bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes
Authors: Zuber Verena , Lewin Alex , Levin Michael G. , Haglund Alexander , Gonzalez Soumaya Ben-Aicha , Emanueli Costanza , Damrauer Scott , Burgess Stephen , Gill Dipender , Bottolo Leonardo 
Published: February 2023

AbstractThe existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce Multi-response Mendelian randomization (MR2), a novel MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, andviceversa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.
Streamlined and sensitive mono- and diribosome profiling in yeast and human cells
Authors: Ferguson Lucas , Upton Heather E. , Pimentel Sydney C. , Mok Amanda , Lareau Liana F. , Collins Kathleen , Ingolia Nicholas T. 
Published: February 2023

AbstractRibosome profiling has unveiled diverse regulations and perturbations of translation through a transcriptome-wide survey of ribosome occupancy, read out by sequencing of ribosome-protected mRNA fragments. Generation of ribosome footprints and their conversion into sequencing libraries is technically demanding and sensitive to biases that distort the representation of physiological ribosome occupancy. We address these challenges by producing ribosome footprints with P1 nuclease rather than RNase I and replacing RNA ligation with Ordered Two-Template Relay, a single-tube protocol for sequencing library preparation that incorporates adapters by reverse transcription. Our streamlined approach reduced sequence bias and enhanced enrichment of ribosome footprints relative to ribosomal RNA. Furthermore, P1 nuclease preserved a myriad of distinct juxtaposed ribosome complexes informative about yeast and human ribosome fates during translation initiation, stalling, and termination. Our optimized methods for mRNA footprint generation and capture provides a richer translatome profile using lower input and fewer technical challenges.
Administration ofBifidobacterium animalissubsp.lactisStrain BB-12®in Healthy Children: Characterization, Functional Composition, and Metabolism of the Gut Microbiome
Authors: Vizioli Carlotta , Jaime-Lara Rosario , Daniel Scott G. , Franks Alexis , Diallo Ana F. , Bittinger Kyle , Tan Tina P. , Merenstein Daniel J. , Brooks Brianna , Joseph Paule V. , Maki Katherine A. 
Published: February 2023

AbstractThe consumption of probiotics may influence children’s gut microbiome and metabolome, which may reflect shifts in gut microbial diversity composition and metabolism. These potential changes might have a beneficial impact on health. However, there is a lack of evidence investigating the effect of probiotics on the gut microbiome and metabolome of children. We aimed to examine the potential impact of a two (Streptococcus thermophilusandLactobacillus delbrueckii; S2)vs. three (S2 +Bifidobacterium animalissubsp.lactisstrain BB-12) strain-supplemented yogurt. Included in this study were 59 participants, aged one to five years old, recruited to phase I of a double-blinded, randomized controlled trial. Fecal samples were collected at baseline, after the intervention, and at twenty days post-intervention discontinuation, and untargeted metabolomics and shotgun metagenomics were performed. Shotgun metagenomics and metabolomic analyses showed no global changes in either intervention group’s gut microbiome alpha or beta diversity indices. The relative abundance of the two and three intervention bacteria increased in the S2 and S2 + BB12 groups, respectively, fromDay 0toDay 10. In the S2+BB12 group, the abundance of several fecal metabolites was reduced atDay 10, including alanine, glycine, lysine, phenylalanine, serine, and valine. These fecal metabolite changes did not occur in the S2 group. Future research using longer probiotic intervention durations and in children at risk for gastrointestinal disorders may elucidate if functional metabolite changes confer a protective gastrointestinal effect.
Concurrent 3D super resolution on intensity and segmentation maps improves detection of structural effects in neurodegenerative disease
Authors: avants brian , Tustison Nicholas J , McMillan Corey T , Gosselin Taylor , Gunn Roger , Hesterman Jacob 
Published: February 2023

AbstractWe propose a new perceptual super resolution (PSR) method for 3D neuroimaging and evaluate its performance in detecting brain changes due to neurodegenerative disease. The method, concurrent super resolution and segmentation (CSRS), is trained on volumetric brain data to consistently upsample both an image intensity channel and associated segmentation labels. The simultaneous nature of the method improves not only the resolution of the images but also the resolution of associated segmentations thereby making the approach directly applicable to existing labeled datasets. One challenge to real world evaluation of SR methods such as CSRS is the lack of high resolution ground truth in the target application data: clinical neuroimages. We therefore evaluate CSRS effectiveness in an adjacent, clinically relevant signal detection problem: quantifying cross-sectional and longitudinal change across a set of phenotypically heterogeneous but related disorders that exhibit known and differentiable patterns of brain atrophy. We contrast several 3D PSR loss functions in this paradigm and show that CSRS consistently increases the ability to detect regional atrophy both longitudinally and cross-sectionally in each of five related diseases.
Identifying and prioritizing demersal fisheries restricted areas based on combined ecological and fisheries criteria: the western Mediterranean
Authors: Ortega Miquel , Castro-Cadenas María D. , Steenbeek Jeroen , Coll Marta 
Published: February 2023

