Molecular differentiation of Pantoea stewartii subsp. indologenes from subspecies stewartii and identification of new isolates from maize seeds.

Abstract:
AIMS
Assays to detect Pantoea stewartii from maize seeds should include differentiation of P. stewartii subsp. stewartii and P. stewartii subsp. indologenes.

METHODS AND RESULTS
Previously published PCR primers for the identification of P. stewartii subsp. stewartii amplified signals from both subspecies using both conventional and quantitative PCR. In MALDI-TOF mass spectroscopy analysis with the Biotyper software (Bruker), subspecies stewartii and indologenes produced identical score values. Analysis against the Biotyper database produced similar score values for both subspecies. From the subtyping methods provided by the Biotyper software, only composite correlation indexing (CCI) separated both groups. By alignment of 16S rRNA sequences, no subspecies distinction was possible. To develop new techniques for the separation of these subspecies, the partial sequences of several housekeeping genes were compared. The type strains of the two subspecies showed characteristic single-nucleotide polymorphisms (SNPs) in the genes galE, glmS and recA. Other reference strains of P. stewartii subsp. stewartii followed the same nucleotide pattern, whereas known P. stewartii subsp. indologenes strains were different. Based on single-nucleotide polymorphisms in galE and recA, PCR primers were created to separate the subspecies by stepdown PCR analysis. Two putative P. stewartii strains were isolated from imported maize seeds. They were not virulent on maize seedlings, were positive in the indole assay with Kovacs reagent and identified as P. stewartii subsp. indologenes. The subspecies-specific PCR primers confirmed they were subspecies indologenes.

CONCLUSIONS
By stepdown PCR, P. stewartii subsp. indologenes can be differentiated from P. stewartii subsp. stewartii.

SIGNIFICANCE AND IMPACT OF THE STUDY
A possible detection of P. stewartii subsp. stewartii, the causative agent of Stewart's wilt of maize, in plant material by immunological or molecular assays must exclude contamination with P. stewartii subsp. indologenes, which would create false positives in seed tests and affect quarantine measurements.

Gehring|I|I|
Wensing|A|A|
Gernold|M|M|
Wiedemann|W|W|
Coplin|D L|DL|
Geider|K|K|

stepdown PCR
Stewart's wilt
MALDI-TOF MS
maize disease


Finafloxacin Is an Effective Treatment for Inhalational Tularemia and Plague in Mouse Models of Infection.

Abstract: Infection with aerosolized Francisella tularensis or Yersinia pestis can lead to lethal disease in humans if treatment is not initiated promptly. Finafloxacin is a novel fluoroquinolone which has demonstrated broad-spectrum activity against a range of bacterial species in vitro, in vivo, and in humans, activity which is superior in acidic, infection-relevant conditions. Human-equivalent doses of finafloxacin or ciprofloxacin were delivered at 24 h (representing prophylaxis) or at 72 or 38 h (representing treatment) postchallenge with F. tularensis or Y. pestis, respectively, in BALB/c mouse models. In addition, a short course of therapy (3 days) was compared to a longer course (7 days). Both therapies provided a high level of protection against both infections when administered at 24 h postchallenge, irrespective of the length of the dosing regimen; however, differences were observed when therapy was delayed. A benefit was demonstrated with finafloxacin compared to ciprofloxacin in both models when therapy was delivered later in the infection. These studies suggest that finafloxacin is an effective alternative therapeutic for the prophylaxis and treatment of inhalational infections with F. tularensis or Y. pestis.

Barnes|Kay B|KB|
Richards|Mark I|MI|
Laws|Thomas R|TR|
Núñez|Alejandro|A|
Thwaite|Joanne E|JE|
Bentley|Christine|C|
Harding|Sarah V|SV|0000-0003-0159-5117


Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake.

Abstract: Stressful and aversive events promote maladaptive reward-seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine's effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast-scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine.

corticosterone dopamine stress cocaine voltammetry


The tumor organismal environment: Role in tumor development and cancer immunotherapy.

Abstract: Tumor immunotherapy has resulted in dramatic effects in some cancer types, including curing of previously untreatable patients. However, the response rates are typically very heterogenous, with some patients showing dramatic responses whereas others do not or only barely respond. Consequently, there has been an ever-increasing research effort to better understand the factors that govern immunotherapy responsiveness and efficiency in order to identify predictive biomarkers and novel therapeutic targets. Clearly, traits of the tumor cells as well as aspects of the tumor microenvironment (TME) play an important role in this regard. However, a growing tumor not only interacts with cells in its immediate vicinity, but also reciprocally communicates with the entire host organism (and its microbiota). Thus, systemic influences on tumor growth and progression are likely to be similarly important as the microenvironment. In this review, we focus on various aspects of the "tumor organismal environment" (TOE), namely the lymphatic, the hematopoietic, the microbial, the neurogenic and the metabolic environment, and discuss their impact on tumor growth and immunotherapy.

Tumor organismal environment
Immunotherapy
Tumor microenvironment
Immune system
Macroenvironment


First-principles modeling of electromagnetic scattering by discrete and discretely heterogeneous random media.

Abstract: A discrete random medium is an object in the form of a finite volume of a vacuum or a homogeneous material medium filled with quasi-randomly and quasi-uniformly distributed discrete macroscopic impurities called small particles. Such objects are ubiquitous in natural and artificial environments. They are often characterized by analyzing theoretically the results of laboratory, in situ, or remote-sensing measurements of the scattering of light and other electromagnetic radiation. Electromagnetic scattering and absorption by particles can also affect the energy budget of a discrete random medium and hence various ambient physical and chemical processes. In either case electromagnetic scattering must be modeled in terms of appropriate optical observables, i.e., quadratic or bilinear forms in the field that quantify the reading of a relevant optical instrument or the electromagnetic energy budget. It is generally believed that time-harmonic Maxwell's equations can accurately describe elastic electromagnetic scattering by macroscopic particulate media that change in time much more slowly than the incident electromagnetic field. However, direct solutions of these equations for discrete random media had been impracticable until quite recently. This has led to a widespread use of various phenomenological approaches in situations when their very applicability can be questioned. Recently, however, a new branch of physical optics has emerged wherein electromagnetic scattering by discrete and discretely heterogeneous random media is modeled directly by using analytical or numerically exact computer solutions of the Maxwell equations. Therefore, the main objective of this Report is to formulate the general theoretical framework of electromagnetic scattering by discrete random media rooted in the Maxwell-Lorentz electromagnetics and discuss its immediate analytical and numerical consequences. Starting from the microscopic Maxwell-Lorentz equations, we trace the development of the first-principles formalism enabling accurate calculations of monochromatic and quasi-monochromatic scattering by static and randomly varying multiparticle groups. We illustrate how this general framework can be coupled with state-of-the-art computer solvers of the Maxwell equations and applied to direct modeling of electromagnetic scattering by representative random multi-particle groups with arbitrary packing densities. This first-principles modeling yields general physical insights unavailable with phenomenological approaches. We discuss how the first-order-scattering approximation, the radiative transfer theory, and the theory of weak localization of electromagnetic waves can be derived as immediate corollaries of the Maxwell equations for very specific and well-defined kinds of particulate medium. These recent developments confirm the mesoscopic origin of the radiative transfer, weak localization, and effective-medium regimes and help evaluate the numerical accuracy of widely used approximate modeling methodologies.

Mishchenko|Michael I|MI|
Dlugach|Janna M|JM|
Yurkin|Maxim A|MA|
Bi|Lei|L|
Cairns|Brian|B|
Liu|Li|L|
Panetta|R Lee|RL|
Travis|Larry D|LD|
Yang|Ping|P|
Zakharova|Nadezhda T|NT|

Electromagnetic scattering
Discrete random media
Radiative transfer
Weak localization
Effective-medium approximation
Statistical electromagnetics


Preparation of immobilized glucose oxidase and its application in improving breadmaking quality of commercial wheat flour.

Abstract: Preparation of immobilized glucose oxidase (GO) on chitosan (CS)-sodium tripolyphosphate (TPP) and its application in improving breadmaking quality of commercial wheat flour were investigated. The optimum conditions for GO immobilization were: viscosity of CS: 700cP, ratio of CS to TPP (w/w): 5 to 1, and GO concentration 100U/mL. The obtained CSTPP-GO was 5μm-diameter particle with a pseudo-spherical shape. By addition of CSTPP-GO (400U/kg flour) and fungal α-amylase (62.5U/kg flour), bread springiness slightly increased from 0.923 to 0.940, specific volume of crumb increased by 13.48% and hardness decreased by 19.22%, compared to addition of KBrO3 (60mg/kg flour). It could be concluded that CSTPP-GO combined with fungal α-amylase had potential application in improving breadmaking quality of commercial wheat flour.

Tang|Lele|L| Yang|Ruijin|R| Hua|Xiao|X| Yu|Chaohua|C| Zhang|Wenbin|W| Zhao|Wei|W|

Immobilization
Glucose oxidase
Breadmaking quality
Commercial wheat flour
Chitosan
Sodium tripolyphosphate


Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling.

Abstract: A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.

Loram|Lisa C|LC|
Taylor|Frederick R|FR|
Strand|Keith A|KA|
Harrison|Jacqueline A|JA|
Rzasalynn|Rachael|R|
Sholar|Paige|P|
Rieger|Jayson|J|
Maier|Steven F|SF|
Watkins|Linda R|LR|

D017868:Cyclic AMP-Dependent Protein Kinases

Intrathecal
Protein kinase
ATL313
Mechanical allodynia
Microglia
Astrocytes
Interleukin-10
Rats


Meta-analysis on surgical management of colonic injuries in trauma: to divert or to anastomose?

Abstract:
BACKGROUND
Primary repair or resection with anastomosis (PR/A) has been gaining increasing recognition for traumatic colonic injuries, with the need for faecal diversion (FD) especially those of penetrating etiology being questioned. However, the role of PR/A in critically ill patients is still controversial with concerns pertaining to safety and anastomotic leak.

AIMS AND METHODS
We performed a systemic review of studies comparing outcomes of FD versus PR/A in traumatic colonic injuries. A systematic review was performed as per PRISMA guidelines utilizing three electronic databases: Pubmed, EMBASE, and Cochrane Library resources. Mortality and anastomotic leak rates are identified as the primary and secondary outcomes, respectively. Data extracted include mortality rates, type of surgical intervention, surgical complications, and need for DC (damage control) surgery.

