 0.05 Gy + 1 mg/kg bw Aroclor 1254, 0.10 Gy + 2 mg/kg bw Aroclor 1254. The samples for sperm count, motility, morphology and DNA integrity of male germ cells estimation were taken from animals just after the end of exposure and 5 weeks later. Irradiation alone deteriorated sperm count and quality. Aroclor 1254 significantly reduced the sperm motility and increased sperm abnormality and at the highest dose also induced DNA damage of gametes. The combined exposure to 0.10 Gy + 2 mg/kg bw of Aroclor 1254 showed the increase in the sperm concentration and the decrease of percentage of abnormal spermatozoa compared to results after irradiation to 0.10 Gy alone. In conclusion, the low doses of Aroclor 1254 used in this study did not significantly reduce the sperm count, but affected the sperm motility, morphology and sometimes also DNA integrity of gametes. In combination with low doses of irradiation, low doses of Aroclor 1254 may ameliorate the harmful effect of irradiation on the male gametes.

A protective role of autophagy in fine airborne particulate matter-induced apoptosis in LN-229 cells. Air pollution is a public health threat and global epidemiological studies have shown that ambient air pollutants are closely related to various poor health conditions, including neurodegenerative diseases. Here, we evaluated the toxic effects and the underlying mechanisms of fine airborne particulate matter (PM2.5) on human glioblastoma LN-229 cells. Our results showed that exposure of LN-229 cells to PM2.5 (≥ 200 μg/mL) significantly reduced cell viability. PM2.5 exposure increased autophagy, apoptosis, and ROS production in the cells. Pre-treatment with a ROS scavenger, catalase, or depletion of mtDNA (ρ0 cells) abolished PM2.5-induced autophagy and apoptosis. PM2.5 exposure also activated MAPK signals in cells, which were blocked by catalase pre-treatment or mtDNA depletion. Furthermore, inhibition of JNK, but not ERK1/2 or p38, attenuated PM2.5-induced autophagy and apoptosis in cells. Finally, suppression of autophagy with Bafilomycin A1 or Beclin 1 siRNA exacerbated PM2.5-induced apoptosis, indicating a protective role of autophagy against PM2.5-induced apoptosis. Our results demonstrated that exposure of LN-229 cells to PM2.5 caused autophagy and apoptosis through PM2.5-induced ROS generation, mainly by mitochondria, and JNK activation. Autophagy may have a transient protective response in PM2.5-induced apoptosis. These findings have important implications for understanding the potential neurotoxicity of PM2.5.

Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out. A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50 ≤ 2 µM), rapid speed of action and cell viability in HepG2 cells (IC50 ≥ 10 µM). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the cognitive and motor functions in rodents: A systematic review and meta-analysis. Memory and motor deficits are commonly identified in Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is transformed to MPP+ via monoamine oxidase B (MAOB), which causes oxidative stress and destroys dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) and is widely used to create animal models of PD. However, to-date, a comprehensive analysis of the MPTP effects on various aspects of PD does not exist. Here, we provide a systematic review and meta-analysis on the MPTP effects on memory and motor functions by analyzing 51 studies on more than one thousand animals mainly including rats and mice. The results showed that in addition to motor functions such as coordination, balance and locomotor activity, MPTP significantly affects various mnemonic processes including spatial memory, working memory, recognition memory, and associative memory compared with the control group with some differences between systemic and intra-nigral injections on spatial memory, familiar object recognition, and anxiety-like behaviors. Nevertheless, our analysis failed to find systematic relationship between MPTP injection protocol parameters reported and the extent of the induced PD symptoms that can be a cause of concern for replicability of MPTP studies.

Contemporary Use of Trochanteric Plates in Periprosthetic Femur Fractures: A Displaced Trochanter Will Not Be Tamed. The objective of this study was to evaluate the reoperation and complication rate following trochanteric plate fixation of greater trochanter (GT) periprosthetic femur fractures associated with total hip arthroplasty and to identify risk factors for subsequent reoperation, nonunion, and hardware failure (plate/cable breakage or migration). Between 2010 and 2020, 44 patients who had 44 periprosthetic greater trochanter fractures at mean follow up of 2 years were retrospectively reviewed. Initial injury radiographs as well as immediate and final follow-up radiographs were evaluated. Subsequent reoperations, nonunion, and cases of hardware failure were identified. There were 22 (50%) Vancouver B2 fractures and 22 (50%) Vancouver A fractures. The 2-year cumulative probability of any subsequent reoperation was 20%. There were 9 total subsequent reoperations. The trochanteric fracture went on to nonunion in 14 patients (39%), and hardware failure occurred in 10 (28%) patients. A trochanteric bolt was used in addition to the trochanteric plate in 6 patients (14%), of which 4 (67%) patients had trochanteric plate displacement and 3 (50%) patients had trochanteric nonunion. Displacement of the greater trochanter prior to fixation was a predictor of subsequent nonunion (77% versus 23%, P = .02). In this large contemporary series, there was a high incidence of reoperation (20%) with in the first 2-years following plating of periprosthetic GT fractures, as well as a high rate of nonunion (39%), and hardware failure (28%). Displacement of the GT prior to plating predicted nonunion. Level IV, retrospective observational study.

Cost Drivers in Two-Stage Treatment of Hip Periprosthetic Joint Infection With an Antibiotic Coated Cement Hip Spacer. The current gold standard for treating chronic Periprosthetic Joint Infection (PJI) is a 2-stage revision arthroplasty. There has been little investigation into what specific patient and operative factors may be able to predict higher costs of this treatment. An institutional electronic health record database was retrospectively queried for patients who developed a PJI after a total hip arthroplasty, and underwent removal of the prosthesis and implantation of an antibiotic-impregnated articulating hip cement spacer. Patient demographics, surgical variables, hospital readmissions, emergency department visits, and post-operative complications were collected. Total costs were captured through an internal accounting database through 2 years post-operatively. Negative binomial regressions were utilized for multivariable analyses. A total of 55 hips with PJI were available for cost analyses. A comorbidity index score was associated with a 70% increase (Odds Ratio (OR): 1.7 [1.18-2.5], P = .003) in total costs at 2-years. Illicit drug use was associated with a 70% increase in costs at 1-year post-operatively (OR 1.7 [1.18-2.5], P = .003). Metal-on-poly liners were associated with a 22% decrease in cost at 2-years post-operatively when compared to Cement-on-Bone articulating spacers, and Metal-on-poly -constrained liners accounted for 38% lower costs at 1-year (OR 0.62 [0.44-0.87], P = .004). Use of an intraoperative extended trochanteric osteotomy was associated with a 46 and 61% increase in cost at 1-year (OR 1.46 [1.14-1.89]) and 2-years (OR 1.61 [1.26-2.07], P < .001) post-operatively. Age, comorbidity index score, drug use, and extended trochanteric osteotomy were associated with increased costs of PJI treatment. This may be used to improve reimbursement models and target areas of cost savings.

The relationship between multisensory associative learning and multisensory integration. Integrating sensory information from multiple modalities leads to more precise and efficient perception and behaviour. The process of determining which sensory information should be perceptually bound is reliant on both low-level stimulus features, as well as multisensory associations learned throughout development based on the statistics of our environment. Here, we explored the relationship between multisensory associative learning and multisensory integration using encephalography (EEG) and behavioural measures. Sixty-one participants completed a three-phase study. First, participants were exposed to novel audiovisual shape-tone pairings with frequent and infrequent stimulus pairings and completed a target detection task. EEG recordings of the mismatch negativity (MMN) and P3 were calculated as neural indices of multisensory associative learning. Next, the same learned stimulus pairs were presented in audiovisual as well as unisensory auditory and visual modalities while both early (<100 ms) and late neural indices of multisensory integration were recorded. Finally, participants completed an analogous behavioural speeded-response task, with behavioural indices of multisensory gain calculated using the Race Model. Significant relationships were found in fronto-central and occipital areas between neural measures of associative learning and both early and late indices of multisensory integration in frontal and centro-parietal areas, respectively. Participants who showed stronger indices of associative learning also exhibited stronger indices of multisensory integration of the stimuli they learned to associate. Furthermore, a significant relationship was found between neural index of early multisensory integration and behavioural indices of multisensory gain. These results provide insight into the neural underpinnings of how higher-order processes such as associative learning guide multisensory integration.

Thirty-Two Weeks of Oral Supplementation with LinPro™ Increases Hoof Growth in Healthy Mares. LinPro™ (LP) is a commercial dietary supplement marketed to increase hoof growth and quality. Ten mature (5-15 years) non-pregnant Quarter Horse mares without existing hoof quality issues were used to test the hypothesis that 32 weeks of daily supplementation with 113 g of LP would increase hoof growth rates as compared to non-supplemented controls. Hooves were trimmed at the start of the study and every 8 weeks thereafter. A mark was applied on the hoof wall surface at 2.5 cm below the junction of the hoof wall and coronary band. At each trimming, the distance between the mark and coronary band was measured and a new mark placed. For front hooves, horses assigned to LP had greater total hoof growth over 32 weeks (2.65 ± 0.15 vs. 2.18 ± 0.12 cm; P = .048) and tended to have greater hoof growth per 8 weeks trimming cycle (0.64 ± 0.03 vs. 0.55 ± 0.03 cm; P = .085) than horses assigned to non-supplemented controls (CON). Horses assigned to LP had greater plasma biotin concentrations (2158 ± 69 vs. 636 ± 62 ng/L; P < .001) and proportions of erucic acid in hoof tissue (1.03 ± 0.08 vs. 0.76 ± 0.07 %; P = .049) as compared to CON. Further, the most abundant fatty acids in hoof tissue were stearic, palmitic, oleic, and linoleic acids. LinPro may provide an effective treatment to improve hoof growth rates in horses with otherwise healthy hooves.

Patient-controlled intravenous versus on-demand oral, intramuscular or mcs intravenous administration of oxycodone during medical induced abortion from 64 to 128 days of Gestation: A randomized controlled trial. To compare oxycodone administration via intravenous patient-controlled analgesia (IVPCA) vs on-demand administration during late-first- and second-trimester medically induced abortion. A prospective randomized controlled study. We enrolled women between 64 to 128 days of gestation in the study between June 2016 and August 2018. Participants were randomized to receive oxycodone either via IVPCA or given on-demand orally, intramuscularly, or intravenously. Pain intensity and satisfaction with care were measured using the visual analogue scale (VAS, 0-100mm). Altogether 99 participants were randomized: 48 in IVPCA group and 51 in on-demand group. Median gestational age was similar between groups (74 days [Interquartile range, IQR 69-81] in the IVPCA group vs 72 [69-80] in the control group, p = 0.587). Peak maximal pain was severe in both groups (median pain VAS was 62 [IQR 44-84] and 71 [IQR 56-90], p = 0.52). The odds for severe pain (highest pain VAS≥70) were similar between the groups (IVPCA group OR 0.51 [95% Confidence Interval 0.22-1.18], p = 0.118). In contrast, the odds for mild or tolerable pain (highest pain VAS≤40) were higher in the IVPCA group (OR 4.06 [95% CI 1.05-16.04], p = 0.043). Nevertheless, satisfaction with care was high (VAS 94 [89-100]) in both groups. Of those experiencing severe pain, 94.0% declared pain medication as adequate. Women often experience severe pain during medical abortion irrespective of the mode of opiate administration. Oxycodone administration via IVPCA permits women to self-administer analgesics when experiencing pain, raising the odds for mild or tolerable pain during abortion care. Satisfaction with care was high. Medical abortion in late-first- and second-trimester is often painful experience. IVPCA offers a good method of choice for analgesia and raises the odds for tolerable pain (pain VAS less than 40) experience when compared to on-demand administration of analgesics.

Society of Family Planning committee consensus on Rh testing in early pregnancy. Historical evidence that fetal red blood cell (RBC) exposure during early spontaneous or induced abortion can cause maternal Rh sensitization is limited. A close reading of these studies indicates that forgoing Rh immunoglobulin administration before 12weeks gestation is highly unlikely to increase risk of Rh (D) antibody development, and recent studies indicate that fetal RBC exposure during aspiration abortion <12 weeks gestation is below the calculated threshold to cause maternal Rh sensitization, and the amount of fetomaternal hemorrhage during dilation and evacuation procedures up to 18weeks gestation is adequately treated with 100mcg of Rh immunoglobulin. We provide updated recommendations for Rh immunoglobulin administration based on this new evidence.

Chronic exposure to methadone impairs memory, induces microgliosis, astrogliosis and neuroinflammation in the hippocampus of adult male rats. Methadone is a centrally-acting synthetic opioid analgesic widely used in methadone maintenance therapy (MMT) programs throughout the world. Given its neurotoxic effects, particularly on the hippocampus, this study aims to address the behavioral and histological alterations in the hippocampus associated with methadone administration. To do so, twenty-four adult male albino rats were randomized into two groups, methadone treatment and control. Methadone was administered subcutaneously (2.5-10 mg/kg) once a day for two consecutive weeks. A comparison was drawn with behavioral and structural changes recorded in the control group. The results showed that methadone administration interrupted spatial learning and memory function. Accordingly, treating rats with methadone not only induced cell death but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. Furthermore, the results demonstrated that treating rats with methadone decreased the complexity of astrocyte processes and the complexity of microglia processes. These findings suggest that methadone altered the special distribution of neurons. Also, a substantial increase was observed in the expression of TNF-α due to methadone. According to the findings, methadone administration exerts a neurodegenerative effect on the hippocampus via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Identification and characterization of three nearly identical linalool/nerolidol synthase from Acorus calamus. Acorus calamus is a perennial aromatic medicinal plant from the Acorusaceae family, known for its pharmaceutical and medicinal value. A combined chemical, biochemical, and molecular study was conducted to evaluate the differential accumulation of volatile organic compounds (VOCs) in rhizomes and leaves of A. calamus essential oil. Here, we performed VOC profiling and transcriptome-based identification and functional characterization of terpene synthase (TPS) genes. A total of 110 VOCs were detected from the rhizomes and leaves of A. calamus, and some VOCs showed significant differences between them. The further transcriptome-based analysis led to the identification of six putative TPSs genes. In phylogenetic analysis, three TPSs belonged to the TPS-g clade, one to each of the TPS-a, TPS-c, and TPS-e clades. The heterologous E. coli-based expression of recombinant TPSs identified three genes (AcTPS3, AcTPS4, and AcTPS5) as bifunctional linalool/nerolidol synthase. The correlation of TPS gene expression and VOC metabolite profiles supported the function of these genes in A. calamus. Our findings provide a roadmap for future efforts to enhance the molecular mechanisms of terpene biosynthesis and our understanding of Acorus-insect interactions.

Toxicity of titanate nanotubes in earthworm (Eisenia fetida): Growth inhibition and integrated biomarker response. Widely use of Titanate Nanotubes (TNTs) as remediation materials for heavy metal polluted water and soil lead to their release into the soil environment, persistently threatening faunal biodiversity and the entire environment. Growth inhibition rates (GIR) and specific growth rates (SGR) are used to evaluate the effect of TNTs on earthworm growth, and the integrated biomarker response (IBR) index is used to comprehensively evaluate the toxicity of eight biomarkers (Protein-body mass ratio, MDA, SOD, CAT, POD, Cellulase, AChE, and Na+/K+-ATPase) on earthworms exposed to TNTs contaminated soil by concentrations of CK, 50, 250, 500 and 2500 mg TNTs/kg dry soil. Results show that TNTs significantly inhibit the growth of earthworms (p < 0.05), and GIR reaches up to 52.34 % at 2500 mg TNTs/kg dry soil for 28 days. IBR index has a dose-time relationship, which indicates that exposure time and concentration of TNTs contaminated soil affect the toxicity degree of contaminant to earthworms.

