Miracle-dz/UniFAR-FTUs huggingface dataset:
Influence of laser photobiomodulation on collagen IV during skeletal muscle tissue remodeling after injury in rats.

OBJECTIVE The aim of the present study was to determine the effect of GaAlAs low-level laser therapy (LLLT) on collagen IV remodeling of the tibialis anterior (TA) muscle in rats after cryolesion. BACKGROUND Considerable interest exists in skeletal muscle regeneration in situations such as repair after exercise-induced muscle injury, after muscle transplantation, in muscular dystrophy, exercise-induced muscle injury, and the recovery of strength after atrophy due to disuse. A number of studies have demonstrated the potential of LLLT in facilitating the muscle-healing process; however, no consensus is found in the literature regarding the best laser-irradiation parameters. METHODS Adult male Wistar rats (n = 45) were used and randomly divided into three groups: control (n = 5); nontreated cryolesioned group (n = 20), and LLLT-cryolesioned group (n = 20). The cryolesioned groups were analyzed at 1, 7, 14, and 21 days after the injury procedure. Laser irradiation was performed 3 times per week on the injured region by using the GaAlAs laser (660 nm; beam spot of 0.04 cm(2), output power of 20 mW, power density of 500 mW/cm(2), and energy density of 5 J/cm(2), for 10 sec). The muscles were removed, frozen, cryosectioned, and then stained with hematoxylin-eosin for the visualization of general morphology or used for immunohistochemical analysis of collagen IV. RESULTS It was demonstrated that LLLT promotes an increase in collagen IV immunolabeling in skeletal muscle in the first 7 days after acute trauma caused by cryoinjury, but does not modify the duration of the tissue-repair process. Even with LLLT, the injured muscle tissue needs ∼21 days to achieve the same state of organization as that in the noninjured muscle. CONCLUSION The collagen IV content is modulated in regenerating skeletal muscle under LLLT, which might be associated with better tissue outcome, although the histologic analysis did not detect tissue improvement in the LLLT group.
Evidence for ASD Recurrence Rates and Reproductive Stoppage From Large UK ASD Research Family Databases

Following a diagnosis of a developmental disorder such as autism spectrum disorder (ASD) in early childhood, parents may decide to have fewer children than previously planned. The tendency for families to halt reproduction after receiving a diagnosis for one child is known as reproductive stoppage. Stoppage may lead to an underestimate of recurrence risk estimates of parents having more than one child with ASD. Using two large UK ASD family databases, we investigated recurrence rates for ASD and evidence for reproductive stoppage for both ASD and undiagnosed ASD/broader autism phenotype in a subgroup of families. Reproductive stoppage was tested for using the Mann–Whitney U‐test to disprove the null hypothesis that affected and nonaffected children were distributed randomly by birth order. Dahlberg's later‐sib method was used to estimate recurrence risk and take stoppage into account. Data were available from 299 families (660 children) including 327 with ASD. Ten percent of the complete families had more than one child with an ASD. Using Dahlberg's later‐sib method, the recurrence risk for ASD was 24.7% overall and 50.0% in families with two or more older siblings with ASD. Children with ASD were born significantly later in families than those without ASD in all sibship combinations. This study shows strong evidence that ASD is associated with reproductive stoppage. These data have important implications for family planning and genetic counseling. Autism Res 2015, 8: 73–81. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
Coffee, caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults

Abstract Objective.To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. Methods. We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses’ Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results. We documented 277 deaths from suicide. Compared to those consuming ≤ 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38–0.78) for those consuming 2–3 cups/day and 0.47 (0.27–0.81) for those consuming ≥ 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63–0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63–0.93) for each increment of 300 mg/day of caffeine. Conclusions. These results from three large cohorts support an association between caffeine consumption and lower risk of suicide.
Quinaldine derivatives: preparation and biological activity.

The series of quinaldine derivatives were prepared, some of them by means of novel synthetic methods. The synthetic approach, analytical and spectroscopic data of all newly synthesized compounds are presented. The prepared compounds were tested for their in vitro antifungal activity as well as for their photosynthesis-inhibiting activity (the inhibition of photosynthetic electron transport in spinach chloroplasts (Spinacia oleracea L.) and the reduction of chlorophyll content in Chlorella vulgaris Beij. ). Structure-activity relationships among the chemical structure, the physical properties and the biological activities of the evaluated compounds are discussed in the article.
The expression of APRIL in Sjogren's syndrome: aberrant expression of APRIL in the salivary gland.

