bluuebunny/crossref_metadata_2025_split huggingface dataset:
When are predictions useful? A new method for evaluating epidemic forecasts
Authors: Marshall Maximilian , Parker Felix , Gardner Lauren M. 
Published: July 2023

AbstractBackgroundCOVID-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.MethodsThe 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).ResultsWe 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.ConclusionsThe 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

AbstractRepeat 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

AbstractSleep 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

AbstractIn-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

AbstractMalaria 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 AbstractHighlightsWe 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

AbstractMotivationMicrobial 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.ResultsTo 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 implementationHostile 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

AbstractMetabotropic 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

AbstractWidely-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

AbstractOne 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 SummaryHere 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

AbstractAcid-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

AbstractThe 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

AbstractAn 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.