bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of indirect genetic effects and heritability under assortative mating
Authors: Young Alexander Strudwick 
Published: July 2023

AbstractBoth direct genetic effects (effects of alleles in an individual on that individual) and indirect genetic effects — effects of alleles in an individual (e.g. parents) on another individual (e.g. offspring) — can contribute to phenotypic variation and genotype-phenotype associations. Here, we consider a phenotype affected by direct and parental indirect genetic effects under assortative mating at equilibrium. We generalize classical theory to derive a decomposition of the equilibrium phenotypic variance in terms of direct and indirect genetic effect components. We extend this theory to show that popular methods for estimating indirect genetic effects or ‘genetic nurture’ through analysis of parental and offspring polygenic predictors (called polygenic indices or scores — PGIs or PGSs) are substantially biased by assortative mating. We propose an improved method for estimating indirect genetic effects while accounting for assortative mating that can also correct heritability estimates for bias due to assortative mating. We validate our method in simulations and apply it to PGIs for height and educational attainment (EA), estimating that the equilibrium heritability of height is 0.699 (S.E. = 0.075) and finding no evidence for indirect genetic effects on height. We estimate a very high correlation between parents’ underlying genetic components for EA, 0.755 (S.E. = 0.035), which is inconsistent with twin based estimates of the heritability of EA, possibly due to confounding in the EA PGI and/or in twin studies. We implement our method in the software packagesnipar, enabling researchers to apply the method to data including observed and/or imputed parental genotypes. We provide a theoretical framework for understanding the results of PGI analyses and a practical methodology for estimating heritability and indirect genetic effects while accounting for assortative mating.
Algal kainoid synthases exhibit substrate-dependent hydroxylation and cyclization activities
Authors: Hopiavuori Austin R. , McKinnie Shaun M. K. 
Published: July 2023

AbstractFeII/α-ketoglutarate-dependent dioxygenases (Fe/αKG) are a large enzyme family that functionalize C-H bonds on diverse organic substrates. Although Fe/αKG homologs catalyze an array of chemically useful reactions, hydroxylation typically predominates. Microalgal DabC uniquely forms a novel C-C bond to construct the bioactive pyrrolidine ring in domoic acid biosynthesis. However, this kainoid synthase exclusively performs a stereospecific hydroxylation reaction on itscissubstrate regioisomer. Mechanistic and kinetic analyses with native and alternative substrates identified a 20-fold rate increase in DabC radical cyclization over β–hydroxylation, with no observable 1,5-hydrogen atom transfer. Moreover, this dual activity was conserved among macroalgal RadC1 and KabC homologs and provided insight into substrate recognition and reactivity trends. Investigation of this substrate-dependent chemistry improves our understanding of Fe/αKG enzymes and their biocatalytic application.
Association between diabetes and levels of micro-nutrients in a Middle Eastern population - A case-control study
Authors: Soliman Nada , Almishal Ruba , Elsayed Basant , Ahmed Ayaaz , Al-Amri Sara , Al-Kuwari Aisha , Al-Muhannadi Shaikha , Nadeer Muhammed , Chivese Tawanda 
Published: July 2023

AbstractObjectiveTo investigate associations between levels of micronutrients and diabetes, controlled and uncontrolled diabetes.MethodsA case-control study, matched on age and gender, was performed on participants with (cases) and without diabetes (controls), who were Qatari or long-term residents. Participants with diabetes were divided into those with controlled and uncontrolled diabetes using an HbA1c cutoff of 7%. Levels of micronutrients were measured from serum and categorized into normal and abnormal levels.ResultsA total of 1118 participants (374 cases and 744 controls) were included with a mean age of 41.7 years (SD 9.9), of whom 53.9% were female. Of those with diabetes, 229 had controlled diabetes and 145 had uncontrolled diabetes. Compared to those without diabetes, participants with diabetes had significantly lower mean magnesium (0.80 mmol/L (SD 0.07) vs 0.84 mmol/L (SD 0.06), respectively, p<0.001). Lower magnesium and iron were observed in participants with uncontrolled compared to participants with controlled diabetes. After multivariable logistic regression, diabetes was associated with hypomagnesemia (OR 3.2, 95% CI 3.4-213.9), and low iron (OR 1.49, 95% CI 1.03-2.15). Uncontrolled diabetes showed stronger odds of association with hypomagnesemia (OR 5.57, 95% CI 3.65-8.52).ConclusionIn an affluent setting in the Middle East and North Africa (MENA) region, diabetes was associated with low magnesium and low iron, and this association was worse in individuals with uncontrolled diabetes.
Anatomy-informed multimodal learning for myocardial infarction prediction
Authors: Sievering Ivan-Daniel , Senouf Ortal , Mahendiran Thabo , Nanchen David , Fournier Stephane , Muller Olivier , Frossard Pascal , Abbé Emmanuel , Thanou Dorina 
Published: July 2023