AbstractThe western Mediterranean basin is a high marine biodiversity area under severe pressure by changing climate and intense human activities. Beyond national jurisdictions, international institutions such as the General Fisheries Commission for the Mediterranean (GFCM) work towards canalizing a regional consensus that fishing practices should evolve to better support the 2030 Agenda for Sustainable Development. In this context, Fisheries Restricted Areas (FRA) are proposed as effective management measures to contribute towards increasing fisheries sustainability in the region that can be considered, under some conditions, as Nature-based Solutions (NbS); however, how to operationalize their framework remains unclear. In this study, based on combined ecological and fisheries criteria, we identify and prioritize six potential priority areas for management (PAMs) in the western Mediterranean Sea. They are specifically aimed at the protection and recovery of Essential Fish Habitats and the conservation of Vulnerable Marine Ecosystems, whilst requiring limited adaptation of fisheries practices due to their relative low fishing pressure. We compare the identified areas to those that are currently under protection, and to areas that have been proposed for protection at the GFCM. Our results show that the FRAs and other spatial management measures introduced in the last years marginally contribute to the protection PAMs in the western Mediterranean region. However, the adoption of FRAs that are currently under discussion at the GFCM could contribute significantly to improve the situation. FRAs could also contribute to operationalize NbS in the western Mediterranean Sea when properly designed and implemented.HighlightsBased on combined ecological and fisheries criteria, six priority areas for management (PAMs) in the western Mediterranean Sea have being identified, with multiple ecological values and relative low trawling.Current spatial management measures implemented have little contribution on PAMs protection.Fisheries Restricted Areas currently under discussion at the GFCM can significantly increase the protection level of high priority PAMs.
Cancer relevance of circulating antibodies against LINE-1 antigens in humans
Authors: Vylegzhanina Alexandra V. , Bespalov Ivan A. , Novototskaya-Vlasova Ksenia A. , Hall Brandon M. , Gleiberman Anatoli S. , Yu Han , Leontieva Olga V. , Leonova Katerina I. , Kurnasov Oleg V. , Osterman Andrei L. , Dy Grace K. , Komissarov Alexey A. , Vasilieva Elena , Gehlhausen Jeff , Iwasaki Akiko , Ambrosone Christine B. , Tsuji Takemasa , Matsuzaki Junko , Odunsi Kunle , Andrianova Ekaterina L. , Gudkov Andrei V. 
Published: February 2023

AbstractLINE-1 (L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues but frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. Here, we established an immunoassay for detecting circulating autoantibodies against L1 proteins in human blood. Using this assay in >3,000 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers compared to healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in cancer patients with disease stages 1 and 2, indicating that immune response to L1 antigens can occur at early phases of carcinogenesis. We conclude that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection.
Evolution of a fatty acyl-CoA elongase underlies desert adaptation inDrosophila
Authors: Wang Zinan , Pu Jian , Richards Cole , Giannetti Elaina , Cong Haosu , Lin Zhenguo , Chung Henry 
Published: February 2023

ABSTRACTTo survive in extreme environments such as hot-arid deserts, desert-dwelling species have evolved physiological traits to withstand the high temperatures and low aridity beyond the physiologically tolerable ranges of most species. Such traits which include reducing water loss have independently evolved in multiple taxa. However, the genetic and evolutionary mechanisms underlying these traits have thus far not been elucidated. Here we show thatDrosophila mojavensis, a fruitfly species endemic to the Sonoran and Mojave deserts, had evolved extremely high desiccation resistance, by producing very long chained methylbranched cuticular hydrocarbons (mbCHCs) that contributes to a cuticular waterproofing lipid layer reducing water loss. We show that the ability to synthesize these longer mbCHCs is due to evolutionary changes in a fatty acyl-CoA elongase (mElo). CRISPR/Cas9 knockout ofmEloinD. mojavensisled to loss of longer mbCHC production and significant reduction of desiccation resistance at high temperatures but did not affect mortality at high temperatures or desiccating conditions individually, indicating that this gene is crucial for desert adaptation. Phylogenetic analysis showed thatmElois aDrosophilaspecific gene with no clear ortholog outside Diptera. This suggests that while the physiological mechanisms underlying desert adaptation are general, the genetic mechanisms may be lineage-specific.
Mapping the genetic evolutionary timeline of human neural and cognitive traits
Authors: Libedinsky Ilan , Wei Yongbin , de Leeuw Christiaan , Rilling James K. , Posthuma Danielle , van den Heuvel Martijn P. 
Published: February 2023

