bluuebunny/crossref_metadata_2025 huggingface dataset:
Small Molecule Arranged Thermal Proximity Coaggregation (smarTPCA)—A Novel Approach to Characterize Protein–Protein Interactions in Living Cells by Similar Isothermal Dose–Responses
Authors: Lenz Thomas , Stühler Kai
Published: May 2022

Chemical biology and the application of small molecules has proven to be a potent perturbation strategy, especially for the functional elucidation of proteins, their networks, and regulators. In recent years, the cellular thermal shift assay (CETSA) and its proteome-wide extension, thermal proteome profiling (TPP), have proven to be effective tools for identifying interactions of small molecules with their target proteins, as well as off-targets in living cells. Here, we asked the question whether isothermal dose–response (ITDR) CETSA can be exploited to characterize secondary effects downstream of the primary binding event, such as changes in post-translational modifications or protein–protein interactions (PPI). By applying ITDR-CETSA to MAPK14 kinase inhibitor treatment of living HL-60 cells, we found similar dose–responses for the direct inhibitor target and its known interaction partners MAPKAPK2 and MAPKAPK3. Extension of the dose–response similarity comparison to the proteome wide level using TPP with compound concentration range (TPP-CCR) revealed not only the known MAPK14 interaction partners MAPKAPK2 and MAPKAPK3, but also the potentially new intracellular interaction partner MYLK. We are confident that dose-dependent small molecule treatment in combination with ITDR-CETSA or TPP-CCR similarity assessment will not only allow discrimination between primary and secondary effects, but will also provide a novel method to study PPI in living cells without perturbation by protein modification, which we named “small molecule arranged thermal proximity coaggregation” (smarTPCA).
Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice
Authors: Kasper Philipp , Selle Jaco , Vohlen Christina , Wilke Rebecca , Kuiper-Makris Celien , Klymenko Oleksiy , Bae-Gartz Inga , Schömig Charlotte , Quaas Alexander , Schumacher Björn , Demir Münevver , Bürger Martin , Lang Sonja , Martin Anna , Steffen Hans-Michael , Goeser Tobias , Dötsch Jörg , Alcazar Miguel A. Alejandre
Published: May 2022

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.
The Metabolic Efficacy of a Cannabidiolic Acid (CBDA) Derivative in Treating Diet- and Genetic-Induced Obesity
Authors: Ben-Cnaan Elad , Permyakova Anna , Azar Shahar , Hirsch Shira , Baraghithy Saja , Hinden Liad , Tam Joseph
Published: May 2022

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2null mouse model for PWS. In addition, when given to standard-diet-fed Magel2null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.
Specific Local Predictors That Reflect the Tropism of Endometriosis—A Multiple Immunohistochemistry Technique
Authors: Istrate-Ofiţeru Anca-Maria , Berbecaru Elena-Iuliana-Anamaria , Zorilă George-Lucian , Roşu Gabriela-Camelia , Dîră Laurențiu Mihai , Comănescu Cristina Maria , Drăguşin Roxana Cristina , Ruican Dan , Nagy Rodica Daniela , Iliescu Dominic Gabriel , Mogoantă Laurențiu , Pirici Daniel
Published: May 2022

Ectopic endometrial epithelium associates a wide spectrum of symptomatology. Their evolution can be influenced by inflammatory and vascular changes, that affect not only the structure and cell proliferation rate, but also symptoms. This prospective study involved tissue samples from surgically treated patients, stained using classical histotechniques and immunohistochemistry. We assessed ectopic endometrial glands (CK7+, CK20−), adjacent blood vessels (CD34+), estrogen/progesterone hormone receptors (ER+, PR+), inflammatory cells (CD3+, CD20+, CD68+, Tryptase+), rate of inflammatory cells (Ki67+) and oncoproteins (BCL2+, PTEN+, p53+) involved in the development of endometriosis/adenomyosis. A CK7+/CK20− expression profile was present in the ectopic epithelium and differentiated it from digestive metastases. ER+/PR+ were present in all cases analyzed. We found an increased vascularity (CD34+) in the areas with abdominal endometriosis and CD3+−:T-lymphocytes, CD20+−:B-lymphocytes, CD68+:macrophages, and Tryptase+: mastocytes were abundant, especially in cases with adenomyosis as a marker of proinflammatory microenvironment. In addition, we found a significantly higher division index-(Ki67+) in the areas with adenomyosis, and inactivation of tumor suppressor genes-p53+ in areas with neoplastic changes. The inflammatory/vascular/hormonal mechanisms trigger endometriosis progression and neoplastic changes increasing local pain. Furthermore, they may represent future therapeutic targets. Simultaneous-multiple immunohistochemical labelling represents a valuable technique for rapidly detecting cellular features that facilitate comparative analysis of the studied predictors.
Intestinal Radiation Protection and Mitigation by Second-Generation Probiotic Lactobacillus-reuteri Engineered to Deliver Interleukin-22
Authors: Espinal Alexis , Epperly Michael W. , Mukherjee Amitava , Fisher Renee , Shields Donna , Wang Hong , Huq M. Saiful , Hamade Diala Fatima , Vlad Anda M. , Coffman Lan , Buckanovich Ronald , Yu Jian , Leibowitz Brian J. , van Pijkeren Jan-Peter , Patel Ravi B. , Stolz Donna , Watkins Simon , Ejaz Asim , Greenberger Joel S.
Published: May 2022