AbstractIn patients with coronary artery disease the prediction of future cardiac events such as myocardial infarction (MI) remains a major challenge. In this work, we propose a novel anatomy-informed multimodal deep learning framework to predict future MI from clinical data and Invasive Coronary Angiography (ICA) images. The images are analyzed by Convolutional Neural Networks (CNNs) guided by anatomical information, and the clinical data by an Artificial Neural Network (ANN). Embeddings from both sources are then merged to provide a patient-level prediction. The performance of our framework on a clinical study of 445 patients admitted with acute coronary syndromes confirms that multimodal learning increases the predictive power and achieves good performance, which outperforms the prediction obtained by each modality independently as well as that of interventional cardiologists. To the best of our knowledge, this is the first attempt towards combining multimodal data through a deep learning framework for future MI prediction.
Impact of environmental factors on calling behavior in midshipman fish across ocean basins
Authors: Kok Annebelle C.M. , Kim Ella B. , Rowell Timothy J. , Margolina Tetyana , Joseph John E. , Reeves Lindsey E. Peavey , Hatch Leila T. , Baumann-Pickering Simone 
Published: July 2023

ABSTRACTChorusing is widespread across the animal kingdom. Animal calling behavior is often driven by phenological and environmental factors such as seasonality, lunar period, and temperature. Now, in the Anthropocene, factors such as increased anthropogenic noise levels are also affecting calling behavior. Many fish call in choruses to attract mates, but the dynamics that drive fish calling behavior have rarely been studied in the field. We investigated how seasonality, lunar period, ambient noise, and temperature influenced the calling behavior of two species of toadfish, the plainfin midshipman (Porichthys notatus) and putatively, the Atlantic midshipman (Porichthys plectrodon). Acoustic recordings from a two-year period in twelve different locations, spanning two ocean basins showed that midshipman chorus presence was driven by seasonality and lunar period. Furthermore, chorus frequency increased with increasing temperature. Chorus levels were strongly influenced by seasonality and increased somewhat with increasing noise levels. Taken together, these results indicate that midshipman calling behavior was strongly influenced by interacting environmental conditions. Understanding the various impacts of each driver will facilitate predictions of changes in midshipman calling due to future changes in environmental conditions.
Specialized mesenteric lymphatic capillaries by-pass the mesenteric lymph node chain to transport peritoneal antigens directly into mediastinal lymph nodes
Authors: Redder Esther , Kirschnick Nils , Fang Shentong , Kuhlmann Michael , González-Loyola Alejandra , Wyss Tania , Stehling Martin , Adams Ralf H. , Petrova Tatiana V. , Alitalo Kari , Rot Antal , Kiefer Friedemann 
Published: July 2023

AbstractLymphatic vessels (LVs) are indispensable for tissue fluid homeostasis and immune cell trafficking. The network of LVs that channel fluids from the gut into mesenteric lymph nodes (MLN) has been recognized as the sole lymphatic system in the mesentery. Here we describe an alternative, functionally autonomous set of capillary mesenteric LVs (capMLVs) that by-pass the MLNs and drain directly into mediastinal LNs. CapMLVs develop perinatally from valves of collective mesenteric lymphatic vessels (colMLVs) in response to arterial endothelial cell-derived VEGF-C. Once extended, capMLVs detach from colMLVs to form an independent elongated network comprised of LYVE1+, CCL21+ endothelial cells. Avascular areas of the mesentery juxtaposed to capMLVs contain cell islets that express ACKR4. This CCL21-scavenging atypical receptor facilitates the migration of mesenteric phagocytes into capMLVs to be channeled directly into mediastinal LNs. This allows peritoneum-derived ominous antigens to be processed separately from alimentary antigens.
Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2
Authors: Pastoors Dorien , Havermans Marije , Mulet-Lazaro Roger , Brian Duncan , Noort Willy , Grasel Julius , Hoogenboezem Remco , Smeenk Leonie , Demmers Jeroen A.A. , Milsom Michael D. , Enver Tariq , Groen Richard WJ , Bindels Eric , Delwel Ruud 
Published: July 2023

