bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions
Authors: Cornish Alex J. , Gruber Andreas J. , Kinnersley Ben , Chubb Daniel , Frangou Anna , Caravagna Giulio , Noyvert Boris , Lakatos Eszter , Wood Henry M. , Arnedo-Pac Claudia , Culliford Richard , Househam Jacob , Cross William , Sud Amit , Law Philip , Ni Leathlobhair Maire , Hawari Aliah , Thorn Steve , Sherwood Kitty , Gül Güler , Fernandez-Tajes Juan , Zapata Luis , Alexandrov Ludmil B. , Murugaesu Nirupa , Sosinsky Alona , Mitchell Jonathan ,   Genomics England Research Consortium, Lopez-Bigas Nuria , Quirke Philip , Church David N , Tomlinson Ian P.M. , Sottoriva Andrea , Graham Trevor A. , Wedge David C. , Houlston Richard S. 
Published: November 2022

ABSTRACTTo characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations inAPCandSMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions ofPIK3R1andPWRN1, as well as amplification ofCCND3andNEDD9. Putative driver structural variants includedBRD4andSOX9regulatory elements, andACVR2AandANKRD11hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenicE. colisignature andTP53mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.
How to determine microbial lag phase duration?
Authors: Opalek Monika , Smug Bogna J. , Wloch-Salamon Dominika 
Published: November 2022

ABSTRACTThe lag phase is a temporary non-replicative period observed when a microbial population is introduced to a new nutrient-rich environment. Its duration can have a pronounced effect on population fitness, and it is often measured in laboratory conditions. However, calculating the lag phase length may be challenging and method and parameters dependent. Moreover, the details of these methods and parameters used throughout experimental studies are often under-reported. Here we discuss the most frequently used methods in experimental and theoretical studies, and we point out some inconsistencies between them. Using experimental and simulated data we study the performance of these methods depending on the frequency of population size measurements, and parameters determining the growth curve shape, such as growth rate. It turns out that the sensitivity to each of these parameters depends on the lag calculation methods. For example, lag duration calculation by parameter fitting to a logistic model is very robust to low frequency of measurements, but it may be highly biased for growth curves with low growth rate. On the contrary, the method based on finding the point where growth acceleration is the highest, is robust to low growth rate, but highly sensitive to low frequency of measurements and the level of noise in the data. Based on our results, we propose a decision tree to choose a method most suited to one’s data. Finally, we developed a web tool where the lag duration can be calculated based on the user-specified growth curve data, and for various explicitly specified methods, parameters, and data pre-processing techniques.GRAPHICAL ABSTRACT
Inferring a cell’s capabilities from omics data with ImmCellFie
Authors: Masson Helen O. , Borland David , Reilly Jason , Telleria Adrian , Shrivastava Shalki , Watson Matt , Bustillo Luthfi , Li Zerong , Capps Laura , Kellman Benjamin P. , King Zachary A. , Richelle Anne , Lewis Nathan E. , Robasky Kimberly 
Published: November 2022

SummaryImmCellFie is a user-friendly, web-based platform for comprehensive analysis of metabolic functions inferred from transcriptomic or proteomic data. It enables researchers to leverage the powerful mechanistic insight provided by complex genome-scale metabolic models with little to no bioinformatics training required. The platform has been integrated with a series of useful tools and richly annotated scientific visualizations for interactive exploration by the user. ImmCellFie pushes beyond simple statistical enrichment and incorporates complex biological mechanisms to quantify cell activity.Graphical abstract
Functional gradients reveal altered functional segregation in patients with amnestic mild cognitive impairment and Alzheimer’s disease
Authors: He Yirong , Li Qiongling , Fu Zhenrong , Zeng Debin , Han Ying , Li Shuyu 
Published: November 2022

AbstractBackgroundAlzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) are associated with disrupted functional organization in brain networks, yet the finer changes in the topological organization in aMCI and AD remain to be investigated. Connectome gradients are a new tool representing brain functional topological organization in a low-dimensional space to smoothly capture the human macroscale hierarchy.MethodsHere, we examined altered topological organization in aMCI and AD by connectome gradient mapping. We further quantified functional segregation by gradient dispersion. Then, we systematically compared the alterations observed in aMCI and AD patients with those in normal controls (NCs) in a two-dimensional functional gradient space from both the whole-brain level and module level.ResultsCompared with NCs, the first gradient, which described the neocortical hierarchy from unimodal to transmodal regions, showed a distributed and significant suppression in AD patients, while abnormalities were only limited to local regions in aMCI patients. The second gradient showed a decreased pattern in the somatomotor module in both aMCI and AD patients. Furthermore, gradient dispersion showed significant decreases in AD patients at both the global level and module level, whereas this alteration was limited only to limbic areas in aMCI. Notably, we demonstrated that suppressed gradient dispersion in aMCI and AD patients was associated with cognitive scores.ConclusionsChanges in functional gradients could reflect different degrees of altered brain network segregation in aMCI and AD. These findings provide new evidence for altered brain hierarchy in aMCI and AD, which strengthens our understanding of the progressive mechanism of cognitive decline.
Subspace partitioning in human prefrontal cortex resolves cognitive interference
Authors: Weber Jan , Iwama Gabriela , Solbakk Anne-Kristin , Blenkmann Alejandro O. , Larsson Pal G. , Ivanovic Jugoslav , Knight Robert T. , Endestad Tor , Helfrich Randolph 
Published: November 2022

AbstractHuman prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task-features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between co-existing representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.
Efficient reliability analysis of spatially resolved transcriptomics at varying resolutions using SpaSEG
Authors: Bai Yong , Guo Xiangyu , Liu Keyin , Zheng Bingjie , Wang Yingyue , Luo Qiuhong , Yin Jianhua , Wu Liang , Li Yuxiang , Zhang Yong , Chen Ao , Xu Xun , Jin Xin 
Published: November 2022

AbstractSpatially resolved transcriptomics (SRT) for characterizing cellular heterogeneities and activities requires systematic analysis approaches to decipher gene expression variations in physiological contexts. Here we develop SpaSEG, an unsupervised convolutional neural network-based model for multiple SRT analysis tasks by jointly learning the transcriptional similarity of spots and their spatial dependence. SpaSEG adopts an edge strength constraint to encourage spatial domain coherence and allows integrative analysis by automatically aligning the spatial domains across multiple adjacent sections. It also enables the detection of domain-specific gene expression patterns and the inference of intercellular interactions and colocalizations within a tissue. In an invasive ductal carcinoma sample analysis, SpaSEG facilitates the unraveling of intratumor heterogeneity and the understanding of immunoregulatory mechanisms. Through comprehensive evaluation over a collection of SRT datasets generated by different platforms at various resolutions, SpaSEG shows superior reliability and computational efficiency over existing methods, endowing it with a great potential for the exploration of tissue architectures and pathological biology.
A stable reference human transcriptome and proteome as a standard for reproducible omics experiments
Authors: Lu Shaohua , Lu Hong , Zheng Tingkai , Yuan Huiming , Du Hongli , Gao Youhe , Liu Yongtao , Pan Xuanzhen , Zhang Wenlu , Fu Shuying , Sun Zhenghua , Jin Jingjie , He Qing-Yu , Chen Yang , Zhang Gong 
Published: November 2022

AbstractIn recent years, the development of high-throughput omics technology has greatly promoted the development of biomedicine. However, the poor reproducibility of omics techniques limits its application. It is necessary to use standard reference materials of complex RNAs or proteins to test and calibrate the accuracy and reproducibility of omics workflows. However, the transcriptome and proteome of most cell lines shift during culturing, which limits their applicability to serve as standard samples. In this study, we demonstrated that the human hepatocellular cell line MHCC97H has a very stable transcriptome (R2=0.966-0.995) and proteome (R2=0.934-0.976 for DDA, R2=0.942-0.986 for DIA) after 9 subculturing generations, which allows this stable standard sample to be stably produced on an industrial scale for several decades. Moreover, this stability was maintained across labs and platforms. In sum, our results justified a omics standard reference material and reference datasets for transcriptomic and proteomics research. This helps to further standardize the workflow and data quality of omics techniques and thus promotes the application of omics technology in precision medicine.
Pioneer factor Pax7 initiates two-step cell-cycle dependent chromatin opening
Authors: Gouhier Arthur , Dumoulin-Gagnon Justine , Lapointe-Roberge Vincent , Harris Juliette , Balsalobre Aurelio , Drouin Jacques 
Published: November 2022

