bluuebunny/crossref_metadata_2025_split huggingface dataset:
Creating an automated tool for a consistent and repeatable evaluation of disability progression in clinical studies for Multiple Sclerosis
Authors: Montobbio Noemi , Carmisciano Luca , Signori Alessio , Ponzano Marta , Schiavetti Irene , Bovis Francesca , Sormani Maria Pia 
Published: February 2024

AbstractBackgroundThe lack of standardized disability progression evaluation in multiple sclerosis (MS) hinders reproducibility of clinical study results, due to heterogeneous and poorly reported criteria.ObjectivesTo demonstrate the impact of using different parameters when evaluating MS progression, and to introduce an automated tool for reproducible outcome computation.MethodsRe-analyzing BRAVO clinical trial data (NCT00605215), we examined the fluctuations in computed treatment effect on confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) when varying different parameters. These analyses were conducted using themsprogpackage for R, which we developed as a tool for CDP assessment from longitudinal data, given a set of criteria that can be specified by the user.ResultsThe BRAVO study reported a hazard ratio (HR) of 0.69 (95%CI:0.46-1.02) for CDP. Using the different parameter configurations, the resulting treatment effect on CDP varied considerably, with HRs ranging from 0.59 (95%CI:0.41-0.86) to 0.72 (95%CI:0.48-1.07). The treatment effect on PIRA varied from an HR=0.62 (95%CI:0.41-0.93) to an HR=0.65 (95%CI:0.40-1.04).ConclusionsThe adoption of an open-access tool validated by the research community, with clear parameter specification and standardized output, could greatly reduce heterogeneity in CDP estimation and promote repeatability of study results.
Structural covariance networks in the fetal brain reveal altered neurodevelopment for specific subtypes of congenital heart disease
Authors: Wilson Siân , Cromb Daniel , Bonthrone Alexandra F. , Uus Alena , Price Anthony , Egloff Alexia , Van Poppe Milou P.M , Steinweg Johannes K , Pushparajah Kuberan , Simpson John , Lloyd David FA , Razavi Reza , O’Muircheartaigh Jonathan , Edwards A. David , Hajnal Joseph V. , Rutherford Mary , Counsell Serena J. 
Published: February 2024

AbstractBackgroundAltered structural brain development has been identified in fetuses with Congenital Heart Disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics.MethodsWe extracted structural covariance networks (SCNs) from the log Jacobian determinants of 429 in utero T2w MRI scans, (n = 67 controls, 362 CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery and CHD diagnosis were significant predictors of structural covariance.ResultsWe identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of SCNs, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra-axial CSF, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester.ConclusionsSCNs offer a sensitive, data-driven approach to explore whole-brain structural changes without anatomical priors. We used them to stratify a heterogenous CHD patient cohort, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.
Cryo-EM structures of human cone visual pigments
Authors: Peng Qi , Li Jian , Jiang Haihai , Cheng Xinyu , Lu Qiuyuan , Zhou Sili , Zhang Yuting , Lv Sijia , Wan Shuangyan , Yang Tingting , Chen Yixiang , Zhang Wei , Nan Weiwei , Che Tong , Li Yanyan , Liao Hongfei , Zhang Jin 
Published: February 2024

AbstractTrichromatic color vision in humans constitutes a pivotal evolutionary adaptation, endowing individuals with the capacity to discern and discriminate a diverse spectrum of colors. This unique visual capability confers a selective advantage crucial for successful adaptation, survival, and reproductive success in the natural environment. Color vision in humans is facilitated by the red, green, and blue cone visual pigments within cone photoreceptor cells. These pigments consist of a G-protein-coupled receptor opsin apoprotein and a chromophore covalently linked to opsins. Despite the elucidated structure of rhodopsin, the structures of cone visual pigments have yet to be determined. Here, we present the cryo-EM structures of three human cone visual pigments in complex with G proteins. Our structural analysis reveals detailed interactions between cone opsins, all-trans-retinal, and G proteins, indicating their active state. We also provide a concise summary and analysis of mutations in human cone opsins, elucidating potential relationships between residue substitutions and spectral tuning. Notably, S1162.67Y, A2335.52S, Y2776.44F were found to induce a blue shift in the absorption spectrum of the red-pigment, while the substitutions W2816.48Y and K3127.43A resulted in the absence of the absorption spectrum. The structural elucidation of human cone visual pigments significantly contributes to our understanding of how distinct types of cone cells perceive light across varying wavelengths. Furthermore, it provides a deeper insight into the functioning of the human trichromatic vision system, probing the mechanisms enabling humans to perceive a broad spectrum of colors.
Upregulated cholesterol biosynthesis facilitates the survival of methylation-retaining AML cells following decitabine treatment
Authors: Bond Danielle R , Burnard Sean M , Uddipto Kumar , Hunt Kooper V , Harvey Brooke M , Reinhardt Luiza Steffens , Lawlor-O’Neill Charley , Roper Ellise A , Humphries Sam , Murray Heather C. , Bowden Nikola A , Enjeti Anoop K , Verrills Nicole M , Riveros Carlos , Cao Kim-Anh Lê , Lee Heather J 
Published: February 2024

