bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence, risk factors, and consequences of hypothyroidism among pregnant women in the health region of Lleida: a cohort study
Authors: Siscart Júlia , Perejón Dani , Serna M. Catalina , Orós Míriam , Godoy Pere , Solé Eduard
Published: November 2022

Background

Primary maternal hypothyroidism is defined as the increase of TSH levels in serum during pregnancy. Hypothyroidism in pregnancy is the second most common endocrine disease, after diabetes mellitus, with a prevalence ranging between 3.2 and 5.5%. Its variability depends on ethnical differences. Hypothyroidism in pregnancy is associated with other chronic diseases and fetal and maternal outcomes.

Objective

To analyze the prevalence of hypothyroidism among multiethnic pregnant women, and to evaluate the comorbidity with chronic diseases and outcomes leaded during pregnancy and newborn.

Methods

Retrospective observational cohort study in pregnant women during the years 2012-2018 in the health region of Lleida. The relationship of hypothyroidism with different variables was analyzed by calculating the adjusted odds ratio (aOR) and the 95% confidence intervals (CI) with multivariate logistic regression models.

Results

We analyzed a sample of 17177 pregnant women, which represents more than 92% of the total of pregnant women in the health region of Lleida. The annual prevalence of hypothyroidism was 5.7-7.1%. According to the region of origin, the lowest prevalence was found in the population from Sub Saharian Africa (2.1%), while the highest was from Asia and the Middle East (8.6%). Other factors associated with hypothyroidism were age, hypertension, diabetes mellitus, and dyslipidemia. In addition, we did not observe an effect of hypothyroidism on the course of pregnancy, childbirth, and on the newborn. Finally, there was a good control of the disease during pregnancy.

Conclusions

The prevalence of hypothyroidism in pregnancy was 6,5% in this study which depends on the country of origin, lower values were found in Sub Saharian African women and higher in those from Asia and the Middle East. Hypothyroidism was associated with age, diabetes mellitus, arterial hypertension, or dyslipidemia, and was not related to the Apgar score or the weight of the newborn.
Psychosocial adversity experienced in utero and early life is associated with variation in gut microbiota: a prospective case-control study
Authors: Warner Barbara B. , Rosa Bruce A. , Ndao I. Malick , Tarr Phillip I. , Miller J. Phillip , England Sara K. , Luby Joan L. , Rogers Cynthia E. , Hall-Moore Carla , Bryant Renay E. , Wang Jacqueline D. , Linneman Laura , Smyser Tara A. , Smyser Christopher D. , Barch Deanna M. , Miller Gregory E. , Chen Edith , Martin John , Mitreva Makedonka
Published: November 2022

Social disadvantage (SD) and psychological stressors (PS) trap some populations in poverty, resulting in health inequities. How these two factors become biologically embedded and the pathways leading to adverse health outcomes is unclear, especially in infants exposed to psychosocial adversity in utero and during early life. Variation in gut microbiome structure and functions, and systemic elevations in circulating cytokines levels as indices of inflammation, offer two possible causative pathways. Here, we interrogate the gut microbiome of mother-child dyads and maternal inflammatory markers, and compare high-SD/high-PS dyads to pairs with low-SD/Low-PS, and demonstrate that the GM of high-SD and high-PS mothers may already be compromised, resulting in the lowest observed inter-individual similarity in that group. The strong predictors of maternal high-SD and high-PS based on mothers and children microbiomes were phylogenetically very distinct bacteria indicating different GM pathways associated with SD versus PS. We identified sets of SD- and PS-discriminatory metabolic pathways in the mothers and in the children, however their predictive power was lower compared to the discriminatory bacterial species. Prediction accuracy was consistently greater for IL-6 than for the other inflammatory markers, supporting an association between systemic inflammation and psychosocial adversity. The gut microbiome of the infants can be used to predict the psychosocial adversity of mothers, and are embedded in the gut microbiota of 4-month-old infants.
Rapid structural remodeling of peripheral taste fibers is independent of taste cell turnover
Authors: Whiddon Zachary D. , Marshall Jaleia , Alston David , McGee Aaron W. , Krimm Robin F.
Published: November 2022