OBJECTIVE A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are B-cell-related mediators and may play a role in the pathogenesis in SS. In this descriptive study we assessed the expression of APRIL and BAFF in the minor salivary gland and serum from SS patients. METHODS Paraffin-embedded minor salivary gland sections from SS patients, non-SS controls and healthy volunteers were analysed by immunohistochemistry. Digital image quantification was performed to evaluate the expression of BAFF, APRIL and transmembrane activator and CAML interactor. Furthermore, serum was analysed for soluble BAFF and APRIL levels by ELISA. All the data were also analysed for subjects with decreased and normal stimulated salivary flow independent of the classification. RESULTS APRIL expression was lower in minor salivary gland biopsies from SS patients compared with healthy volunteers and to a lesser extent non-SS controls, whereas BAFF expression was similar in all groups. Soluble APRIL levels in serum were increased in SS patients and in subjects with decreased salivary flow independent of the classification. CONCLUSION APRIL salivary gland tissue levels are decreased, suggesting that targeting this cytokine locally in the salivary glands would not benefit SS patients. Moreover, the discrepancy between local and systemic levels is striking and future research should assess this in more detail.
Comparison of cefepime pharmacokinetics in neonatal foals and adult dogs.

The pharmacokinetics of cefepime, a new fourth generation cephalosporin with enhanced antibacterial activity, was examined in neonatal foals and adult dogs. Cefepime was administered intravenously (i.v.) at a dose of 14 mg/kg to five neonatal foals and six adult dogs. Blood samples were collected in both groups of animals and plasma cefepime concentrations measured by reverse-phase high-performance liquid chromatography (HPLC). Cefepime concentrations in both groups of animals were described by a two-compartment pharmacokinetic model with elimination half-lives of 1.65 and 1.09 h for the foal and dog, respectively. We tested whether or not pharmacokinetic parameters for cefepime could be scaled across species using principles of allometry. The parameters of elimination half-life (t(1/2)beta), apparent volume of distribution (VDarea), and systemic clearance (CL) were scaled linearly to body weight on a double logarithmic plot with allometric exponents for body weight of 0.26, 1.08 and 0.72, respectively. This study further determined doses for cefepime, a potentially useful antibiotic for neonatal foals and dogs, from the pharmacokinetic values. An i.v. dose of cefepime estimated from this study for treating sensitive bacteria was 11 mg/kg every 8 h for neonatal foals and 40 mg/kg every 6 h for dogs.
Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress.

BACKGROUND Small heat shock proteins are expressed in many tissues and are proposed to regulate actin filament dynamics when dissociated into small aggregates and phosphorylated in a p38 mitogen-activated protein kinase (p38MAPK)-dependent manner. METHODS p38MAPK activity and small heat shock protein-25 (Hsp25) were determined in glomeruli from rats with experimental diabetes induced by streptozotocin administration and in isolated glomeruli exposed to a free radical stress. Contractile responsiveness of mesangial cells was determined by the serum-induced contraction of cell-embedded type I collagen gels. RESULTS In experimental diabetes, there is an activation of p38MAPK, a decrease in the size of Hsp25 molecular aggregates, from large to small homo-oligomers, and an increase in the phosphorylation of Hsp25. In control glomeruli, a free radical stress, H2O2, activated p38MAPK and increased Hsp25 in a concentration-dependent manner. Additionally, H2O2 decreased the contractility of cultured mesangial cells concomitant with an increase in Hsp25 phosphorylation and a reduction in Hsp25 aggregate size. These effects were significantly reduced by SB202190, an imidazole-derivative cell-permeable inhibitor of p38MAPK. CONCLUSIONS It has been proposed that the generation of oxygen-derived free radicals in diabetes may be linked causally to a loss of glomerular contractile reactivity and thus hyperfiltration in the early stages of diabetes mellitus. This study provides a mechanism for alteration of mesangial cell contractile responsiveness through phosphorylation of Hsp25 and may be a mechanism underlying abnormalities in glomerular hemodynamics in diabetes and in the presence of free radical stress.
Skin Test and Gamma Interferon Enzyme-Linked Immunosorbent Assay Results in Sheep Exposed to Dead Mycobacterium Avium Subspecies Paratuberculosis Organisms

