Miracle-dz/UniFAR-FTUs huggingface dataset:
Competitive Fitness of Essential Gene Knockdowns Reveals a Broad-Spectrum Antibacterial Inhibitor of the Cell Division Protein FtsZ

To streamline the elucidation of antibacterial compounds’ mechanism of action, comprehensive high-throughput assays interrogating multiple putative targets are necessary. However, current chemogenomic approaches for antibiotic target identification have not fully utilized the multiplexing potential of next-generation sequencing. ABSTRACT To streamline the elucidation of antibacterial compounds’ mechanism of action, comprehensive high-throughput assays interrogating multiple putative targets are necessary. However, current chemogenomic approaches for antibiotic target identification have not fully utilized the multiplexing potential of next-generation sequencing. Here, we used Illumina sequencing of transposon insertions to track the competitive fitness of a Burkholderia cenocepacia library containing essential gene knockdowns. Using this method, we characterized a novel benzothiadiazole derivative, 10126109 (C109), with antibacterial activity against B. cenocepacia, for which whole-genome sequencing of low-frequency spontaneous drug-resistant mutants had failed to identify the drug target. By combining the identification of hypersusceptible mutants and morphology screening, we show that C109 targets cell division. Furthermore, fluorescence microscopy of bacteria harboring green fluorescent protein (GFP) cell division protein fusions revealed that C109 prevents divisome formation by altering the localization of the essential cell division protein FtsZ. In agreement with this, C109 inhibited both the GTPase and polymerization activities of purified B. cenocepacia FtsZ. C109 displayed antibacterial activity against Gram-positive and Gram-negative cystic fibrosis pathogens, including Mycobacterium abscessus. C109 effectively cleared B. cenocepacia infection in the Caenorhabditis elegans model and exhibited additive interactions with clinically relevant antibiotics. Hence, C109 is an enticing candidate for further drug development.
Paradoxical Bronchoconstriction with Short-Acting Beta Agonist

Patient: Male, 25 Final Diagnosis: Paradoxical bronchospasm Symptoms: Dyspnea on exertion • shortness of breath Medication: Albuterol • levalbuterol Clinical Procedure: Pulmonary function testing Specialty: General and Internal Medicine Objective: Unusual clinical course Background: Asthma is a common disease in the U.S. population. Initial therapy in the stepwise approach for asthma management is short-acting β2-agonist (SABA) therapy as needed for symptom control. However, a significant adverse event that can occur with administration is bronchospasm. Here, we report a case of paradoxical bronchospasm with administration of SABAs during multiple pulmonary function tests (PFTs). Case Report: A 25-year-old, non-smoking, African American male with a history of moderate asthma and allergic rhinitis treated with fluticasone/salmeterol diskus, albuterol hydrofluoroalkane (HFA) inhaler, and montelukast presented to our clinic complaining of recurrent episodes of acute shortness of breath immediately following each administration of albuterol for 4 weeks. PFTs were performed with levalbuterol (Xopenex) and albuterol (ProAir), yielding significant decrease in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Nebulized albuterol and ipratropium bromide also improved FEV1 and FVC. He was successfully transitioned to an ipratropium rescue inhaler for asthma exacerbations. Conclusions: Paradoxical bronchoconstriction is the unexpected constriction of smooth muscle walls of the bronchi that occurs in the setting of an expected bronchodilatory response. This phenomenon has been observed with β2-agonist-containing inhaler formulations and is an under-recognized adverse event. Theories suggest that the formulation excipients can trigger airway hyperresponsiveness in patients with allergically inflamed airways. Removal of excipients or use of anticholinergic inhalers improved respiratory function. Clinicians should be aware of paradoxical bronchospasm as an adverse effect with common inhaler formulations containing β2-agonists and counsel patients accordingly in the appropriate clinical setting.
Multiple roles and diverse regulation of the Ras/cAMP/protein kinase A pathway in Candida albicans

