bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plastid genome evolution in leafless members of the orchid subfamily Orchidoideae, with a focus onDegranvillea dermaptera
Authors: Barrett Craig F. , Pace Matthew C. , Corbett Cameron W. 
Published: November 2023

ABSTRACTPremiseLeafless, heterotrophic plants are prime examples of organismal modification, the genomic consequences of which have received considerable interest. In particular, plastid genomes (plastomes) are being sequenced at a high rate, allowing continual refinement of conceptual models of reductive evolution in heterotrophs. Yet, numerous sampling gaps exist, hindering the ability to conduct comprehensive phylogenomic analyses in these plants.MethodsWe sequenced and analyzed the plastome ofDegranvillea dermaptera, a rarely collected, leafless orchid species from South America about which little is known, including its phylogenetic affinities.Key ResultsWe revealed the most reduced plastome sequenced to date among the orchid subfamily Orchidoideae.Degranvilleahas lost the majority of genes found in leafy autotrophic species, is structurally rearranged, and has similar gene content to the most reduced plastomes among the orchids. We found strong evidence for the placement ofDegranvilleawithin the subtribe Spiranthinae using models that explicitly account for heterotachy, or lineage-specific evolutionary rate variation over time. We further found evidence of relaxed selection on several genes and correlations among substitution rates and several other “traits” of the plastome among leafless members of orchid subfamily Orchidoideae.ConclusionsOur findings advance knowledge on the phylogenetic relationships and paths of plastid genome evolution among the orchids, which have experienced more independent transitions to heterotrophy than any other plant family. This study demonstrates the importance of herbarium collections in comparative genomics of poorly known species of conservation concern.
Evolution in action: Brown-headed Cowbirds (Molothrus ater) adapt songs to 50 years of Ohio urbanization
Authors: Ruscitelli Kristen , Provost Kaiya 
Published: November 2023

ABSTRACTTechnological advances in the last century have allowed humans to rapidly alter the landscape, resulting in a global loss of biodiversity. Of such alterations, is the conversion of rural land into urban space. In birds, urbanization has been found to impact song to facilitate improved auditory communication between conspecifics in areas with increased background noise. Given that birdsong is an important reproductive behavior, it is possible that urbanization promotes the evolution of birdsong through differences in fitness between individuals in urban acoustic environments. Here, we investigated if urbanization across Ohio impacts song characteristics of Brown-headed Cowbirds (Molothrus ater), a brood parasite associated with cropland and other altered habitats. To assess change inM. atersong over space and time, we compared syllable shape and syllable properties with metrics of urbanization. It was found thatM. atersong differs significantly across geographic space and time, and is associated with changes in urbanization. Cowbird song of conspecifics in preferred habitat, such as cropland, demonstrates different syllable shape than conspecifics in urban space. This suggests that urbanization could facilitate change inM. atersong over time. These results provide additional insight into how anthropogenic habitat alteration facilitates cultural evolution in birds, and allows for increased understanding of how human behavior contributes to altered ecological interactions.
The microbial community of rust layer biofilm was driven by seawater microbial community
Authors: Yao Shengxun , Lai Junxiang , Sun Congtao , Pan Zihan , Zhao Maomi , Duan Jizhou , Hou Baorong 
Published: November 2023