AbstractDNA hypomethylating agents (HMAs) are used to treat acute myeloid leukaemia (AML) and myelodysplasia patients who are unsuitable for intensive chemotherapy, but low response rates and therapy-resistant relapse remain significant challenges. To optimise HMA efficacy, we must understand how resistance and relapse arise from cells that survive treatment. Here we combine single-cell multi-omic analysis with parallel colony-forming assays to link HMA-induced molecular heterogeneity with functional consequences in AML cells. HMAs, azacytidine (AZA) and decitabine (DAC), induced global epigenetic heterogeneity associated with upregulation of inflammatory responses and cell death pathways in a subset of hypomethylated cells. Some AML cells maintained high DNA methylation during treatment, and these methylation-retaining cells had increased self-renewal capacity following DAC, but not AZA. Molecular profiling of individual colonies revealed upregulated cholesterol biosynthesis as an adaptation to HMA treatment, and inhibition by rosuvastatin enhanced DAC effectsin vitroandin vivo. Thus, HMA-induced heterogeneity has important implications for AML cell growth and statins are a candidate co-treatment strategy to delay or prevent HMA-resistant relapse.
Simultaneous Identification of Changepoints and Model Parameters in Switching Dynamical Systems
Authors: Fu Xiaoming , Fan Kai , Zozmann Heinrich , Schüler Lennart , Calabrese Justin M. 
Published: February 2024

AbstractMany complex natural systems undergo shifts in dynamics at particular points in time. Examples include phase transitions in gene expression during the cell cycle, introduced species affecting predator-prey interactions, and disease outbreaks responding to intervention measures. Such changepoints partition timeseries into different dynamical regimes characterized by distinct parameter sets, and inference on both the changepoints and regime-specific dynamical parameters is of primary interest. Conventional approaches to analyzing switching dynamical systems first estimate changepoints, and then estimate dynamical parameters assuming the changepoints are fixed and known. Such two-stage approaches are ad-hoc, can introduce biases in the analysis, and do not fully account for uncertainty. Here, we introduce a rigorous, simulation-based inference framework that simultaneously estimates changepoints and model parameters from noisy data while admitting full uncertainty. We use simulation studies of oscillatory predator-prey dynamics and stochastic gene expression to demonstrate that our method yields accurate estimates of changepoints and model parameters together with appropriate uncertainty bounds. We then apply our approach to a real-world case study of COVID-19 intervention effects, and show that our inferred changepoints aligned closely with the actual dates of intervention implementation. Taken together, these results suggest that our framework will have broad utility in diverse scientific domains.
ENT3C: an entropy-based similarity measure for Hi-C and micro-C derived contact matrices
Authors: Lainscsek Xenia , Taher Leila 
Published: February 2024

AbstractHi-C and micro-C sequencing have shed light on the profound importance of 3D genome organization in cellular function by probing 3D contact frequencies across the linear genome. The resulting contact matrices are extremely sparse and susceptible to technical- and sequence-based biases, making their comparison challenging. The development of reliable, robust and efficient methods for quantifying similarity between contact matrix is crucial for investigating variations in the 3D genome organization between different cell types or under different conditions, as well as evaluating experimental reproducibility. We present a novel method, ENT3C, which measures the change in pattern complexity in the vicinity of contact matrix diagonals to quantify their similarity. ENT3C provides a robust, user-friendly Hi-C or micro-C contact matrix similarity metric and a characteristic entropy signal that can be used to gain detailed biological insights into 3D genome organization.Availabilityhttps://github.com/xX3N1A/ENT3C
Sequence, Structure and Functional space ofDrosophila de novoproteins
Authors: Middendorf Lasse , Iyengar Bharat Ravi , Eicholt Lars A. 
Published: February 2024

AbstractDuringde novoemergence, new protein coding genes emerge from previously non-genic sequences. Thede novoproteins they encode are dissimilar in composition and predicted biochemical properties to conserved proteins. However, many functionalde novoproteins indeed exist. Both identification of functionalde novoproteins and their structural characterisation are experimentally laborious. To identify functional and structuredde novoproteinsin silico, we applied recently developed machine learning based tools and refined the results forde novoproteins. We found that mostde novoproteins are indeed different from conserved proteins both in their structure and sequence. However, somede novoproteins are predicted to adopt known protein folds, participate in cellular reactions, and to form biomolecular condensates. Apart from broadening our understanding ofde novoprotein evolution, our study also provides a large set of testable hypotheses for focused experimental studies on structure and function ofde novoproteins inDrosophila.
Community context influences the conjugation efficiency ofE. coli
Authors: Bustamante Misshelle , Koopman Floor , Martens Jesper , Brons Jolanda K. , DelaFuente Javier , Kuipers Oscar P. , van Doorn Sander , de Vos Marjon G.J. 
Published: February 2024