AbstractHuman evolution is characterised by extensive changes of body and brain, with perhaps one of the core developments being the fast increase in cranial capacity and brain volume. Paleontological records are the most direct method to study such changes, but they can unfortunately provide a limited view of how ‘soft traits’ such as brain function and cognitive abilities have evolved in humans. A potential complementary approach is to identify when particular genetic variants associated with human phenotypes (such as height, body mass index, intelligence, and also disease) have emerged in the 6-7 million years since we diverged from chimpanzees. In this study, we combine data from genome-wide association studies on human brain and cognitive traits with estimates of human genome dating. We systematically analyse the temporal emergence of genetic variants associated with modern-day human brain and cognitive phenotypes over the last five million years. Our analysis provides evidence that genetic variants related to neocortex structure (e.g., area, thickness; median evolutionary age = 400,170 years old), cognition (e.g., fluid intelligence; median age = 459,465), education (median age = 637,646), and psychiatric disorders (median age = 412,639) have emerged more recently in human evolution than expected by chance. In contrast, variants related to other physical traits, such as height (median age = 811,305) and body mass index (median age = 794,265), emerged relatively later. We further show that genes containing recent evolutionary modifications (from around 54,000 to 4,000 years ago) are linked to intelligence (P= 2 × 10−6) and neocortical surface area (P= 6.7 × 10−4), and that these genes tend to be highly expressed in cortical areas involved in language and speech (pars triangularis,P= 6.2 × 10−4). Elucidating the temporal dynamics of genetic variants associated with brain and cognition is another source of evidence to advance our understanding of human evolution.
Identification of the novel role of sterol regulatory element binding proteins (SREBPs) in mechanotransduction and intraocular pressure regulation
Authors: Wang Ting , Soundararajan Avinash , Rabinowitz Jeffery , Jaiswal Anant , Osborne Timothy , Pattabiraman Padmanabhan Paranji 
Published: February 2023

AbstractTrabecular meshwork (TM) cells are highly contractile and mechanosensitive to aid in maintaining intraocular pressure (IOP) homeostasis. Lipids are attributed to modulating TM contractility with poor mechanistic understanding. In this study using human TM cells, we identify the mechanosensing role of the transcription factors sterol regulatory element binding proteins (SREBPs) involved in lipogenesis. By constitutively activating SREBPs and pharmacologically inactivating SREBPs, we have mechanistically deciphered the attributes of SREBPs in regulating the contractile properties of TM. The pharmacological inhibition of SREBPs by fatostatin and molecular inactivation of SREBPsex vivoandin vivorespectively results in significant IOP lowering. As a proof of concept, fatostatin significantly decreased the SREBPs responsive genes and enzymes involved in lipogenic pathways as well as the levels of the phospholipid, cholesterol, and triglyceride. Further, we show that fatostatin mitigated actin polymerization machinery and stabilization, and decreased ECM synthesis and secretion. We thus postulate that lowering lipogenesis in the TM outflow pathway can hold the key to lowering IOP by modifying the TM biomechanics.SynopsisIn this study, we show the role of lipogenic transcription factors sterol regulatory element binding proteins (SREBPs) in the regulation of intraocular pressure (IOP). (Synopsis Figure -Created using Biorender.com)SREBPs are involved in the sensing of changes in mechanical stress on the trabecular meshwork (TM). SREBPs aid in transducing the mechanical signals to induce actin polymerization and filopodia/lamellipodia formation.SREBPs inactivation lowered genes and enzymes involved in lipogenesis and modified lipid levels in TM.SREBPs activity is a critical regulator of ECM engagement to the matrix sites.Inactivation of SCAP-SREBP pathway lowered IOP via actin relaxation and decreasing ECM production and deposition in TM outflow pathway signifying a novel relationship between SREBP activation status and achieving IOP homeostasis.
Simultaneous Electrophysiology and Optogenetic Perturbation of the Same Neurons in Chronically Implanted Animals using μLED Silicon Probes
Authors: Kinsky Nathaniel R. , Vöröslakos Mihály , Ruiz Jose Roberto Lopez , Watkins de Jong Laurel , Slager Nathan , McKenzie Sam , Yoon Euisik , Diba Kamran 
Published: February 2023