Candida albicans is a major fungal pathogen of humans, causing both superficial and life‐threatening systemic infections in immunocompromised people. The conserved Ras/cAMP/PKA pathway plays a key role in regulating multiple traits important for the virulence of C. albicans such as cell growth, yeast‐hyphal transition, white‐opaque switching, sexual reproduction and biofilm development. Diverse external signals influence cell physiology by activating this signaling pathway. The key components of the Ras/cAMP/PKA pathway include two Ras GTPases (Ras1 and Ras2), an adenylyl cyclase (Cyr1, also known as Cdc35), two cyclic nucleotide phosphodiesterases (Pde1 and Pde2) and the catalytic (Tpk1 and Tpk2) and regulatory (Bcy1) subunits of PKA kinase. Activation of this pathway dramatically alters the gene expression profile via several transcription factors, leading to the activation of specific biological processes. Here, we review the progress made in the past two decades to elucidate the molecular mechanisms by which the Ras/cAMP/PKA pathway senses diverse environmental cues and controls specific cellular responses and its connection with other signaling pathways in C. albicans.
Very early onset IBD: novel genetic aetiologies

Purpose of review To summarize the current understanding and recent advances on the genetic aetiology in the pathogenesis of very early onset inflammatory bowel disease (VEO-IBD). Recent findings IBD is a chronic disorder of the gastrointestinal tract whose manifestation is a result of complex interactions between genetics, environment, immune system and microbial flora. Over 230 IBD risk loci have been reported in genome wide association studies but the genetic contribution of the majority of these loci in the manifestation of IBD is very low. Patients with VEO-IBD present with a more severe disease than older patients, characterized by poor prognosis and failure of conventional therapy. Recent studies have reported several monogenic diseases with high penetrance that present with IBD and IBD-like intestinal manifestations and overlap with primary immunodeficiencies. Increasing body of evidence supports a prominent role of genetics in the onset of VEO-IBD. New genetic variants and diagnoses in VEO-IBD are reviewed and current challenges in therapy with potential strategy to manage the disease are discussed. Summary Functional analysis of the genes implicated in monogenic IBD has increased the understanding of the underlying pathobiological mechanism of the disease. This knowledge can be used to personalize medicine for specific patients, improving the standard of care and quality of life.
Dance interventions for people with dementia: systematic review and practice recommendations

ABSTRACT Objectives: Dance interventions are pleasant social activities that are often offered to people with dementia in care settings. Effectiveness of dance as a psychosocial intervention for people with dementia has been studied to some extent, but several methodological issues remain unexplored. This review aimed to analyze studies on dance interventions for people with dementia and to identify practice recommendations for the development of these interventions. Methods: An electronic database search was run in December 2017 to identify records of dance interventions for people with dementia. We included all studies regardless of experimental design. Selected records were analyzed according to five criteria: study design and intentions of interventions; profile of participants and in/exclusion criteria; treatment indications and contraindications; description and performance of the interventions; and involved physical, cognitive, psychological, and social processes in dance. Results: Fourteen records were included in which various study designs were observed. Description and performance of the interventions were well documented. Nine practice recommendations for implementing dance interventions were identified according to primary intentions of the intervention (therapeutic or recreational): indications; contra-indications; participant profile; dosage; session sequencing; setting of intervention; observance/attendance; contributors and facilitators;and assessments. Conclusions: Dance is a holistic intervention that can be implemented with a therapeutic or a leisure intention. Practice recommendations about dance interventions remain incomplete and insufficiently studied. Such recommendations could be helpful for clinicians to implement dance interventions in facilities where they work to better target people who could benefit from them, and for researchers to develop research in this field.
Practical advice for selecting or determining trophic magnification factors for application under the European Union Water Framework Directive

