Miracle-dz/UniFAR-FTUs huggingface dataset:
Subpopulation behaviors in lactose metabolism by Streptococcus mutans

When Streptococcus mutans is transferred from a preferred carbohydrate (glucose or fructose) to lactose, initiation of growth can take several hours, and substantial amounts of glucose are released during growth. Here, S. mutans strains UA159 and GS‐5 were examined for stochastic behaviors in transcription of the lac operon. Using a gfp reporter fusion, we demonstrated that induction of the lac operon occurs in only a fraction of the population, with prior exposure to carbohydrate source and strain influencing the magniture of the sub‐population response. Lower glucokinase activity in GS‐5 was associated with release of substantially more glucose than UA159 and significantly lower lac expression. Mutants unable to use lactose grew on lactose as the sole carbohydrate when strains with an intact lac operon were also present in the cultures, indicative of the potential for population cheating. Utilizing a set of engineered obligate cheating and non‐cheating strains, we confirmed that cheating can sustain a heterogeneous population. Futher, obligate cheaters of GS‐5 competed well with the non‐cheaters and showed a high degree of competitive fitness in a human‐derived consortium biofilm model. The results show that bet‐hedging behaviors in carbohydrate metabolism may substantially influence the composition and pathogenic potential of oral biofilms.
Evaluation of molecular inversion probe versus TruSeq® custom methods for targeted next-generation sequencing

Resolving the genetic architecture of painful neuropathy will lead to better disease management strategies. We aimed to develop a reliable method to re-sequence multiple genes in a large cohort of painful neuropathy patients at low cost. In this study, we compared sensitivity, specificity, targeting efficiency, performance and cost effectiveness of Molecular Inversion Probes-Next generation sequencing (MIPs-NGS) and TruSeq® Custom Amplicon-Next generation sequencing (TSCA-NGS). Capture probes were designed to target nine sodium channel genes (SCN3A, SCN8A-SCN11A, and SCN1B-SCN4B). One hundred sixty-six patients with diabetic and idiopathic neuropathy were tested by both methods, 70 patients were validated by Sanger sequencing. Sensitivity, specificity and performance of both techniques were comparable, and in agreement with Sanger sequencing. The average targeted regions coverage for MIPs-NGS was 97.3% versus 93.9% for TSCA-NGS. MIPs-NGS has a more versatile assay design and is more flexible than TSCA-NGS. The cost of MIPs-NGS is >5 times cheaper than TSCA-NGS when 500 or more samples are tested. In conclusion, MIPs-NGS is a reliable, flexible, and relatively inexpensive method to detect genetic variations in a large cohort of patients. In our centers, MIPs-NGS is currently implemented as a routine diagnostic tool for screening of sodium channel genes in painful neuropathy patients.
Ataxin-1 regulates B cell function and the severity of autoimmune experimental encephalomyelitis

Significance Over 200 genomic loci have been found associated with the risk of developing multiple sclerosis (MS). Despite this important body of data, limited information exists on the cellular pathways and molecular mechanisms underlying MS genetic complexity. In this study, we report the functional characterization of the ataxin-1 encoding ATXN1 susceptibility locus. Ataxin-1 is a polyglutamine protein that is classically associated with the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1). Here, we show that ataxin-1 also exerts a protective activity against autoimmune demyelination in a preclinical model of MS. This function is associated with an immunomodulatory role mainly targeting the B cell compartment. Altogether, these findings expand our current knowledge on both MS pathogenesis and ataxin-1 biology. Ataxin-1 (ATXN1) is a ubiquitous polyglutamine protein expressed primarily in the nucleus where it binds chromatin and functions as a transcriptional repressor. Mutant forms of ataxin-1 containing expanded glutamine stretches cause the movement disorder spinocerebellar ataxia type 1 (SCA1) through a toxic gain-of-function mechanism in the cerebellum. Conversely, ATXN1 loss-of-function is implicated in cancer development and Alzheimer’s disease (AD) pathogenesis. ATXN1 was recently nominated as a susceptibility locus for multiple sclerosis (MS). Here, we show that Atxn1-null mice develop a more severe experimental autoimmune encephalomyelitis (EAE) course compared to wildtype mice. The aggravated phenotype is mediated by increased T helper type 1 (Th1) cell polarization, which in turn results from the dysregulation of B cell activity. Ataxin-1 ablation in B cells leads to aberrant expression of key costimulatory molecules involved in proinflammatory T cell differentiation, including cluster of differentiation (CD)44 and CD80. In addition, comprehensive phosphoflow cytometry and transcriptional profiling link the exaggerated proliferation of ataxin-1 deficient B cells to the activation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) pathways. Lastly, selective deletion of the physiological binding partner capicua (CIC) demonstrates the importance of ATXN1 native interactions for correct B cell functioning. Altogether, we report a immunomodulatory role for ataxin-1 and provide a functional description of the ATXN1 locus genetic association with MS risk.
Analysis of the airway registry from an academic emergency department in South Africa.