Exposure to amitriptyline induces persistent gut damages and dysbiosis of the gut microbiota in zebrafish (Danio rerio). Amitriptyline (AMI), the most commonly prescribed tricyclic antidepressant, is widely detected in water environments. Exposure to AMI may lead to diverse adverse effects on aquatic organisms, but little is known about the effect of short-term exposure to AMI on the gut microbiota of aquatic organisms and their recovery characteristics. In the present study, adult zebrafish (Danio rerio) were exposed to AMI (0, 2.5, 10, and 40 μg/L) for seven days, and then allowed to recover in AMI-free culture water for 21 days. The exposure caused gut damages in all the AMI treated groups of zebrafish, which became more severe after recovery compared to the control group. AMI exposure also disturbed the microbiota of zebrafish guts and rearing water even after the 21-day recovery period. Furthermore, AMI exposure affected microbes involved in the substance and energy metabolic functions in zebrafish guts and tended to increase the abundance of microbial genera associated with opportunistic pathogens. In addition, the microbial predicted metabolic functions in AMI-exposed guts of zebrafish were significantly altered after the 21-day recovery period, explaining the persistent effects of short-term exposure to AMI. The results of this study suggest that acute exposure to AMI may have persistent impacts on the gut histomorphology and the gut microbiota in aquatic organisms.

Resistance exercise promotes functional test via sciatic nerve regeneration, and muscle atrophy improvement through GAP-43 regulation in animal model of traumatic nerve injuries. Resistance training improves muscle strength through a combination of neural plasticity and muscle hypertrophy. This study aimed to evaluate the effects of resistance exercise on sciatic nerve regeneration and histology, growth-associated protein 43 (GAP-43) expressions, and soleus muscle atrophy following traumatic nerve injuries in Wistar rats. In the present study, 40 male Wistar rats were randomly assigned into four groups: healthy control (HC) as a sham group was exposed to the surgical procedures without any sciatic nerve compression, lesioned control (LC), resistance training (RT,non-lesioned), and lesioned rats + RT (LRT) (n = 10 in each). The RT group performed a resistance-training program 5 days/week for 4 weeks. Sciatic functional index (SFI) score, beam score and Basso, Beattie, and Bresnahan (BBB) score decreased and the hot plate time increased significantly in the LC‌ group compared to the HC (p < 0.05) group. However, the LRT‌ group showed a significant increase in the SFI score (p = 0.001) and a significant decrease in hot plate time (p = 0.0232) compared to the LC group. The LC group also showed neurological morphological damage and muscle atrophy and a decrease in GAP-43 in nerve tissue. In comparison to the LC group, a significant increase in sciatic nerve caliber, diameter, number of muscle fibers, and the expression of GAP-43‌ (p < 0.05) was observed in the LRT group. Doing resistance training even for four weeks seems to affect sciatic nerve lesions and injuries. It can also repair and regenerate nerve tissue by upregulating GAP-43 expression‌, improving motor behavioral tests, and controlling muscle atrophy.

Inborn errors of immunity associated with elevated immunoglobulin E. To review the characteristic clinical and laboratory features of inborn errors of immunity (IEI) that are associated with elevated immunoglobulin (Ig)E levels. Primary peer-reviewed literature. Original research articles reviewed include interventional studies, retrospective studies, case-control studies, cohort studies, and review articles related to the subject matter. An extensive literature review was completed to allow for comprehensive evaluation of several monogenic IEI. This review includes a description of the classic clinical features, common infections, characteristic laboratory findings, specific diagnostic methods (when applicable), and genetic basis of disease of each syndrome. A comprehensive flow diagram was created to assist them in the diagnosis and evaluation of patients with elevated IgE levels who may require evaluation for an IEI. IEI should be considered in patients with elevated IgE levels, especially if they have recurrent infections, eczematous dermatitis, malignancy, lymphoproliferation, autoimmunity, or connective tissue abnormalities.

Relationship between low serum immunoglobulin E levels and malignancies in 9/11 World Trade Center responders. Individuals with very low immunoglobulin E (IgE) levels have a high risk of developing malignancy. Previous studies have revealed that World Trade Center (WTC) responders exposed to carcinogens have an elevated risk of some cancers. To evaluate the association between low-serum IgE levels and cancer development in WTC-exposed responders. IgE levels were measured in 1851 WTC responders after September 11, 2001. This is the first pilot study in humans comparing the odds of developing cancer in this high-risk population, between the "low-IgE" (IgE in the lowest third percentile) vs "non-low-IgE" participants. A significantly higher proportion of hematologic malignancies was found in low-IgE (4/55, 7.3%) compared with non-low-IgE (26/1796, 1.5%, P < .01) responders. The proportion of solid tumors were similar in both groups (5.5% vs 11.4%, P > .05). After adjustment for relevant confounders (race, sex, age at blood draw, WTC arrival time, smoking status), the low-IgE participants had 7.81 times greater odds (95% confidence interval, 1.77-29.35) of developing hematologic cancer when compared with non-low-IgE participants. The hematologic cancers found in this cohort were leukemia (n = 1), multiple myeloma (n = 1), and lymphoma (n = 2). No statistical significance was found when estimating the odds ratio for solid tumors in relation to IgE levels. WTC responders with low serum IgE levels had the highest odds of developing hematologic malignancies. This hypothesis-generating study suggests that low serum IgE levels might be associated with the development of specific malignancies in at-risk individuals exposed to carcinogens. Larger, multicenter studies with adequate follow-up of individuals with different IgE levels are needed to better evaluate this relationship.

Dietary Quality and Diet-Related Factors Among Female Adults of Reproductive Age With and Without Disabilities Participating in the National Health and Nutrition Examination Surveys, 2013-2018. Female adults of reproductive age (18 to 44 years) with disabilities have higher rates of health-risk behaviors and chronic conditions compared with their counterparts without disabilities; however, there is limited examination of diet. Our aim was to examine associations of self-reported disability status with diet quality and diet-related factors. Cross-sectional data were from the National Health and Nutrition Examination Surveys, 2013-2018. Female adults aged 18 through 44 years were included. Disability was defined as serious difficulty hearing, seeing, concentrating, walking, dressing, and/or running errands due to physical, mental, or emotional conditions. The Healthy Eating Index-2015 assessed diet quality. Diet-related factors included self-rated diet healthfulness, meal characteristics, food security, and food assistance programs. Multivariable linear regression estimated differences in Healthy Eating Index-2015 scores for a given day and multivariable Poisson regression estimated adjusted prevalence ratios and 95% CI of diet-related factors by disability status. Of 3,579 female adults, 557 (16%) reported any disabilities, 207 (6%) of whom reported having 2 or more types of disabilities. Differences in mean Healthy Eating Index-2015 scores for a given day were one-third to one-half a point lower for fruits, total protein foods, and seafood and plant proteins among female adults with 2 or more types of disabilities compared with those without disabilities. Female adults with any disabilities were more likely to rate their diet as poor, have low food security, participate in food-assistance programs, and consume frozen foods or pizza, compared with those without disabilities (adjusted prevalence ratio ranged from 1.35 to 1.93); they were less likely to be the main food planner or preparer or shopper for their households. Some indicators of diet quality and diet-related factors differed between female adults with and without disabilities. Additional investigation of dietary intakes and behaviors, as well as access to and availability of healthy foods, among female adults with disabilities is necessary.

Do neoliberal values provide a fertile soil for suicidal ideation? Values associated with neoliberal ideologies are blamed for damaging the social fabric. They may also have deleterious effects on suicidal ideation. We investigated whether neoliberal values were associated with the risk for suicidal ideation through a set of mediating factors (suicide stigma, help-seeking attitudes, perceived stress, and suicide acceptability). A total of 508 (249 female) adults from the U.S. responded to a self-administered questionnaire that contained measures of suicidal ideation, neoliberal values, suicide stigma, help-seeking attitudes, perceived stress, and suicide acceptability. We tested a path model that linked neoliberal values to suicidal ideation through multiple mediators. We tested total versus partial mediation models. We found empirical evidence for a full mediation of the association of neoliberal values with perceived stress. Neoliberal values were associated with suicide stigma; suicide stigma was associated with negative attitudes towards help-seeking, which, in turn, were associated with high levels of perceived stress. The association of neoliberal values with suicide acceptability was partially mediated. Perceived stress was positively associated with suicide risk directly and indirectly through suicide acceptability. Our findings suggest that values related to neoliberal ideologies prepare a context that fosters the risk for suicide. For a contextualized understanding of suicidal behavior, more research is needed that explores the role of social, cultural, political, and economic ideologies in the suicidal process.

Exploring the correlates of homicidal ideation in Chinese early adolescents: A network analysis. Adolescent homicide rates have aroused global concern and better understanding of factors relating to homicidal ideation is critical. This study aimed to explore the correlates of homicidal ideation in a cross-sectional school-based sample of Chinese early adolescents. The data were obtained from the cross-sectional project 'Health and Risky Behaviors among Middle School Students in Anhui Province, China', which was conducted in November 2020. The entire sample of 5724 middle school students who completed the questionnaires was included in the present study. Network analysis was employed to examine the correlates of homicidal ideation at three levels: individual (sex, academic performance, childhood trauma, aggression, anxiety, severe physical illness), family (family economic status, family violence, parental crime, parental mental illness, relationship with father, relationship with mother), and school (school-bullying victimization and perpetration, relationship with classmates, teacher support). Additionally, sensitivity analyses were performed to evaluate sex differences. In the whole sample, 11.7 % of students reported homicidal ideation in the past six months. Network analyses revealed that individual-level (childhood maltreatment, aggression and anxiety) and school-level (teacher support, school-bullying victimization and perpetration) factors were associated with homicidal ideation. Sensitivity analyses showed that homicidal ideation was associated with academic performance and school-bullying victimization in boys but not in girls, although the sex differences were not significant. The cross-sectional design of this study limited the inference of causality. This study identified some correlates of homicidal ideation and provided some novel insights into homicide prevention and intervention in Chinese early adolescents.

The effects of hormonal contraceptive use on sleep patterns in women of reproductive age. Hormonal contraceptives alter hormone levels in women and have been linked to alterations in sleep patterns; however, previous studies yielded inconsistent results and lacked generalizability. This study examines hormonal contraceptive use and its impact on sleep outcomes, including sleep duration and sleep disturbances. Women self-reported their sleep patterns and use of contraceptives in the 2017 population-based Behavioral Risk Factor Surveillance System Survey (n=1,970). Participants were categorized by use of hormonal or non-hormonal contraceptives for the purpose of pregnancy prevention. Sleep duration was defined as having met the recommended sleep levels of 7-9 hours per 24 hours. Sleep disturbances were defined as trouble falling asleep, staying asleep, or sleeping too much ≥ 6 days within a 14-day period. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated to examine the association between contraceptive use and each sleep outcome. SAS-callable SUDAAN was used for analyses to account for the complex sampling design. Women who used hormonal contraceptives had 6% higher prevalence of sleep disturbances (PR: 1.06, 95% CI: 0.99, 1.14) and 17% lower prevalence of not meeting sleep duration recommendations (PR: 0.83, 95% CI: 0.71, 0.98) compared to those who used non-hormonal contraceptives after adjustment for age. These findings suggest the use of hormonal contraceptives may have negative impacts on sleep disturbances, and positive effects on sleep duration among women using contraceptives for preventing pregnancy. Future studies should be conducted in diverse populations utilizing objective measurements of sleep patterns.

Irisin: A promising treatment for neurodegenerative diseases. The beneficial effects of exercise on human brain function have been demonstrated in previous studies. Myokines secreted by muscle have attracted increasing attention because of their bridging role between exercise and brain health. Regulated by PPARγ coactivator 1α, fibronectin type III domain-containing protein 5 releases irisin after proteolytic cleavage. Irisin, a type of myokine, is secreted during exercise, which induces white adipose tissue browning and relates to energy metabolism. Recently, irisin has been shown to exert a protective effect on the central nervous system. Irisin secretion triggers an increase in brain-derived neurotrophic factor levels in the hippocampus, contributing to the amelioration of cognition impairments. Irisin also plays an important role in the survival, differentiation, growth, and development of neurons. This review summarizes the role of irisin in neurodegenerative diseases and other neurological disorders. As a novel positive mediator of exercise in the brain, irisin may effectively prevent or decelerate the progress of neurodegenerative diseases in models and also improve cognitive functions. We place emphasis herein on the potential of irisin for prevention rather than treatment in neurodegenerative diseases. In ischemic diseases, irisin can alleviate the pathophysiological processes associated with stroke. Meanwhile, irisin has anxiolytic and antidepressant effects. The potential therapeutic effects of irisin in epilepsy and pain have been initially revealed. Due to the pleiotropic and beneficial properties of irisin, the possibility of irisin treating other neurological diseases could be gradually explored in the future.

Neuronal nuclear tau and neurodegeneration. Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging acceleration.

Human exposure to polybrominated diphenyl ethers (PBDEs) through the diet: An update of the scientific literature. Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame-retardants (BFRs). As for other persistent organic pollutants, dietary intake (followed by dust inhalation) is the main route of human exposure to PBDEs. In 2012, we reviewed the scientific literature on the concentrations of PBDEs in foodstuffs and their dietary exposure. The current review is aimed at updating the results of recent studies (2012-2022) focused on determining the levels of PBDEs in food samples, as well as the dietary intake of these compounds. We have revised studies conducted over the world. The current information on the concentrations of PBDEs in food and their dietary intake is now much more notable than that available in our previous review, being China the country contributing with the highest number of studies. Because of the important differences in materials and methods used in the available studies, the comparison of results is certainly complicated. However, there seems to be a general trend towards a decrease in the levels of PBDEs in foods, and consequently, in the dietary intake of these contaminants. The lack of tolerable daily intakes of PBDEs is an issue that needs to be solved for assessing human health risks of these BFRs.

Electrochemical sensing of copper (II) ion in water using bi-metal oxide framework modified glassy carbon electrode. In this research, an electrochemical sensor was fabricated employing the metal-organic framework (MOF) deposited glassy carbon electrode (GCE) for the sensing copper ions in water with high sensitivity. The porous nanostructured MOF was characterized through Transmission electron microscope, scanning electron microscope and X-ray diffraction analysis. The Bi-MOF nanostructure deposited GCE (Bi-MOF/GCE) was fabricated by drop-casting a suspension of Bi-MOF in water on GCE surface. The performance of modified electrode in the presence and absence of heavy metal ions such as Cd2+, Hg2+ As3+, Pb2+ and Cu2+ was determined by the cyclic voltammetry in deionised water within the scan rate range of 25 and 300 mVs-1. The Bi-MOF/GCE displayed highest anodic and cathodic peak current for Cu2+ ions than other metal ions, which was enhanced linearly within the scan rate range of 10-100 mV s-1. Under the employed experimental conditions, the fabricated Bi-MOF/GCE based electrochemical sensor showed an outstanding routine in the determination of copper with a lowest sensing limit of 1 × 10-5 M, wide linear range variation, strong interaction between metal ions and Bi-MOF. It has long-term stability and good reproducibility. The Bi-MOF/GCE electrode was successfully tested to detect Cu2+ in tap water with acceptable results.

Transforming growth factor-β induced protein regulates pulmonary fibrosis via the G-protein signaling modulator 2 /Snail axis. Pulmonary fibrosis, a severe condition that can progress to respiratory failure and death, is characterized by aberrant activation/proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition and has limited therapeutic options. Identifying novel mediators of pulmonary fibrosis is currently needed to facilitate the development of more effective therapeutic strategies targeting pulmonary fibrosis. The present study was designed to investigate whether transforming growth factor-β (TGF-β) induced protein (TGFBI), an extracellular matrix protein, regulates pulmonary fibrosis in vitro and in vivo and the possible mechanism of actions. It was found that protein expressions of TGFBI were significantly upregulated and G-protein signaling modulator 2 (GPSM2) expression downregulated in fibrotic lung tissues from bleomycin (BLM)-induced rats and TGF-β1-stimulated human lung IMR-90 fibroblasts. Either silencing TGFBI with specific siRNA or treatment with the TGF-β signaling inhibitor SB431542 significantly inhibited TGF-β1-induced fibrotic effects and dysregulation of GPSM2 and Snail expressions in IMR-90 fibroblasts. Moreover, GPSM2 overexpression also inhibited TGF-β1-induced fibrotic effects and Snail upregulation in IMR-90 fibroblasts. Silencing Snail with specific siRNA attenuated TGF-β1-induced fibrotic effects. Therefore, our findings suggest that the extracellular matrix protein TGFBI mediates pulmonary fibrosis through regulation of the GPSM2/Snail axis, which identifies TGFBI as a novel mediator of pulmonary fibrosis and may be a potential therapeutic target for the treatment of pulmonary fibrosis.