Taste bud cells are constantly replaced in taste buds as old cells die and new cells migrate into the bud. The perception of taste relies on new taste bud cells integrating with existing neural circuitry, yet how these new cells connect with a taste ganglion neuron is unknown. Do taste ganglion neurons remodel to accommodate taste bud cell renewal? If so, how much of the taste axon structure is fixed and how much remodels? Here we measured the motility and branching of individual taste arbors (the portion of the axon innervating taste buds) over time with two-photonin vivomicroscopy. Terminal branches of taste arbors continuously and rapidly remodel within the taste bud. This remodeling is faster than predicted by taste bud cell renewal, with terminal branches added and lost concurrently. Surprisingly, ablating new taste cells with chemotherapeutic agents revealed that remodeling of the terminal branches of taste arbors does not rely of the renewal of taste bud cells. Although the arbor structure remodeling was fast and intrinsically controlled, no new arbors were added, and few were lost over 100 days. Taste ganglion neurons maintain a stable number of nerve arbors that are each capable of high-speed remodeling. Arbor structural plasticity would permit arbors to locate new taste bud cells, while stability of arbor number could support constancy in the degree of connectivity and function for each neuron over time.
Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma
Authors: Estabrooks Timothy , Gurinovich Anastasia , Pietruska Jodie , Lewis Benjamin , Harvey Garrett , Post Gerald , Lambert Lindsay , Rodrigues Lucas , White Michelle E. , Lopes Christina , London Cheryl A. , Megquier Kate
Published: November 2022

Background

Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells associated with short survival times. Understanding the genomic landscape of HSA is critical to developing more effective therapeutic strategies.

Objectives

To determine the relationships between genomic and clinical features including treatment and outcome in canine splenic HSA.

Animals

109 dogs with primary splenic HSA treated by splenectomy that had tumor sequencing via the FidoCure® Precision Medicine Platform targeted sequencing panel.

Methods

Patient signalment, weight, metastasis at diagnosis, treatment, and survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables and outcome were assessed.

Results

Somatic mutations inTP53(n = 45),NRAS(n = 20), andPIK3CA(n = 19) were most common. Survival was associated with metastases at diagnosis, germline variants inSETD2andNOTCH1, and nominally with breed. Age at diagnosis was associated withNRASmutations and breed.TP53andPIK3CAmutations were found in larger dogs, germlineSETD2variants in smaller dogs. Doxorubicin (DOX) treatment did not significantly improve survival time, while targeted therapies had a significant early survival benefit.

Conclusions and clinical importance

DOX treatment may provide limited clinical benefit for dogs with splenic HSA, while targeted therapy may provide early survival benefit. Genetic signatures associated with splenic HSA may be useful in guiding targeted therapy to improve outcomes. Germline variants, age, size, and breed may be useful prognostic factors and provide insight into the genomic landscape of the tumor.
PhysiCOOL: A generalized framework for model Calibration and Optimization Of modeLing projects
Authors: Gonçalves Inês G. , Hormuth David A. , Prabhakaran Sandhya , Phillips Caleb M. , García-Aznar José Manuel
Published: November 2022

In silico models of biological systems are usually very complex and rely on several parameters describing physical and biological properties that require validation. As such, parameter space exploration is an essential component of computational model development to fully characterize and validate simulation results. Experimental data may also be used to constrain parameter space (or enable model calibration) to enhance the biological relevance of model parameters. One widely used computational platform in the mathematical biology community is PhysiCell which provides a standardized approach to agent-based models of biological phenomena at different time and spatial scales. Nonetheless, one limitation of PhysiCell is that there has not been a generalized approach for parameter space exploration and calibration that can be run without high-performance computing access. Taking this into account, we present PhysiCOOL, an open-source Python library tailored to create standardized calibration and optimization routines of PhysiCell models.
Hypothalamic vasopressin sex differentiation is established during embryonic neurogenesis
Authors: Zheng Jing , Moazen Parisa , Baimoukhametova Dinara , Lebel Catherine , Bains Jaideep , Kurrasch Deborah
Published: November 2022

