bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iterative convergent computation may not be a useful inductive bias for residual neural networks
Authors: Samuel Lippl , Benjamin Peters , Nikolaus Kriegeskorte 
Published: October 2023

AbstractRecent work has suggested that feedforward residual neural networks (ResNets) approximate iterative recurrent computations. Iterative computations are useful in many domains, so they might provide good solutions for neural networks to learn. Here we quantify the degree to which ResNets learn iterative solutions and introduce a regularization approach that encourages learning of iterative solutions. Iterative methods are characterized by two properties: iteration and convergence. To quantify these properties, we define three indices of iterative convergence. Consistent with previous work, we show that, even though ResNets can express iterative solutions, they do not learn them when trained conventionally on computer vision tasks. We then introduce regularizations to encourage iterative convergent computation and test whether this provides a useful inductive bias. To make the networks more iterative, we manipulate the degree of weight sharing across layers using soft gradient coupling. This new method provides a form of recurrence regularization and can interpolate smoothly between an ordinary ResNet and a “recurrent” ResNet (i.e., one that uses identical weights across layers and thus could be physically implemented with a recurrent network computing the successive stages iteratively across time). To make the networks more convergent we impose a Lipschitz constraint on the residual functions using spectral normalization. The three indices of iterative convergence reveal that the gradient coupling and the Lipschitz constraint succeed at making the networks iterative and convergent, respectively. However, neither recurrence regularization nor spectral normalization improve classification accuracy on standard visual recognition tasks (MNIST, CIFAR-10, CIFAR-100) or on challenging recognition tasks with partial occlusions (Digitclutter). Iterative convergent computation, in these tasks, does not provide a useful inductive bias for ResNets.
Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function
Authors: Gourisankar S. , Wenderski W. , Paulo J. A. , Kim S.H. , Roepke K. , Ellis C. , Gygi S.P. , Crabtree G.R. 
Published: October 2023

ABSTRACTGenes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleteriousde novomutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known1,2. Synaptic activity in neurons is critical for learning and memory and proper neural development3. Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers4. While BAF is required for activity-dependent developmental processes such as dendritic outgrowth5–7, the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/Arid2, uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.
Widespread detoxifying NO reductases impart a distinct isotopic fingerprint on N2O under anoxia
Authors: Wang Renée Z. , Lonergan Zachery R. , Wilbert Steven A. , Eiler John M. , Newman Dianne K. 
Published: October 2023

AbstractNitrous oxide (N2O), a potent greenhouse gas, can be generated by compositionally complex microbial populations in diverse contexts. Accurately tracking the dominant biological sources of N2O has the potential to improve our understanding of N2O fluxes from soils as well as inform the diagnosis of human infections. Isotopic “Site Preference” (SP) values have been used towards this end, as bacterial and fungal nitric oxide reductases produce N2O with different isotopic fingerprints. Here we show that flavohemoglobin, a hitherto biogeochemically neglected yet widely distributed detoxifying bacterial NO reductase, imparts a distinct SP value onto N2O under anoxic conditions that correlates with typical environmental N2O SP measurements. We suggest a new framework to guide the attribution of N2O biological sources in nature and disease.One-Sentence SummaryDetoxifying nitric oxide reductases impart a distinct isotopic biosignature on nitrous oxide.
Proteasome inhibition reprograms chromatin landscape in breast cancer
Authors: Kinyamu H Karimi , Bennett Brian D. , Ward James M. , Archer Trevor 
Published: October 2023

ABSTRACTThe 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNAPII transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic super enhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology.HighlightsProteasome inhibition uncoversde novoDifferential Open Chromatin Regions (DOCRs) in breast cancer cells.Proteasome inhibitor sensitive promoters exhibit a distinctive chromatin architecture with discrete transcription initiation patterns.Proteasome inhibition reprograms accessibility of super enhancers.Proteasome inhibitor sensitive super enhancers distinguish basal from non-basal breast cancer subtypes.
Rtf1-dependent transcriptional pausing regulates cardiogenesis
Authors: Langenbacher Adam D. , Lu Fei , Tsang Luna , Huang Zi Yi Stephanie , Keer Benjamin , Tian Zhiyu , Eide Alette , Pellegrini Matteo , Nakano Haruko , Nakano Atsushi , Chen Jau-Nian 
Published: October 2023

