bluuebunny/crossref_metadata_2025 huggingface dataset:
From Medicine to Popular Beverage：The Spread of Singlo (松萝) tea in Europe from the Seventeenth to the Nineteenth century
Authors: Qian Yi-Bing
Published: July 2023

Singlo tea was not only highly sought after in China, but also gained substantial popularity in Europe during the eighteenth and early nineteenth centuries. From European primary sources spanning the eighteenth and nineteenth centuries, the popularity of Singlo tea in Europe may have been attributed to the fascination with exotic fashions and products, as well as its medicinal properties. As a result of its popularity, Singlo became known as standard green tea. This kind of tea was eventually replaced by green and black teas of other varieties. Based on the case study of Singlo, this essay indicated that Europeans showed more interest in green tea than in black tea in the early period of Sino-European tea trade. However, Singlo was eventually replaced by other kinds of green and black tea. Its decline in European markets also marked the beginning of black tea’s gradual dominance in the Sino-European tea trade. The spread history of Singlo tea in Europe showed how medicine and commerce interacted. It provided an opportunity to learn about Chinese medicine and culture from a foreign perspective.
An updated systematic review and quantitative synthesis of physical activity levels in multiple sclerosis
Authors: Jeng Brenda , DuBose Noah G. , Martin Trevor B. , Šilić Petra , Flores Victoria A. , Zheng Peixuan , Motl Robert W.
Published: July 2023

Objective

This paper provided an updated quantitative synthesis of physical activity levels in persons with multiple sclerosis (MS) compared with controls and other clinical populations.

Design

A systematic search through PubMed, Scopus, and PsycINFO was conducted for articles published between August, 2016 and July, 2022. Articles that included a group comparison of at least one measurement of physical activity between adults with MS and controls or other clinical populations were included in the meta-analysis.

Results

Twenty-four studies met the inclusion criteria and yielded a total of 119 comparisons. There was a moderate difference in physical activity levels between persons with MS and controls (effect size [ES] = –0.56,p < 0.01), but no significant difference between persons with MS and other clinical populations (ES = 0.01,p = 0.90). The pooled ESs comparing MS with controls (Q104
= 457.9,p < 0.01) as well as with clinical populations (Q13
= 108.4,p < 0.01) were heterogeneous. Moderating variables included sex, disability status, measurement method, outcome, intensity, and application of an MS-specific cut-point.

Conclusion

Physical activity levels remain significantly lower in persons with MS compared with controls, but the magnitude of difference has become smaller over the past decade. There is a need for continued development of effective physical activity programs that can reach the greater community with MS.
Body composition and physical performance one year after COVID-19
Authors: Peball Marina , Rass Verena , Valent Dora , Beer Ronny , Schiefecker Alois Josef , Limmert Victoria , Putnina Lauma , Heim Beatrice , Ellmerer Philipp , Carbone Federico , Mahlknecht Philipp , Kofler Mario , Lindner Anna , Kindl Philipp , Sahanic Sabina , Coen Maximilian , Pizzini Alex , Pfausler Bettina , Kiechl Stefan , Sonnweber Thomas , Tancevski Ivan , Löffler-Ragg Judith , Djamshidian Atbin , Helbok Raimund , Seppi Klaus
Published: July 2023

Objective

Long-term consequences after coronavirus-disease (COVID-19) include physical complaints which may impair physical recovery and quality of life.

Design

We assessed body composition and physical ability in patients twelve months after COVID-19. Consecutively recruited patients recovering from mild to severe COVID-19 were assessed using bioelectrical impedance analysis, 6-minute-walk-test, additional scales for physical performance, and health-related quality of life.

Results

Overall physical recovery was good (i.e., Glasgow Outcome Scale-Extended ≥7 in 96%, Modified Rankin Scale ≤1 in 87%, Eastern Cooperative Oncology Group ≤1 in 99%). Forty-four-% of the 69 patients experienced a significant BMI-increase in the year post-COVID-19 (≥1 kg/m2) whereas skeletal-muscle-mass-index was reduced in only 12%. Patients requiring intensive-care-treatment (n = 15, 22%) during acute COVID-19 more often had a BMI-increase (p = 0.002), worse 6-minute-walk-test-performance (p = 0.044), and higher body fat mass (p = 0.030) at the one-year-follow-up when compared to patients with mild (n = 22, 32%) and moderate (n = 32, 46%) acute COVID-19. BMI-increase was also more frequent in patients who had no professional rehabilitation (p = 0.014).

Conclusion

Although patients with severe COVID-19 had increased BMI and body fat and performed worse in physical outcome measures one year after COVID-19, overall physical recovery was satisfying. Translating these findings to variants beyond the alpha-strain of SARS-CoV-2-virus needs further studies.
Longitudinal Patterns of Engagement and Clinical Outcomes: Results From a Therapist-Supported Digital Mental Health Intervention
Authors: Aschbacher Kirstin , Rivera Luisa M. , Hornstein Silvan , Nelson Benjamin W. , Forman-Hoffman Valerie L. , Peiper Nicholas C.
Published: July 2023

Objective

Digital mental health interventions (DMHIs) are an effective treatment modality for common mental disorders like depression and anxiety; however, the role of intervention engagement as a longitudinal “dosing” factor is poorly understood in relation to clinical outcomes.