AbstractIn urinary tract infections different bacteria can live in a polymicrobial community, it is unknown how such community members affect the conjugation rate of uropathogenicEscherichia coli. We investigated the influence of the polymicrobial urinary tract infection (UTI) community context on the conjugation rate ofE. coliisolates in artificial urine medium. Pairwise conjugation rate experiments were conducted between a donorE. colistrain containing pOXA-48 and six uropathogenicE. coliisolates in the presence and absence of five community members to elucidate their effect on the rate of conjugation. We found that the basal conjugation rates in the absence of community members are genotype dependent. Interestingly, bacterial interactions have an overall positive effect onE. coliconjugation rates. Particularly Gram-positive enterococcal species were found to enhance the conjugation rates of most uropathogenicE. coliisolates. We hypothesize that the nature and co-culture of the interactions is important for these increased conjugation rates in AUM.
Whole-Genome Analysis of Stress Resistance-Related Genes inListeria monocytogenes
Authors: Dou Xin , Liu Yangtai , Panagou Efstathios Z. , Zhu Huajian , Li Zhuosi , Dong Qingli 
Published: February 2024

AbstractListeria monocytogenesis a crucial foodborne pathogen with significant public health implications. This study analyzed whole-genome sequences (WGS) ofL. monocytogenesstrains from public databases, examining associations between resistance genes, lineage, strain type, isolation source, and geography. Results revealed that after eliminating duplicates and strains with incomplete WGS, a total of 316 strains were deemed suitable for subsequent analyses. Within these strains, lineages I and II were extensively distributed, predominantly isolated from clinical and food sources. 56.65% of these strains fell into seven major Clonal Complexes (CC), identified by Multilocus Sequence Typing (MLST), correlating significantly with isolation information. Analysis of 46 resistance-related genes showed a high consistency of resistance genes in the same type of strains, hinting at a potential causal chain of ‘habits-foods-environments evolutions’. Moreover, the standard strains exhibit similar gene carriage rates as the sample strains, with multiple variations observed in acid-resistance genes. In conclusion, through a comprehensive analysis of theL. monocytogenesgenome sequences, this study deepens our understanding of the differences and associations between its lineage, strain typing, isolation sources, geographical distribution, and resistance genes. It has also explored the potential impact of environmental noise on the expression of these genes, offering a scientific foundation for devising more effective prevention and control strategies againstL. monocytogenes. Future endeavors should further dissect the functions of stress resistance genes and the variations in their expression, with the aim of gaining a deeper insight into the risks posed byL. monocytogenesto public health safety.
KSHV genome harbors both constitutive and lytically induced enhancers
Authors: Chowdhury Nilabja Roy , Gurevich Vyacheslav , Shamay Meir 
Published: February 2024

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus family and is a well-known human oncogenic virus. In infected cells, the viral genome of 165 kbp is circular DNA wrapped in chromatin. The tight control of gene expression is critical for latency, the transition into the lytic phase, and the development of viral-associated malignancies. Distal cis-regulatory elements (CRE), such as enhancers and silencers, can regulate gene expression in a position and orientation-independent manner. Open chromatin is another characteristic feature of enhancers. To systematically search for enhancers, we cloned all the open chromatin regions in the KSHV genome downstream to the luciferase gene and tested their enhancer activity in infected and uninfected cells. A silencer was detected upstream of the latency promoter (LANAp). Two constitutive enhancers were identified in the K12p-OriLyt-R and ORF29 Intron region, where ORF29 Intron is a tissue-specific enhancer. The following promoters: OriLyt-L, PANp, ALTp, and the Terminal Repeats (TRs) acted as lytically induced enhancers. Expression of the Replication and Transcription Activator (RTA), the master regulator of the lytic cycle, was sufficient to induce the activity of lytic enhancers in uninfected cells. We propose that the TRs that span about 24 kbp region serve as a “viral super-enhancer” that integrates the repressive effect of the latency protein LANA with the activating effect of RTA. Utilizing CRISPR activation and interference techniques, we determined the connections between these enhancers and their regulated genes. The silencer and enhancers described here provide an additional layer to the complex gene regulation of herpesviruses.ImportanceIn this study, we performed a systematic functional assay to identify cis-regulatory elements within the genome of the oncogenic herpesvirus, Kaposi sarcoma-associated herpesvirus (KSHV). Similar to other herpesviruses, KSHV presents both latent and lytic phases. Therefore, our assays were performed in uninfected cells, during latent infection, and under lytic conditions. We identified two constitutive enhancers, where one seems to be a tissue- specific enhancer. In addition, four lytically induced enhancers, which are all responsive to the Replication and Transcription Activator (RTA), were identified. Furthermore, a silencer was identified between the major latency promoter and lytic genes locus. Utilizing CRISPR activation and interference techniques, we determined the connections between these enhancers with their regulated genes. The terminal repeats spanning a region of about 24 kbp, seem like a “viral super-enhancer” that integrates the repressive effect of the latency protein LANA with the activating effect of RTA to regulate latency to lytic transition.
Modeling metastatic progression from cross-sectional cancer genomics data
Authors: Rupp Kevin , Lösch Andreas , Hu Y. Linda , Nie Chenxi , Schill Rudolf , Klever Maren , Pfahler Simon , Grasedyck Lars , Wettig Tilo , Beerenwinkel Niko , Spang Rainer 
Published: February 2024