Doxycycline as an antimalarial: Impact on travellers' diarrhoea and doxycycline resistance among various stool bacteria - Prospective study and literature review. Antibiotics predispose travellers to acquire multidrug-resistant bacteria, such as extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE). Although widely used in antimalarial prophylaxis, doxycycline has scarcely been studied in this respect. We explored the impact of doxycycline on rates of traveller's diarrhoea (TD), ESBL-PE acquisition and, particularly, doxycycline co-resistance among travel-acquired ESBL-PE in a sample of 412 visitors to low- and middle-income countries. We reviewed the literature on traveller studies of doxycycline/tetracycline resistance among stool pathogens and the impact of doxycycline on TD rates, ESBL-PE acquisition, and doxycycline/tetracycline resistance. The TD rates were similar for doxycycline users (32/46; 69.6%) and non-users (256/366; 69.9%). Of the 90 travel-acquired ESBL-PE isolates, 84.4% were co-resistant to doxycycline: 100% (11/11) among users and 82.3% (65/79) among non-users. The literature on doxycycline's effect on TD was not conclusive nor did it support a recent decline in doxycycline resistance. Although doxycycline did not increase ESBL-PE acquisition, doxycycline-resistance among stool pathogens proved more frequent for users than non-users. Our prospective data and the literature review together suggest the following: 1) doxycycline does not prevent TD; 2) doxycycline use favours acquisition of doxy/tetracycline-co-resistant intestinal bacteria; 3) although doxycycline does not predispose to travel-related ESBL-PE acquisition per se, it selects ESBL-PE strains co-resistant to doxycycline; 4) doxycycline resistance rates are high among stool bacteria in general with no evidence of any tendency to decrease.

Confederated learning in healthcare: Training machine learning models using disconnected data separated by individual, data type and identity for Large-Scale health system Intelligence. A patient's health information is generally fragmented across silos because it follows how care is delivered: multiple providers in multiple settings. Though it is technically feasible to reunite data for analysis in a manner that underpins a rapid learning healthcare system, privacy concerns and regulatory barriers limit data centralization for this purpose. Machine learning can be conducted in a federated manner on patient datasets with the same set of variables but separated across storage. But federated learning cannot handle the situation where different data types for a given patient are separated vertically across different organizations and when patient ID matching across different institutions is difficult. We call methods that enable machine learning model training on data separated by two or more dimensions "confederated machine learning", which we aim to develop in this study. We propose and evaluate confederated learning for training machine learning models to stratify the risk of several diseases among silos when data are horizontally separated by individual, vertically separated by data type, and separated by identity without patient ID matching. The confederated learning method can be intuitively understood as a distributed learning method with representation learning, generative model, imputation method and data augmentation elements. Our confederated learning method achieves AUCROC (Area Under The Curve Receiver Operating Characteristics) of 0.787 for diabetes prediction, 0.718 for psychological disorders prediction, and 0.698 for Ischemic heart disease prediction using nationwide health insurance claims. Our proposed confederated learning method successfully trained machine learning models on health insurance data separated by two or more dimensions.

Improved biohydrogen evolution through calcium ferrite nanoparticles assisted dark fermentation. Dark fermentation (DF) is a green hydrogen (H2) production process, but it is far below the theoretical H2 yield. In this study, calcium ferrite nanoparticles (CaFe2O4 NPs) were produced to augment H2 yield via DF. The highest H2 yield of 250.1 ± 6.5 mL/g glucose was achieved at 100 mg/L CaFe2O4 NPs. Furtherincreasein CaFe2O4 NPs above 100 mg/L, such as 600 mg/L, would slightly lower H2 yield to 208.6 ± 2.6 mL/g glucose. The CaFe2O4 NPs in DF system released calcium and iron ions, promoting granular sludge formation andDF microbial activity. Soluble metabolites revealed that butyric acid was raised by CaFe2O4 NPs, which indicated the improved metabolic pathway for more H2. Microbial structure composition further illustrated that CaFe2O4 NPs could increase the abundance of dominant microbial populations, with the supremacy of Firmicutes up to 71.22 % in the bioH2 evolution group augmented with 100 mg/L CaFe2O4 NPs.

Multiview Incomplete Knowledge Graph Integration with application to cross-institutional EHR data harmonization. The growing availability of electronic health records (EHR) data opens opportunities for integrative analysis of multi-institutional EHR to produce generalizable knowledge. A key barrier to such integrative analyses is the lack of semantic interoperability across different institutions due to coding differences. We propose a Multiview Incomplete Knowledge Graph Integration (MIKGI) algorithm to integrate information from multiple sources with partially overlapping EHR concept codes to enable translations between healthcare systems. The MIKGI algorithm combines knowledge graph information from (i) embeddings trained from the co-occurrence patterns of medical codes within each EHR system and (ii) semantic embeddings of the textual strings of all medical codes obtained from the Self-Aligning Pretrained BERT (SAPBERT) algorithm. Due to the heterogeneity in the coding across healthcare systems, each EHR source provides partial coverage of the available codes. MIKGI synthesizes the incomplete knowledge graphs derived from these multi-source embeddings by minimizing a spherical loss function that combines the pairwise directional similarities of embeddings computed from all available sources. MIKGI outputs harmonized semantic embedding vectors for all EHR codes, which improves the quality of the embeddings and enables direct assessment of both similarity and relatedness between any pair of codes from multiple healthcare systems. With EHR co-occurrence data from Veteran Affairs (VA) healthcare and Mass General Brigham (MGB), MIKGI algorithm produces high quality embeddings for a variety of downstream tasks including detecting known similar or related entity pairs and mapping VA local codes to the relevant EHR codes used at MGB. Based on the cosine similarity of the MIKGI trained embeddings, the AUC was 0.918 for detecting similar entity pairs and 0.809 for detecting related pairs. For cross-institutional medical code mapping, the top 1 and top 5 accuracy were 91.0% and 97.5% when mapping medication codes at VA to RxNorm medication codes at MGB; 59.1% and 75.8% when mapping VA local laboratory codes to LOINC hierarchy. When trained with 500 labels, the lab code mapping attained top 1 and 5 accuracy at 77.7% and 87.9%. MIKGI also attained best performance in selecting VA local lab codes for desired laboratory tests and COVID-19 related features for COVID EHR studies. Compared to existing methods, MIKGI attained the most robust performance with accuracy the highest or near the highest across all tasks. The proposed MIKGI algorithm can effectively integrate incomplete summary data from biomedical text and EHR data to generate harmonized embeddings for EHR codes for knowledge graph modeling and cross-institutional translation of EHR codes.

A novel fermentation strategy for efficient xylose utilization and microbial lipid production in lignocellulosic hydrolysate. The sugar utilization efficiency and the tolerance of microorganism to inhibitors are essential for lipid production from lignocellulosic biomass. In this study, the sugar consumption and inhibitor tolerance characteristics of Trichosporon dermatis 32,903 were investigated. The results showed that the lipid yield on xylose was much lower than that on glucose, while these substrates exhibited comparative efficiency for cell growth. High inoculum size improved the tolerance of T. dermatis 32,903 to inhibitors. Based on these characteristics, sugar-targeted-utilization and cyclic fermentation strategy was developed. The tolerance of high inoculum size to inhibitors was utilized, glucose was targeted for lipid fermentation and xylose was targeted for cell growth. As a result, the lipid production efficiency was greatly enhanced. The lipid titer in hydrolysate of DLCA (Densifying Lignocellulosic biomass with Chemicals followed by Autoclave) pretreated rice straw was improved to as high as 38.4 g/L with lipid yield of 0.207 g/g consumed sugar.

Conductive biofilms in up-flow anaerobic sludge blanket enhanced biomethane recovery from municipal sewage under ambient temperatures. The feasibility of municipal sewage treatment in laboratory-scale up-flow anaerobic sludge blankets was investigated in this work. Unlike previous studies, granular activated carbon (conductive) or sponge (non-conductive) was introduced to hollow plastic balls as carriers and suspended in the middle and upper layers of the reactors. The two bioreactors were operated at four different hydraulic retention times (stepwise reduced from 24 h to 8 h) for 100 days at ∼18 °C. The conductive-amended treatment was more effective than the non-conductive treatment in enhancing reactor performance. Interestingly, in the reactor containing conductive carriers, microorganisms enriched in the conductive biofilm were also dominant in the suspended sludge. In the reactor containing sponge carriers, the dominant microorganisms differed between the non-conductive biofilm and the suspended sludge. This study underlines that the enrichment of functional microbial communities and the positive impacts of biofilm on suspended sludge are the keys to improving biomethane recovery.

Feedstock-dependent abundance of functional genes related to nitrogen transformation controlled nitrogen loss in composting. The objective of this work was to explore how selection of feedstock affects nitrogen cycle genes during composting, which eventually determines the nitrogen loss. Four composting mixes (CM: chicken manure; SM: sheep manure; MM1/3: mixed manure with CM: SM = 1:3 w/w, MM3/1: CM: SM = 3:1 w/w) were investigated. Results showed that adding 25 % and 75 % SM to CM reduced 26.5 % and 57.9 % nitrogen loss, respectively. CM contained more ammonification genes and nrfA gene, while SM had more denitrification genes. Nitrogen fixation genes in CM were slightly higher than that in SM at the initial stage, but they sharply dropped off as the composting entered the high temperature stage. MM1/3 showed significantly reduced ammonification genes than CM, and increased nitrogen fixation and NH4+ assimilation genes. Therefore, adding SM to CM could change the abundance of genes and enzymes related to nitrogen cycle to reduce nitrogen loss.

Co-fermentation of sewage sludge and lignocellulosic biomass for production of medium-chain fatty acids. Medium-chain fatty acids (MCFAs) production from sewage sludge and lignocellulosic biomass (fallen leaves and grass) was explored. Co-fermentation of sludge and lignocellulosic biomass significantly accelerated the caproate production and promoted the longer-chain MCFAs formation. Co-fermentation of sludge and grass achieved the highest caproate production of 89.50 mmol C/L, which was 18.04 % and 41.73 % higher than the mono-fermentation of grass and sludge, respectively. Co-fermentation of sludge and leaves produced 63.80 mmol C/L caproate, which was 11.09 % and 1.03 % higher than the mono-fermentation of leaves and sludge, respectively. Microbial analysis showed that co-fermentation enriched CE microbes like genus Clostridium_sensu_stricto_13, Caprocipiproducens, Terrisporpbacter and Praraclostridium, and suppressed the competitive microbes like genus norank_f_Caldilineaceae and Desulfomicrobium. Functional enzymes analysis revealed that co-fermentation of sludge and leaves promoted MCFAs production through strengthening reverse β oxidation (RBO) pathway, while co-fermentation of sludge and grass stimulated MCFAs production by strengthening fatty acid biosynthesis (FAB) pathway.

Selection of additive materials for anaerobic co-digestion of fruit and vegetable waste and layer chicken manure. This study aimed to assess the potential of different additive materials in enhancing the stability and methane production of anaerobic co-digestion of fruit and vegetable waste and layer chicken manure. A biochemical methane potential assay was conducted to evaluate the co-digestion of substrates with the addition of additive materials (10 g L-1): biochars produced (450 and 550 °C) (from fruit and vegetable waste, layer chicken manure, and wood pruning waste), powdered activated carbon, and zeolites. All additive materials increased methane production. Biochars showed better results regarding methane production (increments of 17 to 28 %). The surface of biochars favored the adhesion of microorganisms, this was confirmed by spectra after co-digestion. Furthermore, the redox-active groups in the biochars may have contributed to the microbiological syntrophism, increasing methane rates. These materials are viable for application in co-digestion systems, and the use of waste for their production is an option for solid waste management.

Demand-oriented biogas production to cover residual load of an electricity self-sufficient community using a simple kinetic model. Flexible biogas production can enable demand-oriented energy supply without the need for expensive gas storage expansions, but poses challenges to the stability of the anaerobic digestion (AD) process. In this work, biogas production of laboratory-scale AD of maize silage and sugar beets was optimized to cover the residual load of an electricity self-sufficient community using a simple process model based on first-order kinetics. Experiments show a good agreement between biogas demand, predicted, and measured biogas production. By optimizing biogas conversion schedules based on the measured gas production, a gas storage capacity of 7-8 h was identified for maximum flexibility, which corresponds to typical gas storage sizes at industrial biogas plants in Germany. Various stability indicators were continuously monitored and proved resilient process conditions. These results demonstrate that demand-oriented biogas production using model predictive control is a promising approach to enable existing biogas plants to provide balancing energy.

Intensification and biorefinery approaches for the valorization of kitchen wastes - A review. Kitchen wastes (KW) are post-consumption residues from household and food service sector, heterogenous in composition and highly variable depending on the particular origin, which are often treated as municipal. There is a need to improve the management of these continuously produced and worldwidely available resources and their valorization into novel and commercially interesting products will aid in the development of bioeconomy. The successful implementation of such approach requires cooperation between academia, industrial stakeholders, public and private institutions, based on the different dimensions, including social, economic, ecologic and technological involved. This review aims at presenting a survey of technological aspects, regarding current and potential management strategies of KW, following either a single or multiproduct processing according to the biorefineries scheme. Emphasis is given to intensification tools, designed to enhance process efficiency.

Antibiotics in anaerobic digestion: Investigative studies on digester performance and microbial diversity. The ever-increasing consumption of antibiotics in both humans and animals has increased their load in municipal and pharmaceutical industry waste and may cause serious damage to the environment. Impact of antibiotics on the performance of commercially used anaerobic digesters in terms of bioenergy output, antibiotics' removal and COD removal have been compared critically with a few studies indicating >90% removal of antibiotics. AnMBR performed the best in terms of antibiotic removal, COD removal and methane yield. Most of the antibiotics investigated have adverse effects on microbiome associated with different stages and methane generation pathways of AD which has been assessed using high throughput technologies like metatranscriptomics, metaproteomics and flow cytometry. Perspectives have been given for understanding the fate and elimination of antibiotics from AD. The challenge of optimization and process improvement needs to be addressed to increase efficiency of the anaerobic digesters.

Pretreatment of milled and unchopped sugarcane bagasse with vortex based hydrodynamic cavitation for enhanced biogas production. Anaerobic digestion can potentially valorise sugarcane bagasse to biogas and fertiliser. Pretreatment is however required to overcome recalcitrance and enhance the biogas yields. Literature reporting the investigation of various biomass pretreatments often use milled biomass as substrate rather than as-received fibrous biomass. This does not establish the true influence of the pretreatment type on biogas generation. Additionally, milling energy is also ignored when calculating net energy gains from enhanced biogas yields and are thus misleading. In this work, a vortex-based hydrodynamic cavitation device was used to enhance the biomethane yields from fibrous as-received biomass for the first time. Clear justification on why milled biomass must not be used as substrates for demonstrating the effect of pretreatment on biogas production is also discussed. The net energy gain from milled hydrodynamic cavitation pre-treated bagasse can be similar to as-received bagasse only when the specific milling energy is ≤700 kWh/ton.