AbstractDuring heart development, a well-characterized network of transcription factors initiates cardiac gene expression and defines the precise timing and location of cardiac progenitor specification. However, our understanding of the post-initiation transcriptional events that regulate cardiac gene expression is still incomplete. The PAF1C component Rtf1 is a transcription regulatory protein that modulates pausing and elongation of RNA Pol II, as well as cotranscriptional histone modifications. Here we report that Rtf1 is essential for cardiogenesis in fish and mammals, and that in the absence of Rtf1 activity, cardiac progenitors arrest in an immature state. We found that Rtf1’s Plus3 domain, which confers interaction with the transcriptional pausing and elongation regulator Spt5, was necessary for cardiac progenitor formation. ChIP-seq analysis further revealed changes in the occupancy of RNA Pol II around the transcription start site (TSS) of cardiac genes inrtf1morphants reflecting a reduction in transcriptional pausing. Intriguingly, inhibition of pause release inrtf1morphants and mutants restored the formation of cardiac cells and improved Pol II occupancy at the TSS of key cardiac genes. Our findings highlight the crucial role that transcriptional pausing plays in promoting normal gene expression levels in a cardiac developmental context.
Transcriptional Regulation of the AlternativeSex Hormone-Binding GlobulinPromoter by KLF4
Authors: Meyers Warren M. 
Published: October 2023

AbstractIn most mammals the major site of sex hormone-binding globulin (SHBG) synthesis is the liver wherefrom it is secreted into the bloodstream and is the primary determinant of sex steroid access to target tissues. The minor site of SHBG synthesis is the testis and in lower mammals testicular SHBG has long been known to be synthesized and secreted by Sertoli cells. However, human testicularSHBGis expressed in developing germ cells from an upstream alternative promoter (altP-SHBG). Transcripts arising from this region comprise an alternative first exon (1A) with the resultant protein confined to the acrosomal compartment of the mature spermatozoa. I have dissected the regulatory components of the alternativeSHBGpromoter and identified motifs that are required for optimal transcriptional activity from this region. Transcriptional activity is driven by two CACCC elements that appear to be functionally redundant. The transcription factor KLF4 interacts with promoter the region spanning these elementsin vivo. Knockdown ofKlf4results in decreased altP-SHBGactivity, whileKlf4overexpression relieves the effects of knockdown. Based on their shared patterns of expressionin vivo, I conclude that KLF4 is a transcriptional regulator ofSHBGin male germ cells.
Estimating body volumes and surface areas of animals from cross-sections
Authors: Zhao Ruizhe Jackevan 
Published: October 2023

AbstractBody mass and surface area are among the most important biological properties, but such information are lacking for some extant organisms and all extinct species. Numerous methods have been developed for body size estimation for this reason. There are two main categories of mass-estimating methods: volumetric-density approaches and extant-scaling approaches. In this paper, a new 2D volumetric-density approach named cross-sectional method is presented. Cross-sectional method integrates biological cross-sections to obtain volume and surface area accurately. Unlike all previous 2D methods, cross-sectional method processes true cross-sectional profiles directly rather than approximating. Cross-sectional method also has the advantage over others that it can deal with objects with gradually changing cross-sections. It generates very accurate results, with errors always lower than 2% in all cases tested.
Inferring Viral Transmission Pathways from Within-Host Variation
Authors: Specht Ivan O. A. , Petros Brittany A. , Moreno Gage K. , Brock-Fisher Taylor , Krasilnikova Lydia A. , Schifferli Mark , Yang Katherine , Cronan Paul , Glennon Olivia , Schaffner Stephen F. , Park Daniel J. , MacInnis Bronwyn L. , Ozonoff Al , Fry Ben , Mitzenmacher Michael D. , Varilly Patrick , Sabeti Pardis C. 
Published: October 2023

ABSTRACTGenome sequencing can offer critical insight into pathogen spread in viral outbreaks, but existing transmission inference methods use simplistic evolutionary models and only incorporate a portion of available genetic data. Here, we develop a robust evolutionary model for transmission reconstruction that tracks the genetic composition of within-host viral populations over time and the lineages transmitted between hosts. We confirm that our model reliably describes within-host variant frequencies in a dataset of 134,682 SARS-CoV-2 deep-sequenced genomes from Massachusetts, USA. We then demonstrate that our reconstruction approach infers transmissions more accurately than two leading methods on synthetic data, as well as in a controlled outbreak of bovine respiratory syncytial virus and an epidemiologically-investigated SARS-CoV-2 outbreak in South Africa. Finally, we apply our transmission reconstruction tool to 5,692 outbreaks among the 134,682 Massachusetts genomes. Our methods and results demonstrate the utility of within-host variation for transmission inference of SARS-CoV-2 and other pathogens, and provide an adaptable mathematical framework for tracking within-host evolution.
IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes
Authors: Qiu Zhijun , Khalife Jihane , Lin An-Ping , Ethiraj Purushoth , Jaafar Carine , Chiou Lilly , Huelgas-Morales Gabriela , Aslam Sadia , Arya Shailee , Gupta Yogesh K. , Dahia Patricia L. M. , Aguiar Ricardo C.T. 
Published: October 2023