RESULTS
Fourteen studies were identified comprising 11 retrospective, 2 prospective cohort and 1 randomized trial with a total of 2071 patients. Six studies included patients that underwent DC surgery. The overall mortality rate was 3.77% and was higher in the FD group compared to PR/A group (5.38% vs 2.49%, p = 0.07). 71.3% of patients underwent PR/A with an overall leak rate of 4.63%. There was no difference in intra-abdominal collections between the PR/A and FD groups. In the subgroup analysis, anastomotic leak rate was significantly higher in the DC group compared to non-DC group (16.7% vs 3.2%, p = 0.003).

CONCLUSIONS
This meta-analysis supports PR/A in stable patients with traumatic colonic injuries. FD should be considered in critically ill patients who require DC surgery as leak rates are significantly higher.

D016032:Randomized Controlled Trials as Topic

Colon injury
Trauma
Anastomotic leak
Stoma


Aberrant DNA Methylation Pattern may Enhance Susceptibility to Migraine: A Novel Perspective.

Abstract: In today's world, migraine is one of the most frequent disorders with an estimated world prevalence of 14.7% characterized by attacks of a severe headache making people enfeebled and imposing a big socioeconomic burden. The pathophysiology of a migraine is not completely understood however there are pieces of evidence that epigenetics performs a primary role in the pathophysiology of migraine. Here, in this review, we highlight current evidence for an epigenetic link with migraine in particular DNA methylation of numerous genes involved in migraine pathogenesis. Outcomes of various studies have explained the function of DNA methylation of a several migraine related genes such as RAMP1, CALCA, NOS1, ESR1, MTHFR and NR4A3 in migraine pathogenesis. Mentioned data suggested there exist a strong association of DNA methylation of migraine-related genes in migraine. Although we now have a general understanding of the role of epigenetic modifications of a numerous migraine associated genes in migraine pathogenesis, there are many areas of active research are of key relevance to medicine. Future studies into the complexities of epigenetic modifications will bring a new understanding of the mechanisms of migraine processes and open novel approaches towards therapeutic intervention.

Goel|Divya|D|
Un Nisa|Kaiser|K|
Reza|Mohammad Irshad|MI|
Rahman|Ziaur|Z|
Aamer|Shaikh|S|

DNA methylation
Migraine
epigenetics
gene
genetics
headache.


Positive clinical effects of gamma knife capsulotomy in a patient with deep brain stimulation-refractory Tourette Syndrome and Obsessive Compulsive Disorder.

Abstract: We report the first case of a patient with severe, intractable Tourette Syndrome with comorbid Obsessive Compulsive disorder, who recovered from both disorders with gamma-knife (GK) stereotactic radiosurgery following deep brain stimulation (DBS). This case highlights the possible role of the internal capsule within the neural circuitries underlying both TS and OCD, and suggests that in cases of treatment-refractory TS and comorbid OCD, bilateral anterior capsulotomy using stereotactic radiosurgery may be a viable treatment option.

Richieri|Raphaëlle|R|
Blackman|Graham|G|
Musil|Richard|R|
Spatola|Giorgio|G|
Cavanna|Andrea E|AE|
Lançon|Christophe|C|
Régis|Jean|J|

D046690:Deep Brain Stimulation
D005260:Female
D006801:Humans
D020772:Internal Capsule
D008875:Middle Aged
D009771:Obsessive-Compulsive Disorder
D016634:Radiosurgery
D005879:Tourette Syndrome
D016896:Treatment Outcome

Capsulotomy
Tourette syndrome
Obsessive compulsive disorder
Deep brain stimulation


HOMA-IR: An independent predictor of advanced liver fibrosis in nondiabetic non-alcoholic fatty liver disease.

Abstract:
BACKGROUND AND AIM
Although non-alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA-IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD.

METHODS
This was a retrospective, cross-sectional multicenter study. We included 361 patients with biopsy-proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age ≥ 49 years, sex (women), body mass index ≥ 26.7 kg/m2 , the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level ≥ 98 mg/dL, fasting immune reactive insulin level ≥ 12.0 μU/mL, and HOMA-IR ≥ 2.90. The median HOMA-IR of the patients was 2.88 (interquartile range: 2.1-4.8).

RESULTS
In the estimation group, univariate and multivariate analyses showed that age, dyslipidemia, and HOMA-IR were independent predictors of advanced fibrosis. In the validation group, only age and HOMA-IR were found to be independent predictors of advanced fibrosis.

CONCLUSIONS
Homeostasis model assessment parameter of insulin resistance was an independent predictor of advanced liver fibrosis in nondiabetic patients with NAFLD. Given that most patients with NAFLD are nondiabetic, it is important to set goals with respect to improving IR to subsequently reduce liver fibrosis.

D065626:Non-alcoholic Fatty Liver Disease

NAFLD
insulin resistance
type 2 diabetes mellitus
hepatic fibrosis


Raw Animal Meats as Potential Sources of Clostridium difficile in Al-Jouf, Saudi Arabia.

Abstract: Clostridium difficile present in feces of food animals may contaminate their meats and act as a potential source of C. difficile infection (CDI) to humans. C. difficile resistance to antibiotics, its production of toxins and spores play major roles in the pathogenesis of CDI. This is the first study to evaluate C. difficile prevalence in retail raw animal meats, its antibiotics susceptibilities and toxigenic activities in Al-Jouf, Saudi Arabia. Totally, 240 meat samples were tested. C. difficile was identified by standard microbiological and biochemical methods. Vitek-2 compact system confirmed C. difficile isolates were 15/240 (6.3%). Toxins A/B were not detected by Xpect C. difficile toxin A/B tests. Although all isolates were susceptible to vancomycin and metronidazole, variable degrees of reduced susceptibilities to moxifloxacin, clindamycin or tetracycline antibiotics were detected by Epsilon tests. C. difficile strains with reduced susceptibility to antibiotics should be investigated. Variability between the worldwide reported C. difficile contamination levels could be due to absence of a gold standard procedure for its isolation. Establishment of a unified testing algorithm for C. difficile detection in food products is definitely essential to evaluate the inter-regional variation in its prevalence on national and international levels. Proper use of antimicrobials during animal husbandry is crucial to control the selective drug pressure on C. difficile strains associated with food animals. Investigating the protective or pathogenic potential of non-toxigenic C. difficile strains and the possibility of gene transfer from certain toxigenic/ antibiotics-resistant to non-toxigenic/antibiotics-sensitive strains, respectively, should be worthy of attention.

animal meat
resistance
spores
diarrhea
pseudomembranous colitis


Increased CRP: An extended biomarker of microvascular risk in men with type 2 diabetes.

Abstract:
BACKGROUND
The usefulness of C-reactive protein (CRP) to predict cardiovascular disease (CVD) in type 2 diabetes (T2DM) remains controversial. As many factors linked to obesity can modulate CRP in T2DM, we comprehensively revisited the cardiometabolic phenotype of patients with normal or raised CRP, taking into account the sexual dimorphism of its serum value.

METHODS
1005 T2DM patients (651 males, 354 females; macroangiopathy 38%; coronary artery disease 26%; microangiopathy 47%) were divided depending on whether CRP level was ≤ or >3 mg/L. Thirty percent of men (n = 195) and 39% of women (n = 137) had raised CRP. Their cardiometabolic phenotype and presence of micro- and macrovascular complications were compared to those with normal CRP.

RESULTS
In both gender, patients with elevated CRP had higher body mass index, waist circumference, fat mass, visceral fat, insulinemia, HbA1c, and lower muscle mass and insulin sensitivity. They had more atherogenic dyslipidemia, higher non-HDL-C and apolipoprotein B100, and more lipoprotein(a) (+59% in men and +38% in women). In both sexes, there was no difference between patients with normal or high CRP regarding overall macroangiopathy (42% vs. 45% [men]; 27% vs. 28% [women]), coronary and peripheral artery disease, or stroke. Only in men, microangiopathy was more prevalent when CRP was raised (61% vs 44%; p < 0.0001).

CONCLUSIONS
This study shows major sex-related differences in microangiopathies in T2DM patients with high CRP levels. The latter are unrelated to prevalent CVD despite an unfavorable metabolic phenotype. By contrast, increased CRP may represent an extended biomarker of microvascular risk in men with T2DM.

Hermans|Michel P|MP|
Ahn|Sylvie A|SA|
Rousseau|Michel F|MF|

D000368:Aged
D000369:Aged, 80 and over
D015415:Biomarkers
D002097:C-Reactive Protein
D015331:Cohort Studies
D003430:Cross-Sectional Studies
D003924:Diabetes Mellitus, Type 2
D003925:Diabetic Angiopathies
D005260:Female
D006801:Humans
D008297:Male
D008875:Middle Aged
D012189:Retrospective Studies
D012307:Risk Factors
D012737:Sex Factors

CRP
Cardiovascular disease
T2DM
Microangiopathy
Gender
Lipoprotein(a)


The potential utility of integrated reflectance confocal microscopy-optical coherence tomography for guiding triage and therapy of basal cell carcinomas.

Abstract: The increasing rate of incidence and prevalence of basal cell carcinomas (BCCs) worldwide, combined with the morbidity associated with conventional surgical treatment has led to the development and use of alternative minimally invasive non-surgical treatments. Biopsy and pathology are used to guide BCC diagnosis and assess margins and subtypes, which then guide the decision and choice of surgical or non-surgical treatment. However, alternatively, a noninvasive optical approach based on combined reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) imaging may be used. Optical imaging may be used to guide diagnosis and margin assessment at the bedside, and potentially facilitate non-surgical management, along with long-term monitoring of treatment response. Noninvasive imaging may also complement minimally invasive treatments and help further reduce morbidity. In this paper, we highlight the current state of an integrated RCM/OCT imaging approach for diagnosis and triage of BCCs, as well as for assessing margins, which therefore may be ultimately used for guiding therapy.

Iftimia|Nicusor|N|
Sahu|Aditi|A|
Cordova|Miguel|M|
Maguluri|Gopi|G|
Gill|Melissa|M|
Alessi-Fox|Christi|C|
Gonzalez|Salvador|S|
Navarrete-Dechent|Cristian|C|
Marghoob|Ashfaq|A|
Chen|Chih-Shan J|CJ|
Rajadhyaksha|Milind|M|

basal cell carcinomas
invasive non-surgical treatments
reflectance confocal microscopy
optical coherence tomography


The impact of COVID-19 pandemic on glycemic control in patients with diabetes mellitus in Turkey: a multi-center study from Kocaeli.