Clostridium as microbial cell factory to enable the sustainable utilization of three generations of feedstocks. The sustainable production of chemicals and biofuels from non-fossil carbon sources is considered key to reducing greenhouse gas (GHG) emissions. Clostridium sp. can convert various substrates, including the 1st-generation (biomass crops), the 2nd-generation (lignocellulosic biomass), and the 3rd-generation (C1 gases) feedstocks, into high-value products, which makes Clostridia attractive for biorefinery applications. However, the complexity of lignocellulosic catabolism and C1 gas utilization make it difficult to construct efficient production routes. Accordingly, this review highlights the advances in the development of three generations of feedstocks with Clostridia as cell factories. At the same time, more attention was given to using agro-industrial wastes (lignocelluloses and C1 gases) as the feedstocks, for which metabolic and process engineering efforts were comprehensively analyzed. In addition, the challenges of using agro-industrial wastes are also discussed. Lastly, several new synthetic biology tools and regulatory strategies are emphasized as promising technologies to be developed to address the aforementioned challenges in Clostridia and realize the efficient utilization of agro-industrial wastes.

Removal of lignin and silica from rice straw for enhanced accessibility of holocellulose for the production of high-value chemicals. The intricate nature and rigidity of rice straw, particularly the presence of lignin and silica, hinders the catalytic valorization, consequently decreasing the yield of target products. This study reports the concurrent removal of lignin and silica from rice straw to obtain enriched holocellulose, then transforming it to furfural (FUR) and levulinic acid (LA). Interestingly, rice straw in the form of powder displays an improved removal of lignin (51.0%) and silica (92.0%) during ammonia treatment. Encouragingly, adding organic solvents, such as THF, to the aqueous system during the pretreatment of rice straw improves the lignin removal to 60.0%. Upon improving lignin removal to 60%, the obtained holocellulose enriched solid residue yields 71.0% FUR along with 52.0% LA, which is 8 and 4-fold higher than what is obtained with parent rice straw, signifying the importance and the prerequisite of lignin and silica removal from rice straw.

Proposed protocol for rate-limiting step determination during anaerobic digestion of complex substrates. Anaerobic digestion is a complex process, involving various microorganism groups and, consequently, several reactions. An easy-to-use protocol for the rate-limiting step determination of the process is proposed. The hydrogen production, acetate production, and acetate consumption rates can be calculated, according to a structured algorithm. During the rate limiting step determination, several compounds (biopolymer and monomer representatives, as well as sodium acetate) were used, combined or not with the substrate, to draw the corresponding conclusions. Three substrates were tested, characterized by specific organic compound groups (carbohydrates, proteins, and fats). All three substrates followed the acetate-consuming pathway for the organic matter conversion to methane. In this study, the rate-limiting step for the pathway of acetate consumption was acetate production. Determining the rate-limiting step through the proposed protocol can point to the appropriate actions needed to boost methane production, like substrate pretreatment, using an acidogenic reactor, or checking for the presence of inhibitors.

Genetic variation and evolution of attenuated African swine fever virus strain isolated in the field: A review. It has been reported that there were several "mutant isolated in the field " of African swine fever virus (ASFV) since ASFV was reported, which may be the result of the continuous adaptation and evolution of ASFV. The emergence of ASFV field mutants may lead to chronic or asymptomatic "atypical clinical symptoms" in pigs and hinder the development of porcine industry. Here we analyzed the published ASFV "field attenuated strain" gene sequences and reviewed the genetic differences between field attenuated and virulent ASFV strains, hoping for providing a reference for the scientific prevention and control of ASF and the development of new vaccines. In this study we found the deletion of EP153R and EP402R occurred in 4 field attenuated strains, and all the differential genes of field attenuated strains mainly range in regions with low GC content. The evolution of MGF110 family genes was identified by analysis of two field attenuated ASFV strains from Portugal. We also found that some tandem repeat sequence plays an important role in the evolution of strains of NH/P68 and OURT 88/3 but not in strains Estonia 2014, HuB20 and Pig/Heilongjiang/HRB1/2020.

Proteogenomics identification of TBBPA degraders in anaerobic bioreactor. Tetrabromobisphenol A (TBBPA) is the most used flame retardant worldwide and has become a threat to aquatic ecosystems. Previous research into the degradation of this micropollutant in anaerobic bioreactors has suggested several identities of putative TBBPA degraders. However, the organisms actively degrading TBBPA under in situ conditions have so far not been identified. Protein-stable isotope probing (protein-SIP) has become a cutting-edge technique in microbial ecology for enabling the link between identity and function under in situ conditions. Therefore, it was hypothesized that combining protein-based stable isotope probing with metagenomics could be used to identify and provide genomic insight into the TBBPA-degrading organisms. The identified 13C-labelled peptides were found to belong to organisms affiliated to Phytobacter, Clostridium, Sporolactobacillus, and Klebsilla genera. The functional classification of identified labelled peptides revealed that TBBPA is not only transformed by cometabolic reactions, but also assimilated into the biomass. By application of the proteogenomics with labelled micropollutants (protein-SIP) and metagenome-assembled genomes, it was possible to extend the current perspective of the diversity of TBBPA degraders in wastewater and predict putative TBBPA degradation pathways. The study provides a link to the active TBBPA degraders and which organisms to favor for optimized biodegradation.

Viral subpopulation variability in different batches of Infectious bronchitis virus (IBV) vaccines based on GI-23 lineage: Implications for the field. The control of infectious bronchitis (IB) is largely based on routine vaccine administration, often using live-attenuated vaccines. However, their capability to replicate and be transmitted among animals and farms implies significant risks. The detection of strains genetically related to vaccines complicates the diagnostic process and understanding of the viral molecular epidemiology. Moreover, reversion to virulence and associated clinical outbreaks can occur although the underlying mechanism are often unknown. In the present study, three vaccine vials, based on IBV GI-23 lineage (also known as Variant2) were deep sequenced through Next Generation Sequencing (NGS) to investigate the presence and features of viral subpopulations. To elucidate the consequences in the field and identify potential markers suitable for a DIVA strategy, the S1 sequences of strains originating from farms in different countries were sequenced and classified based on the knowledge of their vaccination history and similarity with the applied vaccine. Although all considered vaccine batches shared the same consensus sequence, different subpopulations were identified suggesting independent and poorly constrained evolutionary processes. When compared with strains sampled from farms, the vaccine consensus sequences and the respective subpopulations clustered with vaccine strains and no genetic features were consistently shared with field strains. Therefore, if vaccine-induced outbreaks occur, they are more likely to originate from in vivo evolution rather than selection of already present subpopulations. Although some amino acid residues were most commonly detected in field or vaccine strains, no consistent marker could be identified. The occurrence of subpopulations within IBV GI-23-based vaccines and variability featuring different production batches was demonstrated. Being such a phenomenon apparently driven by random genetic drift rather than directional selection, the differentiation between field and vaccine-derived strains appears extremely challenging based on sequence analysis alone. The knowledge of farm management and vaccination history should thus be considered for a proper epidemiological investigation.

Effects of short-term soil exposure of different doses of ZnO nanoparticles on the soil environment and the growth and nitrogen fixation of alfalfa. The extensive application of nanomaterials has increased their levels in soil environments. Therefore, clarifying the process of environmental migration is important for environmental safety and human health. In this study, alfalfa was used to determine the effects of different doses of ZnO nanoparticles (NPs) on the growth of alfalfa and the soil environment. Results showed that the alfalfa biomass was inversely proportional to the exposure concentration of ZnO NPs. The Zn concentration in the alfalfa tissue and the exposure dose presented a significant positive correlation. A high concentration of ZnO NPs decreased the nitrogen-fixing area of root nodules while the number of bacteroids and root nodules, which in turn affected the nitrogen-fixing ability of alfalfa. At the same time, it caused different degrees of damage to the root nodules and root tip cells of alfalfa. A high dose of ZnO NPs decreased the relative abundance and diversity of the soil microorganisms. Therefore, short-term and high-dose exposure of ZnO NPs causes multiple toxicities in plants and soil environments.

The performance and perspectives of dendritic cell vaccines modified by immune checkpoint inhibitors or stimulants. Therapeutic dendritic cell (DC) vaccines stimulate the elimination of tumor cells by the immune system. However, while antigen-specific T cell responses induced by DC vaccines are commonly observed, the clinical response rate is relatively poor, necessitating vaccine optimization. There is evidence that the suppression of DC function by immune checkpoints hinders the anti-tumor immune responses mediated by DC vaccines, ultimately leading to the immune escape of the tumor cells. The use of immune checkpoint inhibitors (ICIs) and immune checkpoint activators (ICAs) has extended the immunotherapeutic range. It is known that both inhibitory and stimulatory checkpoint molecules are expressed by most DC subsets and can thus be used to manipulate the effectiveness of DC vaccines. Such manipulation has been investigated using strategies such as chemotherapy, agonistic or antagonistic antibodies, siRNA, shRNA, CRISPR-Cas9, soluble antibodies, lentiviruses, and adenoviruses to maximize the efficacy of DC vaccines. Thus, a deeper understanding of immune checkpoints may assist in the development of improved DC vaccines. Here, we review the actions of various ICIs or ICAs shown by preclinical studies, as well as their potential application in DC vaccines. New therapeutic interventional strategies for blocking and stimulating immune checkpoint molecules in DCs are also described in detail.

Floating marine macro litter in the Black Sea: Toward baselines for large scale assessment. The Black Sea is a semi-enclosed basin subject to major anthropogenic pressures, including marine litter and plastic pollution. Due to numerous large rivers draining into the basin and a population settled along the coast, the region could accumulate significant amounts of floating litter over time. Until now, only limited field data were available, and litter quantities and distribution remained unknown. In this study, floating marine macro litter (FMML) was assessed at the regional Black Sea scale for the first time, showing relatively high litter densities across the basin that reached a weighted mean of 81.5 items/km2. Monitoring data revealed an accumulation of floating items offshore in the eastern part of the basin, resembling on a small scale a 'garbage patch', where litter items were trapped, showing elevated densities in comparison to their surrounding areas. Most of these items were made of plastic materials (ca. 96%) and included large numbers of plastic and polystyrene fragments of small size ranges (2.5-10 cm). Harmonised field data collection through consistent and regular monitoring programmes across the region is essential to establish baselines and thresholds for large scale assessment at international level.

Vigilance: A novel conditioned fear response that resists extinction. Attentional bias for threat is an adaptive feature of human psychology, but may become maladaptive in anxiety-related disorders, causing distress, distraction, and distorted perception of danger. Reaction time measures have revealed automatic, covert attention biases to threat, whereas eye tracking has revealed voluntary biases over a larger timescale, with monitoring or avoidance depending on context. Recently, attentional bias for threat has been studied as a conditioned fear response, providing new insight into how attentional biases are acquired and inhibited through learning experiences. However, very few studies have examined voluntary gaze biases during fear learning. In a novel eye tracking paradigm (N = 78), we examine the overt components of attentional bias to threat and safety cues. We found that threat cues, but not safety cues, elicited an initial orienting bias, as well as sustained monitoring bias across 10-second trials. This collective "vigilance" response to threat cues was insensitive to extinction, whereas condition fear responding revealed by pupil size and self-report ratings showed marked extinction. Vigilance may be less prone to extinction, compared to autonomic arousal, because eye movements require less energy than preparing the body for defensive behavior. Implications for understanding vigilance in PTSD are considered.

Psoralen and isopsoralen from Psoraleae Fructus aroused hepatotoxicity via induction of aryl hydrocarbon receptor-mediated CYP1A2 expression. Psoraleae Fructus (PF), a traditional Chinese medicine, has long been used to treat diseases such as cancer, osteoporosis and leukoderma. Psoralen and isopsoralen are main bioactive ingredients of PF with anti-tumor, anti-inflammatory, estrogen-like neuroprotection, etc., meanwhile they are also representative hepatotoxic components of PF. Hepatic CYP1A2 has been reported to be the important metabolic enzymes involved in psoralen and isopsoralen-induced hepatotoxicity. However, the relationship between the hepatotoxicity and CYP1A2 expression, and the underlying mechanism of regulating CYP1A2 expression remain unclear. The aim of this study was to explore the associated mechanism between psoralen or isopsoralen induced hepatotoxicity and activated aryl hydrocarbon receptor (AhR)-mediated transcriptional induction of CYP1A2 in vitro and in vivo. Psoralen and isopsoralen at different doses were treated on HepG2 cells (10, 25, 50, 100, 200 μM for 2, 12, 24, 36, 48 h) and mice (20, 80, 160 mg/kg for 3, 7, 14 days) for different time, to assess the correlation of induced hepatotoxicity and CYP1A2 mRNA and protein expression in vivo and in vitro, as well as the effect on CYP1A2 enzyme activity evaluated by phenacetin metabolism. In addition, the potential mechanism of the regulation of CYP1A2 expression mediated by AhR was explored through nucleocytoplasmic shuttling, immunofluorescence, cellular thermal shift assay and molecular docking, etc. RESULTS: Psoralen and isopsoralen induced cytotoxicity in HepG2 cells, and hepatomegaly, biochemicals disorder and tissue pathological impairment in mice, respectively in dose- and time-dependent manners. Simultaneously accompanied with elevated levels of CYP1A2 mRNA and protein in the same trend, and the CYP1A2 activity was remarkably inhibited in vitro but significantly elevated overall in vivo. Besides, psoralen and isopsoralen bound to AhR and activated translocation of AhR from the cytoplasm to the nucleus, leading to the transcriptional induction of target gene CYP1A2. Hepatotoxicities in HepG2 cells and mice aroused by psoralen and isopsoralen were related to the induction of CYP1A2 expression and activity, whose underlying mechanism might be psoralen or isopsoralen activated AhR translocation and induced increase of CYP1A2 transcriptional expression. Hopefully, these finding are conductive to propose an alert about the combined usage of psoralen or isopsoralen and AhR ligands or CYP1A2 substrates in clinical practice.

Anti-inflammatory, antipyretic efficacy and safety of inhaled Houttuynia cordata thunb. essential oil formulation. Houttuynia cordata Thunb. (H. cordata) is a well-known folk traditional Chinese medicine that is renowned for its use in the management of inflammatory respiratory diseases and pneumonia. Its essential oils have demonstrated their anti-inflammatory efficacy in vitro, however, their in vivo biological effects via inhalation have not been elucidated. This study aims to evaluate the anti-inflammation and toxicology of H. cordata essential oil-containing formulation, H16 aerosol in vivo. A laser diffraction particle size analyser and a Next Generation Impactor were used to measure the mass median aerodynamic diameter (MMAD) of the H16 aerosol. The anti-inflammatory and antipyretic effects of the H16 aerosol were evaluated in the xylene-evoked ear oedema and Brewer's yeast-induced fever models, respectively. The biological safety of the H16 aerosol was evaluated by acute toxicity and local toxicity tests in animal models. Our data showed that the MMAD of the bioactive aerosol was 3-5 μm, which implied tracheal and pharyngeal deposits. Significant anti-inflammatory and antipyretic effects were also observed in the animal models treated with H16 aerosol. The maximum tolerable dose of H16 in rats was >2.5 mL/kg. Irritation was not found on respiratory tract mucosa in the local toxicity test. Taken together, the present study suggested that H16 could be delivered in the form of aerosol and possessed its antipyretic and anti-inflammatory effects. This study provides a new perspective for the development of a new herbal aerosol therapy and herbal modernization.

Psoriasis treatment using Indigo Naturalis: Progress and strategy. In recent years, there are increasing that the number of patients with psoriasis day by day, and it has become a common disease endangering public health. However, there is no specific cure for psoriasis or control of recurrence. Therefore, it's necessity to seek alternative and efficient therapy, such as Traditional Chinese Medicine (TCM). As a TCM and effective medicine for the treatment of psoriasis, Indigo Naturalis (Baphicacanthus Cusia (Nees) Bremek.) has the effect of clearing heat, detoxifying blood, eliminating spots, reducing fire and calming panic, and it is used in many classical prescriptions for the treatment of psoriasis. To review the latest progress and strategies of Indigo Naturalis in the treatment of psoriasis. This manuscript mainly clarifies the traditional medicinal applications, the mechanism of action and application strategies of Indigo Naturalis, and its preparations in the treatment of psoriasis. Detailed information on Indigo Naturalis was collected from various online databases (PubMed, GeenMedical, Web of Science, Google Scholar, China National Knowledge Infrastructure Database, and National Intellectual Property Administration). This manuscript reviews a great deal of information about how Indigo Naturalis can treat psoriasis through immune cells, signal pathways and disease-related mediators. The mechanism of cymbididae is expounded from the aspects of regulating keratinocyte proliferation and differentiation, regulating inflammatory infiltration of cellular immune system and improving microvascular dilation and hyperplasia in skin lesions. The action mechanisms of Indigo Naturalis on psoriasis reflect the characteristics of multiple components, multiple targets, and multiple pathways of Traditional Chinese medicine. However, some pharmacological and clinical research methods are improper, so that the results are difficult to explain at present. Therefore, further in-depth research is needed to provide knowledge in a wider range of areas to confirm the great therapeutic potential of Indigo Naturalis.