Cell-mediated immunity (CMI) diagnostic tests, such as the gamma interferon enzyme-linked immunosorbent assay (IFN-γ ELISA) and the Johnin skin test, have the potential to detect animals infected with Mycobacterium avium subspecies paratuberculosis (MAP) early in the course of the disease. While these CMI tests tend to be relatively specific in noninfected flocks, in MAP-infected flocks, these tests often identify animals that cannot be confirmed infected by any other reference test, including necropsy and culture. The aim of this study was to determine if antigen exposure by inhalation or oral ingestion of killed MAP organisms would cause a detectable CMI response in sheep. Forty-eight lambs 4 months of age were randomly divided into a control group, an orally exposed group (dosed with 1 × 10 10 autoclaved MAP organisms 3 times), and an inhalation-exposed group (dosed once with 1 × 10 5 dead organisms). Lambs were skin tested and/or bled pre-exposure and 1, 2, 3, 4, and 12 months postexposure. No significant difference was seen with either the oral- or inhalation-exposed groups of lambs versus controls with either the IFN-γ ELISA or the skin test at any time pre- or postexposure. These results suggest that infection/invasion of MAP organisms must occur in order to have a positive skin test or IFN-γ ELISA beyond the false-positive rate. Simple exposure is not enough to elicit a detectable CMI response.
Identification of Dantrolene Binding Sites in Porcine Skeletal Muscle Sarcoplasmic Reticulum (*)

Dantrolene, an intracellularly acting skeletal muscle relaxant, inhibits Ca release from the sarcoplasmic reticulum during excitation-contraction coupling by an unknown mechanism. The drug is used to treat malignant hyperthermia, a genetic sensitivity to volatile anesthetics which results in the massive release of intracellular Ca from affected skeletal muscle. We hypothesize that determination of the site of action of dantrolene will lead to further understanding of the regulation of sarcoplasmic reticulum calcium release. We report the identification of specific dantrolene binding sites in porcine skeletal muscle sarcoplasmic reticulum using a rapid filtration binding assay for [3H]dantrolene. The binding isotherm in the heavy sarcoplasmic reticulum fraction indicates a single binding site with a K of 277 ± 25 nM and a Bmax of 13.1 ± 1.5 pmol/mg of protein. Pharmacological specificity is characterized by inhibition of [3H]dantrolene binding with unlabeled dantrolene, or azumolene, a physiologically active congener, but not with aminodantrolene, which is physiologically inactive. Drug binding is maximal at pH 6.5-7.5, requires no Ca or Mg, and is inhibited by salt concentrations above 100 mM. [3H]Dantrolene binding is greatest in the sarcoplasmic reticulum, which contains the ryanodine receptor, the primary calcium release channel. No binding is detected in the fractions enriched for sarcolemma or transverse tubules. We suggest that dantrolene inhibits calcium release from the sarcoplasmic reticulum by either direct or indirect interaction with the ryanodine receptor.
Exploring Diachronic Lexical Semantics with JeSemE

Recent advances in distributional semantics combined with the availability of large-scale diachronic corpora offer new research avenues for the Digital Humanities. JESEME, the Jena Semantic Explorer, renders assistance to a non-technical audience to investigate diachronic semantic topics. JESEME runs as a website with query options and interactive visualizations of results, as well as a REST API for access to the underlying diachronic data sets.
The diagnosis of appendicitis in children: outcomes of a strategy based on pediatric surgical evaluation.

OBJECTIVE To determine the accuracy of a protocol for diagnosis of appendicitis in children based on clinical evaluation by a pediatric surgeon with selective use of diagnostic imaging studies. We performed this study because 1) current reports in the medical, pediatric, emergency medical, and surgical literature advocate imaging, particularly computed tomography (CT), as the gold standard for diagnosis of appendicitis, and 2) the value of pediatric surgical evaluation early in the management of the child with possible appendicitis has rarely been emphasized. METHODS, DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 356 children (mean age: 9.6 years; range: 1-18 years) referred to a regional pediatric surgical center for possible appendicitis from 1999 through 2001. INTERVENTIONS Initial pediatric surgical evaluation consisted of history, physical examination, white blood cell count, differential count, and urinalysis. Children diagnosed with appendicitis underwent appendectomy without additional studies; those with equivocal findings received intravenous fluids, rest, and reevaluation after 4 to 6 hours. Imaging was used selectively by the pediatric surgeon. OUTCOME MEASURES Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the protocol based on final diagnoses; rate of appendiceal perforation; and rate of negative appendectomy. RESULTS Of 356 children evaluated for appendicitis, 220 (62%) had an appendectomy. Two-hundred nine (95%) had histologically proven appendicitis, and 11 (5%) had a normal appendix. Of the 209 children with appendicitis, 139 (66%) had acute appendicitis, 34 (16%) had advanced appendicitis without perforation, and 36 (17%) had advanced appendicitis with perforation. Appendectomy was performed after initial evaluation in 195 (89%) of the 220 children and after a period of supportive care and observation in 25 (11%) of 220. One hundred thirty-six children (38%) did not have an appendectomy and were discharged with other diagnoses. The sensitivity of this protocol was 99%, specificity was 92%, positive predictive value was 95%, and negative predictive value was 99%. The accuracy was 97% compared with an accuracy of 82% for ultrasound alone and 90% for CT scan alone. CONCLUSIONS These data show that a protocol based on clinical evaluation by a pediatric surgeon with selective use of imaging was highly accurate for the diagnosis of appendicitis in children. Low rates of negative appendectomy (5%) and perforation (17%) were achieved without the potential costs and radiation exposure of excess imaging.
Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.

