bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial covariance analysis of FDG-PET and HMPAO-SPECT for the differential diagnosis of dementia with Lewy bodies and Alzheimer’s disease
Authors: Ingram Matthew , Colloby Sean J. , Firbank Michael J. , Lloyd Jim J. , O’Brien John T. , Taylor John-Paul 
Published: October 2021

AbstractWe investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59±0.10), whilst SCA of FDG-PET (AUC 0.83±0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84±0.08) and visual rating (AUC 0.82±0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT and performed similarly to other analytical approaches, with the potential to improve with larger derivation groups. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.
Are reaching and grasping effector-independent? Similarities and differences in reaching and grasping kinematics between the hand and foot
Authors: Liu Yuqi , Caracoglia James , Sen Sriparna , Freud Erez , Striem-Amit Ella 
Published: October 2021

AbstractWhile reaching and grasping are highly prevalentmanualactions, neuroimaging studies provide evidence that their neural representations may be shared between different body parts, i.e. effectors. If these actions are guided by effector-independent mechanisms, similar kinematics should be observed when the action is performed by the hand or by a cortically remote and less experienced effector, such as the foot. We tested this hypothesis with two characteristic components of action: the initial ballistic stage of reaching, and the preshaping of the digits during grasping based on object size. We examined if these kinematic features reflect effector-independent mechanisms by asking participants to reach toward and to grasp objects of different widths with their hand and foot. First, during both reaching and grasping, the velocity profile up to peak velocity matched between the hand and the foot, indicating a shared ballistic acceleration phase. Secondly, maximum grip aperture and time of maximum grip aperture of grasping increased with object size for both effectors, indicating encoding of object size during transport. Differences between the hand and foot were found in the deceleration phase and time of maximum grip aperture, likely due to biomechanical differences and the participants’ inexperience with foot actions. These findings provide evidence for effector-independent visuomotor mechanisms of reaching and grasping that generalize across body parts.
Understanding the Genetics of Viral Drug Resistance by Integrating Clinical Data and Mining of the Scientific Literature
Authors: Goto An , Rodriguez-Esteban Raul , Scharf Sebastian H. , Morris Garrett M. 
Published: October 2021

AbstractDrug resistance caused by mutations is a public health threat for existing and emerging viral diseases. A wealth of evidence about these mutations and their clinically-associated phenotypes is scattered across the literature, but a comprehensive perspective is usually lacking. This work aimed to produce a clinically-relevant view for the case of Hepatitis B virus (HBV) mutations by combining a chronic HBV clinical study with a compendium of genetic mutations systematically gathered from the scientific literature. We enriched clinical mutation data by systematically mining 2,472,725 scientific articles from PubMed Central in order to gather information about the HBV mutational landscape. By performing this analysis, we were able to identify mutational hotspots for each HBV genotype (A-E) and gene (C, X, P, S), as well as the location of disulfide bonds associated with these mutations. Through a modelling study, we also identified a mutational position common in both the clinical data and the literature that is located at the binding pocket for a known anti-HBV drug, namely entecavir. The results of this novel approach shows the potential of integrated analyses to assist in the development of new drugs for viral diseases that are more robust to resistance. Such analyses should be of particular interest due to the increasing importance of viral resistance in established and emerging viruses, such as for newly-developed drugs against SARS-CoV-2.
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation
Authors: Chen Xuyong , Sunkel Benjamin , Wang Meng , Kang Siwen , Wang Tingting , Gnanaprakasam JN Rashida , Liu Lingling , Cassel Teresa A. , Scott David A. , Muñoz-Cabello Ana M. , Lopez-Barneo Jose , Yang Jun , Lane Andrew N. , Xin Gang , Stanton Benjamin , Fan Teresa W.-M. , Wang Ruoning 
Published: October 2021