ABSTRACTOptogenetics are a powerful tool for testing how a neural circuit influences neural activity, cognition, and behavior. Accordingly, the number of studies employing optogenetic perturbation has grown exponentially over the last decade. However, recent studies have highlighted that the impact of optogenetic stimulation/silencing can vary depending on the construct used, the local microcircuit connectivity, extent/power of illumination, and neuron types perturbed. Despite these caveats, the majority of studies employ optogenetics without simultaneously recording neural activity in the circuit that is being perturbed. This dearth of simultaneously recorded neural data is due in part to technical difficulties in combining optogenetics and extracellular electrophysiology. The recent introduction of μLED silicon probes, which feature independently controllable miniature LEDs embedded at several levels of each of multiple shanks of silicon probes, provides a tractable method for temporally and spatially precise interrogation of neural circuits. Here, we provide a protocol addressing how to perform chronic recordings using μLED probes. This protocol provides a schematic for performing causal and reproducible interrogations of neural circuits and addresses all phases of the recording process: introduction of optogenetic construct, implantation of the μLED probe, performing simultaneous optogenetics and electrophysiologyin vivo, and post-processing of recorded data.SUMMARYThis method allows a researcher to simultaneously perturb neural activity and record electrophysiological signal from the same neurons with high spatial specificity using silicon probes with integrated μLEDs. We outline a procedure detailing all stages of the process for performing reliable μLED experiments in chronically implanted rodents.
Mob4 is essential for spermatogenesis inDrosophila melanogaster
Authors: Santos Inês B. , Wainman Alan , Garrido-Maraver Juan , Pires Vanessa , Riparbelli Maria Giovanna , Kovács Levente , Callaini Giuliano , Glover David M. , Tavares Álvaro A. 
Published: February 2023

AbstractGamete formation is essential for sexual reproduction in metazoans. In males, spermatogenesis gives rise to interconnected spermatids that have to differentiate and individualize into mature sperm. InDrosophila melanogaster, individualization of spermatids requires the formation of individualization complexes that synchronously move along the sperm bundles. Here, we show that Mob4, a member of the Mps-one binder family, is essential for male fertility but has no detectable role on female fertility. We describe the function of Mob4 during spermatid individualization, showing that Mob4 is required for proper axonemal structure and that the loss of Mob4 leads to male sterility associated with defective spermatid individualization and absence of mature sperm in the seminal vesicles. Transmission electron micrographs of Mob4RNAideveloping spermatids revealed defects in axoneme structure and abnormal mitochondria biogenesis. Importantly, we find that male fertility is impaired upon depletion of other STRIPAK components, suggesting that Mob4 acts through STRIPAK to support spermiogenesis. As we show that expression of the human Mob4 gene effectively rescues all phenotypes of Mob4 downregulation, the gene is not only evolutionary but also functionally conserved. We propose that Mob4 plays a role in regulating the microtubule- and actin-cytoskeleton during spermatogenesis. This study advances our understanding of male infertility by uncovering Mob4 as a novel gene required for sperm individualization.
Phylogenetically conservative trait correlation: quantification and interpretation
Authors: Westoby Mark , Yates Luke , Holland Barbara , Halliwell Ben 
Published: February 2023

AbstractCorrelation across species between two quantitative traits, or between a trait and a habitat property, can suggest that a trait value is effective in sustaining populations in some contexts but not others. It is widely held that such correlations should be controlled for phylogeny, via phylogenetically independent contrasts PICs or phylogenetic generalised least squares PGLS.Two weaknesses of this idea are discussed. First, the phylogenetically conservative share of the correlation ought not to be excluded from consideration as potentially ecologically functional. Second, PGLS does not yield a complete or accurate breakdown of A-B covariation, because it corresponds to a generating model where B predicts variation in A but not the reverse.Multi-response mixed models using phylogenetic covariance matrices can quantify conservative trait correlation CTC, a share of covariation between traits A and B that is phylogenetically conservative. Because the evidence is from correlative data, it is not possible to split CTC into causation by phylogenetic history versus causation by continuing reciprocal selection between A and B. Moreover, it is quite likely biologically that the two influences have acted in concert, through phylogenetic niche conservatism.Synthesis: The CTC concept treats phylogenetic conservatism as a conjoint interpretation alongside ongoing influence of other traits. CTC can be quantified via multi-response phylogenetic mixed models.