Abstract:
Aims
The aim of this study is to determine the impact of the COVID-19 pandemic on the management and disease control of the patients with diabetes mellitus in Kocaeli.

Methods
This study was carried out in six leading central hospitals in five major districts of Kocaeli. The study was conducted between June 2020 and November 2020. The patients who had previous admissions to these clinics within 6 months prior to the pandemic were enrolled in the study.

Results
A total of 283 patients were enrolled in the study, among them 151 (53%) patients were female, 268 (95%) had type 2 DM and remaining 5% had type 1 DM. The median weight of the patients was similar between the previous and last visits (84 kg vs 83 kg, p = 0,88). Laboratory parameters of previous and current visits revealed that mean fasting plasma glucose (FPG) and HbA1c levels were not significantly changed. The number of the patients who had controlled blood pressure was significantly decreased. The number of those who had neuropathic complains and the severity of dyslipidemia significantly increased during pandemic period.

Conclusion
Our study demonstrated that despite decreased compliance with diet and exercise, and difficulty in accessing medication, there was no significant change in weight, FPG and HbA1c levels in diabetic patients. Since cultural differences, education level and socioeconomic opportunities differ between societies, national and international studies will be more accurate to evaluate the effects of epidemics on the course of chronic diseases.

Selek|Alev|A|0000-0002-0646-8697 Gezer|Emre|E| Altun|Eda|E| Sözen|Mehmet|M|0000-0002-8428-1115 Topaloğlu|Ömercan|Ö| Köksalan|Damla|D| Demirkan|Halil|H| Karakaya|Dilek|D| Cetinarslan|Berrin|B| Cantürk|Zeynep|Z| Taymez|Dilek|D|


Methylphenidate induces state-dependency of social recognition learning: Central components.

Abstract: Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention-deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus.

Garrido Zinn|Carolina|C|
Bühler|Leticia|L|
Cavalcante|Lorena Evelyn|LE|
Schmidt|Scheila Daiane|SD|
Fagundes Ferreira|Flávia|F|
Zanini|Mara Lise|ML|
Guerino Furini|Cristiane Regina|CR|
de Carvalho Myskiw|Jociane|J|
Izquierdo|Ivan|I|

D000697:Central Nervous System Stimulants

Methylphenidate
Social recognition memory
Prefrontal cortex
Hippocampus
State-dependent learning


Host Genetic Factors and Dendritic Cell Responses Associated with the Outcome of Interferon/Ribavirin Treatment in HIV-1/HCV Co-Infected Individuals.

Abstract: HIV-1/HCV co-infection is a significant health problem. Highly active antiretroviral treatment (HAART) against HIV-1 has proved to be fairly successful. On the other hand, direct acting antiviral drugs against HCV have improved cure rates but high cost and development of drug resistance are important concerns. Therefore PEGylated interferon (PEG-IFN) and ribavirin (RBV) still remain essential components of HCV treatment, and identification of host factors that predict IFN/RBV treatment response is necessary for effective clinical management of HCV infection. Impaired dendritic cell (DC) and T cell responses are associated with HCV persistence. It has been shown that IFN/RBV treatment enhances HCV-specific T cell functions and it is likely that functional restoration of DCs is the underlying cause. To test this hypothesis, we utilized an antibody cocktail (consisting of DC maturation, adhesion and other surface markers) to perform comprehensive phenotypic characterization of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in a cohort of HIV-1/HCV co-infected individuals undergoing IFN/RBV treatment. Our results show that pre-treatment frequencies of mDCs are lower in non-responders (NRs) compared to responders (SVRs) and healthy controls. Although, the treatment was able to restore the frequency of mDCs in NRs, it downregulated the frequency of CCR7+, CD54+ and CD62L+ mDCs. Pre-treatment frequencies of pDCs were lower in NRs and decreased further upon treatment. Compared to SVRs, NRs exhibited higher ratio of PD-L1+/CD86+ pDCs prior to treatment; and this ratio remained high even after treatment. These findings demonstrate that enumeration and phenotypic assessment of DCs before/during therapy can help predict the treatment outcome. We also show that before treatment, PBMCs from SVRs secrete higher amounts of IFN-γ compared to controls and NRs. Upon genotyping IFNL3 polymorphisms rs12979860, rs4803217 and ss469415590, we found rs12979860 to be a better predictor of treatment outcome. Collectively, our study led to identification of important correlates of IFN/RBV treatment response in HIV-1/HCV co-infected individuals.

Sehgal|Mohit|M|
Zeremski|Marija|M|
Talal|Andrew H|AH|
Khan|Zafar K|ZK|
Capocasale|Renold|R|
Philip|Ramila|R|
Jain|Pooja|P|

Dendritic cells
Ribavirin
HIV-1
HIV-1/HCV co-infection
HCV
Interferon-α
human chronic viral infections


Specific energy requirements and soil pulverization of a combined tillage implement.

Abstract: Reducing energy use in soil preparation has become increasingly important since it is a major cost in planting. Experiments were conducted with a combined tillage implement consisting of a subsoiler and a rotary harrow to reduce the cost due to step reduction in soil preparation. Three tillage operations, two forward speeds, and two rotational rotor speeds were determined as input factors in this study. Soil clod size, performance parameters, and the specific energy requirements of a combined tillage implement were investigated. The field experiments were using two different soil conditions. Increasing the rotor speed from 299 to 526 rpm decreased the mean soil clod diameter at a depth of 0-200 mm from 22.98 to 19.83 mm and from 31.77 to 26.57 mm for fields 1 and 2, respectively. The specific energy requirement was affected significantly by rotor speed and tillage operation. The specific energy requirements for the combined tillage implement with an on-frame pivot joint and an on-pivotable-shank joint were less by 10.4 and 21.1% and by 18.4 and 24.7%, for fields 1 and 2, respectively, compared to the total power requirement for the separate use of a subsoiler and a rotary harrow.

Soil preparation
Subsoiler
Rotary harrow
Rotor speed
Agricultural engineering
Agriculture
Machine design
Mechanical engineering


17β-Estradiol and testosterone in sarcopenia: Role of satellite cells.

Abstract: The loss of muscle mass and strength with aging, referred to as sarcopenia, is a prevalent condition among the elderly. Although the molecular mechanisms underlying sarcopenia are unclear, evidence suggests that an age-related acceleration of myocyte loss via apoptosis might be responsible for muscle perfomance decline. Interestingly, sarcopenia has been associated to a deficit of sex hormones which decrease upon aging. The skeletal muscle ability to repair and regenerate itself would not be possible without satellite cells, a subpopulation of cells that remain quiescent throughout life. They are activated in response to stress, enabling them to guide skeletal muscle regeneration. Thus, these cells could be a key factor to overcome sarcopenia. Of importance, satellite cells are 17β-estradiol (E2) and testosterone (T) targets. In this review, we summarize potential mechanisms through which these hormones regulate satellite cells activation during skeletal muscle regeneration in the elderly. The advance in its understanding will help to the development of potential therapeutic agents to alleviate and treat sarcopenia and other related myophaties.

La Colla|Anabela|A|
Pronsato|Lucía|L|
Milanesi|Lorena|L|
Vasconsuelo|Andrea|A|

D032496:Satellite Cells, Skeletal Muscle

17β-Estradiol
Testosterone
Sarcopenia
Satellite cells
Aging


Interventions for Primary School Children With Difficulties in Mathematics.

Abstract: Difficulty with arithmetic is a common problem for children and adults, though there has been some work on the topic for a surprisingly long time. This chapter will review some of the research that has been done over the years on interventions with primary school children. Interventions can be of various levels of intensiveness, ranging from whole-class approaches that take account of individual differences through small-group and limited-time individual interventions to extended-time individual interventions. Interventions discussed here include those involving peer tuition and group collaboration; those involving board and computer games; and those that involve assessing children's strengths and weaknesses in different components of mathematics; and targeting remedial activities to the assessed weaknesses. Most of the interventions discussed in this chapter specifically involve mathematics (usually mainly arithmetic), but there is also some discussion of attempts to improve mathematics by training children in domain-general skills, including Piagetian operations, metacognition, and executive functions.

D002648:Child
D002675:Child, Preschool
D003479:Curriculum
D018479:Early Intervention, Educational
D056344:Executive Function
D006126:Group Processes
D006801:Humans
D007859:Learning Disabilities
D055641:Mathematical Concepts
D008433:Mathematics
D008570:Memory, Short-Term
D012073:Remedial Teaching
D006113:United Kingdom

Arithmetical development
Educational interventions
Mathematical difficulties
Primary school age
Young children


Paradoxical reaction associated with cervical lymph node tuberculosis: predictive factors and therapeutic management.

Abstract:
OBJECTIVES
The aims of this study were to determine predictive factors of paradoxical reaction in patients with cervical lymph node tuberculosis (TB) and to discuss the therapeutic management of this condition.

MATERIALS AND METHODS
A retrospective study was performed of 501 patients managed for cervical lymph node TB over a period of 12 years (from January 2000 to December 2011). Statistical data were analyzed using IBM SPSS Statistics version 20.0.

RESULTS
Paradoxical reaction occurred in 67 patients (13.4%), with a median delay to onset after starting TB treatment of 7 months. Lymph node size ≥3cm and associated extra-lymph node TB were independently associated with paradoxical reaction. Treatment consisted of surgical excision (71.6%), restarting quadruple therapy (10.4%), reintroduction of ethambutol (23.8%), and addition of ciprofloxacin (20.8%); steroids were given in two cases . All patients recovered after an average treatment duration of 14.91±7.03 months.

CONCLUSION
The occurrence of paradoxical reaction in cervical lymph node TB seems to be predicted by associated extra-lymph node TB and a swelling size ≥3cm. The treatment of paradoxical reaction remains unclear and more randomized trials are necessary to improve its management.

Chahed|Houda|H|
Hachicha|Hela|H|
Berriche|Aida|A|
Abdelmalek|Rim|R|
Mediouni|Azza|A|
Kilani|Badreddine|B|
Amor|Mohamed Ben|MB|
Benaissa|Hanene Tiouiri|HT|
Besbes|Ghazi|G|

Paradoxical reaction
Cervical lymph node
Tuberculosis
Treatment


Stress adaptation in a pathogenic fungus.