ABSTRACTMicrobiologically influenced corrosion (MIC) accounts for approximately 20% of the total corrosion-related losses worldwide, causing significant economic damage each year, particularly in Marine environments. However, there are still no truly effective and eco-friendly protection solutions against MIC, among which the incomplete understanding of the microbial biofilm development on metallic surface is a key limitation. Using 16S rRNA and ITS sequencing, we studied bacterial and fungal communities in rust layer biofilm and seawater. The results showed that Proteobacteria, Cyanobacteria and Bacteroidota were the dominant bacterial phyla, and Ascomycota and Basidiomycota were the dominant fungal phyla both in the rust layer biofilm and seawater. Bacteria like Erythrobacter and Aquimarina, as well as fungi like Aspergillus and Acremonium were were notable microorganisms in the rust layer biofilm. Source analysis revealed differences between biofilm and seawater communities, with 23.08% bacterial and 21.48% fungal communities originating from seawater. Stochastic processes governed biofilm and seawater microbial communities, and network analysis showed coexistence and interaction among bacteria and fungi.IMPORTANCEThe composition and source analysis of bacterial and fungal communities in the rust layer and seawater were studied, and the interaction of bacteria and fungi in the rust layer was discussed for the first time. Based on these findings, we provided a framework to explain the observed characteristics of microbial communities in rust layer biofilm and presented key evidence supporting the relationship between different microbial structures and interactions with metal corrosion. These findings, from the perspective of microbial ecology, provide a theoretical foundation for studying microbial corrosion in marine environments.
Pseudotime analysis for time-series single-cell sequencing and imaging data
Authors: Li Gang , Kim Hyeon-Jin , Pendyala Sriram , Zhang Ran , Disteche Christine M. , Vert Jean-Philippe , Deng Xinxian , Fowler Douglas M. , Noble William Stafford 
Published: November 2023

AbstractMany single-cell RNA-sequencing studies have collected time-series data to investigate transcriptional changes concerning various notions of biological time, such as cell differentiation, embryonic development, and response to stimulus. Accordingly, several unsupervised and supervised computational methods have been developed to construct single-cell pseudotime embeddings for extracting the temporal order of transcriptional cell states from these time-series scRNA-seq datasets. However, existing methods, such as psupertime, suffer from low predictive accuracy, and this problem becomes even worse when we try to generalize to other data types such as scATAC-seq or microscopy images. To address this problem, we propose Sceptic, a support vector machine model for supervised pseudotime analysis. Whereas psupertime employs a single joint regression model, Sceptic simultaneously trains multiple classifiers with separate score functions for each time point and also allows for non-linear kernel functions. Sceptic first generates a probability vector for each cell and then aims to predict chronological age via conditional expectation. We demonstrate that Sceptic achieves significantly improved prediction power (accuracy improved by 1.4−38.9%) for six publicly available scRNA-seq data sets over state-of-the-art methods, and that Sceptic also works well for single-nucleus image data. Moreover, we observe that the pseudotimes assigned by Sceptic show stronger correlations with nuclear morphology than the observed times, suggesting that these pseudotimes accurately capture the heterogeneity of nuclei derived from a single time point and thus provide more informative time labels than the observed times. Finally, we show that Sceptic accurately captures sex-specific differentiation timing from both scATAC-seq and scRNA-seq data.
Development of a high-throughput pipeline to characterize microglia morphological states at a single-cell resolution
Authors: Kim Jennifer , Pavlidis Paul , Ciernia Annie Vogel 
Published: November 2023

AbstractAs rapid responders to their environments, microglia engage in functions that are mirrored by their cellular morphology. Microglia are classically thought to exhibit a ramified morphology under homeostatic conditions which switches to an ameboid form during inflammatory conditions. However, microglia display a wide spectrum of morphologies outside of this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, which have been observed across brain regions, neurodevelopmental timepoints, and various pathological contexts. We used dimensionality reduction and clustering approaches to consider contributions of multiple morphology measures together to define a spectrum of microglial morphological states. Using ImageJ tools, we first developed a semi-automated approach to characterize 27 morphology features from hundreds to thousands of individual microglial cells in a brain subregion-specific manner. Within this pool of morphology measures, we defined distinct sets of highly correlated features that describe different aspects of morphology, including branch length, branching complexity, territory span, and cell circularity. When considered together, these sets of features drove different morphological clusters. Furthermore, our analysis toolset captured morphological states similarly and robustly when applied to independent datasets and using different immunofluorescent markers for microglia. We have compiled our morphology analysis pipeline into an accessible, easy to use, and fully open-source ImageJ macro and R package that the neuroscience community can expand upon and directly apply to their own analyses. Outcomes from this work will supply the field with new tools to systematically evaluate the heterogeneity of microglia morphological states across various experimental models and research questions.
The chikungunya virus E1 glycoprotein fusion loop and hinge alter glycoprotein dynamics leading to cell and host specific changes in infectivity
Authors: Thannickal Sara A. , Battini Leandro , Spector Sophie N. , Noval Maria G. , Álvarez Diego E. , Stapleford Kenneth A. 
Published: November 2023