AbstractRobust and effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain energetically costly processes like growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By employing complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fuels biosynthetic processes while controlling the ratio of α-ketoglutarate/succinate to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells causes proliferation and survival defects when the TCA cycle is truncated, blocking carbon flux to support nucleosides biosynthesis. Accordingly, replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. Conversely, SDH deficiency induces a pro-inflammatory gene signature in T cells and promotes T helper 1 (TH1) and T helper 17 (TH17) lineage differentiation. Mechanistically, the hypoxia-inducible factor 1 (HIF-1) is not required for succinate-induced inflammation in T cells. A reduced α-ketoglutarate/succinate ratio in SDH deficient T cells promotes inflammation through changing the pattern of the transcriptional and chromatin-accessibility signatures and consequentially increasing the expression of the transcription factor, B lymphocyte-induced maturation protein-1 (Blimp-1). Collectively, our studies revealed a critical role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.
Sign inversion in selection on ploidy
Authors: Raynes Yevgeniy , Weinreich Daniel M. 
Published: October 2021

AbstractPloidy – the number of homologous chromosome sets in a cell – is remarkably variable across the natural world, yet the evolutionary processes that have resulted in such diversity remain poorly understood. Here we use stochastic agent-based simulations to model ploidy evolution under the influence of indirect selection, i.e., selection mediated solely by statistical associations with fitness-affecting mutations. We find that in non-equilibrium asexual populations, the sign of selection on ploidy can change with population size – a phenomenon we have previously termed sign inversion. In large populations, ploidy dynamics are dominated by indirect effects of selection on beneficial mutations, which favors haploids over diploids. However, as population size declines, selection for beneficial mutations is neutralized by random genetic drift before drift can overwhelm selection against the cost of the deleterious mutational load. As a result, in small populations indirect selection is dominated by the cost of the deleterious load, which favors diploids over haploids. Our work adds to the growing body of evidence challenging established evolutionary theory that population size can affect only the efficiency, but not the sign, of natural selection.
DeepMicroClass sorts metagenomes into prokaryotes, eukaryotes and viruses, with marine applications
Authors: Hou Shengwei , Tang Tianqi , Cheng Siliangyu , Chen Ting , Fuhrman Jed A. , Sun Fengzhu 
Published: October 2021

AbstractSequence classification reduces the complexity of metagenomes and facilitates a fundamental understanding of the structure and function of microbial communities. Binary metagenomic classifiers offer an insufficient solution because environmental metagenomes are typically derived from multiple sequence sources, including prokaryotes, eukaryotes and the viruses of both. Here we introduce a deep-learning based (as opposed to alignment-based) sequence classifier, DeepMicroClass, that classifies metagenomic contigs into five sequence classes, i.e., viruses infecting prokaryotic or eukaryotic hosts, eukaryotic or prokaryotic chromosomes, and prokaryotic plasmids. At different sequence lengths, DeepMicroClass achieved area under the receiver operating characteristic curve (AUC) scores >0.98 for most sequence classes, with the exception of distinguishing plasmids from prokaryotic chromosomes (AUC scores≈0.97). By benchmarking on 20 designed datasets with variable sequence class composition, we showed that DeepMicroClass obtained average accuracy scores of ∼0.99, ∼0.97, and ∼0.99 for eukaryotic, plasmid and viral contig classification, respectively, which were significantly higher than the other state-of-the-art individual predictors. Using a 1-300 µm daily time-series metagenomic dataset sampled from coastal Southern California as a case study, we showed that metagenomic read proportions recruited by eukaryotic contigs could be doubled with DeepMicroClass’s classification compared to the counterparts of other alignment-based classifiers. With its inclusive modeling and unprecedented performance, we expect DeepMicroClass will be a useful addition to the toolbox of microbial ecologists, and will promote metagenomic studies of under-appreciated sequence types.
The transcription factor IscR promotesYersiniatype III secretion system activity by antagonizing the repressive H-NS-YmoA histone-like protein complex
Authors: Balderas David , Alvarez Pablo , Ohanyan Mané , Mettert Erin , Tanner Natasha , Kiley Patricia J. , Auerbuch Victoria 
Published: October 2021