Abstract: Candida albicans is a major fungal pathogen of humans. This yeast is carried by many individuals as a harmless commensal, but when immune defences are perturbed it causes mucosal infections (thrush). Additionally, when the immune system becomes severely compromised, C. albicans often causes life-threatening systemic infections. A battery of virulence factors and fitness attributes promote the pathogenicity of C. albicans. Fitness attributes include robust responses to local environmental stresses, the inactivation of which attenuates virulence. Stress signalling pathways in C. albicans include evolutionarily conserved modules. However, there has been rewiring of some stress regulatory circuitry such that the roles of a number of regulators in C. albicans have diverged relative to the benign model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. This reflects the specific evolution of C. albicans as an opportunistic pathogen obligately associated with warm-blooded animals, compared with other yeasts that are found across diverse environmental niches. Our understanding of C. albicans stress signalling is based primarily on the in vitro responses of glucose-grown cells to individual stresses. However, in vivo this pathogen occupies complex and dynamic host niches characterised by alternative carbon sources and simultaneous exposure to combinations of stresses (rather than individual stresses). It has become apparent that changes in carbon source strongly influence stress resistance, and that some combinatorial stresses exert non-additive effects upon C. albicans. These effects, which are relevant to fungus-host interactions during disease progression, are mediated by multiple mechanisms that include signalling and chemical crosstalk, stress pathway interference and a biological transistor.

Brown|Alistair J P|AJ|
Budge|Susan|S|
Kaloriti|Despoina|D|
Tillmann|Anna|A|
Jacobsen|Mette D|MD|
Yin|Zhikang|Z|
Ene|Iuliana V|IV|
Bohovych|Iryna|I|
Sandai|Doblin|D|
Kastora|Stavroula|S|
Potrykus|Joanna|J|
Ballou|Elizabeth R|ER|
Childers|Delma S|DS|
Shahana|Shahida|S|
Leach|Michelle D|MD|

Stress adaptation
Candida albicans
Fungal pathogenicity
Carbon metabolism
Cationic stress
Heat shock
Nitrosative stress
Osmotic stress
Oxidative stress


Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases.

Abstract: Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

Pradhan|Rashmita|R|
Ngo|Phuong A|PA|
Martínez-Sánchez|Luz Dc|LD|
Neurath|Markus F|MF|
López-Posadas|Rocío|R|

Rho GTPases
intestine
inflammation
cancer
intestinal epithelial cells
T cells


Relationship Between Thyroid Hormonal Status in Patients with a Hypothyroid Form of Hashimoto's Thyroiditis and Iodine Concentrations in Drinking Water.

Abstract: The current study aimed to identify correlative and regressive dependencies between the water iodine concentration and the levels of TSH (thyroid-stimulating hormone), thyroglobulin antibodies (TgAbs), and thyroid peroxidase (TPOAb) in the serum of 168 in patients (34 men and 134 women) with a hypothyroid form of Hashimoto's thyroiditis who use water from the supply network and individual wells. Based on the water iodine concentration, low and moderate degrees of iodine endemia in the location of the patients were determined. In the groups of men and women using water from different water supply sources, there were direct correlations between the water iodine concentrations and the TgAbs and TPOAb titers as well as an inverse dependence between iodine and TSH levels. Multivariate regressive analysis indicated that TgAb and TSH in the group of women using water from a supply network and TPOAb titers in the group of women using well water were independent factors associated with water iodine concentrations. Statistically significant correlations and regressive dependencies between the water iodine concentrations and the biomarkers of the thyroid status of the patients indicate the risk of Hashimoto's thyroiditis progression, especially among women with additional iodine intake.

Water iodine concentration
Thyroid-stimulating hormone
Thyroglobulin antibodies
Endemic region
Hashimoto’s thyroiditis
Thyroxine peroxidase


Delivering patient-centered care in Parkinson's disease: Challenges and consensus from an international panel.

Abstract: An international panel of movement disorders specialists explored the views and perceptions of people with Parkinson's disease (PD) about their condition and its treatment, including the potential mismatch between the clinician's view of the patient's condition and their own view of what aspects of the disease most affect their daily lives. The initiative was focused on Asian countries, so participants comprised experts in the management of PD from key centers in Asia, with additional insight provided by European and the North American movement disorders experts. Analysis of peer-reviewed publications on patient perceptions of PD and the factors that they consider important to their wellbeing identified several contributing factors to the mismatch of views, including gaps in knowledge of PD and its treatment, an understanding of the clinical heterogeneity of PD, and the importance of a multidisciplinary approach to patient care. The faculty proposed options to bridge these gaps to ensure that PD patients receive the personalized treatment they need to achieve the best possible outcomes. It was considered essential to improve patient knowledge about PD and its treatment, as well as increasing the awareness of clinicians of PD heterogeneity in presentation and treatment response. A multidisciplinary and shared-care approach to PD was needed alongside the use of patient-centered outcome measures in clinical trials and clinical practice to better capture the patient experience and improve the delivery of individualized therapy.

Bhidayasiri|Roongroj|R|
Panyakaew|Pattamon|P|
Trenkwalder|Claudia|C|
Jeon|Beomseok|B|
Hattori|Nobutaka|N|
Jagota|Priya|P|
Wu|Yih-Ru|YR|
Moro|Elena|E|
Lim|Shen-Yang|SY|
Shang|Huifang|H|
Rosales|Raymond|R|
Lee|Jee-Young|JY|
Thit|Win Min|WM|
Tan|Eng-King|EK|
Lim|Thien Thien|TT|
Tran|Ngoc Tai|NT|
Binh|Nguyen Thanh|NT|
Phoumindr|Appasone|A|
Boonmongkol|Thanatat|T|
Phokaewvarangkul|Onanong|O|
Thongchuam|Yuwadee|Y|
Vorachit|Somchit|S|
Plengsri|Rachaneewan|R|
Chokpatcharavate|Marisa|M|
Fernandez|Hubert H|HH|

D003245:Consensus Development Conferences as Topic

D007722:Health Knowledge, Attitudes, Practice

Patient-centered care
Parkinson's disease
Patient-centered outcomes
International consensus
Knowledge gaps
Patients' perceptions


Fast removal of the antibiotic flumequine from aqueous solution by ozonation: Influencing factors, reaction pathways, and toxicity evaluation.

Abstract: As one of the first generation of fluoroquinolone antibiotics, flumequine (FLU) has been detected ubiquitously in surface waters and municipal wastewaters. In light of FLU's possible adverse effects on aquatic species, the removal of this antibiotic has received worldwide attention. In this study, the kinetics, transformation products, mechanisms and toxicity variations of the ozonation process for FLU were systematically determined. The possible effects of solution pH, addition of inorganic ions, dissolved organic matter, and tert-butyl-alcohol (a radical scavenger), as well as the type of water matrices on FLU removal by ozonation, were studied from the perspective of the degradation kinetics. The data obtained suggested that ozone can be used as an effective oxidant for the fast removal of FLU from natural waters. Using liquid chromatography-mass spectrometry, a total of thirteen transformation products of FLU during ozonation were identified, and their specific reaction mechanisms were also proposed. The degradation pathways involving the hydroxylation, decarboxylation and defluorination were tentatively proposed. Meanwhile, the generation of three low-molecular-weight carboxylic acids was also observed. In addition, the potential toxicity of the transformation mixtures of FLU by ozone was evaluated. Overall, this paper can be a unique contribution to the systematic elucidation of the ozonation process of this antibiotic in water.

Feng|Mingbao|M| Yan|Liqing|L| Zhang|Xiaoling|X| Sun|Ping|P| Yang|Shaogui|S| Wang|Liansheng|L| Wang|Zunyao|Z|

Flumequine
Ozone
Pathways
Toxicity
Kinetics
Transformation products


Microfluidic Device Directly Fabricated on Screen-Printed Electrodes for Ultrasensitive Electrochemical Sensing of PSA.

Abstract: How to fabricate scale low-cost microfluidic device for detection of biomarkers owns a great requirement. Herein, it is for the first time reported that a new microfluidic device based on bonding polydimethylsiloxane microfluidic channels onto the substrate of a screen-printed electrode with coating glass solution was fabricated for electrochemical sensing of prostate-specific antigen (PSA). Compared to traditional microfabrication processes, this method is simple, fast, low cost, and also suitable for mass production. The prepared screen-printed electrode-based microfluidic device (CASPE-MFD) was used for the detection of the PSA in human serum. The prepared CASPE-MFD had a detection limit of 0.84 pg/mL (25.8 fM) and a good linearity with PSA concentration ranging from 0.001 to 10 ng/mL, which showed a great promise platform toward the development of miniaturized, low-cost electrochemical microfluidic device for use in human health, environmental monitoring, and other applications.

Microfluidic devices
Screen-printed electrode
PSA
Detection
Electrochemical sensor


Microplasma Treatment versus Negative Pressure Therapy for Promoting Wound Healing in Diabetic Mice.

Abstract: The delayed healing response of diabetic wounds is a major challenge for treatment. Negative pressure wound therapy (NPWT) has been widely used to treat chronic wounds. However, it usually requires a long treatment time and results in directional growth of wound healing skin tissue. We investigated whether nonthermal microplasma (MP) treatment can promote the healing of skin wounds in diabetic mice. Splint excision wounds were created on diabetic mice, and various wound healing parameters were compared among MP treatment, NPWT, and control groups. Quantitative analysis of the re-epithelialization percentage by detecting Ki67 and DSG1 expression in the extending epidermal tongue (EET) of the wound area and the epidermal proliferation index (EPI) was subsequently performed. Both treatments promoted wound healing by enhancing wound closure kinetics and wound bed blood flow; this was confirmed through histological analysis and optical coherence tomography. Both treatments also increased Ki67 and DSG1 expression in the EET of the wound area and the EPI to enhance re-epithelialization. Increased Smad2/3/4 mRNA expression was observed in the epidermis layer of wounds, particularly after MP treatment. The results suggest that the Smad-dependent transforming growth factor β signaling contributes to the enhancement of re-epithelialization after MP treatment with an appropriate exposure time. Overall, a short-term MP treatment (applied for 30 s twice a day) demonstrated comparable or better efficacy to conventional NPWT (applied for 4 h once a day) in promoting wound healing in diabetic mice. Thus, MP treatment exhibits promise for treating diabetic wounds clinically.