European Union Directive 2013/39/EU, which amended and updated the Water Framework Directive (WFD; 2000/60/EC) and its daughter directive (2008/105/EC), sets Environmental Quality Standards for biota (EQSbiota) for a number of bioaccumulative chemicals. These chemicals pose a threat to both aquatic wildlife and human health via the consumption of contaminated prey or the intake of contaminated food originating from the aquatic environment. EU member states will need to establish programs to monitor the concentration of 11 priority substances in biota and assess compliance against these new standards for the classification of surface water bodies. An EU‐wide guidance effectively addresses the implementation of EQSbiota. Flexibility is allowed in the choice of target species used for monitoring to account for both diversity of habitats and aquatic community composition across Europe. According to that guidance, the consistency and comparability of monitoring data across member states should be enhanced by adjusting the data on biota contaminant concentrations to a standard trophic level by use of the appropriate trophic magnification factor (TMF), a metric of contaminant biomagnification through the food web. In this context, the selection of a TMF value for a given substance is a critical issue, because this field‐derived measure of trophic magnification can show variability related to the characteristics of ecosystems, the biology and ecology of organisms, the experimental design, and the statistical methods used for TMF calculation. This paper provides general practical advice and guidance for the selection or determination of TMFs for reliable application within the context of the WFD (i.e., adjustment of monitoring data and EQS derivation). Based on a series of quality attributes for TMFs, a decision tree is presented to help end users select a reasonable and relevant TMF. Integr Environ Assess Manag 2019;15:266–277. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)
Effectiveness of a multistate quality improvement campaign in reducing risk of surgical site infections following hip and knee arthroplasty

Background Quality improvement (QI) campaigns appear to increase use of evidence-based practices, but their effect on health outcomes is less well studied. Objective To assess the effect of a multistate QI campaign (Project JOINTS, Joining Organizations IN Tackling SSIs) that used the Institute for Healthcare Improvement’s Rapid Spread Network to promote adoption of evidence-based surgical site infection (SSI) prevention practices. Methods We analysed rates of SSI among Medicare beneficiaries undergoing hip and knee arthroplasty during preintervention (May 2010 to April 2011) and postintervention (November 2011 to September 2013) periods in five states included in a multistate trial of the Project JOINTS campaign and five matched comparison states. We used generalised linear mixed effects models and a difference-in-differences approach to estimate changes in SSI outcomes. Results 125 070 patients underwent hip arthroplasty in 405 hospitals in intervention states, compared with 131 787 in 525 hospitals in comparison states. 170 663 patients underwent knee arthroplasty in 397 hospitals in intervention states, compared with 196 064 in 518 hospitals in comparison states. After the campaign, patients in intervention states had a 15% lower odds of developing hip arthroplasty SSIs (OR=0.85, 95% CI 0.75 to 0.96, p=0.01) and a 12% lower odds of knee arthroplasty SSIs than patients in comparison states (OR=0.88, 95% CI 0.78 to 0.99, p=0.04). Conclusions A larger reduction of SSI rates following hip and knee arthroplasty was shown in intervention states than in matched control states.
Reshaping of Bilateral Gait Coordination in Hemiparetic Stroke Patients After Early Robotic Intervention

Hemiparetic gait is a common condition after stroke which alters importantly the quality of life of stroke survivors. In recent years, several robotic interventions have been developed to support and enhance rehabilitation strategies for such population. The Hybrid Assistive Limb® (HAL) robot suit is a unique device able to collect in real time bioelectric signals from the patient to support and enhance voluntary gait. HAL has been used before in early stages of stroke showing gait improvement after the intervention. However, evaluation of the coordination of gait has not been done yet. Coordination is a key factor for an adequate gait performance; consequently, its changes may be closely related to gait recovery. In this study, we used planar covariation to evaluate coordination changes in hemiparetic stroke patients after early HAL intervention. Before starting, impaired intersegmental coordination for the paretic and non-paretic side was evident. HAL intervention was able to induce recovery of the covariation loop shape and deviation from the covariation plane improving intersegmental coordination. Also, there was a tendency of recovery for movement range evidenced by comparison of peak elevation angles of each limb segment of the patients before and after HAL intervention, and also when compared to healthy volunteers. Our results suggest that early HAL intervention contributed to the improvement of gait coordination in hemiparetic stroke patients by reinforcing central pattern generators and therefore reshaping their gait pattern. Trial registration: UMIN000022410 2016/05/23.
PHYTOCHROME INTERACTING FACTOR1 interactions leading to the completion or prolongation of seed germination