AbstractAlphaviruses infect both mammals and insects, yet the distinct mechanisms that alphaviruses use to infect different hosts are not well defined. In this study, we characterize CHIKV E1 variants in the fusion loop (E1-M88L) and hinge region (E1-N20Y)in vitroandin vivoto understand how these regions of the E1 glycoprotein contribute to host-specific infection. Through cell culture assays, we found that CHIKV E1-N20Y enhanced infectivity in mosquito cells while the CHIKV E1-M88L variant enhanced virus binding and infectivity in both BHK-21 and C6/36 cells, and led to changes in the virus cholesterol-dependence in BHK-21 cells. Given thesein vitroresults and that residue E1-M88L is in a defined Mxra8 interacting domain, we hypothesized that this residue may be important for receptor usage. However, while the CHIKV E1-M88L variant increased replication in Mxra8-deficient mice compared to WT CHIKV, it was attenuatedin vitroin mouse fibroblasts, suggesting that residue E1-M88 may function in a cell-type dependent manner to alter entry. Finally, using molecular dynamics to understand how potential changes in the E1 glycoprotein may impact the CHIKV glycoprotein E1-E2 complex, we found that E1-M88L and other E1 domain II variants lead to changes in both E1 and E2 dynamics. Taken together, these studies show that key residues in the CHIKV E1 fusion loop and hinge region function through changes in E1-E2 dynamics to facilitate cell- and host-dependent entry.ImportanceArthropod-borne viruses (arboviruses) are significant global public health threats, and their continued emergence around the world highlights the need to understand how these viruses replicate at the molecular level. The alphavirus class II glycoproteins are critical for virus entry in mosquitoes and mammals, yet how these proteins function is not completely understood. Therefore, to address these gaps in our knowledge, it is critical to dissect how distinct glycoprotein domains functionin vitroandin vivo. Here, we show that changes in the CHIKV E1 fusion loop and hinge contribute to host-specific entry and E1-E2 dynamics, furthering our knowledge of how alphaviruses infect mammals and insects.
Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia
Authors: Figge David A. , de Amaral Oliveira Henrique , Crim Jack , Cowell Rita M. , Standaert David G. , Eskow Jaunarajs Karen L. 
Published: November 2023

AbstractL-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine replacement therapy with L-DOPA for the treatment of Parkinson disease (PD). The emergence of LID is linked to heightened sensitivity of striatal dopaminergic signaling and driven by abnormal fluctuations in synaptic dopamine levels following each administration of L- DOPA. This maladaptive plasticity narrows the therapeutic window for L-DOPA treatment, even as the progressive worsening of PD symptoms demands escalating doses. The heterogeneous composition of the striatum, including diverse subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, has complicated the precise identification of the cell(s) underlying LID development and persistence. To elucidate the cellular and molecular mechanisms of LID, we used single nucleus RNA-sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional profile during the development and maintenance of LID in an animal model. Hemiparkinsonian mice were treated with vehicle or L-DOPA for progressive durations (1, 5, or 10 d) and nuclei from the striata were processed for snRNA-seq. Our analysis found that a limited population of dopamine D1 receptor-expressing MSNs (D1-MSNs), arising from both the patch and matrix compartments, formed three subclusters in response to L-DOPA treatment that expressed cellular markers of activation. These activated D1-MSN subpopulations display many of the transcriptional changes previously associated with LID; however, the prevalence and transcriptional behavior of activated D1-MSNs was differentially influenced by the extent of L-DOPA experience. The differentially expressed genes found in these D1-MSNs indicated that acute L-DOPA induced upregulation of multiple plasticity-related transcription factors and regulators of MAPK signaling, while repeated L-DOPA exposure induced numerous genes associated with synaptic remodeling, learning and memory, and transforming growth factor-ß (TGFß) signaling. Notably, repeated L-DOPA led to a sensitization in the expression ofInhba,a member of the activin/TGFß superfamily, in activated D1-MSNs. We tested pharmacological inhibition of its receptor, ALK4, and found that it impaired LID development. Collectively, these data suggest that distinct subsets of D1-MSNs become differentially responsive to L-DOPA due to the aberrant induction of the molecular mechanisms necessary for neuronal entrainment, similar to those processes underlying hippocampal learning and memory formation. Our data further suggests that activin/TGFß signaling may play an essential role in LID development in this subpopulation of D1-MSNs.
Accurate 3D SMLM localization via Vectorial In-situ PSF Retrieval and Aberration Assessment
Authors: Yang Xinxun , Zhu Hongfei , Sun Yile , Wu Hanmeng , Han Yubing , Hao Xiang , Zhou Renjie , Kuang Cuifang , Liu Xu 
Published: November 2023