Shao|Pei-Lin|PL| Liao|Jiunn-Der|JD| Wu|Shun-Cheng|SC| Chen|Yu-Hsing|YH| Wong|Tak-Wah|TW|0000-0002-0131-7339

D000818:Animals
D051183:Desmoglein 1
D003921:Diabetes Mellitus, Experimental
D066298:In Vitro Techniques
D019394:Ki-67 Antigen
D008297:Male
D051379:Mice
D008817:Mice, Mutant Strains
D054843:Negative-Pressure Wound Therapy
D009569:Nitric Oxide
D058626:Plasma Gases
D058629:Plasma Skin Regeneration
D012333:RNA, Messenger
D062326:Re-Epithelialization
D012039:Regional Blood Flow
D015398:Signal Transduction
D012867:Skin
D051785:Smad Proteins
D016212:Transforming Growth Factor beta
D014945:Wound Healing

diabetic wound
negative pressure wound therapy
re-epithelialization
transforming growth factor β signaling
nonthermal microplasma treatment


Ovarian cancer stage, variation in transvaginal ultrasound examination rates and the impact of an urgent referral pathway: A national ecological cohort study.

Abstract:
INTRODUCTION
The aim of this study was to determine whether variation in transvaginal ultrasound examination rates in Danish general practice populations is associated with ovarian cancer outcomes, and to explore the impact of the introduction of a cancer patient pathway for ovarian cancer.

MATERIAL AND METHODS
We performed a national register-based cohort study of gynecological cancer-free women aged 40 years or above, living in Denmark and listed with a specific general practitioner in 2004-2014. Practice populations were divided into quartiles according to the general practitioners' transvaginal ultrasound propensity in the preceding year. Associations between transvaginal ultrasound rates and ovarian cancer outcomes were analyzed using Poisson and logistic regression.

RESULTS
We included 2769 general practices with 1 739 422 listed women, of whom 5325 were diagnosed with ovarian cancer during the study period. Practices varied twofold in transvaginal ultrasound rates before and after the implementation of the cancer patient pathway. Before the cancer patient pathway was introduced, women listed with practices with the highest transvaginal ultrasound rates were diagnosed with earlier stages of ovarian cancer (odds ratio 1.38, 95% confidence interval 1.06 to 1.81) and had a higher proportion of borderline tumors (incidence rate ratio 1.38, 95% confidence interval 1.10 to 1.75) compared with women least exposed to transvaginal ultrasound. After the cancer patient pathway, no significant differences were identified between the groups.

CONCLUSIONS
Before the cancer patient pathway, women exposed most to transvaginal ultrasound were significantly more likely to be diagnosed with early stage ovarian cancer compared with those least exposed to transvaginal ultrasound. After the cancer patient pathway was implemented, the difference disappeared. This suggests that increased awareness and access to transvaginal ultrasound is useful for diagnosing early-stage ovarian cancer.

ovarian cancer
transvaginal ultrasound
urgent referral
general practice
cancer patient pathway
diagnosis
ovarian neoplasms
ultrasonography


Exposure to multiple metals/metalloids and human semen quality: A cross-sectional study.

Abstract:
BACKGROUND
Exposure to metals/metalloids, including essential and nonessential elements, has been associated to male reproductive health in animals. However, findings from human studies are inconsistent.

OBJECTIVES
To investigate the impact of exposure to multiple metals/metalloids at environmental levels on the conventional human semen-quality parameters.

MATERIALS AND METHODS
Men living in rural or industrial areas were recruited by personalized letters. No exclusion criteria were applied. Each man provided one semen sample and one blood sample. We analyzed the semen sample both to determine conventional sperm parameters (concentration, progressive motility and normal forms) and to quantify lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), vanadium (V) and selenium (Se) levels. The levels of these metals/metalloids were also quantified in venous blood and spermatozoa samples. Associations between the blood/seminal plasma metal/metalloid levels and semen quality parameters were assessed using confounder adjusted logistic regression models. Correlation and interactions between blood/seminal plasma and semen metal/metalloid levels were investigated using the Spearman's correlation.

RESULTS
We found a positive association of seminal plasma cadmium level with lower Total count (OR = 4.48, 95%CI 0.25-80); whereas lead (OR = 4.51, 95%CI 0.86-23) and cadmium (OR = 3.45, 95%CI 0.77-16) seminal plasma levels had a positive association with progressive sperm motility. Overall, these associations remained suggestive after adjustment, though statistically unstable risks. Finally, we found weak interactions between beneficial effects of Se and detrimental ones only for Cd and Pb blood level on sperm concentration, total sperm count and progressive sperm motility.

CONCLUSIONS
Our findings suggest that environmental exposure to Pb and Cd contributes to a decline in human semen quality, whereas Se can have beneficial effects. Measurements of metals/metalloids in the seminal fluid may be more predictable of semen quality than conventional blood measurements.

Calogero|Aldo E|AE|
Fiore|Maria|M|
Giacone|Filippo|F|
Altomare|Maria|M|
Asero|Paola|P|
Ledda|Caterina|C|
Romeo|Giulietta|G|
Mongioì|Laura M|LM|
Copat|Chiara|C|
Giuffrida|Maria|M|
Vicari|Enzo|E|
Sciacca|Salvatore|S|
Ferrante|Margherita|M|

Metals/metalloids
Semen quality
Environmental pollution
Male infertility


The role of TNFRSF11B in development of osteoarthritic cartilage.

Abstract:
OBJECTIVES
Osteoarthritis (OA) is a complex genetic disease with different risk factors contributing to its development. One of the genes, TNFRSF11B, previously identified with gain-of-function mutation in a family with early-onset OA with chondrocalcinosis, is among the highest upregulated genes in lesioned OA cartilage (RAAK-study). Here, we determined the role of TNFRSF11B overexpression in development of OA.

METHODS
Human primary articular chondrocytes (9 donors RAAK study) were transduced using lentiviral particles with or without TNFRSF11B. Cells were cultured for 1 week in a 3D in-vitro chondrogenic model . TNFRSF11B overexpression was confirmed by RT-qPCR, immunohistochemistry and ELISA. Effects of TNFRSF11B overexpression on cartilage matrix deposition, matrix mineralization, and genes highly correlated to TNFRSF11B in RNA-sequencing dataset (r>|0.75|) were determined by RT-qPCR. Additionally, glycosaminoglycans and collagen deposition were visualized with Alcian blue staining and immunohistochemistry (COL1 and COL2).

RESULTS
Overexpression of TNFRSF11B resulted in strong upregulation of MMP13, COL2A1 and COL1A1. Likewise, mineralization and osteoblast characteristic markers RUNX2, ASPN and OGN showed a consistent increase. Among 30 genes highly correlated to TNFRSF11B, expression of only 8 changed significantly, with BMP6 showing highest increase (9-fold) while expression of RANK and RANKL remained unchanged indicating previously unknown downstream pathways of TNFRSF11B in cartilage.

CONCLUSION
Results of our 3D in vitro chondrogenesis model indicate that upregulation of TNFRSF11B in lesioned OA cartilage may act as a direct driving factor for chondrocyte to osteoblast transition observed in OA pathophysiology. This transition does not appear to act via the OPG/RANK/RANKL triad common in bone remodeling.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The Medical Ethics Committee of the LUMC gave approval for the RAAK study (P08.239). Written informed consent was obtained from all donors.

Ruiz|Alejandro Rodríguez|AR|
Tuerlings|Margo|M|
Das|Ankita|A|
de Almeida|Rodrigo Coutinho|RC|
Eka Suchiman|H|H|
Nelissen|Rob G H H|RGHH|
Ramos|Yolande F M|YFM|
Meulenbelt|Ingrid|I|

TNFRSF11B
osteoarthritis
matrix mineralization
chondrogenesis
CCAL1
cartilage hypertrophy


Competitive Salt Precipitation/Dissolution During Free-Water Reduction in Water-in-Salt Electrolyte.

Abstract: Water-in-salt electrolytes based on highly concentrated bis(trifluoromethyl)sulfonimide (TFSI) promise aqueous electrolytes with stabilities nearing 3 V. However, especially with an electrode approaching the cathodic (reductive) stability, cycling stability is insufficient. While stability critically relies on a solid electrolyte interphase (SEI), the mechanism behind the cathodic stability limit remains unclear. Now, two distinct reduction potentials are revealed for the chemical environments of free and bound water and that both contribute to SEI formation. Free water is reduced about 1 V above bound water in a hydrogen evolution reaction (HER) and is responsible for SEI formation via reactive intermediates of the HER; concurrent LiTFSI precipitation/dissolution establishes a dynamic interface. The free-water population emerges, therefore, as the handle to extend the cathodic limit of aqueous electrolytes and the battery cycling stability.

water-in-salt
electrolytes
interfaces
electrochemistry
salt effect


Computational investigation on the binding modes of Rimonabant analogs with CB1 and CB2.

Abstract: The human cannabinoid G-protein-coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse, and type 2 diabetes. Rimonabant (SR141716A), MJ08, and MJ15 are selective CB1 antagonists with selectivity >1,000-folds over CB2 despite 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking, and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity. Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys1923.28 in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp1762.63 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2. The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.

Liu|Cheng|C| Yuan|Congmin|C| Wu|Pinwen|P| Zhu|Chen|C| Fang|Hao|H| Wang|Lili|L| Fu|Wei|W|0000-0002-2335-8908

D001665:Binding Sites
D054314:Drug Inverse Agonism
D006801:Humans
D006860:Hydrogen Bonding
D007700:Kinetics
D062105:Molecular Docking Simulation
D056004:Molecular Dynamics Simulation
D017434:Protein Structure, Tertiary
D043884:Receptor, Cannabinoid, CB1
D043885:Receptor, Cannabinoid, CB2
D000077285:Rimonabant

rimonabant
cannabinoid receptor
molecular modeling


Results From Finland's 2016 Report Card on Physical Activity for Children and Youth.

Abstract:
BACKGROUND
Finland's 2016 Report Card on Physical Activity for Children and Youth gathers and translates research results and assesses the status and promotion of physical activity (PA) among Finnish children and youth less than 18 years of age. This article summarizes the results and provides grades for 9 indicators.