(1) Background: The systemic administration of therapeutic agents to the intestine including cytokines, such as Interleukin-22 (IL-22), is compromised by damage to the microvasculature 24 hrs after total body irradiation (TBI). At that time, there is significant death of intestinal microvascular endothelial cells and destruction of the lamina propria, which limits drug delivery through the circulation, thus reducing the capacity of therapeutics to stabilize the numbers of Lgr5+ intestinal crypt stem cells and their progeny, and improve survival. By its direct action on intestinal stem cells and their villus regeneration capacity, IL-22 is both an ionizing irradiation protector and mitigator. (2) Methods: To improve delivery of IL-22 to the irradiated intestine, we gavaged Lactobacillus-reuteri as a platform for the second-generation probiotic Lactobacillus-reuteri-Interleukin-22 (LR-IL-22). (3) Results: There was effective radiation mitigation by gavage of LR-IL-22 at 24 h after intestinal irradiation. Multiple biomarkers of radiation damage to the intestine, immune system and bone marrow were improved by LR-IL-22 compared to the gavage of control LR or intraperitoneal injection of IL-22 protein. (4) Conclusions: Oral administration of LR-IL-22 is an effective protector and mitigator of intestinal irradiation damage.
Biofabrication of Collagen Tissue-Engineered Blood Vessels with Direct Co-Axial Extrusion
Authors: Bosch-Rué Èlia , Díez-Tercero Leire , Delgado Luis M. , Pérez Román A.
Published: May 2022

Cardiovascular diseases are considered one of the worldwide causes of death, with atherosclerosis being the most predominant. Nowadays, the gold standard treatment is blood vessel replacement by bypass surgery; however, autologous source is not always possible. Thereby, tissue-engineered blood vessels (TEBVs) are emerging as a potential alternative source. In terms of composition, collagen has been selected in many occasions to develop TEBVs as it is one of the main extracellular matrix components of arteries. However, it requires specific support or additional processing to maintain the tubular structure and appropriate mechanical properties. Here, we present a method to develop support-free collagen TEBVs with co-axial extrusion in a one-step procedure with high concentrated collagen. The highest concentration of collagen of 20 mg/mL presented a burst pressure of 619.55 ± 48.77 mmHg, being able to withstand perfusion of 10 dynes/cm2. Viability results showed a high percentage of viability (86.1 and 85.8% with 10 and 20 mg/mL, respectively) of human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVEC) after 24 h extrusion. Additionally, HUVEC and HASMCs were mainly localized in their respective layers, mimicking the native distribution. All in all, this approach allows the direct extrusion of collagen TEBVs in a one-step procedure with enough mechanical properties to be perfused.
Optimization of a Mass Trapping Method against the Striped Cucumber Beetle Acalymma vittatum in Organic Cucurbit Fields
Authors: Tinslay Jessee , Fournier Marc , Couture Isabelle , Lafontaine Pierre J. , Lefebvre Maxime , Lucas Eric
Published: May 2022

The striped cucumber beetle (SCB) Acalymma vittatum (F.) (Coleptera: Chrysomelidae) is a prime problem in North American cucurbit crops. While certain chemical pesticides efficiently control SCB in conventional cucurbit fields, alternative solutions are required due to the ever-evolving regulations on pesticides. For organic producers, very few control methods exist. A novel mass trapping method demonstrates the potential of controlling SCBs using floral-based semiochemical baited traps in cucurbit crops. The goals of this study were to (1) determine whether baited traps capture more SCBs than unbaited ones, and (2) optimize the trapping method by comparing different trap types and different commercially available attractants to maximize SCB captures while minimizing non-target species captures. The results of a first experiment showed that baited traps captured significantly more SCBs than unbaited ones. Baited traps also captured significantly more bees and hoverflies than unbaited ones. In a second experiment these unwanted captures were drastically reduced by using traps with ten 4 mm in diameter holes per side. Finally, a third experiment demonstrated that the attractant 40CT313 was the most efficient at capturing SCB compared to other tested lures. Overall, the optimized mass trapping technique demonstrated a potential to effectively control SCB populations in organic cucurbit crops.
Correction: Pramasivan et al. Multiplex PCR Assay for the Identification of Four Species of the Anopheles Leucosphyrus Sub-Group in Malaysia. Insects 2022, 13, 195
Authors: Pramasivan Sandthya , Liew Jonathan Wee Kent , Jeyaprakasam Nantha Kumar , Low Van Lun , Ngui Romano , Vythilingam Indra
Published: May 2022

In the original publication [...]
Biological Control Services from Parasitic Hymenoptera in Urban Agriculture
Authors: Arnold Joshua Earl
Published: May 2022

