bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOLR3B-variant reveals a Pol III transcriptome response dependent on La protein/SSB
Authors: Mattijssen Sandy , Kerkhofs Kyra , Stephen Joshi , Yang Acong , Han Chen G. , Tadafumi Yokoyama , Iben James R. , Mishra Saurabh , Sakhawala Rima M. , Ranjan Amitabh , Gowda Mamatha , Gahl William A. , Gu Shuo , Malicdan May C. , Maraia Richard J. 
Published: February 2024

ABSTRACTRNA polymerase III (Pol III, POLR3) synthesizes tRNAs and other small non-coding RNAs. HumanPOLR3pathogenic variants cause a range of developmental disorders, recapitulated in part by mouse models, yet some aspects of POLR3 deficiency have not been explored. We characterized a humanPOLR3B:c.1625A>G;p.(Asn542Ser) disease variant that was found to cause mis-splicing ofPOLR3B. Genome-editedPOLR3B1625A>GHEK293 cells acquired the mis-splicing with decreases in multiple POLR3 subunits and TFIIIB, although display auto-upregulation of the Pol III termination-reinitiation subunitPOLR3E. La protein was increased relative to its abundant pre-tRNA ligands which bind via their U(n)U-3’-termini. Assays for cellular transcription revealed greater deficiencies for tRNA genes bearing terminators comprised of 4Ts than of ≥5Ts. La-knockdown decreased Pol III ncRNA expression unlinked to RNA stability. Consistent with these effects, small-RNAseq showed thatPOLR3B1625A>Gand patient fibroblasts express more tRNA fragments (tRFs) derived from pre-tRNA 3’-trailers (tRF-1) than from mature-tRFs, and higher levels of multiple miRNAs, relative to control cells. The data indicate that decreased levels of Pol III transcripts can lead to functional excess of La protein which reshapes small ncRNA profiles revealing new depth in the Pol III system. Finally, patient cell RNA analysis uncovered a strategy for tRF-1/tRF-3 asPOLR3-deficiency biomarkers.
Identification of transcriptional regulators using a combined disease module identification and prize-collecting Steiner tree approach
Authors: Galindez Gihanna , Lopez Ben Anthony , Blumenthal David B. , Kacprowski Tim 
Published: February 2024

AbstractTranscription factors play important roles in maintaining normal biological function, and their dys-regulation can lead to the development of diseases. Identifying candidate transcription factors involved in disease pathogenesis is thus an important task for deriving mechanistic insights from gene expression data. We developed Transcriptional Regulator Identification using Prize-collecting Steiner trees (TRIPS), a workflow for identifying candidate transcriptional regulators from case-control expression data. In the first step, TRIPS combines the results of differential expression analysis with a disease module identification step to retrieve perturbed subnetworks comprising an expanded gene list. TRIPS then solves a prize-collecting Steiner tree problem on a gene regulatory network, thereby identifying candidate transcriptional modules and transcription factors. We compare TRIPS to relevant methods using publicly available disease datasets and show that the proposed workflow can recover known disease-associated transcription factors with high precision. Network perturbation analyses demonstrate the reliability of TRIPS results. We further evaluate TRIPS on Alzheimer’s disease, diabetic kidney disease, and prostate cancer single-cell omics datasets. Overall, TRIPS is a useful approach for prioritizing transcriptional mechanisms for further downstream analyses.
Unprocessed Genomic Uracil as a Source of DNA Replication Stress in Cancer Cells
Authors: Saxena Sneha , Patel Parasvi S. , Nabel Christopher S. , Kawale Ajinkya S. , Crosby Caroline R. , Heiden Matthew G. Vander , Hata Aaron N. , Zou Lee 
Published: February 2024

AbstractAlterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA. ATR inhibition in UNG-deficient cells blocks repair of uracil-induced gaps, increasing replication fork collapse and cell death. Notably, a subset of cancer cells harboring high levels of genomic uracil upregulate UNG2 to limit RS, and these cancer cells are hypersensitive to co-treatment with ATR inhibitors and drugs increasing genomic uracil. These results reveal unprocessed genomic uracil as an unexpected source of RS and a targetable vulnerability of cancer cells.
Large-scale multi-omics analyses identified root-microbiome associations underlying plant nitrogen nutrition
Authors: Li Nannan , Li Guoliang , Wang Danning , Ma Lige , Huang Xiaofang , Bai Zhen , Wang Yongfeng , Luo Meng , Luo Yu , Zhu Yantao , Cao Xulv , Feng Qirui , Xu Ying , Mu Jianxin , An Ran , Yang Cuiling , Chen Hao , Li Xiaodan , Dong Yachen , Zhao Jianhua , Jiang Lixi , Jiang Yong , Reif Jochen C. , Hochholdinger Frank , Chen Xinping , Wang Daojie , Zhang Yanfeng , Bai Yang , Yu Peng 
Published: February 2024

AbstractThe microbiome determines the performance and fitness of the host plant. Nevertheless, the causal interaction between host genetic variation, gene regulation and the impact of the microbiome on the host phenotype remain unknown. Here we generated 1,341 paired root transcriptome, rhizosphere microbiome and root ionome samples and performed a multi-omics analyses of the host-microbe association at the root-soil interface using 175 rapeseeds (Brassica napusL.) resequenced ecotypes at two field environments. We observed the highest statistically explained variance for root nitrogen uptake among natural ionomic variation by overall transcriptome-wide gene expression and microbial abundance variation. Moreover, we identified significant genome-wide associations for 203 highly heritable amplicon sequence variants (ASVs) at multiple genetic loci regulated by eQTL hotspots associated with nitrogen metabolism components. These associations involved a central bacterial genus (Sphingopyxis), which plays a dominant role on gene regulatory effect on its variation regulated by eQTL hotspots. In addition, we performed high-throughput bacterial cultivation from rapeseed roots and subjectedSphingopyxisto whole genome sequencing. Finally, targeted metabolite profiling and confocal imaging assays demonstrated a host-microbiome regulatory effect onSphingopyxisestablished by lateral root development and plant nitrogen nutrition. In summary, our integrative approach reveals the genetic basis of host-microbiome trait associations in the transcriptional, nutritional and environmental domains and suggests that the microbiome might have causal effects on root development with implications towards the breeding of nutrient-efficient crops.
Autorepression of Yeast Hsp70 co-chaperones by intramolecular interactions involving their J-domains
Authors: Rebeaud Mathieu E. , Tiwari Satyam , Fauvet Bruno , Mohr Adelaïde , De Los Rios Paolo , Goloubinoff Pierre 
Published: February 2024

AbstractThe Hsp70 chaperones control protein homeostasis in all ATP-containing cellular compartments. J-domain proteins (JDPs) co-evolved with Hsp70s to trigger ATP-hydrolysis and catalytically upload various substrate polypeptides in need to be structurally modified by the chaperone. Here, we measured the protein disaggregation and refolding activities of the main yeast cytosolic Hsp70, Ssa1, in the presence of its most abundant JDPs, Sis1 and Ydj1, and two swap mutants, in which the J-domains have been interchanged. The observed differences by which the four constructs differently cooperate with Ssa1 and cooperate with each other, as well as their observed intrinsic ability to bind misfolded substrates and trigger Ssa1’s ATPase, indicates the presence of yet uncharacterized intra-molecular dynamic interactions between the J-domains and their remaining C-terminal domains. Taken together, the data suggest an auto-regulatory role to these intra-molecular interactions within both type A and B JDPs, which might have evolved to reduce energy-costly ATPase cycles by the Ssa1-4 chaperones that are the most abundant Hsp70s in the yeast cytosol.Graphical abstract:Lower panel: autoinhibited DnaJA or DnaJB dimers, drawn here as Swiss army knives with sequestered J-domains as folded blades, can bind misfolded polypeptides (violet). Upper panel: DnaJA or DnaJB become active when their J-domains are exposed and can bind ATP-Hsp70s, and transfer the misfolded polypeptides, respectively, onto Hsp70’s nucleotide binding (Cyan) and protein binding domains (Orange and Green). Hsp70’s interdomain linker (DLLLLDV, Magenta).
Restraining Wnt activation and intestinal tumorigenesis by a Rab35 dependent GTPase relay
Authors: Redhai Siamak , Wang Tianyu , Boonekamp Kim. E , Reuter Saskia , Capraz Tümay , Leible Svenja , Bahaguna Shivohum , Port Fillip , Pavlović Bojana , Holzem Michaela , Doll Roman M. , Rindtorff Niklas , Valentini Erica , Schmitt Barbara , Richter Karsten , Engel Ulrike , Huber Wolfgang , Boutros Michael 
Published: February 2024