AbstractThe type III secretion system (T3SS) is a appendage used by many bacterial pathogens, such as pathogenicYersinia, to subvert host defenses. However, because the T3SS is energetically costly and immunogenic, it must be tightly regulated in response to environmental cues to enable survival in the host. Here we show that expression of theYersiniaYsc T3SS master regulator, LcrF, is orchestrated by the opposing activities of the repressive YmoA/H-NS histone-like protein complex and induction by the iron and oxygen-regulated IscR transcription factor. Although IscR has been shown to bind thelcrFpromoter and is required forin vivoexpression oflcrF, in this study we show IscR alone fails to enhancelcrFtranscriptionin vitro. Rather, we find that in aymoAmutant, IscR is no longer required for LcrF expression or T3SS activity. Additionally, a mutation in YmoA that prevents H-NS binding (ymoAD43N) rescues the T3SS defect of a ΔiscRmutant, suggesting that a YmoA/H-NS complex is needed for this repressive activity. Furthermore, chromatin immunoprecipitation analysis revealed that H-NS is enriched at thelcrFpromoter at environmental temperatures, while IscR is enriched at this promoter at mammalian body temperature under aerobic conditions. Importantly, CRISPRi knockdown of H-NS leads to increasedlcrFtranscription. Collectively, our data suggest that as IscR levels rise with iron limitation and oxidative stress, conditionsYersiniaexperiences during extraintestinal infection, IscR antagonizes YmoA/H-NS-mediated repression oflcrFtranscription to drive T3SS activity and manipulate host defense mechanisms.Author SummaryFacultative pathogens must silence virulence gene expression during growth in the environment, while retaining the ability to upregulate these genes upon infection of a host. H-NS is an architectural DNA binding protein proposed to silence horizontally acquired genes, regulating virulence genes in a number of pathogens. Indeed, H-NS was predicted to regulate plasmid-encoded virulence genes in pathogenicYersinia. However,YersiniaH-NS is reported to be essential, complicating testing of this model. We used chromatin immunoprecipitation and inducible CRISPRi knockdown to show that H-NS binds to the promoter of a critical plasmid-encoded virulence gene, silencing its expression. Importantly, under conditions that mimicYersiniainfection of a mammalian host, the transcriptional regulator IscR displaces H-NS to drive virulence factor expression.
Using machine learning to improve diagnostic assessment of ASD in the light of specific differential diagnosis
Authors: Schulte-Rüther Martin , Kulvicius Tomas , Stroth Sanna , Roessner Veit , Marschik Peter , Kamp-Becker Inge , Poustka Luise 
Published: October 2021

AbstractBackgroundDiagnostic assessment of ASD requires substantial clinical experience and is particular difficult in the context of other disorders with behavioral symptoms in the domain of social interaction and communication. Observation measures such as the Autism Diagnostic Observation Schedule (ADOS) do not take into account such comorbid and differential disorders.MethodWe used a well-characterized clinical sample of individuals (n=1262) that had received detailed outpatient evaluation for the presence of an ASD diagnosis (n=481) and covered a range of additional differential or overlapping diagnoses, including anxiety related disorders (ANX, n=100), ADHD (n=440), and conduct disorder (CD, n=192). We focused on ADOS module 3, covering the age range with particular high prevalence of such differential diagnoses. We used machine learning (ML) and trained random forest models on ADOS single item scores to predict a clinical best estimate diagnosis of ASD in the context of these differential diagnoses (ASD vs. ANX, ASD vs. ADHD, ASD vs. CD) and an unspecific model using all available data. We employed nested cross-validation for an unbiased estimate of classification performance (ASD vs. non-ASD).ResultsWe obtained very good overall sensitivity (0.89-0.94) and specificity (0.87-0.89) for the classification of ASD vs. non-ASD. In particular for individuals with less severe symptoms (around the ADOS cut-off) our models showed increases of up to 20% in sensitivity or specificity. Furthermore, we analyzed item importance profiles of the ANX-, ADHD- and CD-models in comparison to the unspecific model. These analyses revealed distinct patterns of importance for specific ADOS-items with respect to differential diagnoses.ConclusionUsing ML-based diagnostic classification may improve clinical decisions by utilizing the full range of information from comprehensive and detailed diagnostic observation such as the ADOS. Importantly, this strategy might be of particular relevance for individuals with less severe symptoms that typically present a very difficult decision for the clinician.
Racial identity and mental health stigma among Black adults in the United States
Authors: Pederson Aderonke Bamgbose , Hawkins Devan 
Published: October 2021

