Miracle-dz/UniFAR-FTUs huggingface dataset:
Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence

Abstract Spinocerebellar ataxia type 2 is a polyglutamine (polyQ) disease associated with an expanded polyQ domain within the protein product of the ATXN2 gene. Interestingly, polyQ repeat expansions in ATXN2 are also associated with amyotrophic lateral sclerosis (ALS) and parkinsonism depending upon the length of the polyQ repeat expansion. The sequence encoding the polyQ repeat also varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in ALS and parkinsonism is typically interrupted with the glutamine encoding CAA codon. Here, we asked if the purity of the CAG sequence encoding the polyQ repeat in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila. We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only repeat failed to confer toxicity, despite expression of the protein at similar levels. Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remained diffuse. The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation factor eIF4H, a known modifier of the toxic GGGGCC repeat in flies. These data indicate that ataxin-2 encoded by a pure CAG versus interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease.
Impaired Behavioral Pattern Separation in Refractory Temporal Lobe Epilepsy and Mild Cognitive Impairment

ABSTRACT Objective: Episodic memory impairment and hippocampal pathology are hallmark features of both temporal lobe epilepsy (TLE) and amnestic mild cognitive impairment (aMCI). Pattern separation (PS), which enables the distinction between similar but unique experiences, is thought to contribute to successful encoding and retrieval of episodic memories. Impaired PS has been proposed as a potential mechanism underling episodic memory impairment in aMCI, but this association is less established in TLE. In this study, we examined behavioral PS in patients with TLE and explored whether profiles of performance in TLE are similar to aMCI. Method: Patients with TLE, aMCI, and age-matched, healthy controls (HCs) completed a modified recognition task that relies on PS for the discrimination of highly similar lure items, the Mnemonic Similarity Task (MST). Group differences were evaluated and relationships between clinical characteristics, California Verbal Learning Test—Second Edition scores, and MST performance were tested in the TLE group. Results: Patients with TLE and aMCI demonstrated poorer PS performance relative to the HCs, but performance did not differ between the two patient groups. Neither the side of seizure focus nor having hippocampal sclerosis affected performance in TLE. However, TLE patients with clinically defined memory impairment showed the poorest performance. Conclusion: Memory performance on a task that relies on PS was disrupted to a similar extent in TLE and aMCI. The MST could provide a clinically useful tool for measuring hippocampus-dependent memory impairments in TLE and other neurological disorders associated with hippocampal damage.
Biodiversity as insurance: from concept to measurement and application

Biological insurance theory predicts that, in a variable environment, aggregate ecosystem properties will vary less in more diverse communities because declines in the performance or abundance of some species or phenotypes will be offset, at least partly, by smoother declines or increases in others. During the past two decades, ecology has accumulated strong evidence for the stabilising effect of biodiversity on ecosystem functioning. As biological insurance is reaching the stage of a mature theory, it is critical to revisit and clarify its conceptual foundations to guide future developments, applications and measurements. In this review, we first clarify the connections between the insurance and portfolio concepts that have been used in ecology and the economic concepts that inspired them. Doing so points to gaps and mismatches between ecology and economics that could be filled profitably by new theoretical developments and new management applications. Second, we discuss some fundamental issues in biological insurance theory that have remained unnoticed so far and that emerge from some of its recent applications. In particular, we draw a clear distinction between the two effects embedded in biological insurance theory, i.e. the effects of biodiversity on the mean and variability of ecosystem properties. This distinction allows explicit consideration of trade‐offs between the mean and stability of ecosystem processes and services. We also review applications of biological insurance theory in ecosystem management. Finally, we provide a synthetic conceptual framework that unifies the various approaches across disciplines, and we suggest new ways in which biological insurance theory could be extended to address new issues in ecology and ecosystem management. Exciting future challenges include linking the effects of biodiversity on ecosystem functioning and stability, incorporating multiple functions and feedbacks, developing new approaches to partition biodiversity effects across scales, extending biological insurance theory to complex interaction networks, and developing new applications to biodiversity and ecosystem management.
Generation and characterization of a tamoxifen‐inducible Vsx1‐CreERT2 line to target V2 interneurons in the mouse developing spinal cord

