Miracle-dz/UniFAR-FTUs huggingface dataset:
Discriminating changes in protein structure using PTAD conjugation to tyrosine

Chemical modification of proteins has been crucial in engineering protein-based therapies, targeted biopharmaceutics, molecular probes, and biomaterials. Here, we explore the use of a conjugation-based approach to sense alternative conformational states in proteins. Tyrosine has both hydrophobic and hydrophilic qualities, thus allowing it to be positioned at protein surfaces, or binding interfaces, or to be buried within a protein. Tyrosine can be conjugated with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD). We hypothesized that individual protein conformations could be distinguished by labeling tyrosine residues in the protein with PTAD. We conjugated tyrosine residues in a well-folded protein, bovine serum albumin (BSA), and quantified labeled tyrosine with LC-MS/MS. We applied this approach to alternative conformations of BSA produced in the presence of urea. The amount of PTAD labeling was found to relate to the depth of each tyrosine relative to the protein surface. This study demonstrates a new use of tyrosine conjugation using PTAD as an analytic tool able to distinguish the conformational states of a protein.
Incidence of Surgical Site Infections in Second Intention Healing After Dermatologic Surgery.

BACKGROUND There are few studies analyzing the surgical site infection (SSI) rate of second intention wounds after dermatologic surgery, and the results are inconclusive. Yet, the current dogma in dermatologic surgery is that wounds healed by second intention have lower infection rates. OBJECTIVE To determine the rate of SSI and associated pathogenic organisms of second intention wounds compared with sutured wounds after skin cancer extirpation. MATERIALS AND METHODS This was a retrospective cohort study of patients who had either Mohs micrographic surgery or wide local excision (WLE) for skin cancer extirpation between 2012 and 2016. Wounds were stratified by closure type, location, and associated organisms. Infection was diagnosed by a positive wound culture. RESULTS The overall infection rate was 3.9%. The infection rate for sutured and second intention wounds was 3.2% and 6.8%, respectively. Second intention wounds were associated with a significantly higher risk of infection compared with sutured wounds (odds ratio = 2.22, 95% confidence interval 1.63-2.99). The lower extremity (LE) had the highest overall infection rate (10.5%). The face had the lowest overall infection rate (2.5%). CONCLUSION Mohs micrographic surgery or WLE performed on the LE or lesions allowed to heal by second intention has an increased risk of SSI.
TRPV4: A Physio and Pathophysiologically Significant Ion Channel

Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences. Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.
Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: Expert opinion from a European consensus panel

The large number of pharmacological agents available to treat type 2 diabetes (T2D) makes choosing the optimal drug for any given patient a complex task. Because newer agents offer several advantages, whether and when sulphonylureas (SUs) should still be used to treat T2D is controversial. Published treatment guidelines and recommendations should govern the general approach to diabetes management. However, expert opinions can aid in better understanding local practices and in formulating individual choices. The current consensus paper aims to provide additional guidance on the use of SUs in T2D. We summarize current local treatment guidelines in European countries, showing that SUs are still widely proposed as second‐line treatment after metformin and are often ranked at the same level as newer glucose‐lowering medications. Strong evidence now shows that sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are associated with low hypoglycaemia risk, promote weight loss, and exert a positive impact on vascular, cardiac and renal endpoints. Thus, using SUs in place of SGLT‐2is and GLP‐1RAs may deprive patients of key advantages and potentially important cardiorenal benefits. In subjects with ascertained cardiovascular disease or at very high cardiovascular risk, SGLT‐2is and/or GLP‐1RAs should be used as part of diabetes management, in the absence of contraindications. Routine utilization of SUs as second‐line agents continues to be acceptable in resource‐constrained settings.
Preoperative Japanese Society for the Surgery of the Foot Lesser toe score and erythrocyte sedimentation rate influence wound healing following rheumatoid forefoot surgery

Abstract Objectives Delayed wound healing is one of the most common complications following forefoot surgery in patients with rheumatoid arthritis. We aimed to identify the risk factors for delayed wound healing following rheumatoid forefoot surgery. Methods Consecutive patients who underwent primary rheumatoid forefoot surgery (86 feet; 53 patients) between April 2008 and February 2019 were retrospectively evaluated. Clinical data, including smoking history, duration of the disease, presence of diabetes mellitus, medication, white blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein, the surgical procedure performed, and the Japanese Society for Surgery of the Foot (JSSF) scores, were collected. Results Delayed wound healing was identified in 20 of 86 (23.3%) feet. In univariate analysis, participants showing delayed healing were older at the time of surgery (p = .04), their ESR was higher (p = .0006), and their total (p = .019) and pain (p = .016) scores on the JSSF Lesser toe scale were lower than those showing normal healing. In multivariable analysis, both the total preoperative JSSF Lesser toe scale score (p = .0239) and ESR (p = .0126) remained significant risk factors for delayed wound healing. Conclusions After rheumatoid forefoot surgery, surgeons should pay more attention to wound care in patients with lower preoperative JSSF Lesser toe score and high ESR.
Clinical effect of computed guided pudendal nerve block for patients with premature ejaculation: a pilot study