ABSTRACTMaintenance of homeostatic processes ensure curtailment of intestinal tumorigenesis. Inactivating mutations to Adenomatous Polyposis Coli (Apc) result in aberrantly activated Wnt signalling and initiates colorectal cancer (CRC) in approx. 80% of cases, yet our understanding of the subcellular mechanisms that modulate dysregulated pathway activity is limited. Here, using a conditionalin vivogenetic screen, we identify Rab35 GTPase as a novel tumour suppressor that modulates regional Wnt activity after loss ofApcin progenitor cells. Single cell analysis revealed that progenitor cells respond toApcdepletion by increasing the expression of a GTPase activating protein, which we namedblackbelt, and triggering Rab35 disassociation from the plasma membrane. Mechanistically, we demonstrate that Rab35 controls the localisation and activation of the Rho GTPase, Cdc42, which functions as a relay to regulate JNK signalling. This in turn tunes the Wnt pathway upstream of β-catenin to direct proliferation and differentiation of progenitor cells. Importantly, we show that maintaining active JNK signalling is important for the propagation ofApcmutant mouse colon organoids. Our findings highlight a novel GTPase cascade that sustains aberrant Wnt activity in specific segments of the intestine and provides impetus to therapeutically exploit this pathway to target CRC.
CD40 Expression by B cells is Required for Optimal Immunity to MurinePneumocystisInfection
Authors: Sassi Monica , Curran Shelly J. , Bishop Lisa R. , Liu Yueqin , Kovacs Joseph A. 
Published: February 2024

AbstractCD40-CD40L interactions are critical for controllingPneumocystisinfection. However, which CD40-expressing cell populations are important for this interaction have not been well-defined. We used a cohousing mouse model ofPneumocystisinfection, combined with flow cytometry and qPCR, to examine the ability of different populations of cells from C57BL/6 mice to reconstitute immunity in CD40 knockout (KO) mice. Unfractionated splenocytes, as well as purified B cells, were able to controlPneumocystisinfection, while B cell depleted splenocytes and unstimulated bone-marrow derived dendritic cells (BMDCs) were unable to control infection in CD40 KO mice.Pneumocystisantigen-pulsed BMDCs showed early, but limited, control of infection. Consistent with recent studies that have suggested a role for antigen presentation by B cells, using cells from immunized animals, B cells were able to presentPneumocystisantigens to induce proliferation of T cells. Thus, CD40 expression by B cells appears necessary for robust immunity toPneumocystis.
Insights into ontogenetic scaling and morphological variation in sharks from near-term brown smooth-hound (Mustelus henlei) embryos
Authors: Gayford Joel H. , Sternes Phillip C. , Seamone Scott G. , Godfrey Hana , Whitehead Darren A. 
Published: February 2024

AbstractElasmobranchs (sharks and rays) exhibit a wide range of body forms adapted to various ecological niches. Body form differs not only between species, but between life stages of individual species as a result of ontogenetic allometry. In sharks, it has been proposed that these ontogenetic shifts in body form result from shifts in trophic and/or spatial ecology (the allometric niche shift hypothesis). Alternatively, it has been suggested that ontogenetic allometry may result from intrinsic morphological constraints associated with increasing body size – e.g. to counteract shifts in form-function relationships that occur as a function of size and could compromise locomotory performance. One major limitation affecting our understanding of ontogenetic scaling in sharks is that existing studies focus on postpartum ontogeny – ignoring the period of growth that occurs prior to birth/hatching. In this study, we report ontogenetic growth trajectories from 39 near-term brown smooth hound (Mustelus henlei) embryos taken from manually collected measurements. We found that unlike most other species and later ontogenetic stages ofM. henlei, these embryos predominantly grow isometrically, and appear to display relatively high levels of morphological disparity. These results provide rudimentary support for the allometric niche shift hypothesis (as in the absence of ontogenetic niche shifts isometry dominates body-form scaling) and provide important insight into early shark ontogeny and morphological/developmental evolution.
The dimensionality of neural coding for cognitive control is gradually transformed within the lateral prefrontal cortex
Authors: Chiou Rocco , Duncan John , Jefferies Elizabeth , Lambon Ralph Matthew A. 
Published: February 2024