AbstractAcute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable. Since transcription factors like EVI1 are notoriously hard to target, insight into the mechanism by which EVI1 drives myeloid transformation could provide alternative avenues for therapy. Applying protein folding predictions combined with proteomics technologies, we demonstrate that interaction with CTBP1 and CTBP2 via a single PLDLS motif in EVI1 is indispensable for leukemic transformation. Furthermore, we show that a 4x PLDLS repeat construct outcompetes binding of EVI1 to CTBP1 and CTBP2 and thereby inhibits proliferation of 3q26/MECOM rearranged AML both in in vitro and in xenotransplant models. This proof-of-concept study opens the possibility to therapeutically target one of the most incurable forms of AML with specific EVI1-CTBP inhibitors. This has important implications for other tumour types with aberrant expression of EVI1 as well as for cancers transformed by distinct CTBP-dependent oncogenic transcription factors.
Effects of noise and metabolic cost on cortical task representations
Authors: Stroud Jake P. , Wójcik Michał , Jensen Kristopher T. , Kusunoki Makoto , Kadohisa Mikiko , Buckley Mark J. , Duncan John , Stokes Mark G. , Lengyel Máté 
Published: July 2023

AbstractCognitive flexibility requires both the encoding of task-relevant and the ignoring of task-irrelevant stimuli. While the neural coding of task-relevant stimuli is increasingly well understood, the mechanisms for ignoring task-irrelevant stimuli remain poorly understood. Here, we study how task performance and biological constraints jointly determine the coding of relevant and irrelevant stimuli in neural circuits. Using mathematical analyses and task-optimized recurrent neural networks, we show that neural circuits can exhibit a range of representational geometries depending on the strength of neural noise and metabolic cost. By comparing these results with recordings from primate prefrontal cortex (PFC) over the course of learning, we show that neural activity in PFC changes in line with a minimal representational strategy. Specifically, our analyses reveal that the suppression of dynamically irrelevant stimuli is achieved by activity-silent, sub-threshold dynamics. Our results provide a normative explanation as to why PFC implements an adaptive, minimal representational strategy.
Salmonella entericaserovar Typhimurium ST313 sublineage 2.2 has emerged in Malawi with a characteristic gene expression signature and a fitness advantage
Authors: Kumwenda Benjamin , Canals Rocío , Predeus Alexander V. , Zhu Xiaojun , Kröger Carsten , Pulford Caisey , Wenner Nicolas , Lora Lizeth Lacharme , Li Yan , Owen Siân V. , Everett Dean , Hokamp Karsten , Heyderman Robert S. , Ashton Philip M. , Gordon Melita A. , Msefula Chisomo L. , Hinton Jay C. D. 
Published: July 2023