In the spinal cord, ventral interneurons regulate the activity of motor neurons, thereby controlling motor activities including locomotion. Interneurons arise during embryonic development from distinct progenitor domains orderly distributed along the dorso‐ventral axis of the neural tube. The p2 progenitor domain generates at least five V2 interneuron populations. However, identification and characterization of all V2 populations remain currently incomplete and the mechanisms that control their development remain only partly understood. In this study, we report the generation of a Vsx1‐CreERT2 BAC transgenic mouse line that drives CreERT2 recombinase expression mimicking endogenous Vsx1 expression pattern in the developing spinal cord. We showed that the Vsx1‐CreERT2 transgene can mediate recombination in V2 precursors with a high efficacy and specificity. Lineage tracing demonstrated that all the V2 interneurons in the mouse developing spinal cord derive from cells expressing Vsx1. Finally, we confirmed that V2 precursors generate additional V2 populations that are not characterized yet. Thus, the Vsx1‐CreERT2 line described here is a useful genetic tool for lineage tracing and for functional studies of the mouse spinal V2 interneurons.
Thrombopoietin, Soluble CD40 Ligand, and Platelet Count During Veno-arterial Extracorporeal Membrane Oxygenation

,§ T hrombocytopenia is common during extracorporeal membrane oxygenation (ECMO), and severe thrombocytopenia occurs in up to 25% of patients. 1 A recent systematic review and meta-analysis confirmed that around a quarter of adult ECMO patients develop thrombocytopenia and up to half of patients require platelet transfusion. 2 The authors concluded that the mechanisms causing thrombocytopenia are multifac-torial and remain poorly understood. 2 Thrombocytopenia is generally classified as consumptive or hypoproliferative, and measurement of plasma thrombopoietin (TPO) concentration helps distinguish between
Mechanisms underlying memory enhancement for disgust over fear

ABSTRACT Disgust is remembered better than fear, despite both emotions being highly negative and arousing. But the mechanisms underlying this effect are not well-understood. Therefore, we compared two proposed mechanisms underlying superior memory for disgust. According to the memory consolidation mechanism, it is harder (but crucial) to remember potentially contaminating vs. threatening stimuli. Hence, disgust elicits additional memory consolidation processes to fear. According to the attention mechanism, it takes longer to establish if disgust (relative to fear) stimuli are dangerous. Hence, people pay more attention to disgust during encoding. Both mechanisms could boost memory for disgust. Ninety-eight participants encoded disgust, fear, and neutral images whilst completing a simple task to measure attention. After 10- or 45-min delay, participants freely recalled the images. We found enhanced memory for disgust relative to fear after 10- and 45-min delay, but this effect was larger after 45-min. Participants paid more attention to disgust than fear images during encoding. However, mixed effect models showed increased attention did not contribute to enhanced memory for disgust. Our results therefore support the memory consolidation mechanism.
Plants and mycorrhizal symbionts acquire substantial soil nitrogen from gaseous ammonia transport.

Nitrogen (N) is an essential nutrient that limits plant growth in many ecosystems. Here we investigate an overlooked component of the terrestrial N cycle-subsurface ammonia (NH3 ) gas transport and its contribution to plant and mycorrhizal N acquisition. We used controlled mesocosms, soil incubations, stable isotopes, and imaging to investigate edaphic drivers of NH3 gas efflux, track lateral subsurface N transport originating from 15 NH3 gas or 15 N-enriched organic matter, and assess plant and mycorrhizal N assimilation from this gaseous transport pathway. NH3 is released from soil organic matter, travels below ground, and contributes to root and fungal N content. Abiotic soil properties (pH and texture) influence the quantity of NH3 available for subsurface transport. Mutualisms with arbuscular mycorrhizal (AM) fungi can substantially increase plant NH3 -N uptake. The grass Brachypodium distachyon acquired 6-9% of total plant N from organic matter-N that traveled as a gas below ground. Colonization by the AM fungus Rhizophagus irregularis was associated with a twofold increase in total plant N acquisition from subsurface NH3 gas. NH3 gas transport and uptake pathways may be fundamentally different from those of more commonly studied soil N species and warrant further research.
Flow cytometry data mining by cytoChain identifies determinants of exhaustion and stemness in TCR‐engineered T cells

The phenotype of infused cells is a major determinant of Adoptive T‐cell therapy (ACT) efficacy. Yet, the difficulty in deciphering multiparametric cytometry data limited the fine characterization of cellular products. To allow the analysis of dynamic and complex flow cytometry samples, we developed cytoChain, a novel dataset mining tool and a new analytical workflow. CytoChain was challenged to compare state‐of‐the‐art and innovative culture conditions to generate stem‐like memory cells (TSCM) suitable for ACT. Noticeably, the combination of IL‐7/15 and superoxides scavenging sustained the emergence of a previously unidentified nonexhausted Fit‐TSCM signature, overlooked by manual gating and endowed with superior expansion potential. CytoChain proficiently traced back this population in independent datasets, and in T‐cell receptor engineered lymphocytes. CytoChain flexibility and function were then further validated on a published dataset from circulating T cells in COVID‐19 patients. Collectively, our results support the use of cytoChain to identify novel, functionally critical immunophenotypes for ACT and patients immunomonitoring.
Pulmonary hypertension is associated with an increased incidence of NAFLD: A retrospective cohort study of 18,910 patients

Pulmonary hypertension (PH) represents a multicausal disease with increasing global incidence that eventually leads to right ventricular failure. In addition to cardiac sequelae, noncardiac comorbidities appear to be of increasing relevance, especially in times of improved therapeutic options that often result in long‐term survival. Here, we examined a potential association between PH and nonalcoholic fatty liver disease (NAFLD) as well as liver cirrhosis in an outpatient cohort in Germany.
Treatment Practices for Adults with Candidemia at Nine Active Surveillance Sites - United States, 2017-2018.