Arginine vasopressin (AVP) is a conserved sexually dimorphic system regulating behaviors and physiologies. Decades of research concludes that AVP sex differentiation in mice occurs around birth when a gonadal surge of testosterone is converted to estrogen in male sexual dimorphic brain regions. We discovered that AVP neurons in the murine hypothalamus are sexually dimorphic much earlier than this surge, with male mice displaying more AVP neurons than females during neurogenesis at E11.In uteroexposure to a pan-ER antagonist blocked AVP masculinization in males, whereas embryonic exogenous 17β-estradiol or xenoestrogen bisphenol A (BPA) masculinized female AVP neurons, causing permanent masculinization effects on adult female AVP cell numbers, projections and intrinsic neuronal properties. Our data reveal that sexual dimorphism of hypothalamic AVP neurons is present from the earliest stages of their differentiation and challenges current dogma that masculinization of the male brain occurs around birth.

One-Sentence Summary

Sexual dimorphism of hypothalamic vasopressin is established during neurogenesis and exposure to the xenoestrogen bisphenol A during pregnancy induces masculinization of female brains
Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways
Authors: Pun Matthew , Pratt Drew , Nano Patricia R. , Joshi Piyush K. , Jiang Li , Englinger Bernhard , Rao Arvind , Cieslik Marcin , Chinnaiyan Arul M. , Aldape Kenneth , Pfister Stefan , Filbin Mariella G. , Bhaduri Aparna , Venneti Sriram
Published: November 2022

Abstract

Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to- methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.
Evaluating the analytical validity of mutation calling pipeline for tumor whole exome sequencing
Authors: Cheng Chinyi , Huang Jia-Hsin , Hsu Jacob Shujui
Published: November 2022

Detecting somatic mutations from the patients’ tumor tissues has the clinical impacts in medical decision making. Library preparation methods, sequencing platforms, read alignment tools and variant calling algorithms are the major factors to influence the data analysis results. Understanding the performance of the tool combinations of the somatic variant calling pipelines has become an important issue in the use of the whole exome sequences (WES) analysis in clinical actions. In this study, we selected four state-of-the-art sequence aligners including BWA, Bowtie2, DRAGMAP, DRAGEN aligner (DragenA) and HISAT2. For the variant callers, we chose GATK Mutect2, Sentieon TNscope, DRAGEN caller (DragenC) and DeepVariant. The benchmarking tumor whole exome sequencing data released from the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium was applied as the true positive variants to evaluate the overall performance.

Multiple combinations of the aligners and variant callers were used to assess the variation detection capability. We measured the recall, precision and F1-score for each combination in both single nucleotide variants (SNVs) and short insertions and deletions (InDels) variant detections. We also evaluated their performances in different variant allele frequencies (VAFs) and the base pair length. The results showed that the top recall, precision and F1-score in the SNVs detection were generated by the combinations of BWA+DragenC(0.9629), Bowtie2+TNscope(0.9957) and DRAGMAP+DragenC(0.9646), respectively. In the InDels detection, BWA+DragenC(0.9546), Hisat2+TNscope(0.7519) and DragenA+DragenC(0.8081) outperformed the other combinations in the recall, precision and F1-Score, respectively. In addition, we found that the variant callers could bias the variant calling results. Finally, although some combinations yielded high accuracies of variant detection, but some variants still could not be detected by these outperformed combinations. The results of this study provided the vital information that no single combination could achieve superior results in detecting all the variants of the benchmarking dataset. In conclusion, applying both merged-based and ensemble-based variants detection approaches is encouraged to further detect variants comprehensively.
Antagonistic role of the BTB-zinc finger transcription factors Chinmo and Broad-Complex in the juvenile/pupal transition and in growth control
Authors: Chafino Sílvia , Giannios Panagiotis , Casanova Jordi , Martín David , Franch-Marro Xavier
Published: November 2022