METHODS
The working group evaluated the evidence and assigned grades of A (highest, 81% to 100%), B, C, D, or F (lowest, 0% to 20%) for 9 PA indicators using the Active Healthy Kids Canada Report Card development process.

RESULTS
The grades varied in Finland as follows: 1) Overall PA/fulfillment of recommendations = D, 2) Organized Sport Participation = C, 3) Active Play = C, 4) Active Transportation = B, 5) Sedentary Behaviors = D, 6) Family and Peers = C, 7) School = B, 8) Community and the Built Environment = B, 9) Government = B.

CONCLUSIONS
Despite good policies and programs to promote PA in Finland, children and youth overall PA levels are low, whereas their time spent sedentary is high. More effective interventions, operation models, concrete tools as well as environmental solutions are needed to support the work toward more physically active childhood and youth.

Tammelin|Tuija H|TH|
Aira|Annaleena|A|
Hakamäki|Matti|M|
Husu|Pauliina|P|
Kallio|Jouni|J|
Kokko|Sami|S|
Laine|Kaarlo|K|
Lehtonen|Kati|K|
Mononen|Kaisu|K|
Palomäki|Sanna|S|
Ståhl|Timo|T|
Sääkslahti|Arja|A|
Tynjälä|Jorma|J|
Kämppi|Katariina|K|


Expression of epithelial glycoprotein (EGP40) in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC).

Abstract:
Aim
To study the expression of Epithelial Glycoprotein (EGP40) in various grades of Oral Epithelial Dysplasia namely mild, moderate and severe epithelial dysplasia and in various grades of Oral Squamous Cell Carcinoma (OSCC) namely well, moderate & in poorly differentiated squamous cell carcinoma.

Material and Methods
This laboratory study comprised of 47 samples in which 27 samples were of three different grades of OSCC, Well (n=10), Moderate (n=10) and Poorly differentiated (n=7) and remaining 20 samples were of three different grades of dysplasia [Mild (n=7), Moderate (n=8), Severe dysplasia (n=5)]. All the 47 cases were subjected to immunohistochemical staining to evaluate the expression of EGP40. Chi square was used to analyze the significance of differences in different grades of oral epithelial dysplasia & in different grades of OSCC.

Results
The percentage of EGP40 immuno positivity was increased from mild to severe dysplasia and the percentage of EGP40 immuno positivity was increased from well to poorly differentiated carcinoma No statistical significance was observed in the immunoreactivity and in the intensity of expression between various grades of oral epithelial dysplasia and oral squamous cell carcinoma.

Conclusion
The epithelial cell adhesion molecule can be considered as an early marker for predicting malignant transformation of dysplastic epithelial lesions and used as a marker in predicting the OSCC prognosis.

D000071858:Epithelial Cell Adhesion Molecule

D000077195:Squamous Cell Carcinoma of Head and Neck

EGP40
oral squamous cell carcinoma
oral potentially malignant


Role of lipid-lowering agents in the management of diabetic retinopathy.

Abstract: Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus (DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined in the last decades, its prevalence increased and is expected to rise further as a result of the increasing incidence of type 2 DM (T2DM) and the longer life expectancy of patients with DM. The pathogenesis of diabetic retinopathy is multifactorial. Some observational studies suggested an association between dyslipidemia and the development and progression of retinopathy in patients with DM but others did not confirm this association. Regarding lipid-lowering agents, studies that evaluated the role of statins in the management of these patients are mostly small and yielded discrepant results. Large randomized studies with statins in patients with T2DM showed no benefit of these agents on diabetic retinopathy but were not designed to address this effect. In contrast, both preclinical data and two large randomized controlled studies, the FIELD and the ACCORD trial, showed that fenofibrate delays the progression of diabetic retinopathy. Even though the mechanisms underpinning this favorable effect are not entirely clear, these findings suggest that fenofibrate might represent a useful tool for the management of diabetic retinopathy.

Lipid-lowering agents
Retinopathy
Diabetes mellitus
Statins
Colesevelam
Ezetimibe
Fibrates


Chronobiology of Acute Aortic Syndromes.

Abstract: Acute aortic syndromes are highly morbid conditions that require prompt diagnosis and management. Aortic dissections have rhythmic patterns, with notable peaks at certain points in every 24 hours as well as weekly and seasonal variations. Several retrospective studies have assessed the chronobiology of acute aortic dissections and there seems to be a winter seasonal peak and morning daily peak in incidence. Although the pathophysiology of this chronobiology is unclear, there are several environmental and physiologic possibilities. This article reviews the major studies examining the chronobiology of acute aortic dissection, and summarizes some theories on the pathophysiology of this phenomenon.

Siddiqi|Hasan K|HK|
Bossone|Eduardo|E|
Pyeritz|Reed E|RE|
Eagle|Kim A|KA|

Chronobiology
Acute aortic syndrome
Aortic dissection
Aortic disease


Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line.

Abstract: Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the "leading circle" and the "spiral wave or rotor" theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level. We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry. Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.

Houston|Charles|C|
Tzortzis|Konstantinos N|KN|
Roney|Caroline|C|
Saglietto|Andrea|A|
Pitcher|David S|DS|
Cantwell|Chris D|CD|
Chowdhury|Rasheda A|RA|
Ng|Fu Siong|FS|
Peters|Nicholas S|NS|
Dupont|Emmanuel|E|

Rotational activity
HL1-6 myocytes
Re-entry
Triggers
Optical mapping
Monolayer culture


Identification of Direct Kinase Substrates Using Analogue-Sensitive Alleles.

Abstract: Identifying the substrates of protein kinases remains a major obstacle in the elucidation of eukaryotic signaling pathways. Promiscuity among kinases and their substrates coupled with the extraordinary plasticity of phosphorylation networks renders traditional genetic approaches or small-molecule inhibitors problematic when trying to determine the direct substrates of an individual kinase. Here we describe methods to label, enrich, and identify the direct substrates of analogue-sensitive kinases by exploiting their steric complementarity to artificial ATP analogues. Using calcium-dependent protein kinases of Toxoplasma gondii as a model for these approaches, this protocol brings together numerous advances that enable labeling of kinase targets in semi-permeabilized cells, quantification of direct labeling over background, and highly specific enrichment of targeted phosphopeptides.

Rothenberg|Daniel A|DA|
Gordon|Elizabeth A|EA|
White|Forest M|FM|
Lourido|Sebastian|S|

D002851:Chromatography, High Pressure Liquid

AS kinase
IMAC
LC MS/MS
Quantitative analysis
SILAC
Toxoplasmosis


Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients.

Abstract:
OBJECTIVES
To validate the functional relevance of resting state networks (RSNs) by means of a comparison of resting state connectivity (RSC) between language regions elicited by direct cortical stimulation versus RSC between random regions; and to evaluate the accuracy of resting state fMRI in surgical planning by assessing the overlap between RSNs and intraoperative functional mapping results.

METHODS
Sensorimotor and language eloquent sites were identified by direct electrical cortical stimulation in 98 patients with a diffuse low-grade glioma. A seed to voxel analysis with inter-language stimulation point connectivity versus inter-random ROIs connectivity was performed (19 patients). An independant component analysis (ICA) was also applied to rsfMRI data. Language and sensorimotor components were selected over 20 independent components and compared to the corresponding stimulation points and resected cortex masks (31 and 90 patients, respectively).

RESULTS
Mean connectivity value between language seeds was significantly higher than the one between random seeds (0.68 ± 0.39 and 0.12 ± 0.21 respectively, P < 10-10 ). 96 ± 11% of sensorimotor stimulation points were located within 10 mm from sensorimotor ICA maps versus 92 ± 21% for language. 3.1 and 15% of resected cortex overlapped sensorimotor and language networks, respectively. Mean sensorimotor stimulation points and resected cortex z-scores were 2.0 ± 1.2 and -0.050 ± 0.60, respectively (P < 10-10 ). Mean language stimulation points and resected cortex z-scores were 1.6 ± 1.9 and 0.68 ± 0.91, respectively, P < 0.005.

CONCLUSION
The significantly higher RSC between language seeds than between random seeds validated the functional relevance of RSC. ICA partly succeeded to distinguish eloquent versus surgically removable areas and may be possibly used as a complementary tool to intraoperative mapping. Hum Brain Mapp 37:3721-3732, 2016. © 2016 Wiley Periodicals, Inc.

Cochereau|Jérôme|J|
Deverdun|Jérémy|J|
Herbet|Guillaume|G|
Charroud|Céline|C|0000-0001-5754-3178
Boyer|Anthony|A|
Moritz-Gasser|Sylvie|S|
Le Bars|Emmanuelle|E|
Molino|François|F|
Bonafé|Alain|A|
Menjot de Champfleur|Nicolas|N|
Duffau|Hugues|H|

glioma
language
brain mapping
functional magnetic resonance imaging
neurosurgery
resting-state fMRI
sensorimotor cortex


Long-term complications of stroke and secondary prevention: an overview for primary care physicians.

Abstract: Despite a decline in mortality from stroke, the annual incidence in the general population is increasing. For many stroke survivors and their families, the acute stroke is the beginning of an ongoing struggle with physical impairment and subsequent disability. Over time, the immediate clinical consequences of the stroke are complicated by a variety of lesser-known medical, musculoskeletal and psychosocial difficulties. The primary care physician is best positioned to optimise chronic disease control, reduce risk and manage complications of stroke. Early screening and appropriate management is key. Instituting secondary prevention and attention to bowel and bladder problems can help reduce medical complications and re-admissions, while adequate analgesia, positioning/splinting of limbs and physiotherapy can lessen discomfort and preventable suffering. Primary care physicians can identify and treat post-stroke mood issues and involve psychological counselling for patients and caregivers. Adequate education and support may restore the independence of patients with stroke or minimise any resultant dependency.

Chohan|Shakil Ahmed|SA|
Venkatesh|Prasanna Kappaganthu|PK|
How|Choon How|CH|

complications
stroke
primary care
psychosocial
rehabilitation


GraphCDR: a graph neural network method with contrastive learning for cancer drug response prediction.