Urban agriculture is practiced in spatially fragmented landscapes with unique characteristics that can impact species occurrence in time and space. As a result, biological control services, an ecosystem service from naturally occurring arthropod natural enemies, can be negatively impacted. Many urban farms forgo pesticides and utilize agroecological pest-management strategies that rely on natural enemies to help regulate pest populations. Understanding how these enemies are affected by landscape composition and on-farm management practices is critical to understanding agroecological pest management in UA and furthering our understanding of landscape-mediated population dynamics. Over two growing seasons, we sampled brassica crops in urban agriculture sites occurring on a spectrum of surrounding landscape imperviousness, spatial composition, size, and management practices to better understand parasitic Hymenoptera abundance, richness, and parasitism rates on the common cabbage aphid (Brevicoryne brassicae). We found that on-farm agroecological pest-management practices such as mulch coverage, floral richness, and overall crop-plant richness impacted parasitic Hymenoptera abundance. Larger proportions of on-farm noncrop area increased parasitoid abundance on urban farms. Aphid parasitism increased in relation to on-farm management practices, including increased crop-plant richness. These findings add to a growing understanding of urban agroecosystem function and support the enemies hypothesis in urban agroecosystems.
Safety of Tacrolimus Monotherapy within 12 Months after Liver Transplantation in the Era of Reduced Tacrolimus and Mycophenolate Mofetil: National Registry Study
Authors: Kim Deok Gie , Kim Sung Hwa , Hwang Shin , Hong Suk Kyun , Ryu Je Ho , Kim Bong-Wan , You Young Kyoung , Choi Donglak , Kim Dong-Sik , Nah Yang Won , Cho Jai Young , Kim Tae-Seok , Hong Geun , Joo Dong Jin , Kim Myoung Soo , Kim Jong Man , Lee Jae Geun ,   KOTRY Study Group
Published: May 2022

Tacrolimus monotherapy is accepted as a feasible option during early post-liver transplantation as per current international consensus guidelines. However, its effects in the recent era of reduced tacrolimus (TAC) and mycophenolate mofetil (MMF) remain unclear. Liver recipients who either received TAC monotherapy from the treatment onset or switched from TAC/MMF to TAC-mono within 12 months (TAC-mono group; n = 991) were chronologically matched to patients who continued to receive TAC/MMF (TAC/MMF group; n = 991) at the corresponding time points on time-conditional propensity scores. Outcomes within 12 months after matched time points were compared. Biopsy-proven rejection (TAC/MMF: 3.5% vs. TAC-mono: 2.6%; p = 0.381) and graft failure (0.2% vs. 0.7%; p = 0.082) were similar in both groups. However, the decline in eGFR was 3.1 mL/min/1.73 m2 (95% CI: 0.8–5.3) greater at six months (p = 0.008) and 2.4 mL/min/1.73 m2 (95% CI: −0.05–4.9) greater at 12 months (p = 0.048) after the matched time points in TAC-mono group than that in TAC/MMF group. TAC trough levels were also higher in the TAC-mono group throughout the study period. TAC-mono within 12 months after liver transplantation is immunologically safe. However, it can increase the required TAC dose and the decline in renal function than that in TAC/MMF combination therapy.
The Impact of Noncontact Tonometry and Icare Rebound Tonometry on Tear Stability and Dry Eye Clinical Practice
Authors: Dogru Murat , Simsek Cem , Kojima Takashi , Aketa Naohiko , Tsubota Kazuo , Shimazaki Jun
Published: May 2022

The purpose of this study was to investigate the possible effects of the noncontact air puff tonometry (NCT) and Icare rebound tonometry (ICT) on the tear film stability by using the tear stability analysis system (TSAS) and dry eye parameters. Fifteen eyes from fifteen normal healthy subjects were investigated in this study. All subjects underwent TSAS surface regularity index (SRI) examinations, TBUT, and IOP measurements. The mean IOP results measured with NCT were 13.3 ± 1.86 mm Hg, and the mean IOP results measured with ICT were 15.88 ± 3.09 mm Hg (p > 0.05). The mean values of baseline, 5 min, and 10 min of the NCT-SRI and ICR-SRI were tested. There were statistically significant differences between NCT-Baseline SRI, NCT-5 min SRI, and NCT-10 min SRI values (p < 0.05). SRI values significantly increased after NCT. The mean values of the baseline, 5 min, and 10 min of the ICT-SRI were also assessed. There were no statistically significant differences between ICT-Baseline SRI, ICT-5 min SRI, and ICT-10 min SRI values (p > 0.05). The mean TBUT values exhibited a significant decrease at 1 min, 5 min, and 10 min compared with baseline values for the NCT and ICT (p < 0.01). NCT-TBUT and ICT-TBUT values were also compared with each other in the same time period. There were no statistically significant differences between NCT-Baseline and ICT-Baseline TBUT values (p > 0.05). In conclusion, intraocular pressure measurements in routine ophthalmology clinical practices by either NCT or ICT cause deterioration in the tear film stability which might affect tear stability testing when performed soon after IOP measurements. It is best to wait at least for 20–30 min after the IOP measurement before evaluating the tear film and the corneal surface or perform tonometry after the tear film-ocular surface evaluation tests.
Association between Pemafibrate Therapy and Triglyceride to HDL-Cholesterol Ratio
Authors: Imamura Teruhiko , Narang Nikhil , Kinugawa Koichiro
Published: May 2022