SummaryPioneer transcription factors direct cell differentiation by deploying new enhancer repertoires through their unique ability to target and initiate remodelling of closed chromatin. The initial steps of their action remain undefined although pioneers were shown to interact with nucleosomal target DNA and with some chromatin remodelling complexes. We now define the sequence of events that enable the pioneer Pax7 with its unique abilities. Chromatin condensation exerted by linker histone H1 is the first constraint on Pax7 recruitment, and this establishes the initial speed of chromatin remodelling. The first step of pioneer action involves recruitment of the KDM1A (LSD1) H3K9me2 demethylase for removal of this repressive mark, as well as recruitment of the MLL complex for deposition of the activating H3K4me1 mark. Further progression of pioneer action requires passage through cell division, and this involves dissociation of pioneer targets from perinuclear lamin B. Only then, the SWI/SNF remodeling complex and the coactivator p300 are recruited, leading to nucleosome displacement and enhancer activation. Thus, the unique features of pioneer actions are those occurring in the lamin-associated compartment of the nucleus. This model is consistent with prior work that showed a dependence on cell division for establishment of new cell fates.
Synergy of HLA class I and II shapes the timing of antitumor immune response
Authors: Papp Benjamin Tamás , Fülöp Anna Tácia , Balogh Gergő Mihály , Koncz Balázs , Spekhardt Dóra , Manczinger Máté 
Published: November 2022

AbstractThe presentation of mutated cancer peptides to T cells by human leukocyte antigen (HLA) class I and II molecules is necessary for antitumor immune response. Both classes are diverse and the variants have distinct peptide-binding specificities. HLA class I diversity was suggested to influence antitumor immunity, however, the findings are controversial. We examined the joint effect of the two HLA classes in melanoma patients. Numerous combinations were associated with better or worse survival in metastatic melanoma patients receiving immune checkpoint blockade (ICB) immunotherapy and they also predicted the survival of ICB-naive patients. Carrying detrimental and beneficial combinations had markedly different effects in primary and metastatic samples. Detrimental combinations were associated with cytotoxic immune response in primary tumors, while metastases showed signs of immune evasion and ineffective antitumor immunity. On the contrary, beneficial combinations were associated with an active cytotoxic immune response only in metastatic samples. HLA class I and II variants in both detrimental and beneficial combinations presented melanoma-associated mutations effectively. However, detrimental combinations were more likely to present immunogenic ones. Our results provide evidence of the joint effect of HLA class I and II variants on antitumor immunity. They potentially influence the strength and timing of antitumor immune response with implications on response to therapy and patient survival.
Amplicon sequencing reveals complex infection in infants congenitally infected withTrypanosoma cruziand informs the dynamics of parasite transmission
Authors: Hakim Jill , Waltmann Andreea , Tinajeros Freddy , Kharabora Oksana , Machaca Edith Málaga , Calderon Maritza , Menduiña María del Carmen , Wang Jeremy , Rueda Daniel , Zimic Mirko , Verástegui Manuela , Juliano Jonathan J , Gilman Robert H , Mugnier Monica R. , Bowman Natalie M ,   Chagas working group
Published: November 2022

AbstractCongenital transmission ofTrypanosoma cruzi, the causative agent of Chagas disease, is an important source of new infections worldwide. The mechanisms of congenital transmission remain poorly understood, but there is evidence that parasite factors could play a role.Investigating changes in parasite strain diversity during transmission could provide insight into the parasite factors that influence the process. Here we use deep amplicon sequencing of a single copy gene in theT. cruzigenome to evaluate the diversity of infection in a collection of clinical blood samples from Chagas positive mothers and their infected infants. We found several infants and mothers infected with more than two parasite haplotypes, indicating infection with multiple parasite strains. Two haplotypes were detected exclusively in infant samples, while one haplotype was never found in infants, suggesting a relationship between the probability of transmission and parasite genotype. Finally, we found an increase in parasite population diversity in children after birth compared to their mothers, suggesting that there is no transmission bottleneck during congenital infection and that multiple parasites breach the placenta in the course of congenital transmission.
Germline determinants of the prostate tumor genome
Authors: Houlahan Kathleen E. , Yuan Jiapei , Schwarz Tommer , Livingstone Julie , Fox Natalie S. , Jaratlerdsiri Weerachai , van Riet Job , Taraszka Kodi , Kurganovs Natalie , Zhu Helen , Sietsma Penington Jocelyn , Jung Chol-Hee , Yamaguchi Takafumi N , Jiang Jue , Heisler Lawrence E , Jovelin Richard , Ramanand Susmita G , Bell Connor , O’Connor Edward , Mutambirwa Shingai B.A. , Seo Ji-Heui , Costello Anthony J. , Pomerantz Mark M. , Pope Bernard J. , Zaitlen Noah , Kishan Amar U. , Corcoran Niall M. , Bristow Robert G. , Waszak Sebastian M. , Bornman Riana M.S. , Gusev Alexander , Lolkema Martijn P. , Weischenfeldt Joachim , Hung Rayjean J. , He Housheng H. , Hayes Vanessa M. , Pasaniuc Bogdan , Freedman Matthew L. , Hovens Christopher M. , Mani Ram S. , Boutros Paul C. 
Published: November 2022