Methods

We studied 4978 participants in a 12-week therapist-supported DMHI (June 2020–December 2021), applying a longitudinal agglomerative hierarchical cluster analysis to the number of days per week of intervention engagement. The proportion of people demonstrating remission in depression and anxiety symptoms during the intervention was calculated for each cluster. Multivariable logistic regression models were fit to examine associations between the engagement clusters and symptom remission, adjusting for demographic and clinical characteristics.

Results

Based on clinical interpretability and stopping rules, four clusters were derived from the hierarchical cluster analysis (in descending order): a) sustained high engagers (45.0%), b) late disengagers (24.1%), c) early disengagers (22.5%), and d) immediate disengagers (8.4%). Bivariate and multivariate analyses supported a dose-response relationship between engagement and depression symptom remission, whereas the pattern was partially evident for anxiety symptom remission. In multivariable logistic regression models, older age groups, male participants, and Asians had increased odds of achieving depression and anxiety symptom remission, whereas higher odds of anxiety symptom remission were observed among gender-expansive individuals.

Conclusions

Segmentation based on the frequency of engagement performs well in discerning timing of intervention disengagement and a dose-response relationship with clinical outcomes. The findings among the demographic subpopulations indicate that therapist-supported DMHIs may be effective in addressing mental health problems among patients who disproportionately experience stigma and structural barriers to care. Machine learning models can enable precision care by delineating how heterogeneous patterns of engagement over time relate to clinical outcomes. This empirical identification may help clinicians personalize and optimize interventions to prevent premature disengagement.
Spousal Synchrony in Allostatic Load Among Older Couples in the Health and Retirement Study
Authors: Yu Yan-Liang , Juster Robert-Paul
Published: July 2023

Objective

Using national data from the Health and Retirement Study, this study examined interpartner associations of allostatic load (AL) among 2338 different-sex couples (N = 4676 individuals) over a 4-year period among older American couples from a dyadic approach.

Methods

AL was indexed by immune (C-reactive protein), metabolic (high-density lipoprotein cholesterol, total cholesterol, and glycosylated hemoglobin), renal (cystatin C), cardiovascular (systolic and diastolic blood pressures, pulse rate), and anthropometric (waist and body mass index) parameters using the traditional count-based formulation. Actor-partner interdependence models were used to assess interpartner concordance in AL.

Results

Higher partners’ baseline AL was significantly associated with higher own AL both at baseline and 4 years later. In addition, partners’ baseline AL was significantly associated with own AL 4 years later only in women but not men. Lastly, we did not observe any significant moderating effect of relationship quality on interpartner AL concordance.

Conclusions

The findings suggest that older couples’ physiological responses to environmental stress are not only linked concurrently, but the associations persist after 4 years, alluding to long-term impacts of couples’ psychosocial context and physiology on each other.
Role of glucose metabolism and signaling pathways at different stages of ovarian folliculogenesis
Authors: Mo Dan , Zeng Zhong-Hong , Sui Xin , Li Rong , Yang Yi-Hua
Published: July 2023

The female ovaries are critical for follicle growth and development in the process known as “folliculogenesis”. This complex process is regulated by various factors, among which the microenvironment around follicles appears to be crucial. According to previous studies, folliculogenesis is an energy-demanding process. In fact, well-balanced follicular energy metabolism is associated with ovarian function and female fertility. Consequently, glucose metabolism has been widely described as the main source of energy during folliculogenesis. Generally, the follicular glucose metabolism profiles change dynamically during follicular development. Metabolic abnormalities during folliculogenesis are associated with aging, primary ovarian insufficiency, and polycystic ovary syndrome, thereby leading to subfertility and infertility in females. The signaling pathways in follicles appear to form a link between glucose metabolism and folliculogenesis. Therefore, a better understanding of glucose metabolism dynamics at different stages of folliculogenesis and the associated signaling pathways will provide potential implications for follicle developmental competence. This review aimed to describe variations in glucose metabolism at different stages of folliculogenesis, provide new insights into glucose metabolic disorder-related diseases, and specifically discuss two major signaling pathways that regulate glucose metabolism during folliculogenesis: phosphatidylinositol 3-kinase, protein kinase B (PI3K-PKB/AKT), and AMP-activated protein kinase (AMPK) signaling pathways.
Functional Role of Phospholipase D in Bone Metabolism
Authors: Kim Hyun-Ju , Lee Dong-Kyo , Choi Je-Yong
Published: July 2023