BACKGROUND Airway management is an essential skill for doctors working in the emergency department (ED). Safety and efficacy are crucial to its success. Analysis of an airway registry can provide feedback that can be used for quality improvement purposes. OBJECTIVES To examine the first airway registry from an ED in South Africa (SA), a low- to middle-income country (LMIC), and compare the findings with international data. METHODS A retrospective analysis of 13 months' data from the airway registry of an academic ED with an annual census of 60 000 patients. Data analysed included demographics, indications for intubation, intubator training level, type of intubation device, number of attempts, adverse events, pre-oxygenation methods, and drug and intravenous fluid use. RESULTS A total of 321 intubations were included. The majority of the patients (71.6%) had non-traumatic indications for intubation. The overall first-pass intubation success (FPS) rate for doctors was 81.8%. Although this rate is lower than the mean rate suggested in an international meta-analysis (84.1%), it is within the 95% confidence interval (80.1 - 87.4%). Overall FPS rates showed no difference between video laryngoscopy (81.7%) compared with direct laryngoscopy (73.3%) (p-value 0.079), although better glottic views were obtained with video laryngoscopy (80.5% were Cormack-Lehane grade 1). Analysis of pre-oxygenation methods found that although sicker patients had received more aggressive pre-oxygenation, e.g. with non-invasive or bag-mask ventilation techniques, they still desaturated more often (35.8% and 62.5%, respectively) than less sick patients who received simple non-rebreather facemask pre-oxygenation (4.5%). CONCLUSIONS This analysis of the first airway registry from an SA ED highlights that airway management in an LMIC can be performed on par with accepted international standards. It serves as a good baseline for further research into airway management in other LMICs and provides useful feedback for quality improvement purposes.
The central domain of cardiac ryanodine receptor governs channel activation, regulation, and stability

Structural analyses identified the central domain of ryanodine receptor (RyR) as a transducer converting conformational changes in the cytoplasmic platform to the RyR gate. The central domain is also a regulatory hub encompassing the Ca2+-, ATP-, and caffeine-binding sites. However, the role of the central domain in RyR activation and regulation has yet to be defined. Here, we mutated five residues that form the Ca2+ activation site and 10 residues with negatively charged or oxygen-containing side chains near the Ca2+ activation site. We also generated eight disease-associated mutations within the central domain of RyR2. We determined the effect of these mutations on Ca2+, ATP, and caffeine activation and Mg2+ inhibition of RyR2. Mutating the Ca2+ activation site markedly reduced the sensitivity of RyR2 to Ca2+ and caffeine activation. Unexpectedly, Ca2+ activation site mutation E3848A substantially enhanced the Ca2+-independent basal activity of RyR2, suggesting that E3848A may also affect the stability of the closed state of RyR2. Mutations in the Ca2+ activation site also abolished the effect of ATP/caffeine on the Ca2+-independent basal activity, suggesting that the Ca2+ activation site is also a critical determinant of ATP/caffeine action. Mutating residues with negatively charged or oxygen-containing side chains near the Ca2+ activation site significantly altered Ca2+ and caffeine activation and reduced Mg2+ inhibition. Furthermore, disease-associated RyR2 mutations within the central domain significantly enhanced Ca2+ and caffeine activation and reduced Mg2+ inhibition. Our data demonstrate that the central domain plays an important role in channel activation, channel regulation, and closed state stability.
Community stakeholder and opinion formation toward end-of-life planning in Chinese community in Australia