Abstract: Predicting the response of a cancer cell line to a therapeutic drug is an important topic in modern oncology that can help personalized treatment for cancers. Although numerous machine learning methods have been developed for cancer drug response (CDR) prediction, integrating diverse information about cancer cell lines, drugs and their known responses still remains a great challenge. In this paper, we propose a graph neural network method with contrastive learning for CDR prediction. GraphCDR constructs a graph neural network based on multi-omics profiles of cancer cell lines, the chemical structure of drugs and known cancer cell line-drug responses for CDR prediction, while a contrastive learning task is presented as a regularizer within a multi-task learning paradigm to enhance the generalization ability. In the computational experiments, GraphCDR outperforms state-of-the-art methods under different experimental configurations, and the ablation study reveals the key components of GraphCDR: biological features, known cancer cell line-drug responses and contrastive learning are important for the high-accuracy CDR prediction. The experimental analyses imply the predictive power of GraphCDR and its potential value in guiding anti-cancer drug selection.

Liu|Xuan|X| Song|Congzhi|C| Huang|Feng|F| Fu|Haitao|H| Xiao|Wenjie|W| Zhang|Wen|W|

Graph neural network
Contrastive learning
Cancer drug response prediction
Multi-omics
Drug structure


The association of calcium channel blockers with β-cell function in type 2 diabetic patients: A cross-sectional study.

Abstract: Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with β-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess β-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-β was computed by Homeostasis Model Assessment model to evaluate β-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-β. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with β-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced β-cell function.

Zhao|Dong|D|
Cao|Yu|Y|
Yu|Cai-Guo|CG|
Yuan|Sha-Sha|SS|
Zhang|Ning|N|
Zhang|Yuan-Yuan|YY|
Staessen|Jan A|JA|
Feng|Ying-Mei|YM|0000-0001-5248-0155

inhibitor of renin-angiotensin-aldosterone system


Investigating isoindoline, tetrahydroisoquinoline, and tetrahydrobenzazepine scaffolds for their sigma receptor binding properties.

Abstract: Substituted norbenzomorphans are known to display high affinity and selectivity for the two sigma receptor (σR) subtypes. In order to study the effects of simplifying the structures of these compounds, a scaffold hopping strategy was used to design several novel sets of substituted isoindolines, tetrahydroisoquinolines and tetrahydro-2-benzazepines. The binding affinities of these new compounds for the sigma 1 (σ1R) and sigma 2 (σ2R) receptors were determined, and some analogs were identified that exhibit high affinity (Ki ≤ 25 nM) and significant selectivity (>10-fold) for σ1R or σ2R. The preferred binding modes of selected compounds for the σ1R are predicted by modeling studies, and the nature of substituents on the aromatic ring and the nitrogen atom of the bicyclic skeleton appears to affect the preferred binding orientation of σ1R-preferring ligands.

Linkens|Kathryn|K|
Schmidt|Hayden R|HR|
Sahn|James J|JJ|
Kruse|Andrew C|AC|
Martin|Stephen F|SF|

Scaffold hopping
Docking
Receptor subtype selectivity
Sigma 1 receptor (σ1R)
Sigma 2 receptor (σ2R)
Transmembrane protein 97 (TMEM97)


A W-Shaped Ga-Dy-Dy-Dy-Ga Cluster: Synthesis, Characterization, and Magnetic Properties.

Abstract: A W-shaped {Ga-Dy-Dy-Dy-Ga} coordination cluster, [Ga2 Dy3 (L)6 (MeO)2 (MeOH)3 ]⋅NO3 ⋅7 MeOH (1) with H2 L, (E)-2-(2-hydroxy-3-methoxy-benzylideneamino)phenol was synthesized, characterized, and the magnetic properties investigated. The magnetic measurements indicate that the compound shows single-molecule magnet (SMM) behavior under zero dc field. This suggests that the combination of GaIII ions and DyIII ions (4 f) is a successful strategy to assemble SMM clusters. The combination of these metal ions also offers prospects in dual functionality therapeutics for medical applications.

magnetic properties
coordination clusters
single-molecule magnets
dysprosium
gallium


High-quality-draft genome sequence of the multiple heavy metal resistant bacterium Pseudaminobacter manganicus JH-7T.

Abstract: Pseudaminobacter manganicus JH-7T (= KCTC 52258T = CCTCC AB 2016107T) is a Gram-staining-negative, aerobic and non-motile strain that was isolated from a manganese mine. The strain JH-7T shows multiple heavy metal resistance and can effectively remove Mn2+ and Cd2+. In addition, it is able to produce exopolysaccharides (EPS), which may contribute to metal remove/adsorption. Thus, strain JH-7T shows a great potential in bioremediation of heavy metal-contaminated environment. In this study, we report the draft genomic sequence of P. manganicus JH-7T and compare it to related genomes. Strain JH-7T has a 4,842,937 bp genome size with a G + C content of 61.2%, containing 4504 protein-coding genes and 71 RNA genes. A large number of putative genes associated with heavy metal resistance and EPS synthesis are found in the genome.

Xia|Xian|X| Li|Jiahong|J| Zhou|Zijie|Z| Wang|Dan|D| Huang|Jing|J| Wang|Gejiao|G|

Exopolysaccharides
Cadmium
Heavy metal resistance and adsorption
Manganese,Pseudaminobacter


Contribution of minced muscle graft progenitor cells to muscle fiber formation after volumetric muscle loss injury in wild-type and immune deficient mice.

Abstract: Volumetric muscle injury (VML) causes an irrecoverable loss of muscle fibers, persistent strength deficits, and chronic disability. A crucial challenge to VML injury and possible regeneration is the removal of all of the in situ native elements necessary for skeletal muscle regeneration. Our first goal was to establish a reliable VML model in the mouse tibialis anterior (TA) muscle. In adult male wild-type and nude mice, a non-repaired ≈20% VML injury to the TA muscle resulted in an ≈59% loss in nerve evoked muscle strength, ≈33% loss in muscle mass, and ≈29% loss of muscle fibers at 28 day post-injury. Our second goal was to investigate if minced muscle grafts (≈1 mm3 tissue fragments) promote recovery of muscle fibers after VML injury and to understand if the graft-derived progenitor cells directly contribute to fiber regeneration. To assess donor cell contribution, donor muscle tissue was derived from UBC-GFP mice in a subset of experiments. Minced grafts restored ≈34% of the lost fibers 28 days post-injury. The number of GFP+ fibers and the estimated number of regenerated fibers were similar, regardless of host mouse strain. The muscle tissue regeneration promoted by minced grafts did not improve TA muscle strength at this time post-injury. These findings demonstrate the direct contribution of minced muscle graft-derived myogenic stem/progenitor cells to recovery of muscle fibers after VML injury and signify the utility of autologous myogenic stem cell therapies for this indication.

Corona|Benjamin T|BT|
Henderson|Beth E P|BE|
Ward|Catherine L|CL|
Greising|Sarah M|SM|

D000818:Animals
D004195:Disease Models, Animal
D051379:Mice
D008819:Mice, Nude
D018485:Muscle Fibers, Skeletal
D018482:Muscle, Skeletal
D009135:Muscular Diseases
D020127:Recovery of Function
D012038:Regeneration
D013234:Stem Cells

Musculoskeletal
orthopedic trauma
regenerative medicine
skeletal muscle injury


Nonmedical prescription stimulant use among youth in the emergency department: prevalence, severity and correlates.

Abstract: This study examined the prevalence, severity and correlates of nonmedical prescription stimulant use (NPSU) among youth in the emergency department (ED). Participants 14-20 years old presenting to the ED completed a survey. A multinomial logistic regression was used to compare those without NPSU, with mild NPSU and with moderate/severe NPSU on demographics, risk factors and ED utilization. There were 4389 participants; 8.3% reported past-year NPSU and 44% of those with past 3-month NPSU reported at least monthly use. After controlling for demographics, participants with mild NPSU or moderate/severe NPSU had higher odds of all substance use risk factors compared to those with no NPSU. Also, those with moderate/severe NPSU were more likely to report dating violence and nonmedical use of opioids or sedatives and less likely to use marijuana compared to those with mild NPSU. Healthcare setting screening and intervention efforts should consider NPSU concomitant with other substance use and explore the association of dating violence with NPSU.

Whiteside|Lauren K|LK|
Cunningham|Rebecca M|RM|
Bonar|Erin E|EE|
Blow|Frederic|F|
Ehrlich|Peter|P|
Walton|Maureen A|MA|

Nonmedical prescription stimulant use
Violence
Emergency medicine
Substance abuse
Young adults


Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation.

Abstract:
Background
Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo.

Method
TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects.

Result
DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR.

Conclusion
The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo.

Sato|Shoki|S| Nakamura|Toru|T| Katagiri|Toyomasa|T| Tsuchikawa|Takahiro|T| Kushibiki|Toshihiro|T| Hontani|Kouji|K| Takahashi|Mizuna|M| Inoko|Kazuho|K| Takano|Hironobu|H| Abe|Hirotake|H| Takeuchi|Shintaro|S| Ono|Masato|M| Kuwabara|Shota|S| Umemoto|Kazufumi|K| Suzuki|Tomohiro|T| Sato|Osamu|O| Nakamura|Yusuke|Y| Hirano|Satoshi|S|

cell-permeable peptide
pancreatic ductal adenocarcinoma
C16orf74
molecular target therapy


Lack of association between polymorphism of IL-2 -330T/G and pulmonary tuberculosis among Caucasians.

Abstract: This meta-analysis was conducted to assess the consistency and strength of the relationship between polymorphism of IL-2 -330T/G and susceptibility to pulmonary tuberculosis (TB). PubMed, Web of Knowledge and CNKI were searched to find eligible studies about the relationship between IL-2 -330T/G polymorphism and susceptibility to pulmonary TB. A total of eight studies comprising 971 cases and 1519 controls were grouped together for the purpose of elucidating the relationship between polymorphism of IL-2 -330T/G and pulmonary TB susceptibility. The allele model (G vs. T: odds ratio (OR) = 1.34; 95% confidence interval (CI) 1.05-1.71, Phet = 0.001) and the recessive model (GG+GT vs. TT: OR = 1.60; 95% CI 1.08-2.38, Phet = 0.0001) showed an increased risk of development of pulmonary TB. However, the homozygous model (GG vs. TT: OR = 1.74; 95% CI 0.98-3.09, Phet = 0.0005) and the dominant model (GG vs. TT + TG: OR = 1.30; 95% CI = 0.80-2.14, Phet =  0.001) failed to show an increased incidence of pulmonary TB. When analysis was stratified by ethnicity, no obvious associations were identified in the Caucasian subgroup under all four genetic models. Additionally, heterogeneity disappeared in the analysis of Caucasian subgroup. Our combined data suggested that there was no association between IL-2 -330T/G polymorphism and pulmonary TB among Caucasians.