ABSTRACT In Arabidopsis thaliana, the basic Helix Loop Helix transcription factor, PHYTOCHROME INTERACTING FACTOR1 (PIF1) is known to orchestrate the seed transcriptome such that, ultimately, proteins repressing the completion of germination are produced in darkness. While PIF1-mediated control of abscisic acid (ABA) and gibberellic acid (GA) anabolism/catabolism is indirect, PIF1 action favors ABA while discriminating against GA, firmly establishing ABA’s repressive influence on the completion of germination. The result is tissue that is more sensitive to and producing more ABA; and is less responsive to and deficient in GA. Illumination of the appropriate wavelength activates phytochrome which enters the nucleus, and binds to PIF1, initiating PIF1’s phosphorylation by diverse kinases, subsequent polyubiquitination, and hydrolysis. One mechanism by which phosphorylated PIF1 is eliminated from the cells of the seed upon illumination involves an F-BOX protein, COLD TEMPERATURE GERMINATING10 (CTG10). Discovered in an unbiased screen of activation tagged lines hastening the completion of seed germination at 10°C, one indirect consequence of CTG10 action in reducing PIF1 titer, should be to enhance the transcription of genes whose products work to increase bioactive GA titer, shifting the intracellular milieu from one that is repressive to, toward one conducive to, the completion of seed germination. We have tested this hypothesis using a variety of Arabidopsis lines altered in CTG10 amounts. Here we demonstrate using bimolecular fluorescence complementation that PIF1 interacts with CTG10 and show that, in light exposed seeds, PIF1 is more persistent in ctg10 relative to WT seeds while it is less stable in seeds over-expressing CTG10. These results are congruent with the relative transcript abundance from three genes whose products are involved in bioactive GA accumulation. We put forth a model of how PIF1 interactions in imbibed seeds change during germination and how a permissive light signal influences these changes, leading to the completion of germination of these positively photoblastic propagules.
Royal jelly does not prevent bone loss but improves bone strength in ovariectomized rats

Abstract Objective: Royal jelly (RJ) has been used for medical and nutritional purposes, and previous studies have indicated that it may have estrogenic activity. The present study investigated the effects of RJ on bone metabolism in ovariectomized (OVX) rats. Methods: Rats (12 weeks old) were randomly divided into four groups, namely Baseline, Sham, OVX, and OVX + RJ groups. Rats in the Baseline group were killed immediately, whereas rats in the OVX and OVX + RJ groups underwent bilateral ovariectomy and those in the Sham group underwent sham operation. RJ was administered to rats in the OVX + RJ group daily for 12 weeks. At the end of the 12-week period, bone mass, bone histomorphometry, and bone mechanics were analyzed. Results: Femur bone mineral density (BMD) was significantly lower in the OVX group than in the Sham group, and this decrease in BMD was not ameliorated by RJ administration. However, femur stiffness, as evaluated by a three-point bending test, was significantly higher in the OVX + RJ group than in the OVX group. Conclusion: The findings of the present study suggest that RJ does not prevent bone loss, but does improve bone strength in OVX rats.
The Inhibitory Effects of Cyclodepsipeptides from the Entomopathogenic Fungus Beauveria bassiana on Myofibroblast Differentiation in A549 Alveolar Epithelial Cells

Pulmonary fibrosis (PF) is a chronic and fatal lung disease with few treatment options. Although the pathogenesis of PF is not clear, a chronic inflammatory response to continuous damage is considered the cause of pulmonary fibrosis. PF is characterized by excessive accumulation of extracellular matrix (ECM), therefore, inhibition of myofibroblast differentiation is a good therapeutic target for PF. As part of our continuing endeavor to explore biologically active metabolites from insect-associated microbes, we found that the MeOH extract of the culture broth from the entomopathogenic fungus Beauveria bassiana inhibited collagen induction and E-cadherin down-regulation. In order to identify active compounds, we carried out chemical analysis of the MeOH extract with the assistance of LC/MS-guided isolation approach, which led to the successful identification of four cyclodepsipeptides 1–4. Among the isolates, compound 2 showed inhibitory effects on myofibroblast differentiation induced by TGF-β1. Compound 2 inhibited induction of α-SMA and N-cadherin, which are myofibroblast markers, and blocked the accumulation of ECM proteins such as collagen and fibronectin. Overall these findings demonstrate that compound 2 can be used to attenuate pulmonary fibrosis by targeting myo- fibroblast differentiation.
Molecular Phylogeny of the Family Capitellidae (Annelida)