AbstractInvasive non-typhoidalSalmonella(iNTS) disease is a serious bloodstream infection that targets immune-compromised individuals, and causes significant mortality in sub-Saharan Africa.Salmonella entericaserovar Typhimurium ST313 causes the majority of iNTS in Malawi, and we performed an intensive comparative genomic analysis of 608 isolates obtained from fever surveillance at the Queen Elizabeth Hospital, Blantyre between 1996 and 2018. We discovered that following the upsurge of the well-characterisedS.Typhimurium ST313 lineage 2 from 1999 onwards, two new multidrug-resistant sublineages designated 2.2 and 2.3, emerged in Malawi in 2006 and 2008, respectively. The majority ofS.Typhimurium isolates from human bloodstream infections in Malawi now belong to sublineage 2.2 or 2.3. To identify factors that characterised the emergence of the prevalent ST313 sublineage 2.2, we performed genomic and functional analysis of two representative strains, D23580 (lineage 2) and D37712 (sublineage 2.2). Comparative genomic analysis showed that the chromosome of ST313 lineage 2 and sublineage 2.2 were broadly similar, only differing by 29 SNPs and small indels and a 3kb deletion in the Gifsy-2 prophage region that spanned thesseIpseudogene. Lineage 2 and sublineage 2.2 have unique plasmid profiles that were verified by long read sequencing. The transcriptome was initially explored in 15 infection-relevant conditions and within macrophages. Differential gene expression was subsequently investigated in depth in the four most importantin vitrogrowth conditions. We identified up-regulation of SPI2 genes in non-inducing conditions, and down-regulation of flagellar genes in D37712, compared to D23580. Following phenotypic confirmation of transcriptional differences, we discovered that sublineage 2.2 had increased fitness compared with lineage 2 during mixed-growth in minimal media. We speculate that this competitive advantage is contributing to the continuing presence of sublineage 2.2 in Malawi.
Potency of CRISPR-Cas Antifungals Is Enhanced by Co-targeting DNA Repair and Growth Regulatory Machinery at the Genetic Level
Authors: Mendoza Brian J. , Zheng Xianliang , Clements Jared C. , Cotter Christopher , Trinh Cong T. 
Published: July 2023

AbstractFungal pathogens are virulent and resistant to antibiotic treatment. Due to their adaptability, specificity, and efficiency, CRISPR-Cas systems can be harnessed for neutralizing these fungal pathogens. However, the conventional design of CRISPR-Cas antimicrobials, based on induction of DNA double-strand-breaks (DSBs), is potentially less effective in fungi due to robust eukaryotic DNA repair machinery. Here, we report a novel design principle to formulate more effective CRISPR-Cas antifungals by co-targeting essential genes with DNA repair defensive genes that remove the fungi’s ability to repair the DSB sites of essential genes. By evaluating this design on the model fungusSaccharomyces cerevisiae, we demonstrated that essential and defensive gene co-targeting is more effective than either essential or defensive gene targeting alone. The top-performing CRISPR-Cas antifungals performed as effectively as the antibiotic Geneticin. Fast growth kinetics ofS. cerevisiaeinduced resistance to CRISPR-Cas antifungals where genetic mutations mostly occurred in defensive genes and guide RNA sequences.SignificanceThe emergence of virulent, resistant, and rapidly evolving fungal pathogens poses a significant threat to public health, agriculture, and the environment. Targeting cellular processes with standard small-molecule intervention may be effective but requires long development times and is prone to antibiotic resistance. To overcome the current limitation of antibiotic development and treatment, this study harnesses CRISPR-Cas systems as antifungals by capitalizing on their adaptability, specificity, and efficiency in target design. Simultaneous co-targeting of both essential and defensive genes is shown to be a novel design principle for formulating effective CRISPR-Cas antimicrobials that can be rapidly tuned to adapt to inevitable escapee events.
The pelvic organs receive no parasympathetic innervation
Authors: Sivori Margaux , Dempsey Bowen , Chettouh Zoubida , Boismoreau Franck , Ayerdi Maïlys , Eymael Annaliese Nucharee , Baulande Sylvain , Lameiras Sonia , Coulpier Fanny , Delattre Olivier , Rohrer Hermann , Mirabeau Olivier , Brunet Jean-François 
Published: July 2023

AbstractThe pelvic organs (bladder, rectum and sex organs) have been represented for a century as receiving autonomic innervation from two pathways — lumbar sympathetic and sacral parasympathetic — by way of a shared relay, the pelvic ganglion, conceived as an assemblage of sympathetic and parasympathetic neurons. Using single cell RNA sequencing, we find that the mouse pelvic ganglion is made of four classes of neurons, distinct from both sympathetic and parasympathetic ones, albeit with a kinship to the former, but not the latter, through a complex genetic signature. We also show that spinal lumbar preganglionic neurons synapse in the pelvic ganglion onto equal numbers of noradrenergic and cholinergic cells, both of which therefore serve as sympathetic relays. Thus, the pelvic viscera receive no innervation from parasympathetic or typical sympathetic neurons, but instead from a divergent tail end of the sympathetic chains, in charge of its idiosyncratic functions.
Core enhancers of the 3’RR optimizeIgHnuclear position and loop conformation for oriented CSR
Authors: Bruzeau Charlotte , Pollet Justine , Thomas Morgane , Ba Zhaoqing , Roulois David , Pinaud Eric , Le Noir Sandrine 
Published: July 2023