AbstractIn diffuse large B-cell lymphoma (DLBCL), the transcription factor IRF8 is the target of a series of potentially oncogenic events, including, chromosomal translocation, focal amplification, and super-enhancer perturbations. IRF8 is also frequently mutant in DLBCL, but how these variants contribute to lymphomagenesis is unknown. We modeled IRF8 mutations in DLBCL and found that they did not meaningfully impact cell fitness. Instead, IRF8 mutants, mapping either to the DNA-binding domain (DBD) or c-terminal tail, displayed diminished transcription activity towards CIITA, a direct IRF8 target. In primary DLBCL, IRF8 mutations were mutually exclusive with mutations in genes involved in antigen presentation. Concordantly, expression of IRF8 mutants in murine B cell lymphomas uniformly suppressed CD4, but not CD8, activation elicited by antigen presentation. Unexpectedly, IRF8 mutation did not modify MHC CII expression on the cell surface, rather it downmodulated CD74 and HLA- DM, intracellular regulators of antigen peptide processing/loading in the MHC CII complex. These changes were functionally relevant as, in comparison to IRF8 WT, mice harboring IRF8 mutant lymphomas displayed a significantly higher tumor burden, in association with a substantial remodeling of the tumor microenvironment (TME), typified by depletion of CD4, CD8, Th1 and NK cells, and increase in T-regs and Tfh cells. Importantly, the clinical and immune phenotypes of IRF8-mutant lymphomas were rescued in vivo by ectopic expression of CD74. Deconvolution of bulk RNAseq data from primary human DLBCL recapitulated part of the immune remodeling detected in mice and pointed to depletion of dendritic cells as another feature of IRF8 mutant TME. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.
Phospholipid Scramblase-1 is required for efficient neurotransmission and synaptic vesicle retrieval at cerebellar synapses
Authors: Caputo Margherita , Ivanova Daniela , Chasserot-Golaz Sylvette , Doussau Frédéric , Haeberlé Anne-Marie , Ozkan Sebahat , Ecard Jason , Bader Marie-France , Vitale Nicolas , Cousin Michael A. , Tóth Petra , Gasman Stéphane , Ory Stéphane 
Published: October 2023

AbstractStructural phospholipids are asymmetrically distributed at the plasma membrane, with phosphatidylethanolamine and phosphatidylserine (PS) virtually absent from the outer leaflet. This asymmetric lipid distribution is transiently altered during specific biological processes including calcium-regulated exocytosis. However, the impact of this transient remodeling of membrane asymmetry on presynaptic function remains unknown.PhosphoLipid SCRamblase 1 (PLSCR1), a protein that randomizes phospholipid distribution between the two leaflets of the plasma membrane in response to calcium activation is an ideal candidate to alter this asymmetry. We therefore set out to determine the role of PLSCR1 in both neurotransmitter release and synaptic vesicle recycling by combining electron microscopy, optical live cell imaging of pHluorin probes and electrophysiology in cerebellar granule cells (GrC) fromPlscr1knock-out mice (Plscr1-/-). We report that PLSCR1 is expressed in GrCs and that PLSCR1-dependent PS egress occurred at synapses in response to neuron stimulation. Furthermore, synaptic transmission is impaired at GrCPlscr1-/-synapses and both PS egress and synaptic vesicle endocytosis are inhibited inPlscr1-/-cultured neurons, demonstrating that PLSCR1 controls phospholipid asymmetry remodeling and synaptic vesicle retrieval following neurotransmitter release. Altogether, our data reveal a key role for PLSCR1 in synaptic vesicle recycling and provide the first evidence that phospholipid scrambling at the plasma membrane is a prerequisite for optimal presynaptic performance.
Deletion of SMC renders FtsK essential inCorynebacterium glutamicum
Authors: Peng Feng , Giacomelli Giacomo , Meyer Fabian , Linder Marten , Haak Markus , Rückert-Reed Christian , Weiß Manuela , Kalinowski Jörn , Bramkamp Marc 
Published: October 2023