Srolo Bzhtang reduces inflammation and vascular remodeling via suppression of the MAPK/NF-κB signaling pathway in rats with pulmonary arterial hypertension. Srolo Bzhtang (SBT), which consists of Solms-laubachia eurycarpa, Bergenia purpurascens, Glycyrrhiza uralensis, and lac secreted by Laccifer lacca Kerr (Lacciferidae Cockerell), is a well-known traditional Tibetan medicinal formula and was documented to cure "lung-heat" syndrome by eliminating "chiba" in the ancient Tibetan medical work Four Medical Tantras (Rgyud bzhi). Clinically, it is a therapy for pulmonary inflammatory disorders, such as pneumonia, chronic bronchitis, and chronic obstructive pulmonary disease. However, whether and how SBT participates in pulmonary arterial hypertension (PAH) is still unclear. We aimed to determine the role of SBT in attenuating pulmonary arterial pressure and vascular remodeling caused by monocrotaline (MCT) and hypoxia. To elucidate the potential mechanism underlying SBT-mediated PAH, we investigated the changes in inflammatory cytokines and mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. MCT- and hypoxia-induced PAH rat models were used. After administering SBT for four weeks, the rats were tested for hemodynamic indicators, hematological changes, pulmonary arterial morphological changes, and the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in serum and lung tissues. Protein expression of the MAPK/NF-κB signaling pathway was determined using western blotting. SBT reduced pulmonary arterial pressure, vascular remodeling, and the levels of inflammatory cytokines induced by MCT and hypoxia in rats. Furthermore, SBT significantly suppressed the MAPK/NF-κB signaling pathway. To our knowledge, this is the first study to demonstrate that SBT alleviates MCT- and hypoxia-induced PAH in rats, which is related to its anti-inflammatory actions involving inhibition of the MAPK/NF-κB signaling pathway.

Designer bacterial cell factories for improved production of commercially valuable non-ribosomal peptides. Non-ribosomal peptides have gained significant attention as secondary metabolites of high commercial importance. This group houses a diverse range of bioactive compounds, ranging from biosurfactants to antimicrobial and cytotoxic agents. However, low yield of synthesis by bacteria and excessive losses during purification hinders the industrial-scale production of non-ribosomal peptides, and subsequently limits their widespread applicability. While isolation of efficient producer strains and optimization of bioprocesses have been extensively used to enhance yield, further improvement can be made by optimization of the microbial strain using the tools and techniques of metabolic engineering, synthetic biology, systems biology, and adaptive laboratory evolution. These techniques, which directly target the genome of producer strains, aim to redirect carbon and nitrogen fluxes of the metabolic network towards the desired product, bypass the feedback inhibition and repression mechanisms that limit the maximum productivity of the strain, and even extend the substrate range of the cell for synthesis of the target product. The present review takes a comprehensive look into the biosynthesis of bacterial NRPs, how the same is regulated by the cell, and dives deep into the strategies that have been undertaken for enhancing the yield of NRPs, while also providing a perspective on other potential strategies that can allow for further yield improvement. Furthermore, this review provides the reader with a holistic perspective on the design of cellular factories of NRP production, starting from general techniques performed in the laboratory to the computational techniques that help a biochemical engineer model and subsequently strategize the architectural plan.

Overexpression of mcr-1 disrupts cell envelope synthesis and causes the dysregulation of carbon metabolism, redox balance and nucleic acids. Rapid dissemination of plasmid-borne polymyxin resistance mcr-1 genes threatens the efficacy of polymyxins. Acquisition of mcr-1 imposes a fitness cost on bacteria; identifying the molecular mechanisms underpinning this fitness cost will help in the development of adjunctive antimicrobial therapies that target polymyxin-resistant Gram-negative pathogens. Phenotypic assays and transcriptomics were acquired to investigate the impact of mcr-1 expression on membrane characteristics and transcriptomic responses in Escherichia coli TOP10 carrying the empty vector pBAD (TOP10+pBAD) and harbouring pBAD-mcr-1 (TOP10+pBAD-mcr-1). The overexpression of mcr-1 increased outer membrane permeability and caused membrane depolarisation, reflective of the transcriptomic results that showed downregulation of multiple genes involved in lipopolysaccharide core and O-antigen biosynthesis. Overexpression of mcr-1 also caused considerable gene expression changes in pathways involving carbohydrate metabolism (phosphotransferase system, pentose phosphate pathway, and pantothenate and coenzyme A biosynthesis), ABC transporters and intracellular responses to stress, especially those associated with oxidative and nucleic acid damage. Expression of mcr-1 also triggered the production of reactive oxygen species. These findings indicate that overexpression of mcr-1 results in persistent transcriptomic changes that primarily involve disruption to cell envelope synthesis via the reduction of LPS modifications, as well as dysregulation of carbon metabolism, redox balance and nucleic acids. These consequences of expression dysregulation may act as the main factors that impose a fitness cost with mcr-1 expression.

The ingredients for an antimicrobial mathematical modelling broth. Mathematical modelling has made significant contributions to the optimization of the use of antimicrobial treatments. This article discusses the key processes that such mathematical modelling should attempt to capture. In particular, this article highlights that the response of the host immune system requires quantification, and this is illustrated with a novel model structure.

Aztreonam-avibactam may not replace ceftazidime/avibactam: the case of KPC-21 carbapenemase and penicillin-binding protein 3 with four extra amino acids. Aztreonam/avibactam is a promising antimicrobial combination with additional coverage for metallo-β-lactamases compared with ceftazidime/avibactam. A carbapenem-resistant blaKPC-2-carrying Escherichia coli clinical isolate had four extra amino acids in penicillin-binding protein 3 (PBP3), which has been known to mediate reduced susceptibility to aztreonam/avibactam. This prompted us to investigate whether the strain could develop resistance to aztreonam/avibactam after exposure to the combination. A mutant with high-level resistance to aztreonam/avibactam [minimum inhibitory concentration (MIC), 512/4 mg/L] was obtained after 5-day exposure to 0.5 × MIC but it remained susceptible to ceftazidime/avibactam (MIC, 4/4 mg/L). The mutant had a single nucleotide polymorphism (SNP) in blaKPC-2 to encode KPC-21 with a Trp105Arg amino acid substitution. By cloning into E. coli BL21, blaKPC-21 could mediate reduced susceptibility to aztreonam/avibactam (MIC, from ≤0.03/4 to 1/4 mg/L), which was still below the breakpoint to define resistance. In contrast, when blaKPC-21 was cloned in E. coli 035125ΔpCMY42 with four extra amino acids in PBP3, which was generated in our previous work, the strain exhibited high-level resistance to aztreonam/avibactam (MIC, 256/4 mg/L). The above findings highlight that although aztreonam/avibactam has a broader spectrum than ceftazidime/avibactam, strains may develop resistance to the former combination but remain susceptible to the latter. The discrepancy is due to mutation of KPC-2 to KPC-21 in combination with the insertion of four extra amino acids in PBP3.

Pleiotropic properties of statins via angiogenesis modulation in cardiovascular disease. Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by statins is affected by inhibiting the active site of the enzyme in a competitive manner. Statins reduce plasma cholesterol by inhibiting its de novo synthesis. In addition, statins impart 'pleiotropic' activities that do not directly relate to their ability to decrease cholesterol. The proangiogenic and antiangiogenic characteristics of statins are among these pleiotropic effects. These angiogenic-modifying properties could offer new therapeutic applications. Statins stimulate or suppress angiogenesis in a biphasic manner. Whereas low doses of statin stimulate angiogenesis, high doses reduce protein prenylation and limit cell development and angiogenesis. In this review, we discuss how statins impact angiogenesis, with a particular focus on angiogenesis in stroke and cardiovascular disease (CVD).

Medicinal products meet medical devices: Classification and nomenclature issues arising from their combined use. When a medicinal product (MP) and a medical device (MD) are combined, their correct classification implies discrimination among different possible scenarios, based on the nature of the combination and the principal mechanism of action. In the European Union (EU), stakeholders deal with a lack of harmonization, which can represent an obstacle toward the development of these products, and a complex nomenclature, emerging from two divergent regulatory philosophies (i.e., that of MPs and that of MDs). In the USA, where the US Food and Drug Administration (FDA) supervises MDs, drugs, and biological products, stakeholders interact with a single authority, where any issue is addressed internally.

Eukaryotic expression and immunogenicity of Ancylostoma ceylanicum calreticulin. Ancylostoma ceylanicum is a zoonotic soil-derived nematode that parasitizes human and animal intestines, causing malnutrition and iron-deficiency anemia. Calreticulin is a multifunctional protein involved in all stages of parasitic infection. Studies have found that parasites can secret calreticulin to regulate the host's immune response. To explore the immunogenicity of the eukaryotic expression plasmid of Ancylostoma ceylanicum calreticulin (Ace-CRT), we constructed a recombinant Ace-CRT eukaryotic expression plasmid (pEGFP-N3-Ace-CRT). Successful expression of the target protein in Human Embryonic Kidney (HEK) 293 T cells was confirmed by indirect immunofluorescence and Western blot analysis. BALB/c mice were immunized with pEGFP-N3-Ace-CRT plasmid. Measuring IgG antibody levels in immunized mice sera by ELISA showed that the recombinant plasmid stimulated IgG antibody production in mice. Spleen lymphocytes were collected from vaccinated mice to determine the proportion of T cell subsets and the expression levels of cytokines. Flow cytometry revealed that the percentage of CD3 + CD4+ and CD3 + CD8+ T cells in mice spleen in the immunization group was significantly higher than that in the control group. Recombinant plasmid immunization increased IL-4, IL-10, IL-12, and IL-13 expression while decreasing IL-5, IL-6, and INF-γ in mice spleens. These results indicate that the eukaryotic plasmid constructed in this study had good immunogenicity and mainly induced a T helper 2 response in the host, laying a foundation for screening candidate molecules for anti-hookworm vaccines.

Ototoxicity in childhood: Recommendations of the CODEPEH (Commission for the Early Detection of Childhood Hearing Loss) for prevention and early diagnosis. Ototoxicity is defined as the damage, reversible or irreversible, produced in the inner ear by various substances that are called ototoxic and that can cause hearing loss and/or an alteration of the vestibular system. Permanent hearing loss significantly affects quality of life and is especially important in children. The lack or delay in its detection is frequent, since it often progresses in an inconspicuous manner until it affects communication and overall development. This impact can be minimized by following a strategy of audiological monitoring of ototoxicity, which allows for its early detection and treatment. This document recommends that children who are going to be treated with cisplatin or aminoglycosides be monitored. This CODEPEH review and recommendation document focuses on the early detection, prophylaxis, otoprotection, monitoring and treatment of ototoxicity caused by aminoglycosides and platinum-based antineoplastics in the paediatric population.

Polyethyleneimine incorporated chitosan/α-MnO2 nanorod honeycomb-like composite foams with remarkable elasticity and ultralight property for the effective removal of U(VI) from aqueous solution. The development of new adsorbents is needed to address the environmental challenges of radioactive wastewater treatment. Herein we reported a novel polyethyleneimine incorporated chitosan/α-MnO2 nanorod honeycomb-like composite (PCM) foam with remarkable elasticity and ultralight property for U(VI) removal. Among different PCM sorbents, PCM-40 possessed the highest sorption capacity for U(VI) due to its highly developed macroporous structure and high content of amine/imine groups. The kinetics were well-simulated by the pseudo-second-order model, indicating chemisorption as the rate-controlling step. The isotherms could be described by the Langmuir model, suggesting mono-layer homogeneous sorption of U(VI). The maximum sorption U(VI) capacity for PCM-40 reaches up to 301.9 mg/g at pH 4.5 and 298 K. The thermodynamic parameters revealed the spontaneous and endothermic nature of the adsorption process. The main sorption mechanism is related to the complexation of uranyl ions with the amine/imine and hydroxyl groups. The high sorption capacity, fast kinetic rate and relatively good selectivity of PCM-40 highlights its promising application in radioactive pollution cleanup.

Sustainable aggregation-induced emission material based on pectin-l-lysine: Potential antibacterial and monitoring in food spoilage. The demand of smart food detection system which in detecting food spoilage is increasing. In this work, a new type of aggregation-induced emission (AIE) compound was synthesized based on pectin (P) and l-lysine (Lys). P-Lys is an AIE active compound which has the advantages of simple synthesis, easy modification and processability, it also has good water solubility and biocompatibility. Moreover, P-Lys has potential application in detecting Fe3+ (oxidation from Fe2+) and bacterial in monitoring pork spoilage. In addition, P-Lys also has spectral antibacterial properties which can prevent pork spoilage. The research results shown that P-Lys, as a new type of food testing agent has a useful future in monitoring and protecting the freshness of food.

The K218 capsular polysaccharide produced by Acinetobacter baumannii isolate 52-249 includes 5,7-di-N-acetylpseudaminic acid linked by a KpsS3 glycosyltransferase. Two acylated forms of the higher sugar, 5,7-diamino-3,5,7,9-tetradeoxy-l-glycero-l-manno-non-2-ulosonic acid called pseudaminic acid, Pse5Ac7Ac and Pse5Ac7RHb where R indicates (R)-3-hydroxybutanoyl, have been found to occur in many capsular polysaccharide (CPS) types produced by isolates of an important human pathogen, Acinetobacter baumannii. The presence of either a psaABCEDF or psaABCGHF gene module at the K locus (KL) for CPS biosynthesis determines the type of the variant produced. Here, an A. baumannii clinical isolate 52-249, recovered in 2015 in Moscow, Russia, was found to include a novel psaABCIJF gene module in the KL218 sequence at the K locus. The CPS from 52-249 was extracted and studied by sugar analysis and partial acid hydrolysis along with one- and two-dimensional 1H and 13C NMR spectroscopy. A branched tetrasaccharide repeating unit was identified, which included a →3)-α-d-Galp-(1→6)-α-d-GlcpNAc-(1→3)-β-d-GalpNAc-(1→ main chain and Pse5Ac7Ac attached as a side branch, indicating that the psaABCIJF gene module is associated with synthesis of this variant. The K218 CPS was found to be structurally related to the K46 CPS of A. baumannii, and a comparison of the two structures enabled the assignment of glycosyltransferases. A KpsS3 protein for the α-(2→6) linkage of the Pse5Ac7Ac residue to D-Galp in K218 was identified.

Polysaccharide-based nanofibers for pharmaceutical and biomedical applications: A review. Nanofibers are fibrous nanocarriers that can be synthesized from natural polymers, synthetic polymers, semiconducting materials, composite materials, and carbon-based materials. Recently, natural polysaccharides-based nanofibers are gaining attention in the field of pharmaceuticals and biomedical as these are biocompatible, biodegradable, non-toxic, and economic. Nanofibers can deliver a significant amount of drug to the targeted site and provide effective interaction of therapeutic agent at the site of action due to a larger surface area. Other important advantages of nanofibers are low density, high porosity, small pore size, high mechanical strength, and low cost. In this review, natural polysaccharides such as alginate, pullulan, hyaluronic acid, dextran, cellulose, chondroitin sulfate, chitosan, xanthan gum, and gellan gum are discussed for their characteristics, pharmaceutical utility, and biomedical applications. The authors have given particular emphasis to the several fabrication processes that utilize these polysaccharides to form nanofibers, and their recent updates in pharmaceutical applications such as drug delivery, tissue engineering, skin disorders, wound-healing dressings, cancer therapy, bioactive molecules delivery, anti-infectives, and solubility enhancement. Despite these many advantages, nanofibers have been explored less for their scale-up and applications in advanced therapeutic delivery.