Phospholipase D (PLD) proteins are major enzymes that regulate various cellular functions, such as cell growth, cell migration, membrane trafficking, and cytoskeletal dynamics. As they are responsible for such important biological functions, PLD proteins have been considered promising therapeutic targets for various diseases, including cancer and vascular and neurological diseases. Intriguingly, emerging evidence indicates that PLD1 and PLD2, 2 major mammalian PLD isoenzymes, are the key regulators of bone remodeling; this suggests that these isozymes could be used as potential therapeutic targets for bone diseases, such as osteoporosis and rheumatoid arthritis. PLD1 or PLD2 deficiency in mice can lead to decreased bone mass and dysregulated bone homeostasis. Although both mutant mice exhibit similar skeletal phenotypes, PLD1 and PLD2 play distinct and nonredundant roles in bone cell function. This review summarizes the physiological roles of PLD1 and PLD2 in bone metabolism, focusing on recent findings of the biological functions and action mechanisms of PLD1 and PLD2 in bone cells.
Bone Mineral Density, Trabecular Bone Score and Fractures in Patients Hospitalized for Heart Failure
Authors: Oliveira Lucian Batista de , de Figueiredo Martins Siqueira Mariana Andrade , de Macedo Gadêlha Rafael Buarque , Barreto Beatriz Pontes , Correia Alice Rodrigues Pimentel , Leão Vinicius Belfort , Garcia Jessica , Bandeira Francisco
Published: July 2023

Background: This study aimed to evaluate the bone mineral density (BMD), trabecular bone score (TBS), and fracture history of middle-aged patients hospitalized for heart failure (HF), as well as analyze the association of these factors with cardiometabolic parameters and muscle strength.Methods: A cross-sectional study with patients aged 40 to 64 years hospitalized for HF was performed. Dual energy X-ray absorptiometry was performed to obtain BMD and TBS. Fracture history, handgrip strength (HGS), and clinical and laboratory cardiometabolic parameters of the patients were evaluated.Results: Altogether, 109 patients were evaluated (female 50.5%). Medians and interquartile ranges for age and length of hospital stay were 58.0 (53.0–61.0) years and 20.0 (11.0–32.0) days, respectively. Osteoporosis was observed in 15.6% of the patients, low TBS was observed in 22.8%, and 6 patients had a history of fragile fracture. No differences between the sexes regarding BMD (p=0.335) or TBS (p=0.736) classifications were observed. No association was observed between low BMD and HF classification (p>0.05) regarding the ejection fraction, ischemic etiology, or New York Heart Association Functional Classification. However, there was a significant association between high serum parathyroid hormone (PTH) and the presence of osteoporosis (62.5 [37.2–119.0] pg/mL vs. 34.2 [25.0–54.1] pg/mL; p=0.016). There was a negative correlation between serum PTH and TBS (r=−0.329, p=0.038) and a higher frequency of reduced HGS in patients with low TBS (92.3% vs. 50.0%; p=0.009).Conclusions: We found relevant frequencies of osteoporosis and bone microarchitecture degradation in middle-aged patients with HF, which were related to high serum PTH concentrations.
BioSignal Copilot: Leveraging the power of LLMs in drafting reports for biomedical signals
Authors: Liu Chunyu , Ma Yongpei , Kothur Kavitha , Nikpour Armin , Kavehei Omid
Published: July 2023

Recent advances in Large Language Models (LLMs) have shown great potential in various domains, particularly in processing text-based data. However, their applicability to biomedical time-series signals (e.g. electrograms) remains largely unexplored due to the lack of a signal-to-text (sequence) engine to harness the power of LLMs. The application of biosignals has been growing due to the improvements in the reliability, noise and performance of front-end sensing, and back-end signal processing, despite lowering the number of sensing components (e.g. electrodes) needed for effective and long-term use (e.g. in wearable or implantable devices). One of the most reliable techniques used in clinical settings is producing a technical/clinical report on the quality and features of collected data and using that alongside a set of auxiliary or complementary data (e.g. imaging, blood tests, medical records).

This work addresses the missing puzzle in implementing conversational artificial intelligence (AI), a reliable, technical and clinically relevant signal-to-text (Sig2Txt) engine. While medical foundation models can be expected, reports of Sig2Txt engine in large scale can be utilised in years to come to develop foundational models for a unified purpose. In this work, we propose a system (SignalGPT or BioSignal Copilot) that reduces medical signals to a freestyle or formatted clinical, technical report close to a brief clinical report capturing key features and characterisation of input signal. In its ideal form, this system provides the tool necessary to produce the technical input sequence necessary for LLMs as a step toward using AI in the medical and clinical domains as an assistant to clinicians and patients. To the best of our knowledge, this is the first system for bioSig2Txt generation, and the idea can be used in other domains as well to produce technical reports to harness the power of LLMs. This method also improves the interpretability and tracking (history) of information into and out of the AI models. We did implement this aspect through a buffer in our system.