Background: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator, which was demonstrated to reduce serum triglyceride level with few drug-related adverse events in phase II and III clinical trials. However, its clinical implication in real-world practice remains unknown. Triglyceride/HDL-cholesterol ratio is a surrogate of small dense LDL-cholesterol, which is a newly proposed cardiovascular risk factor independent of LDL-cholesterol levels. Methods: Consecutive patients who received pemafibrate between April 2020 and September 2021 and continued therapy for at least 3 months were included in this retrospective analysis. The primary outcome was the trend in triglyceride/HDL-cholesterol ratio during the 3-month treatment period. The change in cardiovascular event rate between the one-year pre-treatment period and the on-treatment period was also analyzed. Results: A total of 19 patients (median age 63 years, 74% men) were included and continued pemafibrate therapy for 3 months without any drug-related adverse events. Sixteen were add-on and three were conversions from other fibrates. Triglyceride/HDL-cholesterol ratio decreased significantly from 5.85 (4.19, 16.1) to 3.14 (2.39, 4.62) (p < 0.001). The cardiovascular event rate decreased significantly from 0.632 events/year to 0.080 events/year (p < 0.001). Conclusions: Pemafibrate therapy might have the potential to lower triglyceride/HDL-cholesterol ratio and decrease cardiovascular events.
Independent and Joint Associations of Pessimism, Total Calorie Intake and Acid-Producing Diets with Insomnia Symptoms among Breast Cancer Survivors
Authors: Wu Tianying , Arevalo Cesar , Hsu Fang-Chi , Hong Suzi , Parada Humberto , Yang Mingan , Pierce John P.
Published: May 2022

Insomnia is prevalent in up to 40% of breast cancer survivors. Few studies have examined pessimism and dietary factors as risk factors for insomnia among breast cancer survivors. We leveraged a cohort of 2944 breast cancer survivors who enrolled in the Women’s Healthy Eating and Living study; these survivors provided dietary, insomnia, mental health, demographic, and lifestyle information at baseline and at 1- and 4-year follow-up assessments. Insomnia symptoms were assessed using the Women’s Health Initiative (WHI)-Insomnia Rating Scale, and pessimism was assessed using the Life Orientation Test Revised (LOT-R). Total calorie intake and acid-producing diets were assessed using 24 h dietary recalls. Multivariable-adjusted generalized estimating equation (GEE) models were used to test the independent and joint effects of psychological and dietary factors on insomnia. In the multivariable model, women in the third tertile of pessimism had greater odds (OR = 1.57 95% CI [1.37–1.79]) of insomnia when compared to women in the lowest tertile. Total calorie intake and acid-producing diets were each independently and significantly associated with insomnia symptoms. Further, pessimism and calorie intake/acid-producing diets were jointly associated with insomnia. For instance, women with pessimism scores in tertile 3 and total calorie intakes < median reported 2 times the odds (OR = 2.09; 95% CI [1.51–3.47]) of insomnia compared to women with pessimism score in tertile 1 and calorie intakes < median. Our results highlight the need for patient care regarding mental health, and recommendations of healthy dietary intakes for breast cancer survivors.
Patients with a Higher Number of Periodic Limb Movements Have Higher Nocturnal Blood Pressure
Authors: Krzyzaniak Klaudia , Partinen Eemil , Partinen Markku , Sieminski Mariusz
Published: May 2022

There is growing evidence that periodic limb movements in sleep (PLMS) may lead to increased blood pressure (BP) values during the night. The aim of this study was to assess if patients with disordered sleep and an increased number of PLMS have higher BP values at night. We analyzed 100 polysomnographic (PSG) recordings of patients with disordered sleep, with the exclusion of sleep-related breathing disorders. Patients also registered beat-to-beat blood pressure during PSG. We compared the BP of patients with an increased number of PLMS (more than 5 PLMS per hour of sleep) during the night (examined group, n = 50) to the BP of patients with a PLMS number within the normal range (up to 5 PLMS per hour of sleep) (control group, n = 50). Patients from the examined group had significantly higher values of systolic BP during the night (119.7 mmHg vs. 113.3 mmHg, p = 0.04), sleep (119.0 mmHg vs. 113.3 mmHg, p = 0.04), and wake (122.5 mmHg vs. 117.2 mmHg, p = 0.04) periods and of diastolic BP during the night (75.5 mmHg vs. 70.6 mmHg, p = 0.04) and wake (77.6 mmHg vs. 71.5 mmHg, p = 0.01) periods. Our results suggest a relationship between the number of PLMS during the night and the values of nocturnal blood pressure. It is possible that their treatment could lower nocturnal BP in patients with sleep disorders, therefore improving their vascular risk profile.
Prevalence and Factors of Osteoporosis and High Risk of Osteoporotic Fracture in Patients with Ankylosing Spondylitis: A Multicenter Comparative Study of Bone Mineral Density and the Fracture Risk Assessment Tool
Authors: Kim Ji-Won , Park Sunghoon , Jung Ju-Yang , Kim Hyoun-Ah , Kwon Seong-Ryul , Choi Sang Tae , Kim Sung-Soo , Kim Sang-Hyeon , Suh Chang-Hee
Published: May 2022