AbstractImplementing cognitive control relies on neural representations that are inherently high-dimensional and distribute across multiple subregions in the prefrontal cortex (PFC). Traditional approaches tackle prefrontal representations by reducing them into a unidimensional measure (univariate amplitude) or using them to distinguish a limited number of alternatives (pattern classification). By contrast, representational similarity analysis (RSA) enables flexibly formulating various hypotheses about informational contents underlying the neural codes, explicitly comparing hypotheses, and examining the representational alignment between brain regions. Here, we used a multifaceted paradigm wherein the difficulty of cognitive control was manipulated separately for five cognitive tasks. We used RSA to unveil representational contents, measure the representational alignment between regions, and quantify representational generalityvs.specificity. We found a graded transition in the lateral PFC: The dorsocaudal PFC was tuned to the information about behavioural effort, preferentially connected with the parietal cortex, and representationally generalisable across domains. The ventrorostral PFC was tuned to the abstract structure of tasks, preferentially connected with the temporal cortex, and representationally specific. The middle PFC (interposed between dorsocaudal and ventrorostral PFC) was tuned to individual task-sets, ranked in the middle in terms of connectivity and generalisability. Furthermore, whether a region was dimensionally rich or thin co-varied with its functional profile: Low dimensionality (only gist) in the dorsocaudal PFC dovetailed with better generality, whereas high dimensionality (gist plus details) in the ventrorostral PFC corresponded with better ability to encode subtleties. Our findings, collectively, demonstrate how cognitive control is decomposed into distinct facets that transition steadily along prefrontal subregions.SignificanceCognitive control is known to be a high-dimensional construct, implemented along the dorsocaudal-ventrorostral subregions of PFC. However, it remains unclear how prefrontal representations could be dissected in a multivariate fashion to reveal (1) what information is encoded in each subregion, (2) whether information systematically transforms across contiguous PFC subregions as a gradient, (3) how this transformation is affected by functional connectivity. Here we shed light on these issues by using RSA to decode informational composition in the PFC while using participant-specific localisers to facilitate individually-tailored precision. Our findings elucidate the functional organisation of PFC by revealing how a trade-off between dimensionality and generalisability unfolds in the PFC and highlight the strength of RSA in deciphering the coding of cognitive control.
A Functional and Non-Homuncular Representation of the Larynx in the Primary Motor Cortex of Mice, a Vocal Non-Learner
Authors: Vargas César D. M. , Agravat Rajvi K. , Waidmann Elena N. , Bochalis Christodoulos , Bermudez Hector , Giannakopoulos Theodoros , Jarvis Erich D. 
Published: February 2024

SummaryVocalization is a complex behavior ranging from fully innate to advanced vocal learning. Vocal learning species possess a vocal primary motor cortex (M1) region that makes direct projections to brainstem vocal motor neurons, which are thought to facilitate learning and fine modulation of vocalizations. Surprisingly, a similar, albeit sparse, direct projection from M1 was found in mice. Mice produce ultrasonic vocalizations (USV) which appear to be mostly innate. Modulation of these USVs is impacted by lesions to this M1 region, but genetic ablation of the cortex leads to few, if any, changes to USVs. It remained unclear whether M1 has any control over the vocal organ in a vocal non-learning species. In the current study, we found that stimulation in different parts of M1 in mice can generate contractions in laryngeal and jaw muscles, with different latencies suggestive of both direct and indirect projections to brainstem vocal motor neurons. Viral tracing reveals both single- and double-labeled populations of cortical neurons that simultaneously innervate laryngeal, jaw, and forelimb motor circuits. Chemical lesions reveal that an anterolateral orofacial region of M1 regulates the number of syllables in vocal sequences. Our results provide evidence that M1 in a vocal non-learner has some influence on vocal musculature, consistent with the continuum hypothesis of vocal learning. They also reveal that the representations of muscles for different behaviors across mouse M1 are more intermixed than previously considered. We discuss how these results impact hypotheses on the evolution of cortical vocal control and motor cortex organization.
Electric field characteristics of rotating permanent magnet stimulation
Authors: Robins Pei L. , Makaroff Sergey N. , Dib Michael , Lisanby Sarah H. , Deng Zhi-De 
Published: February 2024