As a preliminary step, we verify the feasibility of the BioSignal Copilot (SignalGPT) using a clinical ECG dataset to demonstrate the advantages of the proposed system. In this feasibility study, we used prompts and fine-tuning to prevent fluctuations in response. The combination of biosignal processing and natural language processing offers a promising solution that improves the interpretability of the results obtained from AI, which also leverages the rapid growth of LLMs.
When are predictions useful? A new method for evaluating epidemic forecasts
Authors: Marshall Maximilian , Parker Felix , Gardner Lauren M.
Published: July 2023

Background

COVID-19 will not be the last pandemic of the 21st century. To better prepare for the next one, it is essential that we make honest appraisals of the utility of different responses to COVID. In this paper we focus specifically on epidemiologic forecasting. Characterizing forecast efficacy over the history of the pandemic is challenging, especially given its significant spatial, temporal, and contextual variability. In this light, we introduce the Weighted Contextual Interval Score (WCIS), a new method for retrospective interval forecast evaluation. The WCIS reflects the potential utility of predictions, resulting in a score that is easily comparable across different pandemic scenarios despite remaining intuitively representative of the in-situ quality of individual forecasts.

Methods

The central tenet of the WCIS is a direct incorporation of contextual utility into the evaluation. This necessitates a specific characterization of forecast efficacy depending on the use case for predictions, accomplished via defining a utility threshold parameter. In essence, changes in forecast accuracy beyond this threshold do not map to changes in the utility of a prediction. This idea is generalized to probabilistic interval-form forecasts, which are the preferred prediction format for epidemiological modeling, as an adaptation of the existing Weighed Interval Score (WIS).

Results

We apply the WCIS to two different forecasting scenarios. The first assesses the performance of facility-level COVID-19 hospital bed occupancy predictions for the state of Maryland during the Omicron wave, and the second evaluates state-level hospitalization forecasts drawn from the COVID-19 Forecast Hub. We use these applications to demonstrate the parameterization of contextual utility, compare the WCIS to the WIS, and explore the utility of the WCIS.

Conclusions

The WCIS provides a pragmatic utility-based characterization of probabilistic predictions. This method is expressly intended to enable practitioners and policymakers who may not have expertise in forecasting but are nevertheless essential partners in epidemic response to use and provide insightful analysis of predictions. We note that the WCIS is intended specifically for retrospective forecast evaluation and should not be used as a minimized penalty in a competitive context as it lacks statistical propriety.
Increased frequency of repeat expansion mutations across different populations
Authors: Ibañez Kristina , Jadhav Bharati , Zanovello Matteo , Gagliardi Delia , Clarkson Christopher , Facchini Stefano , Garg Paras , Martin-Trujillo Alejandro , Gies Scott J , Deforie Valentina Galassi , Dalmia Anupriya , Moss Davina J. Hensman , Vandrovcova Jana , Rocca Clarissa , Moutsianas Loukas , Marini-Bettolo Chiara , Walker Helen , Turner Chris , Shoai Maryam , Long Jeffrey D ,   EUROSCA network, Fratta Pietro , Langbehn Douglas R , Tabrizi Sarah J , Caulfield Mark J , Cortese Andrea , Escott-Price Valentina , Hardy John , Houlden Henry , Sharp Andrew J , Tucci Arianna
Published: July 2023

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and technological limitations leading to under-ascertainment. Here, leveraging whole genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modelling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating under-diagnosis and/or incomplete penetrance. While some REDs are population-specific, e.g. Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (i.e. Europeans, Africans, Americans, East Asians, and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counselling of REDs.
Sleep spindle architecture associated with distinct clinical phenotypes in older adults at risk for dementia
Authors: Orlando Isabella F. , O’Callaghan Claire , Lam Aaron , McKinnon Andrew C. , Tan Joshua B. , Michaelian Johannes C. , Kong Shawn D.X. , D’Rozario Angela L. , Naismith Sharon L.
Published: July 2023

Sleep spindles are a hallmark of non-REM sleep and play a fundamental role in memory consolidation. Alterations in these spindles are emerging as sensitive biomarkers for neurodegenerative diseases of ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate the functional role of these distinct electroencephalographic oscillations and the pathophysiology of sleep and neurodegenerative disorders. Here, we use a data-driven approach to examine the sleep, memory and default mode network connectivity phenotypes associated with sleep spindle architecture in older adults (mean age = 66 years). Participants were recruited from a specialist clinic for early diagnosis and intervention for cognitive decline, with a proportion showing mild cognitive deficits on neuropsychological testing. In a sample of 88 people who underwent memory assessment, overnight polysomnography and resting state fMRI, a k-means cluster analysis was applied to spindle measures of interest: fast spindle density, spindle duration and spindle amplitude. This resulted in three clusters, characterised by preserved spindle architecture with higher fast spindle density and longer spindle duration (Cluster 1), and alterations in spindle architecture (Clusters 2 and 3). These clusters were further characterised by reduced memory (Clusters 2 and 3) and nocturnal hypoxemia, associated with sleep apnea (Cluster 3). Resting state fMRI analysis confirmed that default mode connectivity was related to spindle architecture, although directionality of this relationship differed across the cluster groups. Together these results confirm a diversity in spindle architecture in older adults, associated with clinically meaningful phenotypes, including memory function and sleep apnea. They suggest that resting state default mode connectivity during the awake state can be associated with sleep spindle architecture, however this is highly dependent on clinical phenotype. Establishing relationships between clinical and neuroimaging features and sleep spindle alterations, will advance our understanding of the bidirectional relationships between sleep changes and neurodegenerative diseases of ageing.
Allelic bias when performing in-solution enrichment of ancient human DNA
Authors: Davidson Roberta , Williams Matthew P. , Roca-Rada Xavier , Kassadjikova Kalina , Tobler Raymond , Fehren-Schmitz Lars , Llamas Bastien
Published: July 2023