Lignin-carbohydrate complexes suppress SCA3 neurodegeneration via upregulating proteasomal activities. Lignin-carbohydrate complexes (LCCs) represent a group of macromolecules with diverse biological functions such as antioxidative properties. Polyglutamine (polyQ) diseases such as spinocerebellar ataxia type 3 (SCA3) comprise a set of neurodegenerative disorders characterized by the formation of polyQ protein aggregates in patient neurons. LCCs have been reported to prevent such protein aggregation. In this study, we identified a potential mechanism underlying the above anti-protein aggregation activity. We isolated and characterized multiple LCC fractions from bamboo and poplar and found that lignin-rich LCCs (BM-LCC-AcOH and PR-LCC-AcOH) effectively eliminated both monomeric and aggregated mutant ataxin-3 (ATXN3polyQ) proteins in neuronal cells and a Drosophila melanogaster SCA3 disease model. In addition, treatment with BM-LCC-AcOH or PR-LCC-AcOH rescued photoreceptor degeneration in vivo. At the mechanistic level, we demonstrated that BM-LCC-AcOH and PR-LCC-AcOH upregulated proteasomal activity. When proteasomal function was impaired, the ability of the LCCs to suppress ATXN3polyQ aggregation was abolished. Thus, we identified a previously undescribed proteasome-inducing function of LCCs and showed that such activity is indispensable for the beneficial effects of LCCs on SCA3 neurotoxicity.

Structure of the K98 capsular polysaccharide from Acinetobacter baumannii REV-1184 containing a cyclic pyruvic acid acetal. The K98 capsular polysaccharide (CPS) from the Acinetobacter baumannii clinical isolate, REV-1184, was studied by sugar analysis and Smith degradation along with one- and two-dimensional 1H and 13C NMR spectroscopy and high-resolution electrospray ionization mass spectrometry. The CPS was found to consist of linear tetrasaccharide repeats (K-units) that include one residue each of d-GlcpNAc, d-GalpNAc, 2-acetamido-2-deoxy-d-galacturonic acid (d-GalpNAcA), and 2-acetamido-2,6-dideoxy-d-glucose (N-acetylquinovosamine, d-QuipNAc), with the GalpNAc residue decorated with a (R)-configurated 4,6-pyruvic acid acetal group. The CPS has a similar composition to that of A. baumannii K4 but the topology of the tetrasaccharide K-unit is different (linear in K98 versus branched in K4). This was due to a difference in sequence for the Wzy polymerases encoded by the CPS biosynthesis gene clusters KL98 and KL4, with the WzyK98 polymerase forming a β-d-QuipNAc-(1→3)-d-GalpNAc linkage between the K98 units.

The matrix protein of Newcastle disease virus inhibits inflammatory response through IRAK4/TRAF6/TAK1/NF-κB signaling pathway. The matrix (M) protein of several cytoplasmic RNA viruses has been reported to be an NF-κB pathway antagonist. However, the function and mechanism of NDV M protein antagonizing NF-κB activation remain largely unknown. In this study, we found that the expression levels of IRAK4, TRAF6, TAK1, and RELA/p65 were obviously reduced late in NDV infection. In addition, the cytoplasmic M protein rather than other viral proteins decreased the expression of these proteins in a dose-dependent manner. Further indepth analysis showed that the N-terminal 180 amino acids of M protein were not only responsible for the reduced expression of these proteins, but also responsible for the inhibition of NF-κB activation and nuclear translocation of RELA/p65, as well as the production of inflammatory cytokines. Moreover, small interference RNA-mediated knockdown of IRAK4 or overexpression of IRAK4 markedly enhanced or reduced NDV replication by decreasing or increasing inflammatory cytokines production through the IRAK4/TRAF6/TAK1/NF-κB signaling pathway. Strangely, there were no interactions detected between NDV M protein and IRAK4, TRAF6, TAK1 or RELA/p65. Our findings described here contribute to a better understanding of the innate immune antagonism function of M protein and the molecular mechanism underlying the replication and pathogenesis of NDV.

Tunicate inspired gelatin-based tough hydrogel wound dressing containing twisted phthalazinone with adhesive, self-healing and antibacterial properties. As a hydrolytic product of collagen, gelatin is a polypeptide of biological origin. Gelatin hydrogels emerge as promising material candidates for traditional dressings due to good biocompatibility and the ability to keep wounds moist. However, it is difficult to simultaneously achieve gelatin hydrogel with robust mechanical property for long-term usage, reliable tissue adhesion, self-healing and antibacterial properties. Herein, we propose a simply synthesized strategy of a multifunctional gelatin hydrogel dressing, which is constructed by conjugating a newly synthesized 2-(4'-aldehydephenyl)-4-(2',3',4'-trihydroxyphenyl)-2,3-phthalazine-1(2H)-one (THPZB) to gelatin with Schiff base and chelating with Fe3+ ions (termed G/THPZB/Fe hydrogel). The twisted structure of phthalazinone in THPZB leads to entanglement of gelatin molecular chains, which resolves the stiffness-toughness conflict of the hydrogel. Furthermore, the strong tissue adhesion and fast self-healing capability mainly originate from the hydrogen bonding of the pyrogallol in THPZB. In vitro study shows that the hydrogels possess good biocompatibility with L929 cells, hemostatic and antibacterial activity. In the rat model of skin infection, the hydrogel dressing not only have no adverse effects on vital organs, but also can effectively promote wound healing of bacterial infection. Considering that it has multiple functions, G/THPZB/Fe hydrogel can be used as a promising wound dressing for biomedical applications.

Comprehensive approach to the protection and controlled release of extremely oxygen sensitive probiotics using edible polysaccharide-based coatings. The human intestinal system is a complex of various anaerobes including extremely oxygen-sensitive (EOS) bacteria, some of which have been credited with significant health benefits. Among these, Faecalibacterium prausnitzii, which is one of the most abundant anaerobic bacterial strains in the human intestinal tract, has been proved to be a promising probiotic for the treatment of inflammatory bowel diseases. However, because of its extremely sensitive nature, there are many difficulties when passing through the harsh environment of the gastrointestinal tract. Hence, in this study, a comprehensive physicochemical characterization was performed for the use of polysaccharides from several origins (hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, chitosan, low-methoxylated pectin, kappa-carrageenan, sodium alginate and pullulan) as encapsulating agents to protect and deliver this bacterium. First, the apparent viscosity and surface tension of the polymer solutions were tested. Then, the mechanical properties, water vapor and oxygen barrier properties of these biopolymers as self-standing films were investigated. Lastly, in vitro release profiles of small molecules and bacterial cells from these biopolymer matrices in contact with a simulated gastrointestinal tract were evaluated. The results showed that chitosan, low-methoxylated pectin, kappa-carrageenan, sodium alginate and pullulan films exhibited good oxygen barrier properties to protect EOS probiotics. Among all the biopolymers tested, sodium alginate exhibited the best oxygen barrier properties and release profile. The release kinetics can be modulated by several factors including biopolymer type, plasticizer concentration and active molecules or bacteria to be encapsulated. On that basis and integrating the other parameters analyzed, a multicriteria strategy for probiotic encapsulation was proposed.

Exogenous expression of barley HvWRKY6 in wheat improves broad-spectrum resistance to leaf rust, Fusarium crown rot, and sharp eyespot. Systemic acquired resistance (SAR) is a broad-spectrum plant defense phenomena controlled by the salicylic acid receptor NPR1. Key regulators of the SAR signaling pathway showed great potentials to improve crop resistance to various diseases. In our previous investigation, a barley transcription factor gene HvWRKY6 was identified as downstream of NPR1 during SAR. However, the broad-spectrum resistance features and molecular mechanisms of HvWRKY6 remain to be explored. In this study, a transgenic wheat line exogenously expressing HvWRKY6 showed improved resistance to leaf rust, Fusarium crown rot (FCR), and sharp eyespot. The model pathogen Pseudomonas syringae pv. tomato DC3000 was employed to induce the SAR response in wheat plants' leaf region adjacent to the infiltration area. Transcriptome sequencing revealed activation of broad-spectrum defense responses by expressing HvWRKY6 in a pathogen-independent manner. Based on the differentially expressed genes in plant hormone signal transduction, we speculated that the enhanced resistance in HvWRKY6-OE wheat transgenic line was associated with activation of the salicylic acid pathway and suppression of the abscisic acid and jasmonic acid pathways. These findings suggest that the transgenic line HvWRKY6-OE might be applied for the genetic improvement of wheat to several fungal diseases; the underlying resistance mechanism was clarified.

Effects of gelation concentration on cyclic deformation behavior of κ-carrageenan hydrogels. The aim of this study is to elucidate the relationship between the network structure of κ-carrageenan hydrogels and their mechanical properties. First κ-carrageenan hydrogels have been prepared at different gelation concentrations, and then the mechanical behavior during four cyclic deformations has been examined at the same κ-carrageenan concentration. Young's modulus is higher for the gel prepared at 5 gL-1 (C05) compared to that for the gel prepared at 30 gL-1 (C30). C30 shows almost linear relation between the stress and the strain like an ideal rubber, while a residual strain appears in each cyclic deformation for C05. The extent of the residual strain depends on the maximum strain and the deformation speed, indicating that C05 deforms plastically to some extent. The residual strain for C05 decreases gradually even after a cyclic deformation and disappears in the case of a small strain as if there were a memory of the structure. The effects of the gelation concentration on the mechanical properties have been explained based on the network structure specific to κ-carrageenan hydrogels. The higher modulus for C05 has been attributed to the higher helix content and the plastic deformation of C05 to the loosely-aggregated crosslinks.

Cross reacting material (CRM197) as a carrier protein for carbohydrate conjugate vaccines targeted at bacterial and fungal pathogens. This paper gives an overview of conjugate glycovaccines which contain recombinant diphtheria toxoid CRM197 as a carrier protein. A special focus is given to synthetic methods used for preparation of neoglycoconjugates of CRM197 with oligosaccharide epitopes of cell surface carbohydrates of pathogenic bacteria and fungi. Syntheses of commercial vaccines and laboratory specimen on the basis of CRM197 are outlined briefly.

High performance hydrogel electrodes based on sodium alginate-g-poly(AM-c o-ECA-co-AMPS for supercapacitor application. Electrochemical conductive hydrogels are being extensively explored in the fabrication of portable batteries and high-performance supercapacitors. Herein, the rational design of a new polyanionic electrically conductive hydrogels based on sodium alginate-g-poly(AM-co-ECA-co-AMPS) are described. rGO was incorporated into the hydrogel during the polymerization process generating rGO@ sodium alginate-g-poly(AM-co-ECA-co-AMPS) composite hydrogels to study the impact of rGO on the performance of the hydrogels. FT-IR, XRD, and SEM-EDX characterized the chemical composition, crystalline, and morphological structure of the new synthesized hydrogels. The electrochemical performance of as-synthesized hydrogels was investigated by cyclic voltammetry, galvanostatic, charge-discharge rate, and electrochemical impedance spectroscopy. The supercapacitor performance for ECH2.5 composite hydrogel showed a capacitance of 753 F. g-1 at 1 A. g-1 with good rate capability and cycling stability up to 5000 cycles. Thus, ECH2.5 hydrogel is a good candidate as electrode material in supercapacitor applications.

Silymarin nanocrystals-laden chondroitin sulphate-based thermoreversible hydrogels; A promising approach for bioavailability enhancement. Hydrogels has gained tremendous interest as a controlled release drug delivery. However, currently it is a big challenge to attain high drug-loading as well as stable and sustained release of hydrophobic drugs. The poor aqueous solubility and low bioavailability of many drugs have driven the need for research in new formulations. This manuscript hypothesized that incorporation of nanocrystals of hydrophobic drug, such as silymarin into thermoreversible hydrogel could be a solution to these problems. Herein, we prepared nanocrystals of silymarin by antisolvent precipitation technique and characterized for morphology, particle size, polydispersity index (PDI) and zeta potential. Moreover, physical cross-linking of hydrogel formulations based on chondroitin sulphate (CS), kappa-Carrageenan (κ-Cr) and Pluronic® F127 was confirmed by Fourier transformed infrared spectroscopy (FT-IR). The hydrogel gelation time and temperature of optimized hydrogel was 14 ± 3.2 s and 34 ± 0.6 °C, respectively. The release data revealed controlled release of silymarin up to 48 h and in-vivo pharmacokinetic profiling was done in rabbits and further analyzed by high-performance liquid chromatography (HPLC). It is believed that the nanocrystals loaded thermoreversible injectable hydrogel system fabricated in this study provides high drug loading as well as controlled and stable release of hydrophobic drug for extended period.

Urban environment and physical activity and capacity in patients with chronic obstructive pulmonary disease. Physical activity and exercise capacity are key prognostic factors in chronic obstructive pulmonary disease (COPD) but their environmental determinants are unknown. To test the association between urban environment and objective physical activity, physical activity experience and exercise capacity in COPD. We studied 404 patients with mild-to-very severe COPD from a multi-city study in Catalonia, Spain. We measured objective physical activity (step count and sedentary time) by the Dynaport MoveMonitor, physical activity experience (difficulty with physical activity) by the Clinical visit-PROactive (C-PPAC) instrument, and exercise capacity by the 6-min walk distance (6MWD). We estimated individually (geocoded to the residential address) population density, pedestrian street length, slope of terrain, and long-term (i.e., annual) exposure to road traffic noise, nitrogen dioxide (NO2) and particulate matter (PM2.5). We built single- and multi-exposure mixed-effects linear regressions with a random intercept for city, adjusting for confounders. Patients were 85% male, had mean (SD) age 69 (9) years and walked 7524 (4045) steps/day. In multi-exposure models, higher population density was associated with fewer steps, more sedentary time and worse exercise capacity (-507 [95% CI: 1135, 121] steps, +0.2 [0.0, 0.4] h/day and -13 [-25, 0] m per IQR). Pedestrian street length related with more steps and less sedentary time (156 [9, 304] steps and -0.1 [-0.1, 0.0] h/day per IQR). Steeper slope was associated with better exercise capacity (15 [3, 27] m per IQR). Higher NO2 levels related with more sedentary time and more difficulty in physical activity. PM2.5 and noise were not associated with physical activity or exercise capacity. Population density, pedestrian street length, slope and NO2 exposure relate to physical activity and capacity of COPD patients living in highly populated areas. These findings support the consideration of neighbourhood environmental factors during COPD management and the attention to patients with chronic diseases when developing urban and transport planning policies.

Effects of ciprofloxacin, trimethoprim, and amoxicillin on microbial structure and growth as emerging pollutants reaching crop soils. The presence of emerging pollutants, and specifically antibiotics, in agricultural soils has increased notably in recent decades, causing growing concern as regards potential environmental and health issues. With this in mind, the current study focuses on evaluating the toxicity exerted by three antibiotics (amoxicillin, trimethoprim, and ciprofloxacin) on the growth of soil bacterial communities, when these pollutants are present at different doses, and considered in the short, medium, and long terms (1, 8 and 42 days of incubation). Specifically, the research was carried out in 12 agricultural soils having different physicochemical characteristics and was performed by means of the leucine (3H) incorporation method. In addition, changes in the structure of soil microbial communities at 8 and 42 days were studied in four of these soils, using the phospholipids of fatty acids method for this. The main results indicate that the most toxic antibiotic was amoxicillin, followed by trimethoprim and ciprofloxacin. The results also show that the toxicity of amoxicillin decreases with time, with values of Log IC50 ranging from 0.07 ± 0.05 to 3.43 ± 0.08 for day 1, from 0.95 ± 0.07 to 3.97 ± 0.15 for day 8, and from 2.05 ± 0.03 to 3.18 ± 0.04 for day 42, during the incubation period. Regarding trimethoprim, 3 different behaviors were observed: for some soils the growth of soil bacterial communities was not affected, for a second group of soils trimethoprim toxicity showed dose-response effects that remained persistent over time, and, finally, for a third group of soils the toxicity of trimethoprim increased over time, being greater for longer incubation times (42 days). As regards ciprofloxacin, this antibiotic did not show a toxicity effect on the growth of soil bacterial communities for any of the soils or incubation times studied. Furthermore, the principal component analysis performed with the phospholipids of fatty acids results demonstrated that the microbial community structure of these agricultural soils, which persisted after 42 days of incubation, depended mainly on soil characteristics and, to a lesser extent, on the dose and type of antibiotic (amoxicillin, trimethoprim or ciprofloxacin). In addition, it was found that, in this research, the application of the three antibiotics to soils usually favored the presence of fungi and Gram-positive bacteria.