AbstractA person’s germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of individual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates ofTMPRSS2-ERGgene fusions and 67.3% of ancestry-biases in rates ofFOXA1point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.
New insights into CFTR modulation in reproduction: testicular microenvironment imbalance leads to over-activated caspase signalling in spermatogenesis and adversely affects fertility
Authors: Chen Guan-Ru , Chiang Han-Sun , Chung Shiu-Dong , Tseng Xiao-Wen , Rajneesh Chellappan Praveen , Chen Kuo-Chiang , Wang Kuan-Lin , Wu Yi-No 
Published: November 2022

AbstractCystic fibrosis transmembrane conductance regulator (CFTR) is a prominent chloride channel that governs mucous secretion in multiple organs, including the reproductive tract. According to earlier reports, defective CFTR results in infertility due to congenital bilateral absence of the vas deferens (CBAVD). However, obstruction in the vas deferens is not the only reason CFTR deficiency causes male infertility. The mechanism underlying the loss of mature sperm owing to CFTR deficiency remains elusive. This study aimed to assess the role of CFTR in spermatogenesis, for which 6- and 8-week-old male mice withCftr+/+,Cftr+/-, andCftr-/-genotypes were chosen. Furthermore, we assessed the correlation between CFTR deficiency and delayed development of the reproductive system, anomalous apoptosis activation in spermatogenesis, and ionic alterations of the testis lumen. The results demonstrated that the growth ofCftr-/-mice were delayed, with underweight reproductive organs and mild hypospermatogenesis. CFTR depletion destabilizes spermatogenesis by producing abnormal sperm and triggers activation of the Bax/Bcl-2 ratio inCftr-/-andCftr+/-mice, causing caspase-mediated irreversible intrinsic apoptosis. Stage-specific apoptosis in germ cells targeted the sexually mature mice, and the testis microenvironment affirmed that ion concentrations influence sperm capacitation. The blood pH determines apoptosis induction, as CFTR is a bicarbonate transporter. In conclusion,Cftr-/-mice were infertile because CFTR deficiency generated an ionic imbalance in the testis lumen, leading to Bax expression and Bcl-2 blockage, which triggered caspases or further activation of voltage-dependent anion-selective channel 1 (VDAC1). Cumulatively, cytochromeCwas released due to altered mitochondrial membrane potential. Eventually, anomalous up-regulated apoptosis activation affected spermatogenesis, thus rendering the Cftr-/-male mice infertile. The results supplied new insights into CFTR modulation in reproduction: an imbalanced testicular microenvironment due to CFTR deficiency affects spermatogenesis and fertility in mice through the overactivation of spermatocyte caspase signalling, thus driving us to focus on updated treatments for CFTR deficiency-caused infertility.
Dynamics of alpha suppression index both modality specific and general attention processes
Authors: Clements Grace M. , Gyurkovics Mate , Low Kathy A. , Kramer Arthur F. , Beck Diane M. , Fabiani M. , Gratton G. 
Published: November 2022

AbstractEEG alpha power varies under many circumstances requiring visual attention. However, mounting evidence indicates that alpha may not only serve visual processing, but also the processing of stimuli presented in other sensory modalities, including hearing. We previously showed that alpha dynamics during an auditory task vary as a function of competition from the visual modality (Clements et al., 2022) suggesting that alpha may be engaged in multimodal processing. Here we assessed the impact of allocating attention to the visual or auditory modality on alpha dynamics, during the preparatory period of a bimodal-cued conflict task. In this task, precues indicated the modality (vision, hearing) relevant to a subsequent reaction stimulus. This task afforded us the opportunity to assess alpha during modality-specific preparation and while switching between modalities. Alpha suppression following the precue occurred in all conditions indicating that it may reflect general preparatory mechanisms. However, we observed a switch effect when preparing to attend to the auditory modality, in which greater alpha suppression was elicited when switching to the auditory modality compared to repeating. No switch effect was evident when preparing to attend to visual information (although robust suppression did occur in both conditions). In addition, waning alpha suppression preceded error trials, irrespective of sensory modality. These findings indicate that alpha can be used to monitor the level of preparatory attention to process both visual and auditory information. These results support the emerging view that alpha band activity may index a general attention control mechanism used across modalities, at least vision and hearing.