In-solution hybridisation enrichment of genetic variation is a valuable methodology in human paleogenomics. It allows enrichment of endogenous DNA by targeting genetic markers that are comparable between sequencing libraries. Many studies have used the 1240k reagent—which enriches 1,237,207 genome-wide SNPs—since 2015, though access was restricted. In 2021, Twist Biosciences and Daicel Arbor Biosciences independently released commercial kits that enabled all researchers to perform enrichments for the same 1240k SNPs. We used the Daicel Arbor Biosciences Prime Plus kit to enrich 132 ancient samples from three continents. We identified a systematic assay bias that increases genetic similarity between enriched samples and that cannot be explained by batch effects. We present the impact of the bias on population genetics inferences (e.g., Principal Components Analysis, ƒ-statistics) and genetic relatedness (READ). We compare the Prime Plus bias to that previously reported of the legacy 1240k enrichment assay. In ƒ-statistics, we find that all Prime-Plus-generated data exhibit artefactual excess shared drift, such that within-continent relationships cannot be correctly determined. The bias is more subtle in READ, though interpretation of the results can still be misleading in specific contexts. We expect the bias may affect analyses we have not yet tested. Our observations support previously reported concerns for the integration of different data types in paleogenomics. We also caution that technological solutions to generate 1240k data necessitate a thorough validation process before their adoption in the paleogenomic community.
Drug repurposing approach for potential Pfmrk inhibitors as antimalarial agents: anIn-silicoanalysis
Authors: Sahu Abhishek , Handa Tanuj , Kundu Debanjan
Published: July 2023

Malaria is a major global health issue due to the emergence of resistance to most of the available antimalarial drugs. There is an urgent need to discover new antimalarials to tackle the resistance issue. A CDK-like protein, Pfmrk fromPlasmodium falciparum, plays a crucial role in regulating cell proliferation and shares 36.28% homology with humans CDK (hCDK7). Pfmrk complex with Pfcyc-1 and stimulates kinase activity. Also, Pfcyc-1 from P. falciparum, which has the highest sequence homology with human cyclin (Cyclin H), binds to and activates Pfmrk in a cyclin-dependent way. This is the first indication that cyclin subunits regulate human and plasmodial CDKs in a similar manner. In this study, molecular docking analysis of Pfmrk against the selected FDA-approved drugs acquired from the ZINC15 database. The top five drugs, Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap, were screened based on binding energies of best-docked scores ranging between -8 kcal/mol and -12 kcal/mol. Based on Molecular dynamics simulations for 100ns, Lurasidone showed the highest binding affinity (-105.90 ± 57.72 kJ/mol), followed by Donovex (-92.877 ± 17.872 kJ/mol) and exhibited stable interactions with the amino acid residues present in the active site of Pfmrk. The outcomes ofin silicoinvestigation putatively suggested that Lurasidone and Donovex exhibit antimalarial potency and could be translated as potential Pfmrk inhibitors and developing new drugs based on furtherin-vitrostudies.

Graphical Abstract

Highlights

We investigated the potential FDA-approved drugs for repurposing against the modelled protein Pfmrk.

Alvesco, Donovex, Lurasidone, Orap, and Vorapaxar are potential FDA-approved drugs firmly binding with Pfmrk.

Molecular docking and simulation studies show that Donovex and Lurasidone are potential inhibitors of the modelled Pfmrk protein.

Donovex and Lurasidone are potential drugs that act as kinase inhibitors by binding to the ATP -binding site of the enzyme Pfmrk.
Hostile: accurate host decontamination of microbial sequences
Authors: Constantinides Bede , Hunt Martin , Crook Derrick W
Published: July 2023

Motivation

Microbial sequences generated from clinical samples are often contaminated with human host sequences that must be removed for ethical and legal reasons. Care must be taken to excise host sequences without inadvertently removing target microbial sequences to the detriment of downstream analyses such as variant calling andde novoassembly.