During development, the growing organism transits through a series of temporally regulated morphological stages to generate the adult form. In humans, for example, development progresses from childhood through to puberty and then to adulthood, when sexual maturity is attained. Similarly, in holometabolous insects, immature juveniles transit to the adult form through an intermediate pupal stage when larval tissues are eliminated and the imaginal progenitor cells form the adult structures. The identity of the larval, pupal and adult stages depends on the sequential expression of the transcription factorschinmo, Br-CandE93. However, how these transcription factors determine temporal identity in developing tissues is poorly understood. Here we report on the role of the larval specifierchinmoin larval and adult progenitor cells during fly development. Interestingly,chinmopromotes growth in larval and imaginal tissues in a Br-C-independent and -dependent manner, respectively. In addition, we found that the absence ofchinmoduring metamorphosis is critical for proper adult differentiation. Importantly, we also provide evidence that, in contrast to the well-known role ofchinmoas a pro-oncogene, Br-C and E93 act as tumour suppressors. Finally, we reveal that the function ofchinmoas a juvenile specifier is conserved in hemimetabolous insects as its homolog has a similar role inBlatella germanica. Taken together, our results suggest that the sequential expression of the transcription factors Chinmo, Br-C and E93 during larva, pupa an adult respectively, coordinate the formation of the different organs that constitute the adut organism.
Network plasticity in the honey bee antennal lobe during odor presentation
Authors: Paoli Marco , Antonacci Yuri , Faes Luca , Haase Albrecht
Published: November 2022

Odorant processing presents multiple parallels across animal species, and insects became relevant models for the study of olfactory coding because of the tractability of the underlying neural circuits. Within the insect brain, odorants are received by olfactory sensory neurons and processed by the antennal lobe network. Such a network comprises multiple nodes, named glomeruli, that receive sensory information and are interconnected by local interneurons participating in shaping the neural representation of an odorant. The study of functional connectivity between the nodes of a sensory networkin vivois a challenging task that requires simultaneous recording from multiple nodes at high temporal resolutions. Here, we used fast two-photon microscopy to follow the calcium dynamics of antennal lobe glomeruli and applied Granger causality analysis to assess the functional directed connectivity among network nodes during and after olfactory stimulation. Our findings show that there is a significant causal coupling between network nodes also in the absence of olfactory stimulation. However, connectivity patterns change upon odorant arrival, showing an increase in connection density and conveying odorant-specific information. Furthermore, we show that causal functional connectivity is unique in individual subjects, and cannot be detected upon artificial glomerular scrambling across individuals. This demonstrates that network states do not consist solely of correlations of mean glomerular responses, which are known to be conserved across bees.
Bioinformatic methods for stratification of obese patients and identification of cancer susceptibility biomarkers based on the analysis of the gut microbiome
Authors: Lacruz-Pleguezuelos Blanca , Fernández Lara P. , Ramírez de Molina Ana , Carrillo de Santa Pau Enrique , Marcos-Zambrano Laura Judith
Published: November 2022