Background: We investigated the prevalence of and the factors associated with a high risk of osteoporotic fractures in Korean patients with ankylosing spondylitis (AS). Methods: This was a multicenter, retrospective study including 219 AS patients from five university hospitals; the control group was selected by matching age and sex with those of the AS patients. The fracture risk was evaluated based on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and the fracture risk assessment tool (FRAX) with/without BMD. Results: The mean age of the patients was 47.6 years, and 144 (65.8%) patients were men. According to the WHO criteria and FRAX with/without BMD, the candidates for pharmacological treatment were 44 (20.1%), 20 (13.2%), and 23 (15.1%) patients, respectively, significantly more than those in the healthy control group. Among them, the proportion of patients receiving osteoporosis treatment was 39.1–75%. In logistic regression analysis, menopause was an independent factor for the high risk of fracture according to the WHO criteria and FRAX with/without BMD. C-reactive protein level (odds ratio (OR) 3.8 and OR 6) and glucocorticoid use (OR 1.5 and OR 1.7) were associated with a high risk of osteoporotic fracture based on FRAX without BMD and osteoporosis diagnosed according to the WHO criteria. Conclusions: Our study suggests that both FRAX and WHO criteria may be complementary for treatment decisions to reduce osteoporotic fractures in patients with AS.
Predictive Value of Blood Coagulation Parameters in Poor Outcomes in COVID-19 Patients: A Retrospective Observational Study in Romania
Authors: Citu Cosmin , Burlea Bogdan , Gorun Florin , Motoc Andrei , Gorun Oana Maria , Malita Daniel , Ratiu Adrian , Margan Roxana , Grigoras Mirela Loredana , Bratosin Felix , Citu Ioana Mihaela
Published: May 2022

SARS-CoV-2 infection produces alterations in blood clotting, especially in severe cases of COVID-19. Abnormal coagulation parameters in patients with COVID-19 are important prognostic factors of disease severity. The objective of this study was to evaluate the predictive value of aPTT, D-dimer, INR and PT in the mortality of patients with COVID-19. A retrospective, single-center, observational study was conducted on COVID-19 patients admitted to the Municipal Emergency Clinical Hospital in Timisoara, Romania, between August and October 2021. Patients were confirmed as COVID-19 positive by reverse transcription-polymerase chain reaction (RT-PCR) assay. After applying the inclusion/exclusion criteria, a total of 82 patients were included in the analysis. Receiver operating characteristic (ROC) curves of D-Dimer, INR, PT and aPTT were generated to assess whether the baseline of each of these biomarkers was accurately predictive for mortality in patients with COVID-19. Mortality among patients enrolled in this study was 20.7%, associated with older age and presence of heart disease. The areas under the ROC curve (AUC-ROC) of D-Dimer, INR, PT, and aPTT were 0.751, 0.724, 0.706 and 0.753. Differences in survival for patients with coagulation biomarker levels above cut-off values compared to patients below these values were statistically significant. All evaluated parameters had significant differences and good performance in predicting mortality of COVID-19 patients, except fibrinogen, which had no significant difference. Moreover, aPTT and D-dimer were the best performing parameters in predicting mortality in patients with SARS-CoV-2 infection.
Flow Cytometry Analysis of Blood Large Extracellular Vesicles in Patients with Multiple Sclerosis Experiencing Relapse of the Disease
Authors: Soukup Jakub , Kostelanská Marie , Kereïche Sami , Hujacová Andrea , Pavelcová Miluše , Petrák Jiří , Kubala Havrdová Eva , Holada Karel
Published: May 2022

The number of people living with multiple sclerosis (MS) in developed countries is increasing. The management of patients is hindered by the absence of reliable laboratory tests accurately reflecting the disease activity. Extracellular vesicles (EVs) of different cell origin were reportedly elevated in MS patients. We assessed the diagnostic potential, with flow cytometry analysis, of fresh large EVs (lEVs), which scattered more light than the 590 nm silica beads and were isolated from the blood plasma of relapsing remitting MS patients. Venous blood was collected from 15 patients and 16 healthy controls (HC). The lEVs were isolated from fresh platelet-free plasma by centrifugation, labelled with antibodies and the presence of platelet (CD41+, CD36+), endothelial (CD105+), erythrocyte (CD235a+), leukocyte (CD45+, CD19+, CD3+) and phosphatidylserine (Annexin V+) positive lEVs was analyzed using standard flow cytometry. Cryo-electron microscopy was used to verify the presence of EVs in the analyzed plasma fractions. MS patients experiencing acute relapse had slightly reduced relative levels (% of positive lEVs) of CD105+, CD45+, CD3+, CD45+CD3+ or CD19+ labelled lEVs in comparison to healthy controls. An analysis of other markers or a comparison of absolute lEV counts (count of lEVs/µL) did not yield any significant differences. Our data do not support the hypothesis that the exacerbation of the disease in RRMS patients leads to an increased numbers of circulating plasma lEVs which can be monitored by standard flow cytometry.
Pax3 Hypomorphs Reveal Hidden Pax7 Functional Genetic Compensation in Utero
Authors: Zhou Hong-Ming , Conway Simon J.
Published: May 2022