Capitellids have emerged as monophyletic in most but not all recent molecular phylogenies, indicating that more extensive taxon sampling is necessary. In addition, monophyly of most or all capitellid genera was questionable, as some diagnostic characters vary ontogenetically within individuals. We tested the monophyly of Capitellidae and eight capitellid genera using phylogenetic analyses of combined 18S, 28S, H3, and COI gene sequences from 36 putative capitellid species. In our trees, Capitellidae formed a monophyletic sister group to Echiura, and Capitella was also monophyletic, separated by a long branch from other capitellids. Well-supported clades each containing representatives of different genera, or containing a subset of species within a genus, indicated that Barantolla, Heteromastus, and Notomastus are likely not monophyletic. We mapped three morphological characters traditionally used to define capitellid genera (head width relative to width of first segment, number of thoracic segments, and number of segments with capillary chaetae) onto our tree. While Capitella showed unique character states, states in the other genera were decidedly not phylogenetically informative. Morphology-based capitellid taxonomy will require a fine-scale reevaluation of character states and detection of new characters.
Prescribing Hemodialysis or Hemodiafiltration: When One Size Does Not Fit All the Proposal of a Personalized Approach Based on Comorbidity and Nutritional Status

There is no simple way to prescribe hemodialysis. Changes in the dialysis population, improvements in dialysis techniques, and different attitudes towards the initiation of dialysis have influenced treatment goals and, consequently, dialysis prescription. However, in clinical practice prescription of dialysis still often follows a “one size fits all” rule, and there is no agreed distinction between treatment goals for the younger, lower-risk population, and for older, high comorbidity patients. In the younger dialysis population, efficiency is our main goal, as assessed by the demonstrated close relationship between depuration (tested by kinetic adequacy) and survival. In the ageing dialysis population, tolerance is probably a better objective: “good dialysis” should allow the patient to attain a stable metabolic balance with minimal dialysis-related morbidity. We would like therefore to open the discussion on a personalized approach to dialysis prescription, focused on efficiency in younger patients and on tolerance in older ones, based on life expectancy, comorbidity, residual kidney function, and nutritional status, with particular attention placed on elderly, high-comorbidity populations, such as the ones presently treated in most European centers. Prescription of dialysis includes reaching decisions on the following elements: dialysis modality (hemodialysis (HD) or hemodiafiltration (HDF)); type of membrane (permeability, surface); and the frequency and duration of sessions. Blood and dialysate flow, anticoagulation, and reinfusion (in HDF) are also briefly discussed. The approach described in this concept paper was developed considering the following items: nutritional markers and integrated scores (albumin, pre-albumin, cholesterol; body size, Body Mass Index (BMI), Malnutrition Inflammation Score (MIS), and Subjective Global Assessment (SGA)); life expectancy (age, comorbidity (Charlson Index), and dialysis vintage); kinetic goals (Kt/V, normalized protein catabolic rate (n-PCR), calcium phosphate, parathyroid hormone (PTH), beta-2 microglobulin); technical aspects including vascular access (fistula versus catheter, degree of functionality); residual kidney function and weight gain; and dialysis tolerance (intradialytic hypotension, post-dialysis fatigue, and subjective evaluation of the effect of dialysis on quality of life). In the era of personalized medicine, we hope the approach described in this concept paper, which requires validation but has the merit of providing innovation, may be a first step towards raising attention on this issue and will be of help in guiding dialysis choices that exploit the extraordinary potential of the present dialysis “menu”.