Results

To facilitate accurate host decontamination of both short and long sequencing reads, we developed Hostile, a tool capable of accurate host read removal using a laptop. We demonstrate that our approach removes at least 99.6% of real human reads and retains at least 99.989% of simulated bacterial reads. Using Hostile with a masked reference genome further increases bacterial read retention (>=99.997%) with negligible (<=0.001%) reduction in human read removal performance. Compared with an existing tool, Hostile removes 21-23% more human short reads and 22-43x fewer bacterial reads with comparable execution time.

Availability and implementation

Hostile is implemented as an MIT licensed Python package available fromhttps://github.com/bede/hostiletogether with supplementary material.
SCA44- and SCAR13-associatedGRM1mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms
Authors: Wang Yuyang , Muraleetharan Ashwin , Gregory Karen J , Hellyer Shane D
Published: July 2023

Metabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally-occurring mGlu1mutations in rare SCA subtypes and clinical symptoms of mGlu1mutations have been described. However, how mutations alter mGlu1function remains unknown. We explored SCA-associated mutation effects on mGlu1cell surface expression and canonical signal transduction. Orthosteric agonists and positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+mobilisation and IP1accumulation). mGlu1mutants exhibited differential impacts on receptor expression, with a truncating C-terminus mutation significantly reducing mGlu1expression. Mutations differentially influenced orthosteric ligand affinity, efficacy, and functional cooperativity between allosteric and orthosteric ligands. Loss-of-function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. Gain-of-function Y792C mutant mGlu1displayed enhanced constitutive activity in IP1assays, which manifested as reduced orthosteric agonist activity. mGlu1PAMs restored glutamate potency in iCa2+mobilisation for loss-of-function mutations, and mGlu1NAMs displayed enhanced inverse agonist activity at Y792C relative to wild-type mGlu1. Collectively, these data highlight distinct mechanisms by which mGlu1mutations affect receptor function and show allosteric modulators may present a means to restore aberrant mGlu1function in rare SCA subtypes.
Evolution of circadian behavioral plasticity throughcis-regulatory divergence of a neuropeptide gene
Authors: Shahandeh Michael P. , Abuin Liliane , De Decker Lou Lescuyer , Cergneux Julien , Koch Rafael , Nagoshi Emi , Benton Richard
Published: July 2023

Widely-distributed species experience substantial environmental variation, which they often accommodate through behavioral plasticity. Although this ability is integral to fitness, we have little understanding of the mechanistic basis by which plasticity evolves. One factor that varies seasonally and by latitude is photoperiod (day length). Many organisms, including the cosmopolitanDrosophila melanogasterdisplay circadian plasticity, adjusting to fluctuating photoperiod by varying the timing of their activity to coincide with changing dawn/dusk intervals1. Here, we compareD. melanogasterwith the closely-related ecological specialistDrosophila sechellia, an equatorial island endemic that experiences minimal photoperiod variation, to investigate the molecular-genetic basis of circadian plasticity evolution2,3. We discover thatD. sechelliadisplays exceptionally little circadian plasticity compared toD. melanogasterand other non-equatorial drosophilids. Through a screen of circadian mutants inD. melanogaster/D. sechelliahybrids, we identify a role of the neuropeptide Pigment-dispersing factor (Pdf) in this loss. While the coding sequence ofPdfis conserved, we show thatPdfhas undergonecis-regulatory divergence in these drosophilids. We document species-specific temporal dynamic properties ofPdfRNA and protein expression, as well as Pdf neuron morphological plasticity, and demonstrate that modulating Pdf expression inD. melanogastercan influence the degree of behavioral plasticity. Furthermore, we find that thePdfregulatory region exhibits signals of selection across populations ofD. melanogasterfrom different latitudes. Finally, we provide evidence that plasticity confers a selective advantage forD. melanogasterat higher latitudes, whileD. sechellialikely suffers fitness costs through reduced copulation success outside its range. Our work definesPdfas a locus of evolution for circadian plasticity, which might have contributed to bothD. melanogaster’s global distribution andD. sechellia’s habitat specialization. Moreover, together with spatial changes in Pdf expression reported in high-latitude drosophilid species4,5, our findings highlight this neuropeptide gene as a hotspot for circadian plasticity evolution.
Second messenger c-di-AMP regulates multiple antibiotic sensitivity pathways inMycobacterium smegmatisby discrete mechanisms
Authors: Pal Aditya Kumar , Ghorai Dipankar , Ge Xueliang , Sarkar Biplab , Sahu Amit Kumar , Chaudhary Vikas , Sanyal Suparna , Singh Mahavir , Ghosh Anirban
Published: July 2023