Pax3 and Pax7 transcription factors are paralogs within the Pax gene family that that are expressed in early embryos in partially overlapping expression domains and have distinct functions. Significantly, mammalian development is largely unaffected by Pax7 systemic deletion but systemic Pax3 deletion results in defects in neural tube closure, neural crest emigration, cardiac outflow tract septation, muscle hypoplasia and in utero lethality by E14. However, we previously demonstrated that Pax3 hypomorphs expressing only 20% functional Pax3 protein levels exhibit normal neural tube and heart development, but myogenesis is selectively impaired. To determine why only some Pax3-expressing cell lineages are affected and to further titrate Pax3 threshold levels required for neural tube and heart development, we generated hypomorphs containing both a hypomorphic and a null Pax3 allele. This resulted in mutants only expressing 10% functional Pax3 protein with exacerbated neural tube, neural crest and muscle defects, but still a normal heart. To examine why the cardiac neural crest appears resistant to very low Pax3 levels, we examined its paralog Pax7. Significantly, Pax7 expression is both ectopically expressed in Pax3-expressing dorsal neural tube cells and is also upregulated in the Pax3-expressing lineages. To test whether this compensatory Pax7 expression is functional, we deleted Pax7 both systemically and lineage-specifically in hypomorphs expressing only 10% Pax3. Removal of one Pax7 allele resulted in partial outflow tract defects, and complete loss of Pax7 resulted in full penetrance outflow tract defects and in utero lethality. Moreover, combinatorial loss of Pax3 and Pax7 resulted in severe craniofacial defects and a total block of neural crest cell emigration from the neural tube. Pax7Cre lineage mapping revealed ectopic labeling of Pax3-derived neural crest tissues and within the outflow tract of the heart, experimentally confirming the observation of ectopic activation of Pax7 in 10% Pax3 hypomorphs. Finally, genetic cell ablation of Pax7Cre-marked cells is sufficient to cause outflow tract defects in hypomorphs expressing only 10% Pax3, confirming that ectopic and induced Pax7 can play an overlapping functional genetic compensational role in both cardiac neural crest lineage and during craniofacial development, which is normally masked by the dominant role of Pax3.
Restoration in Vertebral Compression Fractures (VCF): Effectiveness Evaluation Based on 3D Technology
Authors: Noriega González David C. , Ardura Aragón Francisco , Crespo Sanjuan Jesús , Santiago Maniega Silvia , Labrador Hernández Gregorio , Bragado González María , Pérez-Valdecantos Daniel , Caballero-García Alberto , Córdova Alfredo
Published: May 2022

There are few studies about anatomical reduction of the fractured vertebral body before stabilization for treatment of vertebral compression fracture (VCF). Although restoration on vertebral height has been useful, the reduction of fractured endplates is limited. The vertebra is part of a joint, and vertebral endplates must be treated like other weight-bearing joint to avoid complications. The aim of this study was to evaluate the feasibility of anatomic reduction of vertebral compression fracture, in different bone conditions, fracture types, and ages (VCF). Under methodological point of view, we followed different steps: first was the placement of two expandable titanium implants just below the fracture. Later, to push the fractured endplates into a more anatomical position, the implants were expanded. Finally, with the implants perfectly positioned, PMMA cement was injected to avoid any loss of correction. To evaluate the effectiveness of this procedure in anatomical fracture reduction, a method based on 3D CT reconstructions was developed. In this paper, we have developed the procedure in three case studies. In all of them, we were able to demonstrate the efficacy of this procedure to reduce the VCF. The percentage of correction of the kyphotic angle varied range between 49% and 62% with respect to the value after the fracture preoperative value. This was accompanied by a reduction of the pain level on the VAS scale around 50%. In conclusion, this novel approach to the vertebral fracture treatment (VCF) associated with 3D assessment have demonstrated the possibility of reducing the vertebral kyphosis angle and the vertebral endplate fractures. However, given the few cases presented, more studies are necessaries to confirm these results.
Intraretinal Layer Segmentation Using Cascaded Compressed U-Nets
Authors: Yadav Sunil Kumar , Kafieh Rahele , Zimmermann Hanna Gwendolyn , Kauer-Bonin Josef , Nouri-Mahdavi Kouros , Mohammadzadeh Vahid , Shi Lynn , Kadas Ella Maria , Paul Friedemann , Motamedi Seyedamirhosein , Brandt Alexander Ulrich
Published: May 2022