RATIONALE Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN RESULTS Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. CONCLUSIONS Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.
A Novel Interleukin-17 Receptor-like Protein Identified in Human Umbilical Vein Endothelial Cells Antagonizes Basic Fibroblast Growth Factor-induced Signaling*

We have previously utilized a combination of high throughput sequencing and genome-wide microarray profiling analyses to identify novel cell-surface proteins expressed in human umbilical vein endothelial cells. One gene identified by this approach encodes a type I transmembrane receptor that shares sequence homology with the intracellular domain of members of the interleukin-17 (IL-17) receptor family. Real-time quantitative PCR and Northern analyses revealed that this gene is highly expressed in human umbilical vein endothelial cells and in several highly vascularized tissues such as kidney, colon, skeletal muscle, heart, and small intestine. In addition, we also found that it is also highly expressed in the ductal epithelial cells of human salivary glands, seminal vesicles, and the collecting tubules of the kidney by in situ hybridization. This putative receptor, which we have termed human SEF (hSEF), is also expressed in a variety of breast cancer tissues. In co-immunoprecipitation assays, this receptor is capable of forming homomeric complexes and can interact with fibroblast growth factor (FGF) receptor 1. Overexpression of this receptor inhibits FGF induction of an FGF-responsive reporter gene in human 293T cells. This appears to occur as a result of specific inhibition of p42/p44 ERK in the absence of upstream MEK inhibition. This inhibitory effect is dependent upon a functional intracellular domain since deletion mutants missing the IL-17 receptor-like domain lack this inhibitory effect. These findings are consistent with the recent discovery of the zebrafish homologue, Sef (similar expression to fgf genes), which specifically antagonizes FGF signaling when ectopically expressed in zebrafish or Xenopus laevis embryos. Based on sequence and functional similarities, this novel IL-17 receptor homologue represents a potential human SEF and is likely to play critical roles in endothelial or epithelial functions such as proliferation, migration, and angiogenesis.
N-Formyl Peptide Receptor Phosphorylation Domains Differentially Regulate Arrestin and Agonist Affinity*

Arrestins regulate the signaling and endocytosis of many G protein-coupled receptors (GPCRs). It has been suggested that the functions of arrestins are dependent upon both the number and pattern of phosphorylation sites present in an activated GPCR. However, little is currently known about the relationships between the sites of receptor phosphorylation, the resulting affinities of arrestin binding, and the ensuing mechanisms of receptor regulation for any given GPCR. To investigate these interactions, we used an active truncated mutant of arrestin (amino acids 1–382) and phosphorylation-deficient mutants of the N-formyl peptide receptor (FPR). In contrast to results with wild type arrestins, the truncated arrestin-2 protein bound to the unphosphorylated wild type FPR, although with lower affinity and a low affinity for the agonist as revealed by competition studies with heterotrimeric G proteins. Using FPR mutants, we further demonstrated that the phosphorylation status of serines and threonines between residues 328–332 is a key determinant that regulates the affinity of the FPR for arrestins. Furthermore, we found that the phosphorylation status of serine and threonine residues between amino acids 334 and 339 regulates the affinity of the receptor for agonist when arrestin is bound. These results suggest that the agonist affinity state of the receptor is principally regulated by phosphorylation at specific sites and is not simply a consequence of arrestin binding as has previously been proposed. Furthermore, this is the first demonstration that agonist affinity of a GPCR and the affinity of arrestin binding to the phosphorylated receptor are regulated by distinct receptor phosphodomains.