Obesity has an impact on health by increasing the risk of various diseases. However, these risks might also depend on the metabolic health status, as it seems that metabolically healthy obese subjects are under a reduced risk of suffering comorbidities such as colorectal cancer. The gut microbiome has an effect on obesity and metabolic disorders through several integration pathways, making it a potential therapeutic target for these diseases. In this study, we characterized the gut microbiota of 356 obese and non-obese European individuals with different comorbidities associated with obesity. Using approaches based on supervised machine learning and network biology, we found a set of biomarkers of interest for differentiating metabolically healthy from unhealthy subjects. Then, we performed a linear discriminant analysis of effect size on a population of 1593 colorectal cancer, adenoma and control subjects assembled by the COST Action ML4Microbiome to investigate their role in colorectal cancer risk. Four of our biomarkers appeared in both approaches, suggesting their possible role in colorectal cancer development, prognosis and follow up:Clostridium leptum, Gordonibacter pamelaeae, Eggerthella lentaandCollinsella intestinalis. Further research via longitudinal studies or experimental validation of these microbial species would be necessary to confirm this association.
A novel fishing cat reference genome for the evaluation of potential germline risk variants
Authors: Carroll Rachel A. , Rice Edward S. , Murphy William J. , Lyons Leslie A. , Coghill Lyndon , Swanson William F. , Terio Karen A. , Boyd Tyler , Warren Wesley C.
Published: November 2022

The fishing cat,Prionailurus viverrinus, displays a fish hunting behavior uncommon among most other cats. Estimated population declines in the wild increase the significance of its existing zoo populations, particularly with a recent high prevalence of transitional cell carcinoma (TCC), a form of bladder cancer. We hypothesize that its small captive population may harbor TCC risk variants at the germline level. To aid conservation efforts and investigate the genetics of TCC, we present a new fishing cat chromosomescale assembly, reaffirm its close genetic relationship with the Asian leopard cat (Prionailurus bengalensis), and identify and characterize single nucleotide variants (SNVs) from whole genome sequencing (WGS) data of healthy and TCC cats. Among genes previously associated with bladder cancer risk in humanBRCA2was found to have the highest number of missense mutations in fishing cats, with only two variants exhibiting a predominance in TCC cats. These new fishing cat genomic resources will aid efforts to improve their genetic fitness and enhance the comparative study of feline genomes.
Evaluation of Renal Markers in Systemic Autoimmune Diseases
Authors: Krishnamurthy Hari , Yang Yuanyuan , Song Qi , Krishna Karthik , Jayaraman Vasanth , Wang Tianhao , Bei Kang , Rajasekaran John J.
Published: November 2022

Renal involvement is a common occurrence in subjects with systemic autoimmune diseases. The renal manifestation and its severity depend on the underlying condition and may reversely complicate the clinical course of autoimmune diseases. Renal function markers have been widely used in the assessment of normal functioning of kidneys including glomerular filtration rate and concentrating and diluting capacity of the kidney. An increase or decrease in the values of these markers may indicate kidney dysfunction. In this study, a number of critical renal markers were examined in seropositive autoimmune diseases including systemic lupus erythematosus (SLE), connective tissue disorder (CTD), and rheumatoid arthritis (RA). The data from three cohorts of subjects enrolled in renal markers and autoimmune antibody testing between January 2015 to August 2019 were retrospectively studied. The prevalence of renal markers that were out of the reference range and their average levels in female and male subgroups across SLE, CTD, and RA cohorts were compared and analyzed. The levels of renal markers are significantly affected by the presence of autoantibodies, in particular eGFR, cystatin C, and albumin. Autoantibodies were also more frequent in subjects with severe renal function damage. Close follow-up of both renal markers and autoantibodies may potentially assist in the early diagnosis of kidney diseases and improve the survival and life expectancy of autoimmune patients.
The fission yeast cell size control system integrates pathways measuring cell surface area, volume, and time
Authors: Miller Kristi E. , Vargas-Garcia Cesar , Singh Abhyudai , Moseley James B.
Published: November 2022

Eukaryotic cells tightly control their size, but the relevant aspect of size is unknown in most cases. Fission yeast divide at a threshold cell surface area due in part to the protein kinase Cdr2. We find that fission yeast cells only divide by surface area under a size threshold but shift to volume-based divisions when they reach a larger size. The size threshold for changing from surface area to volume-based control is set by ploidy. Within this size control system, we identified the mitotic activator Cdc25 as a volume-based sizer molecule, while the mitotic cyclin Cdc13 accumulates as a timer. We propose an integrated model for cell size control based on multiple signaling pathways that report on distinct aspects of cell size and growth, including cell surface area (Cdr2), cell volume (Cdc25), and time (Cdc13). Combined modeling and experiments show how this system can generate both sizer and adder-like properties.