Reliable biomarkers quantifying neurodegeneration and neuroinflammation in central nervous system disorders such as Multiple Sclerosis, Alzheimer’s dementia or Parkinson’s disease are an unmet clinical need. Intraretinal layer thicknesses on macular optical coherence tomography (OCT) images are promising noninvasive biomarkers querying neuroretinal structures with near cellular resolution. However, changes are typically subtle, while tissue gradients can be weak, making intraretinal segmentation a challenging task. A robust and efficient method that requires no or minimal manual correction is an unmet need to foster reliable and reproducible research as well as clinical application. Here, we propose and validate a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments eight intraretinal layers with high fidelity. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. Additionally, we propose a weighted version of focal loss to minimize the foreground–background pixel imbalance in the training data. We train our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e., multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3 μm, outperforming current state-of-the-art methods on the same data set. Voxel-wise comparison against external glaucoma data leads to a mean absolute error of 2.6 μm when using the same gold standard segmentation approach, and 3.7 μm mean absolute error in an externally segmented data set. In scans from patients with severe optic atrophy, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method. The validation results suggest that the proposed method can robustly segment macular scans from eyes with even severe neuroretinal changes.
The Penicillium brasilianum Histone Deacetylase Clr3 Regulates Secondary Metabolite Production and Tolerance to Oxidative Stress
Authors: Akiyama Daniel Yuri , Rocha Marina Campos , Costa Jonas Henrique , Teles Caroline Brandão , da Silva Zuccoli Giuliana , Malavazi Iran , Fill Taicia Pacheco
Published: May 2022

Most of the biosynthetic gene clusters (BGCs) found in microbes are silent under standard laboratory cultivation conditions due to the lack of expression triggering stimuli, representing a considerable drawback in drug discovery. To access the full biosynthetic potential, studies towards the activation of cryptic BGCs are essential. Histone acetylation status is an important regulator of chromatin structure, which impacts cell physiology and the expression of BGCs. In this study, clr3, a gene encoding a histone deacetylase in Penicillium brasilianum LaBioMMi 136, is deleted and associated phenotypic and metabolic changes are evaluated. The results indicate reduced growth under oxidative stress conditions in the ∆clr3 strain, higher intracellular reactive oxygen species (ROS) levels, and a different transcriptional profile of 13 ROS-related genes of both strains under basal and ROS-induced conditions. Moreover, the production of 14 secondary metabolites, including austin-related meroterpenoids, brasiliamides, verruculogen, penicillic acid, and cyclodepsipeptides was evaluated in the ∆clr3 strain, most of them being reduced. Accordingly, the addition of epigenetic modulators responsible for HDAC inhibition into P. brasilianum’s growth media also culminated in the reduction in secondary metabolite production. The results suggest that Clr3 plays an essential role in secondary metabolite biosynthesis in P. brasilianum, thus offering new strategies for the regulation of natural product synthesis by assessing chromatin modification.
Effects of Pelvic-Floor Muscle Training in Patients with Pelvic Organ Prolapse Approached with Surgery vs. Conservative Treatment: A Systematic Review
Authors: Espiño-Albela Andrea , Castaño-García Carla , Díaz-Mohedo Esther , Ibáñez-Vera Alfonso Javier
Published: May 2022

The aim of this systematic review was to explore the effectiveness of pelvic-floor muscle training (PFMT) in the treatment of women with pelvic organ prolapse (POP) who had undergone either surgery or only conservative treatment, based on a selection of randomized clinical trials (RCT). The search was carried out in PubMed, Cochrane, Scopus, CINAHL, and PEDro databases between April 2021 and October 2021 using the following MeSH terms or keywords: “pelvic organ prolapse”, “POP”, “pelvic floor muscle training”, “pelvic floor muscle exercise”, “kegel exercise”, and “surgery”. The methodological quality of the studies was assessed using the PEDro scale. Eighteen RCTs were included in this review. The findings showed improvements in symptoms associated with POP, in pelvic-floor function, and in quality of life in women who performed a PFMT protocol. However, PFMT did not produce significant changes in sexual function, and the results of the change in POP stage were inconclusive. When viewing PFMT as a complementary treatment to surgery, no significant improvements were observed in any of the analyzed variables. In conclusion, a PFMT program is an effective way to improve the pelvic, urinary, and intestinal symptoms associated with POP; function of the pelvic floor; and quality of life. PFMT as an adjunct to surgery does not seem to provide a greater benefit than surgical treatment alone. RCTs of higher methodological quality, with a larger sample size and a longer follow-up, are needed to confirm the results.
Local Residents’ Social-Ecological Adaptability of the Qilian Mountain National Park Pilot, Northwestern China
Authors: Li Jing , Ma Guoqiang , Feng Jinghua , Guo Liying , Huang Yinzhou
Published: May 2022

Protected areas are critical for biodiversity conservation and ecosystem services. In the last few years, there has been growing recognition of the role of indigenous peoples and local communities in the management of government designated protected areas, and thus their perceptions and adaptability were paid much attention. Drawing on a survey of 487 residents in the Qilian Mountain National Park Pilot of Northwestern China, this study used the adaptive analysis framework to study the adaptability of local residents. The main contribution of this paper is to select a typical social-ecological system to study the adaptability of local residents, and using Elinor Ostrom’s Social-Ecological System framework to analyze the adaptability mechanism. The results show that different types of residents had different adaptability to environmental change. People whose income mainly depends on work salary with a small part of herding have the highest level of adaptability, while people whose income mostly comes from farming with a small part of herding have the lowest level. This result is related to people’s living location, as people living in the core zone and buffer zone of the reserve mainly earned from grazing, and people living in the experimental zone and peripheral zone earned mainly from outside work. Moreover, people living in the core zone and buffer zone are mostly elders and ethnic groups, while people in the experimental zone and buffer zone are Han people. To improve management effectiveness and to avoid conflict between local residents and managers, this paper suggests that more attention should be paid to these who have lived for a long time in the core zone and buffer zone. They are the most vulnerable groups and show low adaptability in almost all domains. For the long run, education quality should be improved to decrease the population in the reserve.
Exploring Compound Eyes in Adults of Four Coleopteran Species Using Synchrotron X-ray Phase-Contrast Microtomography (SR-PhC Micro-CT)
Authors: Giglio Anita , Vommaro Maria Luigia , Agostino Raffaele Giuseppe , Lo Lai Ka , Donato Sandro
Published: May 2022