AbstractStructural maintenance of chromosomes (SMC) are ubiquitously distributed proteins involved in chromosome organization. Deletion ofsmccauses severe growth phenotypes in many organisms. Surprisingly,smccan be deleted inCorynebacterium glutamicum, a member of the Actinomycetota phylum, without any apparent growth phenotype. Earlier work has shown that SMC inC. glutamicumis loaded in a ParB-dependent fashion to the chromosome and functions in replichore cohesion. The unexpected absence of a growth phenotype in thesmcmutant prompted us to screen for unknown synthetic interactions withinC. glutamicum. Therefore, we generated a high-density Tn-5 library based on wild-type andsmc-deletedC. glutamicumstrains. The transposon sequencing (Tn-seq) data revealed that the DNA-translocase FtsK is essential in asmcdeletion strain. FtsK localized to the septa and cell poles in wild type cells, however deletion ofsmcresulted in a decreased polar FtsK localization. Single-particle tracking analysis further suggests that prolonged FtsK complex activity is both required and sufficient to make up for the absence of SMC, thus achieving efficient chromosome segregation inC. glutamicum. Further, single molecule dynamics of FtsK is influenced, albeit indirectly, by DNA-loaded SMC. Deletion of ParB results in an increased of both SMC and FtsK mobility. While the first change agrees with previous data that show how ParB is essential for SMC loading on DNA, the latter suggests that FtsK mobility is affected in cells with defects in chromosome organization. Based on our data we propose a simple, yet efficient mechanism for efficient DNA segregation inC. glutamicum, even in absence of SMC proteins.ImportanceFaithful DNA segregation is of fundamental importance for life. Bacteria have efficient systems to coordinate chromosome compaction, DNA segregation and cell division. A key factor in DNA compaction is the SMC-complex that is found to be essential in many bacteria. In members of the Actinomycetotasmcis dispensable, but the reason for this was unclear. We show here that the divisome associated DNA-pump FtsK can compensate SMC loss and the subsequent loss in correct chromosome organization. In cells with distorted chromosomes, FtsK functions for an extended period of time at the septum, until chromosomes are segregated.
Non-responsive Celiac disease symptoms associated with microbiome network structure and function
Authors: Marcos-Zambrano Laura Judith , Lacruz-Plegezuelos Blanca , Valdés Alberto , Aguilar-Aguilar Elena , Loria-Kohen Viviana , Cifuentes Alejandro , Ramírez de Molina Ana , Carrillo de Santa Pau Enrique 
Published: October 2023

ABSTRACTNon-responsive celiac disease (NRCD) poses a challenge for clinicians due to the persistence of symptoms despite maintaining a gluten-free diet (GFD). This study investigated the gut microbiome, mucosal integrity, and metabolomic profiles of 39 NRCD patients to gain insights into the underlying mechanisms contributing to symptom persistence. Two distinct clusters of patients were identified based on clinical and demographic variables not influenced by gluten consumption.Cluster 1, labelled “Low-grade symptoms,” displayed milder symptoms and lower inflammatory markers. In contrast, Cluster 2, named “High-grade symptoms,” exhibited more severe gastrointestinal and extraintestinal symptoms, along with elevated inflammatory markers and increased intestinal permeability.Despite similar mucosal damage in both clusters, network analysis of the gut microbiome revealed specific microbial taxa with potential functional implications. Cluster 1 displayed a microbiome associated with immune homeostasis and gut barrier integrity, potentially lowering inflammation and symptom severity. In contrast, Cluster 2 had a distinct microbiome linked to lactate production, Th17 activation, possibly contributing to heightened inflammation and gastrointestinal symptoms.Metabolomic analysis revealed differential metabolites between clusters, particularly in amino acid metabolism pathways. Metabolites associated with specific symptoms were identified, implicating their potential role in symptom manifestation. Notably, vitamin D deficiency was observed in both clusters, suggesting its relevance in the context of NRCD.The study highlights the importance of the gut microbiome, mucosal integrity, and metabolic pathways in symptom persistence among NRCD patients. The associations between microbial-derived metabolites and symptom severity provide valuable insights into potential therapeutic targets. Further research is needed to validate these findings and develop targeted interventions for improving clinical outcomes in NRCD patients.
The genetic basis of novel trait gain in walking fish
Authors: Herbert Amy L , Allard Corey AH , McCoy Matthew J , Wucherpfennig Julia I , Krueger Stephanie P , Chen Heidi I , Gourlay Allex N , Jackson Kohle D , Abbo Lisa A , Bennett Scott H , Sears Joshua D , Rhyne Andrew L , Bellono Nicholas W , Kingsley David M 
Published: October 2023

SummaryA major goal in biology is to understand how organisms evolve novel traits. Multiple studies have identified genes contributing to regressive evolution, the loss of structures that existed in a recent ancestor. However, fewer examples exist for genes underlying constructive evolution, the gain of novel structures and capabilities in lineages that previously lacked them. Sea robins are fish that have evolved enlarged pectoral fins, six mobile locomotory fin rays (legs) and six novel macroscopic lobes in the central nervous system (CNS) that innervate the corresponding legs. Here, we establish successful husbandry and use a combination of transcriptomics, CRISPR-Cas9 editing, and behavioral assays to identify key transcription factors that are required for leg formation and function in sea robins. We also generate hybrids between two sea robin species with distinct leg morphologies and use allele-specific expression analysis and gene editing to explore the genetic basis of species-specific trait diversity, including a novel sensory gain of function. Collectively, our study establishes sea robins as a new model for studying the genetic basis of novel organ formation, and demonstrates a crucial role for the conserved limb genetbx3ain the evolution of chemosensory legs in walking fish.