One of the debilitating causes of high mortality in the case of tuberculosis and other bacterial infections is the resistance development against standard drugs. There are limited studies so far to describe how a bacterial second messenger molecule can directly participate in distinctive antibiotic tolerance characteristics of a cell in a mechanism-dependent manner. Here we show that intracellular cyclic di-AMP (c-di-AMP) concentration can modulate drug sensitivity ofMycobacterium smegmatisby directly interacting with either a protein effector or with the 5’-UTR regions in mRNA of the genes and thus causing transcriptional downregulation of important genes in the pathways. We studied four antibiotics with different mechanisms of action: rifampicin, ciprofloxacin, erythromycin, and tobramycin and subsequently found that the level of drug sensitivity of the bacteria is directly proportional to the c-di-AMP concentration inside the cell. Further, we unraveled the underlying molecular mechanisms to delineate the specific genes and pathways regulated by c-di-AMP and hence result in differential drug sensitivity inM. smegmatis. Thus, our findings of c-di-AMP messenger controlling drug resistance phenotypes of mycobacteria against four different classes of antibiotics is a unique observation that will contribute to scientific advancement in the field.

One Sentence Summary

Here we describe how second messenger c-di-AMP modulates the antibiotic sensitivity and resistance profile ofM. smegmatisby diverse mechanisms.
Dynamic landscape of the intracellular termini of acid-sensing ion channel 1a
Authors: Cullinan Megan M. , Klipp Robert C. , Camenisch Abigail , Bankston John R.
Published: July 2023

Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recently it has been shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of the channel is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is hypothesized to be inhibited at rest via an interaction between the C-terminus and the N-terminus which blocks the RIPK1 binding site. Here, we use a combination of two transition metal ion FRET methods to investigate the conformational dynamics of the termini while the channel is closed and desensitized. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together when desensitized. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The distal end of the C-terminus may also spend time close to the membrane at rest. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.
Upstream ribosome impediments activate roles of internal Shine-Dalgarno sequence for translation initiation inE. coli
Authors: Li Xin , Wang Huihui , Chen Yan , Zhang Yanyan , Liu Jie , Zhou Dan , Wu Zhihua , Sun Meihao
Published: July 2023

The initiation of protein translation, one of the four phases of translation, had been proved to be the rate limiting step for translation. The specific interaction of bacterial 30S ribosomal subunit with Shine-Dalgarno sequence (SD) contributes the initiation significantly. It had been shown that SD-like sequence in coding region of mRNA, designated as internal SD, can direct translation initiation as regular SD does. The ribosome impediments were demonstrated to be one of the factors contributing the non-uniform translation elongation rate, but their effects on internal SD translation initiation role (ISTIR) remains unclear. To investigate effects of upstream ribosome impediments on ISTIR, a fragment consisting of pyruvate kinase (PK) gene, translation initiation needed mRNA elements (including an A/U-rich region, SD sequence and start codon AUG) and red fluorescent protein (RFP) gene was constructed and RFP expression levels representing translation initiation efficiency induced by internal SD was analyzed. Surprisingly, RFP expression was not detected with this primary construct, further experiments of inclusion of stem loop structure preceding to internal SD or co-expression of engineered RNA binding scaffold (ERBS) targeting to preceding sequence of internal SD could activate ISTIR. These results suggest that upstream ribosome impediments would activate ISTIR to initiate the downstream gene translation, which manifests the potential for developing new method to test interactions between RNA binding proteins and their target RNA moleculesin vivo.
Variations in bacterial community at Chlorophyll Maximum (C-Max) depths along the west coast of India due to seasonal changes in the primary productivity
Authors: Parab Ashutosh Shankar , Ghose Mayukhmita Prithunandan , Manohar Cathrine Sumathi
Published: July 2023

An increase in primary productivity is recorded annually during the southwest monsoon season along the west coast of India, an important upwelling zone. The influence of the seasonal variations in thein situprimary productivity on the bacterial dynamics and community structure was explored during the non-monsoon and productive monsoon seasons. In the monsoon season, shallower mixed layer depth, increased nutrient concentration and a significant, positive correlation of bacterial carbon (p < 0.01) with primary productivity was observed. Bacterial diversity was assessed in the chlorophyll maxima depths during both seasons based on next-generation, metagenomic analysis. In the non-monsoon season, genera such asIdiomarina,Salinimonas,Marinobacterof Proteobacteria andBacillusandLactobacillusof Firmicutes were dominant. These major bacterial genera are shown through canonical correspondence analysis to play an important ecological role. They could be responsible for the increased heterotrophic activity recorded through predicted functional gene profiles in this season. In the monsoon season, increased abundance in the autotrophic Cyanobacteria community and its photosynthetic activity was recorded in the gene profiles. Higher diversity of heterotrophic phyla such as Bacteroidetes, Actinobacteria and a few Candidatus phyla and changes in the diversity of Proteobacteria with a representation ofAlteromonas, SAR86 clade and OM60 (NOR5) was observed. These results highlight the bacterial dynamics associated with seasonal variations in primary productivity along the west coast of India.
Bam complex associated proteins inEscherichia coliare functionally linked to peptidoglycan biosynthesis, membrane fluidity and DNA replication
Authors: Bryant Jack A. , Staunton Kara A. , Doherty Hannah M. , Alao Micheal B. , Ma Xuyu , Morcinek-Orłowska Joanna , Goodall Emily C. A. , Gray Jessica , Milner Mathew , Cole Jeffrey A. , de Cogan Felicity , Knowles Timothy J. , Glinkowska Monika , Moradigaravand Danesh , Henderson Ian R. , Banzhaf Manuel
Published: July 2023