Compound eyes in insects are primary visual receptors of surrounding environments. They show considerable design variations, from the apposition vision of most day-active species to the superposition vision of nocturnal insects, that sacrifice resolution to increase sensitivity and are able to overcome the challenges of vision during lightless hours or in dim habitats. In this study, Synchrotron radiation X-ray phase-contrast microtomography was used to describe the eye structure of four coleopteran species, showing species-specific habitat demands and different feeding habits, namely the saproxylic Clinidium canaliculatum (Costa, 1839) (Rhysodidae), the omnivorous Tenebrio molitor (Linnaeus, 1758) and Tribolium castaneum (Herbest, 1797) (Tenebrionidae), and the generalist predator Pterostichus melas italicus (Dejean, 1828) (Carabidae). Virtual sections and 3D volume renderings of the heads were performed to evaluate the application and limitations of this technique for studying the internal dioptrical and sensorial parts of eyes, and to avoid time-consuming methods such as ultrastructural analyses and classic histology. Morphological parameters such as the area of the corneal facet lens and cornea, interocular distance, facet density and corneal lens thickness were measured, and differences among the studied species were discussed concerning the differences in lifestyle and habitat preferences making different demands on the visual system. Our imaging results provide, for the first time, morphological descriptions of the compound eyes in these species, supplementing their ecological and behavioural traits.
Molecular Mechanisms Underlying the Pain-Relieving Effects of Extracorporeal Shock Wave Therapy: A Focus on Fascia Nociceptors
Authors: Ryskalin Larisa , Morucci Gabriele , Natale Gianfranco , Soldani Paola , Gesi Marco
Published: May 2022

In recent years, extracorporeal shock wave therapy (ESWT) has received increasing attention for its potential beneficial effects on various bone and soft-tissue pathologies, yielding promising outcomes for pain relief and functional recovery. In fact, ESWT has emerged as an alternative, non-invasive, and safe treatment for the management of numerous musculoskeletal disorders, including myofascial pain syndrome (MPS). In particular, MPS is a common chronic painful condition, accounting for the largest proportion of patients affected by musculoskeletal problems. Remarkably, sensory innervation and nociceptors of the fascial system are emerging to play a pivotal role as pain generators in MPS. At the same time, increasing evidence demonstrates that application of ESWT results in selective loss of sensory unmyelinated nerve fibers, thereby inducing long-lasting analgesia. The findings discussed in the present review are supposed to add novel viewpoints that may further enrich our knowledge on the complex interactions occurring between disorders of the deep fascia including changes in innervation, sensitization of fascial nociceptors, the pathophysiology of chronic musculoskeletal pain of MPS, and EWST-induced analgesia. Moreover, gaining mechanistic insights into the molecular mechanisms of pain-alleviating effects of ESWT may broaden the fields of shock waves clinical practice far beyond the musculoskeletal system or its original application for lithotripsy.
Altitude Effect on Cutaneous Melanoma Epidemiology in the Veneto Region (Northern Italy): A Pilot Study
Authors: Del Fiore Paolo , Russo Irene , Dal Monico Alessandro , Tartaglia Jacopo , Ferrazzi Beatrice , Mazza Marcodomenico , Cavallin Francesco , Tropea Saveria , Buja Alessandra , Cappellesso Rocco , Nicolè Lorenzo , Chiarion-Sileni Vanna , Menin Chiara , Vecchiato Antonella , Dei Tos Angelo Paolo , Alaibac Mauro , Mocellin Simone
Published: May 2022

The incidence of cutaneous melanoma has been increasing in the last decades among the fair-skinned population. Despite its complex and multifactorial etiology, the exposure to ultraviolet radiation (UVR) is the most consistent modifiable risk factor for melanoma. Several factors influence the amount of UVR reaching the Earth’s surface. Our study aimed to explore the relationship between melanoma and altitude in an area with mixed geographic morphology, such as the Veneto region (Italy). We included 2752 melanoma patients who were referred to our centers between 1998 and 2014. Demographics, histological and clinical data, and survival information were extracted from a prospectively maintained local database. Head/neck and acral melanoma were more common in patients from the hills and the mountains, while limb and trunk melanoma were more common in patients living in plain and coastal areas. Breslow thickness, ulceration and mitotic rate impaired with increased altitude. However, the geographical area of origin was not associated with overall or disease-free survival. The geographical area of origin of melanoma patients and the “coast-plain-hill gradient” could help to estimate the influence of different sun exposure and to explain the importance of vitamin D levels in skin-cancer control.