AbstractNeurostimulation devices that use rotating permanent magnets are being explored for their potential therapeutic benefits in patients with psychiatric and neurological disorders. This study aims to characterize the electric field (E-field) for ten configurations of rotating magnets using finite element analysis and phantom measurements. Various configurations were modeled, including single or multiple magnets, bipolar or multipolar magnets, rotated at 10, 13.3, and 400 Hz. E-field strengths were also measured using a hollow sphere (r= 9.2 cm) filled with a 0.9% sodium chloride solution and with a dipole probe. The E-field spatial distribution is determined by the magnets’ dimensions, number of poles, direction of the magnetization, and axis of rotation, while the E-field strength is determined by the magnets’ rotational frequency and magnetic field strength. The induced E-field strength on the surface of the head ranged between 0.0092 and 0.59 V/m. At the range of rotational frequencies applied, the induced E-field strengths were approximately an order or two of magnitude lower than those delivered by conventional transcranial magnetic stimulation. The impact of rotational frequency on E-field strength represents a previously unrecognized confound in clinical trials that seek to personalize stimulation frequency to individual neural oscillations and may represent a mechanism to explain some clinical trial results.
Increased pediatric RSV case counts following the emergence of SARS-CoV-2 are attributable to increased testing
Authors: Petros Brittany A. , Milliren Carly E. , Sabeti Pardis C. , Ozonoff Al 
Published: February 2024

AbstractBackgroundThe incidence of respiratory syncytial virus (RSV) dropped markedly early in the COVID-19 pandemic, followed by a resurgence with heightened case counts. The “immunity debt” hypothesis proposes that the RSV-naive pediatric population increased during the period of low transmission, resulting in a subsequent increased risk of infection. However, the evidence supporting this hypothesis is limited, and no studies have comprehensively evaluated the role of changing respiratory viral testing practices in the perceived surge.MethodsWe conducted a multicenter, retrospective analysis of 342,530 RSV encounters and 980,546 RSV diagnostic tests occurring at 32 United States pediatric hospitals between 2013 and 2023. We used interrupted time series analysis to estimate pandemic-associated changes in RSV patient and testing volume, and to quantify changes in the proportions of patients admitted from the emergency department (ED), admitted to the intensive care unit (ICU), and receiving mechanical ventilation. We quantified the fraction of the observed shifts in case counts and in the age of diagnosed patients attributable to changes in RSV testing practices. Finally, we analyzed 524,404 influenza virus encounters and 1,768,526 influenza diagnostic tests to address the specificity of the findings to RSV.FindingsRSV patient volume increased 2.4-fold (95% CI: 1.7, 3.5) in 2021-2023 relative to the pre-pandemic phase, and was accompanied by an 18.9-fold increase (95% CI: 15.0, 23.9) in RSV test volume. Over two-thirds of the apparent shifts in patient volume and in patient age were attributable to increased testing, which was concentrated among older pediatric patients. The proportions of patients with RSV requiring hospitalization, intensive care, or mechanical ventilation declined significantly across all patient age groups. These declines were not observed for patients with influenza virus.InterpretationA surge in RSV testing, rather than in viral circulation, likely underlies the increased case counts observed in 2021-2023. We identify expected consequences of increased testing, including the diagnosis of less severe cases and a shift in the patient age distribution. These findings warrant a critical assessment of the immunity debt hypothesis, while highlighting the importance of considering the testing denominator when surveillance strategies are dynamic.FundingNational Institutes of Health & Howard Hughes Medical Institute