BACKGROUND Candidemia is a common opportunistic infection causing substantial morbidity and mortality. Because of an increasing proportion of non-albicans Candida species and rising antifungal drug resistance, the Infectious Diseases Society of America (IDSA) changed treatment guidelines in 2016 to recommend echinocandins over fluconazole as first-line treatment for adults with candidemia. We describe candidemia treatment practices and adherence to the updated guidelines. METHODS During 2017-2018, the Emerging Infections Program conducted active population-based candidemia surveillance at nine U.S. sites using a standardized case definition. We assessed factors associated with initial antifungal treatment for the first candidemia case among adults using multivariable logistic regression models. To identify instances of potentially inappropriate treatment, we compared the first antifungal drug received with species and antifungal susceptibility testing (AFST) results from initial blood cultures. RESULTS Among 1,835 patients who received antifungal treatment, 1,258 (68.6%) received an echinocandin and 543 (29.6%) received fluconazole as initial treatment. Cirrhosis (adjusted odds ratio = 2.06, 95% confidence interval: 1.29-3.29) was the only underlying medical condition significantly associated with initial receipt of an echinocandin (versus fluconazole). Over half (n = 304, 56.0%) of patients initially treated with fluconazole grew a non-albicans species. Among 265 patients initially treated with fluconazole and with fluconazole AFST results, 28 (10.6%) had a fluconazole-resistant isolate. CONCLUSIONS A substantial proportion of patients with candidemia were initially treated with fluconazole, resulting in potentially inappropriate treatment for those involving non-albicans or fluconazole-resistant species. Reasons for non-adherence to IDSA guidelines should be evaluated, and clinician education is needed.
Cutaneous adverse reactions associated with antiseizure medication: clinical characteristics and implications in epilepsy treatment.

OBJECTIVE To describe the clinical characteristics of cutaneous adverse reactions and cross-sensitivity induced by antiseizure medications and compare the pattern of use of antiseizure medications in patients with epilepsy according to skin rash history. METHODS We analysed patients with a history of skin rash presenting for up to 12 weeks after initiating antiseizure medication. The history of skin rash was verified by medical charts, interviews, and identification of skin lesions by patients based on illustrative images. The minimum follow-up period was eight months. The control group comprised epilepsy patients with regular antiseizure medication use for at least 12 weeks without skin rash. We included 109 cases and 99 controls. RESULTS The median (interquartile range) period from the index rash was six years (2-11). Carbamazepine was the trigger medication in 48% of cases and induced skin rashes in all patients with cross-sensitivity and carbamazepine exposure. Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reactions with eosinophilia and systemic symptoms affected 36% of cases. Carbamazepine- or oxcarbazepine-induced maculopapular exanthema occurred earlier (median: one week) than that induced by other antiseizure medications (median: three weeks) (p=0.006). Cross-sensitivity was more common in patients with at least one episode of Stevens-Johnson syndrome (29%) and Stevens-Johnson/toxic epidermal necrolysis overlap (50%) than in patients with maculopapular exanthema (8%) (p=0.01). Although most cases were mild, the pattern of antiseizure medication use differed from that of controls, with a lower proportion of antiseizure medication typically associated with severe cutaneous adverse reactions (carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, and lamotrigine) (p<0.001). Most cases exposed to high-risk medication, however, did not develop cross-sensitivity. SIGNIFICANCE Cutaneous adverse reaction history may influence antiseizure medication use. Cross-sensitivity is more common in severe cases and most patients are affected by mild, self-limited skin rashes. Further research should consider the relevance of mild skin rashes in lifelong epilepsy treatment.
N400 Evidence That the Early Stages of Lexical Access Ignore Knowledge About Phonological Alternations

Hearing a word that was already expected often facilitates comprehension, attenuating the amplitude of the N400 event-related brain potential component. On the other hand, hearing a word that was not expected elicits a larger N400. In the present study, we examined whether the N400 would be attenuated when a person hears something that is not exactly what they expected but is a viable alternative pronunciation of the morpheme they expected. This was done using Mandarin syllables, some of which can be pronounced with different lexical tones depending on the context. In two large-sample experiments (total n = 160) testing syllables in isolation and in phonologically viable contexts, we found little evidence that hearing an alternative pronunciation of the expected word attenuates the N400. These results suggest that comprehenders do not take advantage of their knowledge about systematic phonological alternations during the early stages of prediction or discrimination.
Longitudinal effects of gender minority stressors on substance use and related risk and protective factors among gender minority adolescents