Abstract Background: Premature ejaculation has a complex etiology, and its pathophysiology is still unclear, with penile hypersensitivity being the most accepted hypothesis. The aim was to investigate the efficacy and safety of a computed tomography-guided pudendal nerve block at the level of the sacrospinous ligament and the Alcock’s canal in patients with premature ejaculation refractory to conventional pharmacological treatment. Methods: This is a prospective pilot study involving five patients suffering from premature ejaculation refractory to standard treatment and clinical features of pudendal nerve entrapment. A CT-guided infiltration of ropivacaine and methylprednisone was done at the levels of sacrospinous ligament and Alcock’s canal. Intra-vaginal ejaculatory latency time (IELT) was recorded several times for each patient before and after infiltration. International Index of Erectile Function (IIEF-5), Premature Ejaculation Diagnostic Tool (PEDT) and Sexual Quality of Life–Male version (SQoL-M) questionnaire were also evaluated before and after infiltration. Results: Overall IELT differed significantly before and after treatment (21.94 vs 215.42 s; p = 0.039). IIEF-5, PEDT and SQoL-M also differed significantly before and after treatment. No complications for the CT-guided infiltration were recorded. Conclusion: CT-guided pudendal nerve block at the sacrospinous ligament and the Alcock’s canal was effective in improving premature ejaculation. Therefore, pudendal nerve entrapment may be a curable cause of sensory premature ejaculation.
Prevalence estimates of mental health problems in children and adolescents with intellectual disability: A systematic review and meta-analysis

Background: Children and adolescents with intellectual disability are at risk of developing psychiatric symptoms and disorders; yet, the estimates reported in the literature have been inconsistent, presenting a potential barrier for service planning and delivery. Sources of variability could arise from differences in measurement instruments as well as subgroup membership by severity of intellectual disability, gender and age. This systematic review aimed to address these gaps. Method: MEDLINE and PsycINFO databases were searched from inception to 2018 and selected studies were reviewed. Studies were included if they reported point prevalence estimates of mental health symptomology or diagnoses in a general population of 6- to 21-year-old individuals with intellectual disability. The Joanna Briggs Institute Prevalence Critical Appraisal Checklist was applied to eligible papers to appraise their scientific strength. Pooled prevalence for mental health symptomology was determined using a random-effects meta-analysis. Results: A total of 19 studies were included, including 6151 children and adolescents. The pooled prevalence estimate captured by the Developmental Behaviour Checklist was 38% (95% confidence interval = [31, 46]), contrasting with 49% (95% confidence interval = [46, 51]) captured by the Child Behaviour Checklist; both rates were higher than a non-intellectual disability population. Severity of intellectual disability did not significantly influence the Developmental Behaviour Checklist risks. Insufficient data were available to conduct statistical analyses on the effects of age, gender and socioeconomic status. Of diagnosed psychiatric disorders, attention deficit/hyperactivity disorder (30%), conduct disorder (3–21%) and anxiety disorders (7–34%) were the most prevalent conditions. Conclusion: This review consists of the largest sample hitherto evaluated. In the intellectual disability population, mental health comorbidities could be better detected by a symptom phenotype than a psychiatric diagnostic phenotype. Crucially, future research needs to address the effect of measurement validity in the intellectual disability population. Estimated prevalence rates were high compared to the general population, indicating the importance of systematic screening, case detection and appropriate management.
Safety and Tolerability of Subcutaneous Methotrexate in Routine Clinical Practice