AbstractObjectivesMental illness stigma is a barrier to engagement in mental health services. This study assesses our hypothesis that specific racial identity dimensions influences mental health behavior including stigma.MethodsWe performed an online cross sectional observational study among Black adults (n = 248, ages 18-65). We examined the relationship between an individual’s approach to their racial identity in the community and stigma behavior towards mental health; generalized linear models were performed. We assessed demographic characteristics as moderators of the primary association.ResultsBlack adults with higher centrality reported lower past stigma behavior (RR=1.57, CI: 1.11–2.21, p=0.01), but higher future intended stigma behavior (RR=0.93, CI: 0.88–0.99, p=0.02). Majority of respondents reported high centrality and high assimilation; however, assimilation did not appear to correlate with mental health stigma behavior. Age, education and ethnicity appeared to have a limited moderating effect on the association between centrality and stigma behavior.ConclusionsCentrality was associated with mental health stigma behavior. By understanding the intersecting characteristics that may increase the likelihood for mental illness stigma, we will be better able to reduce mental illness stigma and optimize engagement in mental health services.
A spatial fingerprint of land-water linkage of biodiversity uncovered by remote sensing and environmental DNA
Authors: Zhang Heng , Mächler Elvira , Morsdorf Felix , Niklaus Pascal A. , Schaepman Michael E. , Altermatt Florian 
Published: October 2021

AbstractAquatic and terrestrial ecosystems are tightly connected via spatial flows of organisms and resources. Such land-water linkages integrate biodiversity across ecosystems and suggest a spatial association of aquatic and terrestrial biodiversity. However, knowledge about this spatial extent is limited. By combining satellite remote sensing (RS) and environmental DNA (eDNA) extraction from river water across a 740-km2mountainous catchment, we identify a characteristic spatial land-water fingerprint. Specifically, we find a spatial association of riverine eDNA diversity with RS spectral diversity of terrestrial ecosystems upstream, peaking at a 400 m distance yet still detectable up to a 3.3 km radius. Our findings testify that biodiversity patterns in rivers can be linked to the functional diversity of surrounding terrestrial ecosystems and provide a dominant scale at which these linkages are strongest. Such spatially explicit information is necessary for a functional understanding of land-water linkages and provides a reference scale for adequate conservation and landscape management decisions.
The structure of a native orthobunyavirus ribonucleoprotein reveals a key role for viral RNA in maintaining its helical architecture
Authors: Hopkins Francis R. , Álvarez-Rodríguez Beatriz , Heath George R. , Panayi Kyriakoulla , Hover Samantha , Edwards Thomas A. , Barr John N. , Fontana Juan 
Published: October 2021