AbstractIn single-molecule localization microscopy (SMLM), achieving precise localization hinges on obtaining an authentic point spread function (PSF) influenced by system and sample-induced aberrations. Here, we introduce VISPR (Vectorial in-situ PSF retrieval) retrieving precise 3D PSF models considering both system and sample-induced aberrations under SMLM conditions. By employing the theory of vectorial PSF model and maximum likelihood estimation (MLE) phase retrieval, VISPR is capable of reconstructing an accurate 3D PSF model achieving the theoretically minimum uncertainty and accurately reflecting three-dimensional information of single molecules. This capability empowers accurate 3D super-resolution reconstruction in 3D SMLM. Additionally, VISPR applies to low signal-to-noise ratio circumstances and is adept at retrieving high-frequency details of the experimental PSF across an extensive depth range—a challenging feat for alternative approaches. As an effective tool, VISPR enables the quantitative assessment of aberrations induced by the system and sample environment. From the simulations and experiments, we verified the superiority and effectiveness of VISPR. It is essential to highlight that VISPR applies to various SMLM microscope modalities.
Deep Reinforcement Learning Enables Better Bias Control in Benchmark for Virtual Screening
Authors: Shen Tao , Li Shan , Wang Xiang Simon , Wang Dongmei , Wu Song , Xia Jie , Zhang Liangren 
Published: November 2023

AbstractVirtual screening (VS) has been incorporated into the paradigm of modern drug discovery. This field is now undergoing a new wave of revolution driven by artificial intelligence and more specifically, machine learning (ML). In terms of those out-of-the- box datasets for model training or benchmarking, their data volume and applicability domain are limited. They are suffering from the biases constantly reported in the ML application. To address these issues, we present a novel benchmark named MUBDsyn. The utilization of synthetic decoys (i.e., presumed inactives) is the main feature of MUBDsyn, where deep reinforcement learning was leveraged for bias control during decoy generation. Then, we carried out extensive validations on this new benchmark. First, we confirmed that MUBDsynwas superior to the classical benchmarks in control of domain bias, artificial enrichment bias and analogue bias. Moreover, we found that the assessment of ML models based on MUBDsynwas less biased as revealed by the analysis of asymmetric validation embedding bias. In addition, MUBDsynshowed better setting of benchmarking challenge for deep learning models compared with NRLiSt- BDB. Overall, we have proven that MUBDsynis the close-to-ideal benchmark for VS. The computational tool is publicly available for the easy extension of MUBDsyn.
Drug target Mendelian randomization supports apolipoprotein C3-lowering for lipoprotein-lipid levels reductions and cardiovascular diseases prevention
Authors: Gagnon Eloi , Arsenault Benoit J. 
Published: November 2023