To show the safety and efficacy of subcutaneous (SC) methotrexate (MTX) compared to oral MTX, alternative disease‐modifying antirheumatic drugs (DMARDs) monotherapy, biologic monotherapy, and combinations (conventional and biologic combination groups) in routine clinical practice.
Smoking Pattern in Men and Women: A Possible Contributor to Sex Differences in Smoke-related Lung Diseases

hoc test probability of 7.6% [0.076/(11 0.076)]) (8). We designed the classifier to assess organ quality for donor pool expansion strategies, to identify organs for possible rehabilitation on ex vivo lung perfusion, and to identify potential targets for directed therapies in clinical trials. The validation of the pathways identified in this transcript panel highlights the importance of the innate immune system in the development of PGD and identifies its constituent genes as potential therapeutic targets. This work builds on previous work identifying associated pathways and developing clinical predictors important in PGD to assess risk prior to procurement to facilitate decision making for potential therapeutics and advanced surgical therapies (3, 4, 7). Although these results are promising, there are limitations to consider. The cohort sample size was small, therefore reducing overall power. Nonetheless, this study represents a temporal validation in tissue of prior findings in blood and BAL using a conventional machine learning approach. Tissue biopsy is an invasive procedure with associated risks. We validated our classifier in tissue to ensure that all lung compartments were sampled (endothelial, epithelial, and lymphoid), and we acknowledge that further refinement will be necessary to scale to clinical practice. Additionally, translating gene expression prediction to the bedside will require development of point-of-care technologies using abbreviated gene sets, such as those using microfluidics (9). As this study cohort did not overlap with our prior cohorts, we were unable to assess interactions between blood, BAL, and tissue compartments. Although this work is supported by several other studies that show association (3, 4, 10), additional validation will be necessary to confirm discriminant and diagnostic validity and generalizability. In summary, we have demonstrated that transcript analysis of donor lung tissue, using an innate immunity pathway classifier, can be used in conjunction with clinical variables to predict PGD with excellent discrimination and precision. With the ability to identify organ risk, this panel has the potential to alter future PGD clinical trial designs and lead to the development of precision medical approaches. As PGD drives morbidity and mortality associated with lung transplant, further research in this area has the potential to improve outcomes following transplantation. n
Prevalence and characteristics of carbapenemase-producing Enterobacteriaceae in three tertiary-care Korean university hospitals between 2017 and 2018.

The aim of this study was to evaluate the prevalence and characteristics of carbapenemase-producing Enterobacteriaceae (CPE) from three tertiary-care Korean university hospitals between 2017 and 2018. Non-duplicated clinical isolates of Enterobacteriaceae revealing resistance to any carbapenem agents were collected prospectively from three tertiary university hospitals between 2017 and 2018. The presence of carbapenemase genes was detected by multiplex PCR and sequencing for blaKPC, blaVIM, blaNDM, blaIMP, blaOXA, and blaGES. Among the 690 carbapenem-resistant Enterobacteriaceae (CRE) isolates, 66.8% (N=461) were CPE. The species distribution of CPE was as follows: K. pneumoniae was most common (75.9%), followed by E. coli (15.0%), C. freundii (4.6%), E. cloacae (2.6%), K. aerogenes (0.7%), and K. oxytoca (0.4%). All 11 CPE genes were detected, particularly KPC-2 (87.6%), NDM-1 (7.4%), NDM-5 (1.7%), KPC-3 (1.3%), OXA-232 (1.1%), and OXA-181 (1.1%). Six isolates produced two or three carbapenemases. Most of the carbapenemase-producing C. freundii were positive for NDM-1. We confirmed a high proportion of CPE among CRE with a high prevalence of KCP-2-producing K. pneumoniae and E. coli. We need to institute continuous surveillance to monitor the prevalence of CPE.
Clinical features of LRP4/agrin‐antibody–positive myasthenia gravis: A multicenter study

Abstract Introduction Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin‐antibody–positive double‐seronegative myasthenia gravis (DNMG). Methods DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results Of 181 DNMG patients, 27 (14.9%) were positive for either low‐density lipoprotein receptor–related protein 4 (LRP4) or agrin antibodies. Twenty‐three DNMG patients (12.7%) were positive for both antibodies. More antibody‐positive patients presented with generalized symptoms (69%) compared with antibody‐negative patients (43%) (P ≤ .02). Antibody‐positive patients’ maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody‐negative patients (P ≤ .005). Seventy percent of antibody‐positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody‐negative patients. Most LRP4‐ and agrin‐antibody–positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow‐up of 11 years. Discussion Antibody‐positive patients had more severe clinical disease than antibody‐negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.
Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal

Significance While Yap/Tead signaling is well known to influence tissue growth and organ size during development, the molecular outputs of the pathway are tissue- and context-dependent and remain poorly understood. Our work expands the mechanistic understanding of how Yap/Tead signaling controls the precise number of progenitor cells that will be laid down within the developing inner ear to ultimately regulate the final size and function of the sensory organs. We also provide evidence that restoration of hearing and vestibular function may be amenable to YAP-mediated regeneration. Our data show that reactivation of Yap/Tead signaling after hair cell loss induces a proliferative response in vivo—a process thought to be permanently repressed in the mammalian inner ear. Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium—the organ of Corti—progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.
The acute lethal toxicity of mixtures of cyanide and ammonia to smolts of salmon, Salmo salar L. at low concentrations of dissolved oxygen

The survival of Atlantic salmon smolts on exposure to constant concentrations of cyanide and ammonia, singly and together, has been measured under laboratory conditions at a concentration of 5 mgl-1 of carbon dioxide. The 24-h LC50 values of cyanide and of un-ionised ammonia, in fresh water, were 0·073 mg HCN l-1 and 0·20 mg NH3l-1 respectively at a concentration of dissolved oxygen of 10 mg l-1, and 0·024 mg HCN l-1 and 0·08 mgNH3l-1 respectively at a concentration of dissolved oxygen of 3·5 mg l-1. In 30% sea water the corresponding values were similar for cyanide but markedly higher for ammonioa. In 80% sea water the values were intermediate between those of fresh water and 30% sea water. Prior acclimation of the fish to the respective toxicant increased the resistance of the fish only slightly to cyanide, but with ammonia the 24-h LC50 was increased between 1·4 and 2-fold after acclimation for 1–3 days to between 0·2 and 0·5 of the 24-h LC50 value. Mixtures of cyanide and ammonia were between 0·6 and 1·25 times as toxic as expected, assuming simple additivity of toxicity.
Characterization of native Escherichia coli populations from bovine vagina of healthy heifers and cows with postpartum uterine disease

Even though Escherichia coli are common bacteria of the bovine vaginal microbiota, they represent an important pathogen that causes diseases in the reproductive tract and subfertility. However, the actual endometrial virulence profile of E. coli is poorly understood. The present study aims to characterize the phylogenetic structure and virulence potential of native vaginal populations of E. coli from healthy heifers (H), and cows with postpartum uterine diseases (PUD), such as metritis/endometritis (MT) or repeat breeder cows (RB). To this end, the virulence repertoire of 97 E. coli isolates was genotypically and phenotypically assessed. Most of them were assigned to phylogenetic group A (74%), followed by B1 (17%) and D (9%); RB strains were significantly (p < 0.05) more represented by B1. Seven of the 15 evaluated virulence genes (VFG) were detected and the most prevalent were fimH (87%), agn43 (41%) and csgA (35%); while traT (27%), fyuA (11%), hlyA (5%) and kpsMT II (5%) were observed in a lower proportion. Particularly, fyuA was significantly higher (p < 0.05) in MT cows whereas csgA showed the same behavior in PUD animals (p < 0.05). When comparing H and PUD strains, these last ones were associated to positive expression of biofilm, fimbriae curli/cellulose and motility; yet RB strains did not show motility. Vaginal B1 E. coli populations, that possess VFG (fyuA and csgA) as well as the expression of motility, curli fimbriae/cellulose and biofilm, may represent risk factors for endometrial disorders; specifically, those that also, have kpsMT II may have a pathogenic potential for causing the RB syndrome. Future research focusing on the detection of these strains in the vaginal microbiota of cows with postpartum uterine diseases should be done since the control of their presence in vagina could reduce the risk that they access the uterus during the postpartum period.
Observations on the seasonal occurrence of marine endophytic and parasitic fungi

Information is presented on three fungal–algal associations on intertidal marine algae. They comprise two members of the Ascomycotina, Lautitia danica parasitic on Chondrus crispus, and Mycosphaerella ascophylli, an obligate endophyte of Ascophyllum nodosum, and a member of the Basidiomycotina, Mycaureola dilseae, that is parasitic on Dilsea carnosa. Details are given of life cycles and seasonal periodicity. The reproductive cycles of Mycosphaerella ascophylli and Ascophyllum nodosum are synchronised, with the fungal sporocarps being confined to the algal receptacles. Lautitia danica occurs on cystocarpic Chondrus crispus throughout the year, with older fronds being more likely to have fungal sporocarps on them. Mycaureola dilseae infecting Dilsea carnosa was only found during September and October. The systemic nature of the association between Mycosphaerella ascophylli and Ascophyllum nodosum is compared with the apparently localized occurrence of Lautitia danica and Mycaureola dilseae. Key words: marin.