Purpose Gender minority (GM) adolescents, who have a different gender identity than their sex assigned at birth, may use substances as a coping strategy in response to GM-related stressors. This study examined longitudinal effects of gender minority stressors on substance use in GM adolescents, and related risk factors (internalized transphobia, depressive symptoms, anxious symptoms) and protective factors (resilience, gender-related pride, family functioning, social support, gender-related community connectedness). Methods Participants were 30 GM adolescents, ages 13–17 years, from the U.S. community-based longitudinal Trans Teen and Family Narratives Project. Participants completed an online survey every 6 months across 2 years (5 waves; data collected 2015–2019). Results Exposure to gender minority stressors was associated with higher odds of alcohol use. Across models, internalized transphobia (risk factor), resilience (protective factor), and gender-related pride (protective factor) were the most significant mediators of associations between gender minority stressors and substance use. Family functioning and social support (protective factors) significantly moderated the association between gender minority stressors and alcohol use, such that family functioning and social support were protective for alcohol use at lower levels of gender minority stress, but not at higher levels. Conclusion Results suggest that GM adolescents engage in substance use as a coping strategy in response to gender minority stressors. A number of hypothesized risk and protective factors mediated or moderated these associations. Future interventions with GM adolescents should focus efforts on addressing internalized transphobia as a risk factor and strengthening resilience, gender-related pride, and family functioning as protective factors for substance use.
Metabolomic analysis reveals reliance on secondary plant metabolites to facilitate carnivory in the Cape sundew, Drosera capensis

Abstract Background and Aims Secondary metabolites are integral to multiple key plant processes (growth regulation, pollinator attraction and interactions with conspecifics, competitors and symbionts) yet their role in plant adaptation remains an underexplored area of research. Carnivorous plants use secondary metabolites to acquire nutrients from prey, but the extent of the role of secondary metabolites in plant carnivory is not known. We aimed to determine the extent of the role of secondary metabolites in facilitating carnivory of the Cape sundew, Drosera capensis. Methods We conducted metabolomic analysis of 72 plants in a time-series experiment before and after simulated prey capture. We used ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) and the retention time index to identify compounds in the leaf trap tissue that changed up to 72 h following simulated prey capture. We identified associated metabolic pathways, and cross-compared these compounds with metabolites previously known to be involved in carnivorous plants across taxa. Key Results For the first time in a carnivorous plant, we have profiled the whole-leaf metabolome response to prey capture. Reliance on secondary plant metabolites was higher than previously thought – 2383 out of 3257 compounds in fed leaves had statistically significant concentration changes in comparison with unfed controls. Of these, ~34 compounds are also associated with carnivory in other species; 11 are unique to Nepenthales. At least 20 compounds had 10-fold changes in concentration, 12 of which had 30-fold changes and are typically associated with defence or attraction in non-carnivorous plants. Conclusions Secondary plant metabolites are utilized in plant carnivory to an extent greater than previously thought – we found a whole-metabolome response to prey capture. Plant carnivory, at the metabolic level, likely evolved from at least two distinct functions: attraction and defence. Findings of this study support the hypothesis that secondary metabolites play an important role in plant diversification and adaptation to new environments.
Should Equity Factors Be Betting on Industries?

Asset managers are increasingly incorporating equity factors that deviate from traditional academic definitions in their stock selection process. The authors show that these factors frequently exhibit strong industry biases, making it crucial to understand the interaction between factor exposure and traditional industry exposure. Industry exposure plays a major role in the risk profile of a portfolio, making unintended industry exposures costly. For an extensive set of 21 equity factors, beyond the standard academic factors, the authors examine which equity factors are rewarded for their industry allocation. This set spans the value, quality, momentum, low-volatility, and size investment styles. The authors use a global and liquid investment universe, as is commonly used by large institutional asset managers. They find that equity factors from the same investment style, most notably momentum and quality, exhibit strong differences in their returns from industry allocation. Understanding the interaction between factors and industry exposures can lead to higher return premiums and lower portfolio volatility without harming performance. Key Findings ▪ Asset managers are increasingly using nontraditional equity factors to select stocks. Many of these factors have biases toward and away from certain industries. ▪ Some equity factors are rewarded for industry exposure; for others, this is an unrewarded risk. We assess industry allocation efficacy for 21 equity factors. ▪ Industry allocation efficacy differs significantly across equity factors, even among factors associated with the same investment style.