Abstract We examine the role of stakeholders in constructing new socio-cultural narratives of advance care planning in the Chinese community in Australia. Applying the communication theory of opinion leader(ship) and drawing on data from 41 interviews and field observation notes, we explore how stakeholders establish their authority and perform their expertise. Data analysis shows stakeholders have gained their opinion leadership status through demonstrating their ability to link the Chinese cultural values of family harmony and parental duty and the notions of self-empowerment and independence in official advance care planning promotions in Australia.
The Microbiome of Neotropical Water Striders and Its Potential Role in Codiversification

Simple Summary Insects host a highly diverse bacterial community. Although we have a good understanding of the role that this microbiome plays in insects, the composition and diversity of microbiomes associated with Neotropical freshwater insects is virtually unknown. Here, we describe, for the first time, the microbiome associated with six species of Neotropical water striders in Panama. We also performed phylogenetic analyses to explore potential codiversification or coevolution between water strider species and their associated microbiome. We found a diverse microbiome associated with the six species of water striders, with the dominant bacterial taxa belonging to the phyla Proteobacteria and Tenericutes. Although some bacterial lineages were shared across species, some lineages were also uniquely associated with different water strider species. Our results suggest that both environmental variation and host phylogenetic identity are important drivers of the microbiome associated with water striders. Understanding the evolution of the host-microbiome interaction is crucial to our understanding of Neotropical freshwater ecosystems. Abstract Insects host a highly diverse microbiome, which plays a crucial role in insect life. However, the composition and diversity of microbiomes associated with Neotropical freshwater insects is virtually unknown. In addition, the extent to which diversification of this microbiome is associated with host phylogenetic divergence remains to be determined. Here, we present the first comprehensive analysis of bacterial communities associated with six closely related species of Neotropical water striders in Panama. We used comparative phylogenetic analyses to assess associations between dominant bacterial linages and phylogenetic divergence among species of water striders. We found a total of 806 16S rRNA amplicon sequence variants (ASVs), with dominant bacterial taxa belonging to the phyla Proteobacteria (76.87%) and Tenericutes (19.51%). Members of the α- (e.g., Wolbachia) and γ- (e.g., Acinetobacter, Serratia) Proteobacteria, and Mollicutes (e.g., Spiroplasma) were predominantly shared across species, suggesting the presence of a core microbiome in water striders. However, some bacterial lineages (e.g., Fructobacillus, Fluviicola and Chryseobacterium) were uniquely associated with different water strider species, likely representing a distinctive feature of each species’ microbiome. These findings indicate that both host identity and environmental context are important drivers of microbiome diversity in water striders. In addition, they suggest that diversification of the microbiome is associated with diversification in water striders. Although more research is needed to establish the evolutionary consequences of host-microbiome interaction in water striders, our findings support recent work highlighting the role of bacterial community host-microbiome codiversification.
Non-surgical treatment before hip and knee arthroplasty remains underutilized with low satisfaction regarding performance of work, sports, and leisure activities