AbstractClass switch recombination is an essential process which enabling B cells to adapt immunoglobulin subtypes to antigens. Transcription plays a crucial role in regulating CSR in which theIgH 3’Regulatory Region(3’RR) was identified as a key player. The3’RRstands at the 3’ end ofIgHlocus and is composed of four core enhancers surrounded by inverted repeated sequences, forming a quasi-palindrome. In addition to transcriptional control, nuclear organization appears to be an important level in CSR regulation. Furthermore, the chromatin loops atIgHlocus facilitate an efficient CSR recombination by bringing the donor and acceptor switch regions closer together. However, the precise control mechanisms governing both of these processes remain partially understood. Here, using the reference DNA 3D-FISH technique combined with various high throughput approaches, we showed that 3’RR core enhancers are necessary and sufficient to preorganize resting B cell nuclei to facilitate a deletional CSR mechanism at activated stage. We demonstrated that the 3’RR core enhancers regulateIgHlocus addressing in the nuclei, controlIgHlocus accessibility and orchestrateIgHloops formation. Our findings pinpointed an additional regulation level of mechanisms underlying B cell diversification.Graphical abstractPosition ofIgHloci through B cell development (from transitional to stimulated stages) is represented by the red spots. Inwtandc3’RRcontext,IgHloci get closer from each other and from nucleus center during evolution from transitional to mature resting stage and they relocates more at nuclear periphery, away one from each other, uponin vitrostimulation. InΔ3’RRmodel, this dynamic is lost and, moreover,IgHloci are more localized to pericentromeric heterochromatin (represented by green area) since the mature resting B cell stage and remain in afterin vitrostimulation.
Cross-modal interactions between auditory attention and oculomotor control
Authors: Zhao Sijia , Contadini-Wright Claudia , Chait Maria 
Published: July 2023

AbstractMicrosaccades are small, involuntary eye movements that occur during fixation. Their role is debated with recent hypotheses proposing a contribution to automatic scene sampling. Microsaccade inhibition (MSI) refers to the abrupt suppression of microsaccades, typically evoked within 0.1 seconds after new stimulus onset. The functional significance and neural underpinnings of MSI are subjects of ongoing research. It has been suggested that MSI is a component of the brain’s attentional re-orienting network which facilitates the allocation of attention to new environmental occurrences by reducing disruptions or shifts in gaze that could interfere with processing.The extent to which MSI is reflexive or influenced by top-down mechanisms remains debated. We developed a task that examines the impact of auditory top-down attention on MSI, allowing us to disentangle ocular dynamics from visual sensory processing. Participants (N=24 and 27; both sexes) listened to two simultaneous streams of tones and were instructed to attend to one stream while detecting specific task “targets.” We quantified MSI in response to occasional task-irrelevant events presented in both the attended and unattended streams (frequency steps in Experiment 1, omissions in Experiment 2).The results show that initial stages of MSI are not affected by auditory attention. However, later stages (∼0.25s post event-onset), affecting the extent and duration of the inhibition, are enhanced for sounds in the attended stream compared to the unattended stream. These findings provide converging evidence for the reflexive nature of early MSI stages and robustly demonstrate the involvement of auditory attention in modulating the later stages.Significance StatementMicrosaccades are rapid eye movements occurring during fixation. Their precise role is not known but a major hypothesis is that they reflect automatic sampling of the environment. A feature of microsaccades is that they exhibit abrupt suppression (MSI) after the presentation of new stimuli. This is thought to be part of attentional re-orienting. To understand the neural circuit that controls MSI, and by extension, the brain’s response to novel events in the environment, it is essential to determine which factors affect MSI. We show, for the first time, that auditory attention affects the latter (but not initial) stages of MSI. Thus, the early stages of MSI are automatic, but subsequent phases are affected by the perceptual state of the individual.