Biogenesis of the bacterial outer membrane is key to bacterial survival and antibiotic resistance. Central to this is the β-barrel assembly machine (Bam) complex and its associated chaperones, which are responsible for transport, folding and insertion of outer membrane proteins (OMPs). TheEscherichia coliBam complex is composed of two essential subunits, BamA and BamD, and three non-essential accessory lipoproteins, BamB, BamC and BamE. Optimal Bam function is further dependent on the non-essential periplasmic chaperones DegP, Skp and SurA. Despite intensive study, the specific function of these non-essential Bam-associated proteins remains unknown. Here, we analysed ΔbamB, ΔbamC, ΔbamE, ΔsurA, Δskpand ΔdegPknockout strains by phenotypic screening, conservation analysis and high-throughput genetics. We reveal that Bam complex activity is impacted by changes in outer membrane lipid composition and that enterobacterial common antigen is essential in the absence of the chaperone SurA. We also show components of peptidoglycan are conditionally essential with Bam accessory lipoproteins and that DNA replication control is perturbed in the absence of specific OMP assembly components. Together, our data indicates potential mechanisms for coordination of OMP biogenesis with other cellular growth processes such as LPS and peptidoglycan biogenesis, and DNA replication control.
The Cellular Underpinnings of the Human Cortical Connectome
Authors: Zhang Xi-Han , Anderson Kevin M. , Dong Hao-Ming , Chopra Sidhant , Dhamala Elvisha , Emani Prashant S. , Margulies Daniel , Holmes Avram J.
Published: July 2023

The functional properties of the human brain arise, in part, from the vast assortment of cell types that pattern the cortex. The cortical sheet can be broadly divided into distinct networks, which are further embedded into processing streams, or gradients, that extend from unimodal systems through higher-order association territories. Here, using transcriptional data from the Allen Human Brain Atlas, we demonstrate that imputed cell type distributions are spatially coupled to the functional organization of cortex, as estimated through fMRI. Cortical cellular profiles follow the macro-scale organization of the functional gradients as well as the associated large-scale networks. Distinct cellular fingerprints were evident across networks, and a classifier trained on post-mortem cell-type distributions was able to predict the functional network allegiance of cortical tissue samples. These data indicate that thein vivoorganization of the cortical sheet is reflected in the spatial variability of its cellular composition.
Synaptophysin Chaperones the Assembly of 12 SNAREpins under each Ready-Release Vesicle
Authors: Bera Manindra , Radhakrishnan Abhijith , Coleman Jeff , Sundaram Ramalingam Venkat Kalyana , Ramakrishnan Sathish , Pincet Frederic , Rothman James E.
Published: July 2023

The synaptic vesicle protein Synaptophysin has long been known to form a complex with the v-SNARE VAMP, but a more specific molecular function or mechanism of action in exocytosis has been lacking because gene knockouts have minimal effects. Utilizing fully-defined reconstitution and single-molecule measurements, we now report that Synaptophysin functions as a chaperone that determines the number of SNAREpins assembling between a ready-release vesicle and its target membrane bilayer. Specifically, Synaptophysin directs the assembly of 12 ± 1 SNAREpins under each docked vesicle, even in the face of an excess of SNARE proteins. The SNAREpins assemble in successive waves of 6 ± 1 and 5 ± 2 SNAREpins, respectively, tightly linked to oligomerization of and binding to the vesicle Ca++sensor Synaptotagmin. Templating of 12 SNAREpins by Synaptophysin is likely the direct result of its hexamer structure and its binding of VAMP2 dimers, both of which we demonstrate in detergent extracts and lipid bilayers.

Significance Statement

Synaptophysin is the most abundant protein and a unique constituent of synaptic vesicles, yet it has no known function, due to minimal genetic phenotypes and the lack of biochemical assays. Here, we directly establish using two independent methods that the synaptic vesicle protein Synaptophysin forms a hexameric complex containing 12 copies of the v-SNARE VAMP2. These v-SNAREs assemble into SNAREpins as ready-release vesicles are formed in a fully-defined cell-free system, and do so in two equal waves organized by oligomerization of the Ca++sensor Synaptotagmin. In the absence of Synaptophysin, two waves are also observed, but the number of SNAREpins in each varies widely. We suggest that a single Synaptophysin hexamer in each vesicle symmetrically organizes 6 pairs of peripheral and central SNAREpins, the latter being directly bound to the Synaptotagmin ring. This gives rise to the symmetrical ring-like arrangement of densities observed by cryo-EM tomography under each synaptic vesicle (1, 2).