AbstractThe Bunyavirales order of RNA viruses comprises emerging pathogens for which approved preventative or therapeutic measures for human use are not available. The genome of all Bunyavirales consists of negative-sense RNA segments wrapped by the virus-encoded nucleocapsid protein (NP) to form ribonucleoproteins (RNPs). RNPs represent the active template for RNA synthesis and the form in which the genome is packaged into virions, functions that require inherent flexibility. We present a pseudo-atomic model of a native RNP purified from Bunyamwera virus (BUNV), the prototypical Bunyavirales member, based on a cryo-electron microscopy (cryo-EM) average at 13 Å resolution with subsequent fitting of the BUNV NP crystal structure by molecular dynamics. We show the BUNV RNP possesses relaxed helical architecture, with successive helical turns separated by ∼18 Å. The model shows that adjacent NP monomers in the RNP chain interact laterally through flexible N- and C-terminal arms, with no helix-stabilizing interactions along the longitudinal axis. Instead, EM analysis of RNase-treated RNPs suggests their chain integrity is dependent on the encapsidated genomic RNA, thus providing the molecular basis for RNP flexibility. Overall, this work will assist in designing anti-viral compounds targeting the RNP and inform studies on bunyaviral RNP assembly, packaging and RNA replication.SignificanceBunyaviruses are emerging RNA viruses that cause significant disease and economic burden and for which vaccines or therapies approved for human use do not exist. The bunyavirus genome does not exist as naked RNA; instead it is wrapped up by the nucleoprotein (NP) to form a ribonucleoprotein (RNP). Using the prototypical bunyavirus, Bunyamwera virus, we determined the 3D structure of the native RNP, revealing a helical architecture with NP molecules linked by lateral contacts only, with no helix-stabilizing longitudinal contacts. Instead, the RNA genome itself plays a role in maintaining the helical architecture, allowing a high degree of flexibility that is critical for several stages of the virus replication cycle, such as segment circularization and genome packaging into virions.
Clonal gametogenesis is triggered by intrinsic stimuli in the hybrid’s germ cells but is dependent on sex differentiation
Authors: Tichopád Tomáš , Franěk Roman , Doležálková-Kaštánková Marie , Dedukh Dmitrij , Marta Anatolie , Halačka Karel , Steinbach Christoph , Janko Karel , Pšenička Martin 
Published: October 2021

AbstractInterspecific hybridization may trigger the transition from sexual reproduction to asexuality, but mechanistic reasons for such a change in a hybrid’s reproduction are poorly understood. Gametogenesis of many asexual hybrids involves a stage of premeiotic endoreduplication (PMER), when gonial cells duplicate chromosomes and subsequent meiotic divisions involve bivalents between identical copies, leading to production of clonal gametes. Here, we investigated the triggers of PMER and whether its induction is linked to intrinsic stimuli within a hybrid’s gonial cells or whether it is regulated by the surrounding gonadal tissue.We investigated gametogenesis in theCobitis taeniahybrid complex, which involves sexually reproducing species (Cobitis elongatoidesandC. taenia) as well as their hybrids, where females reproduce clonallyviaPMER while males are sterile. We transplanted spermatogonial stem cells (SSCs) fromC. elongatoidesand triploid hybrid males into embryos of sexual species and of asexual hybrid females, respectively, and observed their development in an allospecific gonadal environment. Sexual SSCs underwent regular meiosis and produced normally reduced gametes when transplanted into clonal females. On the other hand, the hybrid’s SSCs lead to sterility when transplanted into sexual males, but maintained their ability to undergo asexual development (PMER) and production of clonal eggs, when transplanted into sexual females.This suggests that asexual gametogenesis is under complex control when somatic gonadal tissue indirectly affects the execution of asexual development by determining the sexual differentiation of stem cells and once such cells develop to female phenotypes, hybrid germ cells trigger the PMER from their intrinsic signals.Significance StatementAlthough sexual reproduction is a dominant trait among all eukaryotes, many taxa have evolved the ability to reproduce asexually. While asexuality appears to be linked to interspecific hybridization, it remains unknown how the coexistence of diverged genomes may initiate such a swap in reproduction. In our study, we transplanted germ cells between asexual hybrids and their parents. On one hand, the ability of clonal gametogenesis occurred exclusively in hybrid germ cells, suggesting that asexual development is directly triggered by the hybrid genomic constitution of the cell. On the other hand, clonality was observed only in cells transplanted into females, suggesting that the execution of clonal development is influenced by signals from the gonadal environment and regulated by somatic factors.