In-vivo protein nitration facilitates Vibrio cholerae cell survival under anaerobic, nutrient deprived conditions. Protein tyrosine nitration (PTN), a highly selective post translational modification, occurs in both prokaryotic and eukaryotic cells under nitrosative stress. However, its physiological function is not yet clear. Like many gut pathogens, Vibrio cholerae also faces nitrosative stress, which makes its proteome more vulnerable to PTN. Here, we report for the first time in-vivo PTN in V. cholerae by immunoblotting and LC-ESI-MS/MS proteomic analysis. Our results indicated that in-vivo PTN in V. cholerae was culture media independent. Surprisingly, in-vivo PTN was reduced in V. cholerae proteome under anaerobic or hypoxic condition in a nutrient deprived state. Interestingly, intracellular nitrate content was more than the nitrite content in V. cholerae under anaerobic conditions. Additionally, biochemical measurement of GSH/GSSG ratio, activities of catalase and SOD, ROS and RNS imaging by confocal microscopy confirmed a relative intracellular oxidizing environment in V. cholerae under anaerobic conditions. This altered redox environment favors the oxidation of nitrite which may be generated from protein denitration enriching the intracellular nitrate pool. The cell survival of V. cholerae can finally be facilitated by nitrate reductase (NapA) utilizing that nitrate pool. Our cell viability study using wild type and ΔnapA strain of V. cholerae also supported the role of NapA mediated cell survival under nutrient deprived anaerobic conditions. In spite of having nitrate reductase (NapA), V. cholerae lacks any nitrite reductase (NiR). Hence, in-vivo nitration may provide an avenue for toxic nitrite storage and also may help in nitrosative stress tolerance mechanism preventing further unnecessary protein nitration in V. cholerae proteome.

Integrins in cardiac fibrosis. Cells sense mechanical stress and changes in their matrix environment through the integrins, a family of heterodimeric surface receptors that bind to extracellular matrix ligands and trigger cytoskeletal remodeling, while transducing a wide range of intracellular signals. Integrins have been extensively implicated in regulation of inflammation, repair and fibrosis in many different tissues. This review manuscript discusses the role of integrin-mediated cascades in myocardial fibrosis. In vitro studies have demonstrated that β1 and αv integrins play an important role in fibrogenic conversion of cardiac fibroblast, acting through direct stimulation of FAK/Src cascades, or via accentuation of growth factor signaling. Fibrogenic actions of αv integrins may be mediated, at least in part, through pericellular activation of latent TGF-β stores. In vivo evidence supporting the role of integrin heterodimers in fibrotic cardiac remodeling is limited to associative evidence, and to experiments using pharmacologic inhibitors, or global loss-of-function approaches. Studies documenting in vivo actions of integrins on fibroblasts using cell-specific strategies are lacking. Integrin effects on leukocytes may also contribute to the pathogenesis of fibrotic myocardial responses by mediating recruitment and activation of fibrogenic macrophages. The profile and role of integrins in cardiac fibrosis may be dependent on the underlying pathologic condition. Considering their cell surface localization and the availability of small molecule inhibitors, integrins may be attractive therapeutic targets for patients with heart failure associated with prominent fibrotic remodeling.

Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity. Loss of heterozygosity (LOH) is a hallmark feature of cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported that loss of drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 could be targeted for collateral lethality anticancer therapy in colorectal cancer (CRC). Here, we report a novel compound CBK034026C that exhibits specific toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed that CBK034026C elicited a response pattern related to ATPase inhibitors. Similar to ouabain, a potent inhibitor of the Na+/K+-ATPase, CBK034026C activated the Nf-kB pathway. Further metabolomic profiling revealed downregulation of pathways associated with antioxidant defense and mitochondrial metabolism in CRC cells with high NAT2 activity, thereby weakening the protective response to oxidative stress induced by CBK034026C. The identification of a small molecule targeting metabolic vulnerabilities caused by NAT2 activity provides novel avenues for development of anticancer agents.

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre. Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.

How neutron scattering techniques benefit investigating structures and dynamics of monoclonal antibody. Over the past several decades, great progresses have been made for the pharmaceutical industry of monoclonal antibody (mAb). More and more mAb products were approved for human therapeutics. This review describes the state of art of utilizing neutron scattering to investigate mAbs, in the aspects of structures, dynamics, physicochemical stability, functionality, etc. Firstly, brief histories of mAbs and neutron scattering, as well as some basic knowledges and principles of neutron scattering were introduced. Then specific examples were demonstrated. For the structure and structural evolution investigation of in dilute and concentrated mAbs solution, in situ small angle neutron scattering (SANS) was frequently utilized. Neutron reflectometry (NR) is powerful to probe the absorption behaviors of mAbs on various surfaces and interfaces. While for dynamic investigation, quasi-elastic scattering techniques such as neutron spin echo (NSE) demonstrate the capabilities. With this review, how to utilize and take advantages of neutron scattering on investigating structures and dynamics of mAbs were demonstrated and discussed.

Use of an app-based exercise therapy program including cognitive-behavioral techniques for the management of intermittent claudication. Clinical practice guidelines recommend supervised exercise therapy (SET) as first-line therapy for patients with peripheral artery disease (PAD) and intermittent claudication (IC). The Society for Vascular Surgery Appropriate Use Criteria for IC deems excercise therapy (ET) as appropriate for all patients with IC. However, compliance with recommendations for the use of ET is often poor owing to the lack of availability, patient travel requirements, and cost. Results of home-based ET programs have been mixed with a trend toward improved results with more frequent patient engagement. The feasibility, use, and effectiveness of a 12-week app-based structured ET program using cognitive-behavioral therapy (CBT) techniques for IC was evaluated. Patients with PAD confirmed by an abnormal ankle-brachial index or toe-brachial index and IC were recruited prospectively to participate in Society for Vascular Surgery SET, a 12-week app-based ET program. Participants performed home 6-minute walk tests, completed quality-of-life surveys, received education options via micro learning courses (eg, What is PAD?, Exercise, and Nutrition), and ongoing health coaching using CBT techniques. They were instructed to record at least three 30-minute ET walks a week using their personal mobile phones. Programming also included daily doses of health education, coaching, and reminders sent via text message. One hundred thirty-nine patients (37% women; mean age, 65 years) were enrolled across 20 institutions (44% offered in-person ET programs). One hundred twenty patients (86%) completed the program. Participants recorded 201,163 minutes of walking 8,013,520 steps with the ET program, completing a total of 5049 SET walks. Nineteen enrolled participants (14%) became inactive because they either paused (14 participants: medical reasons, travel, or other) or withdrew (5 participants: security concerns, lack of motivation). Ninety-two percent of patients met their stated CBT specific, measurable, achievable, relevant, and time-bound goals. Freedom from intervention at 6 months was 92% and 69% at 12 months. Deployment of a 12-week app-based ET program for PAD incorporating CBT was feasible in achieving 86% program completion and effective at meeting guideline recommended activity goals. Ninety-two percent of participants achieved their CBT specific, measurable, achievable, relevant, and time-bound goals. The use of ET was increased by virtue of offering this program at institutions that did not offer ET.

Center volume and failure to rescue after open or endovascular repair of ruptured abdominal aortic aneurysms. The correlation between center volume and elective abdominal aortic aneurysm (AAA) repair outcomes is well established; however, these effects for either endovascular aneurysm repair (EVAR) or open aneurysm repair (OAR) of ruptured AAA (rAAA) remains unclear. Notably, the capacity to either avert or manage complications associated with postoperative mortality is an important cause of outcome disparities after elective procedures; however, there is a paucity of data surrounding nonelective presentations. Therefore, the purpose of this analysis was to describe the association between annual center volume, complications, and failure to rescue (FtR) after EVAR and OAR of rAAA. All consecutive endovascular and open rAAA repairs from 2010 to 2020 in the Vascular Quality Initiative were examined. Annual center volume (procedures/year per center) was grouped into quartiles: EVAR-Q1 (<14), 3.4%; Q2 (14-23), 12.8%; Q3 (24-37), 24.7%; and Q4 (>38), 59.1%; OAR-Q1 (<3), 5.4%; Q2 (4-6), 12.8%; Q3 (7-10), 22.7%; and Q4 (>10), 59.1%. The primary end point was FtR, defined as in-hospital death after experiencing one of six major complications (cardiac, renal, respiratory, stroke, bleeding, colonic ischemia). Risk-adjusted analyses for intergroup comparisons were completed using multivariable logistic regression. The unadjusted in-hospital death rate was 16.5% and 28.9% for EVAR and OAR, respectively. Complications occurred in 45% of EVAR (n = 1439/3188) and 70% of OAR (n = 1366/1961) patients with corresponding FtR rates of 14% (EVAR) and 26% (OAR). For OAR, Q4-centers had a 43% lower FtR risk (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.4-0.9; P = .017) compared with Q1 centers. Centers performing fewer than five OARs/year had a 43% lower risk (OR, 0.57; 95% CI, 0.4-0.7; P < .001) of FtR and this decreased 4% for each additional five procedures performed annually (95% CI, 0.93-0.991; P = .013). However, there was no significant relationship between center volume and FtR after EVAR. The risk of FtR was strongly associated with a greater number of complications for both procedures (OR multiplied by 6.5 for EVAR and 1.5 for OAR for each additional complication; P < .0001). Among OAR patients with a single recorded complication, return to the operating room for bleeding had highest risk of in-hospital mortality (OR, 4.1; 95% CI, 1.1-4.8; P = .034), whereas no specific type of complication increased FtR risk after EVAR. FtR occurs commonly after EVAR and OAR of rAAA within Vascular Quality Initiative centers. Importantly, increasing center volume was associated with decreased FtR risk after OAR, but not EVAR. Complication pattern and frequency predicted FtR after either repair strategy. For stable patients, especially those deemed anatomically ineligible for EVAR, these findings emphasize the need to improve the coordination of regional referral networks that centralize rAAAs to high-volume centers. Moreover, hospitals that treat rAAA should invest in resources that develop protocols targeting specific complications to mitigate risk of preventable postoperative death.

Effects of obesity on neuroinflammatory and neurochemical parameters in an animal model of reserpine-induced Parkinson's disease. Obesity is associated with low-grade chronic inflammation and oxidative stress, affecting the brain's reward system by decreasing dopaminergic neurotransmission. It is known that dopaminergic neurotransmission is also reduced in Parkinson's disease (PD), and high adiposity is considered a risk factor for the development of several neurodegenerative diseases, including PD. This study aimed to assess the effects of obesity on neuroinflammatory and neurochemical parameters in an animal model of reserpine-induced PD. The obese group showed increased inflammation and oxidative damage as well as inhibition of mitochondrial respiratory chain complexes I and II and DNA damage in the evaluated structures. The PD group did not show inflammation or mitochondrial dysfunction but exhibited oxidative damage in the hippocampus. The combination group (obesity + PD) showed reduced inflammation and oxidative stress and increased activity of complexes I and II of the mitochondrial respiratory chain in most of the analyzed structures. On the other hand, obesity + PD caused oxidative damage to proteins in the liver, prefrontal cortex, striatum, and cerebral cortex and oxidative stress in the hypothalamus, resulting in reduced catalase activity. Furthermore, the combination group showed DNA damage in blood, liver, and cerebral cortex. In conclusion, it was observed that the association of obesity and PD did not increase inflammation, oxidative stress, or mitochondrial dysfunction in most of the evaluated structures but increased oxidative damage and induced mechanisms that led to DNA damage in peripheral tissues and brain structures.

Different maturation patterns for sensorimotor gating and startle habituation deficits in male and female RHA vs RLA rats. Neurodevelopmental anomalies are thought to play a crucial role in the emergence of schizophrenia. The Roman high-avoidance (RHA) rats exhibit impaired prepulse inhibition (PPI), as well as other behavioral and cognitive singularities related to schizophrenia syndromes compared to the Roman low-avoidance (RLA) rats. In the present study, we aimed at elucidating whether PPI deficits in the RHA rats take place during prepubescence, adolescence, or adulthood. Thus, we evaluated the levels of PPI of both strains and both sexes during these three developmental phases. Additionally, we also investigated the onset of startle habituation deficits in the same groups. The results showed that male RHA rats exhibit a clear-cut PPI reduction compared to their RLA counterparts in adulthood. In female RHA rats, we observed lower levels of PPI since adolescence and through adulthood. We also found no differences between PPI percentages among the three ages in RHA male rats. Contrarily, in male RLA rats, PPI levels were increased in adults compared to their adolescent and prepubescent counterparts. Finally, a deficit in startle habituation was observed in adulthood of both male and female RHA rats, although in the latter case the disturbance in startle habituation was more profound. These results further the description of the maturational trajectory of cognitive markers relevant to schizophrenia prodrome and they add face validity to the RHA rats as a model of schizophrenia-relevant phenotypes.

Mechanochemically assisted persulfate activation for the facile recovery of metals from spent lithium ion batteries. A novel mechanochemically assisted persulfate activation method was proposed in this study to enhance the leaching of valuable metals from lithium-ion batteries by combining ball-milling, advanced oxidation processes and sucrose reduction. By optimizing leaching parameters including temperature, pH, milling time and solid-to-liquid ratio, high leaching efficiencies of 97.1%, 94.0%, 87.6% and 93.8% can be achieved for Li, Ni, Co and Mn respectively. In the mechanochemical process, the breakage of covalent bonds in cathode material is facilitated by free radicals generated from zero valent iron activated ammonia persulfate as well as mechanochemical activation. To further explore the role of free radicals, the mechanism of ammonia persulfate activation by zero valent iron was elucidated, and SO4•- was identified as the dominant reactive oxygen species in the mechanochemical process. Meanwhile, the synergistic effect of mechanochemically driven crystal dissolution and sulfate radical facilitated bond cleavage was revealed by ab initio molecular dynamics simulation. Moreover, the released metal was reduced by sucrose to a lower valent state of high solubility to promote transfer to the aqueous phase during the subsequent leaching process with dilute sulfuric acid. In this work, the insight on the mechanism of mechanochemical processes strengthened by free radicals may provide an inspiration for the recovery of valuable metals from LIBs.

Tools and techniques for rational designing of antimicrobial peptides for aquaculture. Fisheries and aquaculture industries remain essential sources of food and nutrition for millions of people worldwide. Indiscriminate use of antibiotics has led to the emergence of antimicrobial-resistant bacteria and posed a severe threat to public health. Researchers have opined that antimicrobial peptides (AMPs) can be the best possible alternative to curb the rising tide of antimicrobial resistance in aquaculture. AMPs may also help to achieve the objectives of one health approach. The natural AMPs are associated with several shortcomings, like less in vivo stability, toxicity to host cell, high cost of production and low potency in a biological system. In this review, we have provided a comprehensive outline about the strategies for designing synthetic mimics of natural AMPs with high potency. Moreover, the freely available AMP databases and the information about the molecular docking tools are enlisted. We also provided in silico template for rationally designing the AMPs from fish piscidins or other peptides. The rationally designed piscidin (rP1 and rp2) may be used to tackle microbial infections in aquaculture. Further, the protocol can be used to develop the truncated mimics of natural AMPs having more potency and protease stability.