D020022:Genetic Predisposition to Disease

polymorphism
IL-2
pulmonary tuberculosis
meta-analysis


Oligoasthenoteratospermia and sperm tail bending in PPP4C-deficient mice.

Abstract: Protein phosphatase 4 (PPP4) is a protein phosphatase that, although highly expressed in the testis, currently has an unclear physiological role in this tissue. Here, we show that deletion of PPP4 catalytic subunit gene Ppp4c in the mouse causes male-specific infertility. Loss of PPP4C, when assessed by light microscopy, did not obviously affect many aspects of the morphology of spermatogenesis, including acrosome formation, nuclear condensation and elongation, mitochondrial sheaths arrangement and '9 + 2' flagellar structure assembly. However, the PPP4C mutant had sperm tail bending defects (head-bent-back), low sperm count, poor sperm motility and had cytoplasmic remnants attached to the middle piece of the tail. The cytoplasmic remnants were further investigated by transmission electron microscopy to reveal that a defect in cytoplasm removal appeared to play a significant role in the observed spermiogenesis failure and resulting male infertility. A lack of PPP4 during spermatogenesis causes defects that are reminiscent of oligoasthenoteratospermia (OAT), which is a common cause of male infertility in humans. Like the lack of functional PPP4 in the mouse model, OAT is characterized by abnormal sperm morphology, low sperm count and poor sperm motility. Although the causes of OAT are probably heterogeneous, including mutation of various genes and environmentally induced defects, the detailed molecular mechanism(s) has remained unclear. Our discovery that the PPP4C-deficient mouse model shares features with human OAT might offer a useful model for further studies of this currently poorly understood disorder.

Han|F|F|
Dong|M Z|MZ|
Lei|W L|WL|
Xu|Z L|ZL|
Gao|F|F|
Schatten|H|H|
Wang|Z B|ZB|
Sun|X F|XF|
Sun|Q Y|QY|

oligoasthenoteratospermia
protein phosphatase 4
PPP4
PPP4C
spermatogenesis
cytoplasm removal
spermiogenesis
mouse model
male fertility


The prevalence of depressive symptoms among older patients with hypertension in rural China.

Abstract:
OBJECTIVE
The comorbidity of depression and hypertension (HTN) is common and complicates the management of both conditions. This study investigated the prevalence of depressive symptoms among older patients with HTN in rural China and explored the relationship between the two conditions.

METHODS
The baseline data of older patients diagnosed with HTN included in the depression/HTN in Chinese Older Adults-Collaborations for Health Study were used for the analysis. The Chinese Older Adults-Collaborations for Health Study was conducted in rural villages of Tonglu County, Zhejiang Province, China. In all, 10 389 older village residents had HTN (57.2% female, mean age 71.5 ± 8.1 years). Blood pressure was measured by using a calibrated manual sphygmomanometer and stethoscope. Depressive symptom was measured by using the Chinese version of the nine-item Patient Health Questionnaire.

RESULTS
Among 10 389 patients with HTN, 12.8% had significant depressive symptoms (nine-item Patient Health Questionnaire ≥ 10). Rates of significant depressive symptoms were 5.3% and 32.8% among patients with controlled and uncontrolled HTN (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90), respectively (χ2  = 8.701, p < 0.001). Logistic regression analysis indicated that those in older age group (≥70 years) and with uncontrolled HTN have higher rates of significant depressive symptoms than those who are younger (age 60 to <70) and with controlled HTN.

CONCLUSION
Our findings show high rates of depressive symptoms among patients with HTN in rural China and higher rates of depressive symptoms among patients with uncontrolled HTN. These support the development and dissemination of integrative care approaches for older adults with HTN and depression in rural China. Copyright © 2016 John Wiley & Sons, Ltd.

Xue|Jiang|J|
Chen|Shulin|S|
Bogner|Hillary R|HR|
Tang|Wan|W|
Li|Lydia|L|
Conwell|Yeates|Y|

prevalence
depressive symptoms
hypertension
rural China
older adults


Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.

Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-β peptide (Aβ). Numerous studies have established Aβ amyloidogenesis as a hallmark of AD pathogenesis, particularly with respect to mitochondrial dysfunction. We have previously shown that glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms amyloid-like aggregates upon exposure to oxidative stress and that these aggregates contribute to neuronal cell death. Here, we report that GAPDH aggregates accelerate Aβ amyloidogenesis and subsequent neuronal cell death both in vitro and in vivo. Co-incubation of Aβ40 with small amounts of GAPDH aggregates significantly enhanced Aβ40 amyloidogenesis, as assessed by in vitro thioflavin-T assays. Similarly, structural analyses using Congo red staining, circular dichroism, and atomic force microscopy revealed that GAPDH aggregates induced Aβ40 amyloidogenesis. In PC12 cells, GAPDH aggregates augmented Aβ40-induced cell death, concomitant with disruption of mitochondrial membrane potential. Furthermore, mice injected intracerebroventricularly with Aβ40 co-incubated with GAPDH aggregates exhibited Aβ40-induced pyramidal cell death and gliosis in the hippocampal CA3 region. These observations were accompanied by nuclear translocation of apoptosis-inducing factor and cytosolic release of cytochrome c from mitochondria. Finally, in the 3×Tg-AD mouse model of AD, GAPDH/Aβ co-aggregation and mitochondrial dysfunction were consistently detected in an age-dependent manner, and Aβ aggregate formation was attenuated by GAPDH siRNA treatment. Thus, this study suggests that GAPDH aggregates accelerate Aβ amyloidogenesis, subsequently leading to mitochondrial dysfunction and neuronal cell death in the pathogenesis of AD.

Itakura|Masanori|M| Nakajima|Hidemitsu|H| Kubo|Takeya|T| Semi|Yuko|Y| Kume|Satoshi|S| Higashida|Shusaku|S| Kaneshige|Akihiro|A| Kuwamura|Mitsuru|M| Harada|Naoki|N| Kita|Akinori|A| Azuma|Yasu-Taka|YT| Yamaji|Ryoichi|R| Inui|Takashi|T| Takeuchi|Tadayoshi|T|

Alzheimer disease
mitochondrial dysfunction
GAPDH
mitochondrial membrane potential
amyloid-beta (AB)
protein aggregation
transgenic mice


Enhanced anaerobic co-digestion performance by using surface-annealed titanium spheres at different atmospheres.

Abstract: A series of surface-annealed titanium spheres (Ti-A, Ti-B, and Ti-C) in different atmospheres were used as accelerants in anaerobic co-digestion (AcoD) systems under magnetic field (MF). Surface-annealed titanium spheres and MF exhibit remarkable coupling and promoting effects on the AcoD performance. The cumulative biogas yield (435.84-552.60 mL/g VS) and total chemical oxygen demand (COD) degradation efficiency (59.76%-71.28%) of the AcoD systems with TiMF, Ti-AMF, Ti-BMF, and Ti-CMF were significantly higher than control (357.66 mL/g VS and 51.5%). The digestates of the AcoD system with surface-annealed Ti spheres delivered excellent stability (49.83%-59.90%) and fertilizer (4.21%-4.56%). This work clarifies the possible role of surface-annealed Ti spheres in enhancing methanogenesis.

Ke|Teng|T| Yun|Sining|S| Wang|Kaijun|K| An|Jinhang|J| Liu|Lijianan|L| Liu|Jiayu|J|

Anaerobic co-digestion
Surface-annealed titanium spheres
Magnetic field
Biogas yield
Fertilizer utilization


Toxicology of long-term and high-dose administration of methylphenidate on the kidney tissue - a histopathology and molecular study.

Abstract: The present study aims to assess the influences of oral methylphenidate on kidney function and structure versus vehicle treatment in adult male rats. In this study, thirty adult male rats equally into two treatment groups divided randomly, and among them, MPH has been administered for 21 days, at doses of 20 mg/kg, and the control group has received salin. In renal, under the effect of MPH applying quantitative real-time PCR, we analyzed nephrotoxicity-related molecular pathways like autophagy, inflammation, and apoptosis. Moreover, the levels of GSH, CAT, and SOD were investigated as antioxidant enzymes. Afterward, stereological analysis in MPH-treated rats has been performed. Analysis of qPCR displayed inflammation, impaired autophagy, and enhanced apoptosis with histological changes in the kidney's tissue, also an important rise in the antioxidant enzymes' level. Besides, 20 mg/kg of MPH led to a decline in the mean of Bowman's space thickness and renal corpuscle's volume in comparison to the control rats. Collectively, our histological and molecular data implicit that in the kidney region, administrating of MPH evoked discriminative expression alterations in nephrotoxicity-associated signaling cascades, specifically autophagy, inflammation, and apoptosis paired with important damage to kidney tissue.

methylphenidate kidney Autophagy inflammation apoptosis nephrotoxicity


Antitumor Activity of Small Activating RNAs Induced PAWR Gene Activation in Human Bladder Cancer Cells.

Abstract: Small double-stranded RNAs (dsRNAs) have been proved to effectively up-regulate the expression of particular genes by targeting their promoters. These small dsRNAs were also termed small activating RNAs (saRNAs). We previously reported that several small double-stranded RNAs (dsRNAs) targeting the PRKC apoptosis WT1 regulator (PAWR) promoter can up-regulate PAWR gene expression effectively in human cancer cells. The present study was conducted to evaluate the antitumor potential of PAWR gene induction by these saRNAs in bladder cancer. Promisingly, we found that up-regulation of PAWR by saRNA inhibited the growth of bladder cancer cells by inducing cell apoptosis and cell cycle arrest which was related to inhibition of anti‑apoptotic protein Bcl-2 and inactivation of the NF-κB and Akt pathways. The activation of the caspase cascade and the regulation of cell cycle related proteins also supported the efficacy of the treatment. Moreover, our study also showed that these saRNAs cooperated with cisplatin in the inhibition of bladder cancer cells. Overall, these data suggest that activation of PAWR by saRNA may have a therapeutic benefit for bladder cancer.

Yang|Kai|K| Shen|Jie|J| Tan|Fu-Qing|FQ| Zheng|Xiang-Yi|XY| Xie|Li-Ping|LP|

small activating RNA
PAWR
bladder cancer
cell cycle arrest
RNA activation
apoptosis.