Background and purpose — Guidelines for managing hip and knee osteoarthritis (OA) advise extensive non-surgical treatment prior to surgery. We evaluated what percentage of hip and knee OA patients received non-surgical treatment prior to arthroplasty, and assessed patient satisfaction regarding alleviation of symptoms and performance of activities. Patients and methods — A multi-center cross-sectional study was performed in 2018 among 186 patients who were listed for hip or knee arthroplasty or had undergone surgery within the previous 6 months in the Netherlands. Questions concerned non-surgical treatments received according to the Stepped Care Strategy and were compared with utilization in 2013. Additionally, satisfaction with treatment effects for pain, swelling, stiffness, and activities of daily life, work, and sports/leisure was questioned. Results — The questionnaire was completed by 175 patients, age 66 years (range 38–84), 57% female, BMI 29 (IQR 25–33). Step 1 treatments, such as acetaminophen and lifestyle advice, were received by 79% and 60% of patients. Step 2 treatments, like exercise-based therapy and diet therapy, were received by 66% and 19%. Step 3—intra-articular injection—was received by 47%. Non-surgical treatment utilization was lower than in 2013. Nearly all treatments showed more satisfied patients regarding pain relief and fewer regarding activities of work/sports/leisure. Hip and knee OA patients were mostly satisfied with NSAIDs for all outcomes, while exercise-based therapy was rated second best. Interpretation — Despite international guideline recommendations, non-surgical treatment for hip and knee OA remains underutilized in the Netherlands. Of the patients referred for arthroplasty, more were satisfied with the effect of non-surgical treatment on pain than on work/sports/leisure participation.
Changes in MicroRNA Expression during Rabbit Hemorrhagic Disease Virus (RHDV) Infection

Current knowledge on the role of microRNAs (miRNAs) in rabbit hemorrhagic disease virus (RHDV) infection and the pathogenesis of rabbit hemorrhagic disease (RHD) is still limited. RHDV replicates in the liver, causing hepatic necrosis and liver failure. MiRNAs are a class of short RNA molecules, and their expression profiles vary over the course of diseases, both in the tissue environment and in the bloodstream. This paper evaluates the expression of miRNAs in the liver tissue (ocu-miR-122-5p, ocu-miR-155-5p, and ocu-miR-16b-5p) and serum (ocu-miR-122-5p) of rabbits experimentally infected with RHDV. The expression levels of ocu-miR-122-5p, ocu-miR-155-5p, and ocu-miR-16b-5p in liver tissue were determined using reverse transcription quantitative real-time PCR (RT-qPCR), and the expression level of circulating ocu-miR-122-5p was established using droplet digital PCR (ddPCR). The expression levels of ocu-miR-155-5p and ocu-miR-16b-5p were significantly higher in the infected rabbits compared to the healthy rabbits (a fold-change of 5.8 and 2.5, respectively). The expression of ocu-miR-122-5p was not significantly different in the liver tissue from the infected rabbits compared to the healthy rabbits (p = 0.990), while the absolute expression level of the circulating ocu-miR-122-5p was significantly higher in the infected rabbits than in the healthy rabbits (p < 0.0001). Furthermore, a functional analysis showed that ocu-miR-155-5p, ocu-miR-16b-5p, and ocu-miR-122-5p can regulate the expression of genes involved in processes correlated with acute liver failure (ALF) in rabbits. Search tool for the retrieval of interacting genes/proteins (STRING) analysis showed that the potential target genes of the three selected miRNAs may interact with each other in different pathways. The results indicate the roles of these miRNAs in RHDV infection and over the course of RHD and may reflect hepatic inflammation and impairment/dysfunction in RHD.
Drug interactions with apixaban: A systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports

Apixaban, a direct oral anticoagulant, has emerged over the past few years because it is considered to have a low risk of drug‐drug interactions compared to vitamin K antagonists. To better characterize these interactions, we systematically reviewed studies evaluating the drug‐drug interactions involving apixaban and analyzed the drug‐drug interactions resulting in an adverse drug reaction reported in case reports and VigiBase. We systematically searched Medline, Embase, and Google Scholar up to 20 August 2018 for articles that investigated the occurrence of an adverse drug reaction due to a potential drug interacting with apixaban. Data from VigiBase came from case reports retrieved up to the 2 January 2018, where identification of potential interactions is performed in terms of two drugs, one adverse drug reaction triplet and potential signal detection using Omega, a three‐way measure of disproportionality. We identified 15 studies and 10 case reports. Studies showed significant variations in the area under the curve for apixaban and case reports highlighted an increased risk of hemorrhage or thromboembolic events due to a drug‐drug interaction. From VigiBase, a total of 1617 two drugs and one adverse drug reaction triplet were analyzed. The most reported triplet were apixaban—aspirin—gastrointestinal hemorrhage. Sixty‐seven percent of the drug‐drug interactions reported in VigiBase were not described or understood. In the remaining 34%, the majority were pharmacodynamic drug‐drug interactions. These data suggest that apixaban has significant potential for drug‐drug interactions, either with CYP3A/P‐gp modulators or with drugs that may impair hemostasis. The most described adverse drug reactions were adverse drug reactions related to hemorrhage or thrombosis, mostly through pharmacodynamic interactions. Pharmacokinetic drug‐drug interactions seem to be poorly detected.
Impact of supervisory behavior on sustainable employee performance: Mediation of conflict management strategies using PLS-SEM

This study investigates the relationship between supervisory behavior, conflict management strategies, and sustainable employee performance and inquires the mediating effect of conflict management strategies. Data were collected from the SMEs of the manufacturing industry of Pakistan. The significance of the model was assessed using the PLS-SEM (structural equation modeling). The findings of the study revealed a positive and significant relationship between supervisory behavior and sustainable employee behavior. Similarly, conflict management strategies had a positive effect on the relationship between supervisory behavior and sustainable employee behavior. This study adds in the current literature of supervisory behavior as a critical predictor of sustainable employee performance in two ways. Firstly, this study validates Conflict management strategies as an influential mediator between the relationship of supervisory behavior and sustainable employee performance. Secondly, this study provides substantial practical implications for managers at SMEs to enhance sustainable employee performance through supervisory behavior, stimulated by conflict management strategies. This study is based on cross-sectional data; more longitudinal studies can further strengthen the generalizability of relationships between the constructs. The study adds in the current literature of PLS-SEM as an assessment model for direct and mediation relationships.
Inability to increase the neural drive to muscle is associated with task failure during submaximal contractions.

We investigated changes in motor unit (MU) behaviour and vasti-muscle contractile properties during sustained submaximal fatiguing contractions with a new time-domain tracking technique in order to understand the mechanisms responsible for task failure. Sixteen participants performed a non-fatiguing 15s isometric knee-extension at 50% of the maximum voluntary torque (MVC), followed by a 30% MVC sustained contraction until exhaustion. Two grids of 64 surface electromyography electrodes were placed over vastus medialis and lateralis. Signals were decomposed into MU discharge-times and the MUs from the 30% MVC sustained contraction were followed until task failure by overlapping decomposition intervals. These MUs were then tracked between 50% and 30% MVC. During the sustained fatiguing contraction, MUs of the two muscles decreased their discharge rate until ~40% of the endurance time, referred to as the reversal time, and then increased their discharge rate until task failure. This reversal in firing behaviour predicted total endurance time and was matched by opposite changes in twitch force (increase followed by a decrease). Despite the later increase in MU firing rates, peak discharge rates at task failure did not reach the frequency attained during a non-fatiguing 50% MVC contraction. These results show that changes in MU firing properties are influenced by adjustments in contractile properties during the course of the contraction, allowing the identification of two phases. Nevertheless, the contraction cannot be sustained possibly due to progressive motoneuron inhibition/decreased excitability, as the later increase in firing rate saturates at a much lower frequency compared to a higher-force non-fatiguing contraction.
Clinical and laboratory detection of nonpolio enteroviruses among different age groups of aseptic meningitis patients in Alexandria, Egypt

Viral meningitis is the most common type of meningitis. Worldwide, nonpolio enteroviruses (NPEVs) account for 23%–60% of all cases of viral meningitis. We aimed to detect NPEV among aseptic meningitis cases using reverse transcription‐polymerase chain reaction (RT‐PCR) and evaluate molecular testing versus clinical and laboratory parameters.