Effects of dietary chenodeoxycholic acid supplementation in a low fishmeal diet on growth performance, lipid metabolism, autophagy and intestinal health of Pacific white shrimp, Litopenaeus vannamei. An 8-week feeding trial was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) on growth performance, body composition, lipid metabolism, and intestinal health of juvenile white shrimp, Litopenaeus vannamei fed a low fishmeal diet. Four practical diets were formulated: HFM (25% fishmeal), LFM (15% fishmeal), LB1 (LFM + 0.04% CDCA), LB2 (LFM + 0.08% CDCA). Each diet was assigned to four tanks with forty shrimp (initial weight 0.33 ± 0.03 g) per tank. The results indicated that the growth performance of shrimp were similar between the four groups; the crude lipid content of shrimp fed the LB2 diet was significantly lower than those fed the HFM diet (P < 0.05). The lipase activity content in hepatopancreatic were significantly higher in the two CDCA supplemented groups than that in LFM group; the contents of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol in hemolymph were significantly lower in LFM group, LB1 group and LB2 group than that in HFM group (P < 0.05). The shrimp fed LB1 diet was significantly decreased the intestinal expression levels of tube than those fed in HFM diet; the intestinal gene expression of imd and toll were significantly lower in LB2 group than those in HFM group (P < 0.05). The results of hepatopancreas gene expression suggest that shrimp fed the LFM diet showed significantly upregulated expression levels of sterol regulatory element-binding protein (srebp), acetyl-CoA carboxylase (acc), and carnitine palmitoyltransferase 1 (cpt-1) than those fed the HFM diet; shrimp fed the LB1 diet showed significantly upregulated expression levels of srebp, acc, and AMP-activated protein kinase (ampk) than those fed the HFM diet; shrimp fed the LB2 diet had higher expression levels of srebp, acc, and cpt-1 than those fed the HFM diet (P < 0.05). In the hepatopancreas, the shrimp fed the LFM diet shown significantly up-regulated the expression levels of beclin1 compared to those fed HFM diet; the expression levels of autophagy-related protein13 (atg3), autophagy-related protein 12 (atg12) of in shrimp fed the LB1 diet were significantly higher than those fed the HFM diet; and the expression levels of autophagy-related protein13 (atg13), beclin1, atg3, atg12, autophagy-related protein 9 (atg9) of shrimp fed LB2 diet were significantly higher than those fed the HFM diet (P < 0.05). The atg3 in intestine of shrimp fed the LB2 diet were significantly higher than those fed the HFM diet (P < 0.05). Intestinal mucous fold were damaged, hepatic tubules were disorganized and B cells appeared to be swollen in LFM group. The fold height and width of shrimp fed the diets supplemented with CDCA increased significantly than those fed the LFM diet (P < 0.05), the hepatic tubules were neatly arranged, and R cells increased. In conclusion, supplementary CDCA in a low fishmeal diet promoted lipid metabolism, enhanced autophagy of shrimp, also improved the health of the intestine and hepatopancreas.

Novel development of cationic surfactant-based mucoadhesive nanovaccine for direct immersion vaccination against Francisella noatunensis subsp. orientalis in red tilapia (Oreochromis sp.). Francisella noatunensis subsp. orientalis (Fno) is one of the infectious diseases that causes economic losses associated with tilapia mortality. Even though direct immersion administration of vaccines is more practicable for small fish and fry compared with oral and injection vaccination in the fields, the efficacy is still insufficient due to lower potency of antigen uptake. Herein, we accomplished the development of a mucoadhesive nanovaccine platform using cetyltrimethylammonium bromide (CTAB), a cationic surfactant, to improve the efficiency of immersion vaccination against Fno in tilapia. Cationic Fno nanovaccine (CAT-Fno-NV) was prepared though emulsification using an ultrasonic method. In our investigation, the CAT-Fno-NV increased the opportunity of Fno vaccine uptake by extending the contact time between vaccine and mucosal surface of fish gills and enhancing the protective efficacy against Fno infection. Fish were vaccinated with the CAT-Fno-NV by a direct immersion protocol. The challenge trial by Fno injection revealed that CAT-Fno-NV at the concentration 1:100 ratio (approximately 1 × 106 cfu/mL) had the highest efficacy to protect fish from Fno infection at day 30 after post challenge period according to the total number of Fno detected in head kidney, spleen and liver. A significant upregulation of IgM gene was observed in gills, skin, head kidney, serum and peripheral blood lymphocytes (PBLs) and spleen tissues treated with WC and CAT-Fno-NV (1:100) vaccines, while IgT gene was highly expressed in only gills and skin tissues for treated WC and CAT-Fno-NV (1:100) groups. We anticipate that the cationic surfactant-based nanovaccine developed in this study could become an efficient alternative for direct immersion vaccination to induce humoral immune responses against Fno in vaccinated tilapia.

Evidence of impaired mitochondrial cellular bioenergetics in ocular fibroblasts derived from glaucoma patients. Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration of the retinal ganglion cells (RGCs) resulting in irreversible visual impairment and eventual blindness. RGCs are extremely susceptible to mitochondrial compromise due to their marked bioenergetic requirements and morphology. There is increasing interest in therapies targeting mitochondrial health as a method of preventing visual loss in managing glaucoma. The bioenergetic profile of Tenon's ocular fibroblasts from glaucoma patients and controls was investigated using the Seahorse XF24 analyser. Impaired mitochondrial cellular bioenergetics was detected in glaucomatous ocular fibroblasts including basal respiration, maximal respiration and spare capacity. Spare respiratory capacity levels reflect mitochondrial bio-energetic adaptability in response to pathophysiological stress. Basal oxidative stress was elevated in glaucomatous Tenon's ocular fibroblasts and hydrogen peroxide (H2O2) induced reactive oxygen species (ROS) simulated the glaucomatous condition in normal Tenon's ocular fibroblasts. This work supports the role of therapeutic interventions to target oxidative stress or provide mitochondrial energetic support in glaucoma.

Targeting cyclin-dependent kinases 4/6 inhibits survival of megakaryoblasts in acute megakaryoblastic leukaemia. Acute megakaryoblastic leukaemia (AMKL) is characterized by expansion of megakaryoblasts, which are hyper-proliferative cells that fail to undergo differentiation. Insight to the cell-cycle regulation revealed important events in early or late megakaryocytes (MKs) maturation; the cyclin-dependent kinases 4 and 6 (CDK4/6) have been reported to participate in the development of progenitor megakaryocytes, mainly by promoting cell cycle progression and DNA polyploidization. However, it remains unclear whether the continuous proliferation, but not differentiation, of megakaryoblasts is related to an aberrant regulation of CDK4/6 in AMKL. Here, we found that CDK4/6 were up regulated in patients with AMKL, and persistently maintained at a high level during the differentiation of abnormal megakaryocytes in vitro, according to a database and western blot. Additionally, AMKL cells were exceptionally reliant on the cell cycle regulators CDK4 or 6, as blocking their activity using an inhibitor or short hairpin RNA (shRNA) significantly reduced the proliferation of 6133/MPL megakaryocytes, reduced DNA polyploidy, induced apoptosis, decreased the level of phosphorylated retinoblastoma protein (p-Rb), and activation of caspase 3. Additionally, CDK4/6 inhibitors and shRNA reduced the numbers of leukemia cells in the liver and bone marrow (BM), alleviated hepatosplenomegaly, and prolonged the survival of AMKL-transplanted mice. These results suggested that blocking the activity of CDK4/6 may represent an effective approach to control megakaryoblasts in AMKL.

Editor's Choice - Endovascular Aneurysm Repair in High Risk Patients: A Systematic Review and Meta-Analysis. To investigate outcomes of endovascular aneurysm repair (EVAR) in high risk patients. Bibliographic sources (MEDLINE, EMBASE, CINAHL, and CENTRAL) were searched using combinations of thesaurus and free text terms. The review protocol was registered in PROSPERO (CRD42021287207) and reported according to PRISMA 2020. Pooled estimates were calculated using odds ratio (OR) or hazard ratio (HR) and 95% confidence interval (CI) applying the Mantel-Haenszel or inverse variance method. EVAR peri-operative mortality in high risk patients over time was examined with mixed effects meta-regression. The GRADE framework was used to rate the certainty of evidence. The pooled peri-operative mortality in 18 416 high risk patients who underwent EVAR was 3% (95% CI 2.3 - 4%) and has significantly reduced over time (year of publication p = .003; median study point p = .023). The peri-operative mortality was significantly lower in high risk patients treated with EVAR compared with open repair (OR 0.64; 95% CI 0.45 - 0.92), but no significant difference was found in overall (HR 1.06; 95% CI 0.76 - 1.49) or aneurysm related mortality (HR 0.57; 95% CI 0.21 - 1.55). No significant difference was found in overall mortality between high risk patients treated with EVAR vs. no intervention (HR 0.42; 95% CI 0.14 - 1.26), but the aneurysm related mortality was significantly lower in the former (HR 0.30; 95% CI 0.14 - 0.63). The peri-operative mortality was higher in high risk than normal risk patients treated with EVAR (OR 2.33; 95% CI 1.75 - 3.10), as was the overall mortality (HR 3.50; 95% CI 2.55 - 4.80). The certainty of evidence was very low for EVAR vs. open surgery or no intervention and low for high vs. normal risk patients. The EVAR peri-operative mortality in high risk patients has improved over time. Even though the aneurysm related mortality of EVAR is lower compared with no intervention, EVAR may confer no overall survival benefit.

Exploring the roles of the Cdc2-like kinases in cancers. The Cdc2-like kinases (CLKs 1-4) are involved in regulating the alternative splicing of a variety of genes. Their activity contributes to important cellular processes such as proliferation, differentiation, apoptosis, migration, and cell cycle regulation. Abnormal expression of CLKs can lead to cancers; therefore, pharmacological inhibition of CLKs may be a useful therapeutic strategy. This review summarises what is known about the roles of each of the CLKs in cancerous cells, as well as the effects of relevant small molecule CLK inhibitors.

Calcium Challenge to Confirm Secondary Hyperparathyroidism Caused by Decreased Calcium Intake. Secondary hyperparathyroidism commonly occurs in the setting of mid-to low-normal serum calcium levels, often in the setting of chronic kidney disease, phosphate loading, vitamin D deficiency, or insufficient calcium intake or absorption. In this article, we report 9 patients who had adequate kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2) and normal 25-hydroxy vitamin D level (≥30 ng/dL) and whose secondary hyperparathyroidism resolved after starting adequate oral calcium intake. Our retrospective case series included 8 women and 1 man; the mean age was 69.0 ± 12.2 years (mean ± standard deviation). The initial intact parathyroid hormone (iPTH) level was 80.6 ± 13.4 pg/mL (reference range [ref], 10-65 pg/mL), corrected serum calcium level was 9.2 ± 0.2 mg/dL (ref, 8.5-10.5 mg/dL), serum phosphate level was 3.6 ± 0.4 mg/dL (ref, 2.5-4.9 mg/dL), 25-hydroxy vitamin D level was 42.2 ± 10.5 mg/dL (ref, 20-50 ng/mL), and estimated glomerular filtration rate was 72.6 ± 14.4 mL/min/1.73 m2. Patients were treated clinically with oral calcium 600 mg twice a day. iPTH was retested after a mean duration of 17.6 ± 12.7 days of calcium supplementation; the iPTH level decreased to 51.0 ± 10.6 pg/mL, with all patients achieving iPTH in the normal range with normocalcemia, consistent with hyperparathyroidism being because of insufficient calcium intake or absorption. All patients were normocalcemic after supplementation. Secondary hyperparathyroidism can result from insufficient oral calcium intake. Calcium challenge is an efficacious and cost-effective tool for confirming and treating secondary hyperparathyroidism in the setting of normal vitamin D levels and kidney function.

One miniplate versus two miniplates in the fixation of mandibular angle fractures. An updated systematic review and meta-analysis. The aim of this study is to compare the outcomes after using one miniplate fixation in the external oblique ridge versus two miniplate fixation for mandibular angle fractures. A systematic review of MEDLINE (via PubMed), Scopus and Cochrane Library database was performed (last search date: 04 February 2022) according to the PRISMA guidelines. The research question was addressed using the PICO criteria. Only comparative studies between the two techniques were included. Random-effects model meta-analyses were performed. Seventeen studies, comprising a total of 1667 patients, 846 undergoing one miniplate fixation and 854 undergoing two miniplate fixation for mandibular angle fractures were identified. No statistically significant differences were observed regarding surgical site infection (odds ratio [OR]= 0.94, 95% confidence interval [CI]: [0.69] - [1.28], p = 0.68, I2=0.00%), post-operative malocclusion (OR= 0.97, 95% CI: [0.53] - [1.18], p = 0.25, I2=0.00%), post-operative neurosensory dysfunction (OR= 0.67, 95% CI: [0.37] - [1.22], p = 0.19, I2=73.93%), pseudoarthrosis formation (OR=0.90, 95% CI: [0.58] - [(1.39], p = 0.63, I2=0.00%). Wound dehiscence was marginally less common in the one miniplate group (OR=0.52, 95% CI: [0.28] - [0.98], p = 0.04, I2=54.34%). The probability of scarring formation (OR=0.13, 95% CI: [0.05] - [0.32], p = 0.00, I2=0.00%) and hardware failure (OR=0.36, 95% CI [0.21] - [0.62], p = 0.00, I2=29.33%) were statistically significantly higher in the two miniplates arm. One miniplate fixation and two miniplates fixation of mandibular angle fractures have similar results regarding post operative infection, malocclusion, neurosensory dysfunction and pseudoarthrosis formation while wound dehiscence, hardware failure and scarring seem to be more common when two miniplates are used as a fixation technique.

Photoinactivation of Aedes aegypti larvae using riboflavin as photosensitizer. More than half of the global population lives in areas where the Aedes aegypti mosquito is present. Efforts have been made to deal with the population of this mosquito in the larval and adult stages to prevent outbreaks of diseases (Dengue, Zika, Chikungunya, and Yellow Fever). In this scenario, photodynamic inactivation may be an effective alternative method to control this vector population. To evaluate the efficacy of the riboflavin - B2 vitamin - as photosensitizer (PS) in the photodynamic inactivation of Ae. aegypti larvae, different concentrations (0; 0.005; 0.010; 0.025; 0.050; 0.075 and 0.100 mg mL-1) were evaluated under white light from RGB LEDs at a light dose of 495.2 J cm-2. The results reveal that riboflavin can be successfully applied as a PS agent to photoinactivate Ae. aegypti larvae, showing its potential to deal with the larvae population.

The implications of ortho-, meta- and para- directors on the in-vitro photodynamic antimicrobial chemotherapy activity of cationic pyridyl-dihydrothiazole phthalocyanines. Cationic Zn phthalocyanine complexes were derived by alkylation reaction of tetra-(pyridinyloxy) phthalocyanines (Pcs) at the ortho, meta, and para positions to form Zn (II) tetrakis 3-(4-(2-pyridin-1-ium-1-yl) butyl)-2-mercapto-4,5-dihydrothiazol-3-ium phthalocyanine (2), Zn (II) tetrakis 3-(4-(3-pyridin-1-ium-1-yl) butyl)-2-mercapto-4,5-dihydrothiazol-3-ium phthalocyanine (4) and Zn (II) tetrakis 3-(4-(4-pyridin-1-ium-1-yl) butyl)-2-mercapto-4,5-dihydrothiazol-3-ium phthalocyanine (6). The photophysicochemical behaviors of the Pc complexes were assessed. The meta and para-substituted complexes gave high singlet oxygen quantum yields. The cationic Pcs demonstrated good planktonic antibacterial activity against Staphylococcus aureus and Escherichia coli with the high log reduction values of 9.29 and 8.55, respectively. The cationic complexes also showed a significant decrease in the viability of in vitro biofilms after photo-antimicrobial chemotherapy at 100 µM for both Staphylococcus aureus and Escherichia coli biofilms.