AbstractMetastasis formation is a hallmark of cancer lethality. Yet, metastases are generally unobservable during their early stages of dissemination and spread to distant organs. Genomic datasets of matched primary tumors and metastases may offer insights into the underpinnings and the dynamics of metastasis formation. We present metMHN, a cancer progression model designed to deduce the joint progression of primary tumors and metastases using cross-sectional cancer genomics data. The model elucidates the statistical dependencies among genomic events, the formation of metastasis, and the clinical emergence of both primary tumors and their metastatic counterparts. metMHN enables the chronological reconstruction of mutational sequences and facilitates estimation of the timing of metastatic seeding. In a study of nearly 5000 lung adenocarcinomas, metMHN pinpointed TP53 and EGFR as mediators of metastasis formation. Furthermore, the study revealed that post-seeding adaptation is predominantly influenced by frequent copy number alterations. All datasets and code are available on GitHub athttps://github.com/cbg-ethz/metMHN.
Repression ofMRP51in cis does not contribute to the synthetic growth defect conferred by anhphMX4-marked deletion ofDBP1in aded1-tsmutant
Authors: Zhang Fan , Sen Neelam Dabas , Hinnebusch Alan G. 
Published: February 2024

ABSTRACTPowers et al. recently demonstrated that thehphMX6cassette used to deleteDPB1indbp1Δ::hphMX6yeast mutants leads to reduced expression incisof the adjacent geneMRP51, encoding the mitochondrial small subunit (SSU) ribosomal protein Mrp51. Here we provide evidence that elimination of Dbp1, not reducedMRP51expression, underlies the synthetic growth defect of adbp1Δ::hphMX6 ded1-tsmutant on glucose-containing medium, where respiration is dispensable, consistent with our previous conclusion that Dbp1 and Ded1 perform overlapping functions in stimulating translation initiation on mRNAs burdened with long or structured 5’UTRs in cells cultured with glucose.
Investigate the causality and genetic association between migraine and Parkinson’s disease
Authors: Deng Ming-Gang , Zhou Xiuxiu , Liu Fang , Wang Kai , Luo Lingli , Zhang Min-Jie , Feng Qianqian , Liu Jiewei 
Published: February 2024

AbstractBackgroundThe relationship between migraine and Parkinson’s disease (PD) remains controversial. We intend to investigate the causal and genetic association between migraine and PD.MethodsData related to migraine [any migraine (AM), migraine without aura (MO), and migraine with aura (MA)] and PD were respectively obtained from the latest Genome-wide meta-analysis conducted by the International Headache Genetics Consortium and the International Parkinson’s Disease Genomics Consortium. Univariate Mendelian Randomization (UMR) and multivariate MR (MVMR) were conducted to estimate their bidirectional causality, and global/local genetic correlation and tissue expression analyses were utilized to assess their genetic associations.ResultsThe UMR presented that AM (OR: 1.016, 95% CI: 0.908-1.135,p= 0.785), MO (OR: 0.944, 95% CI: 0.836-1.067,p= 0.358) and MA (OR: 1.006, 95% CI: 0.951, 1.064,p= 0.846) were unlikely to be associated with PD risk. Similarly, the reverse UMR analyses demonstrated that PD was unrelated to the risks of migraine and its subtypes. These null associations were supported by the MVMR when adjusted for coronary heart disease and hypertension. The global genetic correlation analyses presented that AM (rg= -0.061,p= 0.127), MA (rg= -0.047,p= 0.516), MO (rg= -0.063,p= 0.492) were generally not related to PD, and the local genetic correlation analyses shown they were also uncorrelated in any region. Additionally, the tissue expression analyses found they had no shared tissues.ConclusionThis study suggested no causality or association between migraine and PD from the genetic perspective.