AbstractBackground and aimsInhibitors of apolipoprotein C-III (apoC3) are currently approved for the reduction of triglyceride levels in patients with Familial Chylomicronemia Syndrome. We used drug target Mendelian randomization (MR) to assess the effect of genetically predicted decrease in APOC3 blood protein levels on cardiometabolic traits and diseases.MethodsWe quantified lifelong reductions in APOC3 blood levels by selecting all genome wide significant and independent (r2<0.1) single nucleotide polymorphisms (SNPs) in theAPOC3gene region ±1Mb, from three genome-wide association studies (GWAS) of apoC3 blood protein levels (deCODE, n = 35,378, Fenland, n = 10,708 and ARIC, n = 7,213). We included the largest GWASes on 18 cardiometabolica traits and 9 cardiometabolic diseases as study outcomes.ResultsA one standard deviation lowering in apoC3 blood protein levels was associated with lower triglycerides, apolipoprotein B, density lipoprotein cholesterol, alanine aminotransferase, and glomerular filtration rate as well as higher high-density lipoprotein cholesterol levels. APOC3 lowering was also associated with lower risk of acute pancreatitis (odds ratio [OR] = 0.91 95% CI=0.82 to 1.00), aortic stenosis (OR = 0.82 95% CI=0.73 to 0.93), and coronary artery disease (OR = 0.86 95% CI=0.80 to 0.93), and was associated with increased parental lifespan (0.06 95% CI=0.03 to 0.09 years). These results were concordant across robust MR methods, the three protein datasets and upon adjustment for APOA1, APOA4 and APOA5 using a multivariable MR framework.ConclusionsThese results provide evidence that apoC3 lowering could result in widespread benefits for cardiometabolic health and encourage the launch of trials on apoC3 inhibition for coronary artery disease prevention.
DNA methylation effects on Van der Woude Syndrome phenotypic variability
Authors: Seaberg Amanda , Awotoye Waheed , Qian Fang , Dunlay Lindsey , Butali Azeez , Murray Jeff , Moreno-Uribe Lina , Petrin Aline 
Published: November 2023

AbstractOBJECTIVEVan der Woude Syndrome (VWS) classically presents with combinations of lip pits (LP) and orofacial clefts, with marked phenotypic discordance even amongst individuals carrying the same mutation. Such discordance suggests a possible role for epigenetic factors as phenotypic modifiers. BothIRF6, causal for 70% of VWS cases, andTP63interact in a regulatory loop to coordinate epithelial proliferation and differentiation for palatogenesis. We hypothesize that differential DNA methylation (DNAm) in CpG sites within regulatory regions ofIRF6andTP63are associated with VWS phenotypic discordance.METHODSWe measured DNAm levels of CpG sites located in the promoter regions ofIRF6andTP63and in anIRF6enhancer element (MCS9.7) in 83 individuals with VWS grouped within 5 phenotypes for primary analysis: 1=CL+/-P+LP, 2=CL+/-P, 3=CP+LP, 4=CP, 5=LP and 2 phenotypes for secondary analysis: 1=any cleft and LP, 2= any cleft without LP. DNA samples were bisulfite converted and pyrosequenced with target-specific primers. Methylation levels were compared amongst phenotypes.RESULTSCpG sites in theIRF6promoter showed statistically significant differences in methylation among phenotypic groups in both analyses (P<0.05). Individuals with any form of cleft (Groups 1-4) had significantly higher methylation levels than individuals with lip pits only (Group 5). In the secondary analysis, individuals in Group 1 (cleft+LP) had significantly higher methylation than Group 2 (cleft only).CONCLUSIONResults indicated that hypermethylation of theIRF6promoter is associated with more severe phenotypes (any cleft +/- lip pits); thus, possibly impacting an already genetically weakenedIRF6protein and leading to a more severe phenotype.
Genomic structures and regulation patterns at HPV integration sites in cervical cancer
Authors: Porter Vanessa L. , O’Neill Kieran , MacLennan Signe , Corbett Richard D. , Ng Michelle , Culibrk Luka , Hamadeh Zeid , Iden Marissa , Schmidt Rachel , Tsaih Shirng-Wern , Chang Glenn , Fan Jeremy , Nip Ka Ming , Akbari Vahid , Chan Simon K. , Hopkins James , Moore Richard A. , Chuah Eric , Mungall Karen L. , Mungall Andrew J. , Birol Inanc , Jones Steven J. M. , Rader Janet S. , Marra Marco A. 
Published: November 2023

AbstractHuman papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression inciswith the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.