HIGHLIGHTS

Fission yeast use surface area or volume-based cell size control depending on overall size and ploidy

Mitotic activator Cdc25 exhibits properties of a volume-based sizer molecule

Mitotic cyclin Cdc13 accumulates in the nucleus dependent on time, not size

Combined modeling and experiments identify conditions for sizer versus adder behavior
Standardization of Data Analysis for RT-QuIC-based Detection of Chronic Wasting Disease
Authors: Rowden Gage R. , Picasso-Risso Catalina , Li Manci , Schwabenlander Marc D. , Wolf Tiffany , Larsen Peter
Published: November 2022

Chronic wasting disease (CWD) is a disease affecting cervids and is caused by prions accumulating as pathogenic fibrils in lymphoid tissue and the central nervous system. Approaches for detecting CWD prions historically relied on antibody-based assays. However, recent advancements in protein amplification technology provided the foundation for a new class of CWD diagnostic tools. In particular, real-time quaking-induced conversion (RT-QuIC) has rapidly become a feasible option for CWD diagnosis. Despite its increased usage for CWD-focused research, there lacks consensus regarding the interpretation of RT-QuIC data for diagnostic purposes. It is imperative then to identify a standardized and replicable method for determining CWD status from RT-QuIC data. Here, we assessed variables that could impact RT-QuIC results and explored the use of maxpoint ratios (maximumRFU/backgroundRFU) to improve the consistency of RT-QuIC analysis. We examined a variety of statistical analyses to retrospectively analyze CWD status based on RT-QuIC and ELISA results from 668 white-tailed deer lymph nodes. Our results revealed an MPR threshold of 2.0 for determining the rate of amyloid formation, and MPR analysis showed excellent agreement with independent ELISA results. These findings suggest that the use of MPR is a statistically viable option for normalizing between RT-QuIC experiments and defining CWD status.
Integrated single cell analysis reveals co-evolution of malignant B cells and the tumor microenvironment in transformed follicular lymphoma
Authors: Sarkozy Clémentine , Wu Shaocheng , Takata Katsuyoshi , Aoki Tomohiro , Neriah Susana B , Milne Katy , Goodyear Talia , Strong Celia , Rastogi Tashi , Lai Daniel , Sehn Laurie H , Farinha Pedro , Nelson Brad H , Weng Andrew , Scott David W , Craig Jeffrey W , Steidl Christian , Roth Andrew
Published: November 2022

Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma. Histological transformation of FL to a more aggressive form of lymphoma occurs with a linear incidence of 2-3% per year and is associated with poor outcome. Divergent clonal evolution and an altered tumour microenvironment (TME) have both been implicated in the transformation process. However, the phenotypic consequences of this evolution and its implication in reshaping the TME remain unknown. To address this knowledge gap we performed single cell whole genome (scWGS) and single cell whole transcriptome sequencing (scWTS) of paired pre/post transformation samples of 11 FL patients. We further performed scWTS analysis of additional 11 FL samples from patients that had not undergone transformation within 7 years. Our comprehensive single cell analysis revealed the evolutionary dynamics of transformation at unprecedented resolution. Computational integration of scWGS and scWTS allowed us to identify gene programs upregulated and positively selected during evolution. Furthermore, our scWTS analysis revealed a shifting TME landscape, with an exhausted CD8 T cell signature emerging during transformation. Using multi-color immunofluorescence we transferred these findings to a novel TME based biomarker of transformation, subsequently validated in 2 independent cohorts of pretreatment FL samples. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation, and the shifting cross-talk between malignant cells and the TME.

Graphical abstract
Integration of event experiences to build relational knowledge in the human brain
Authors: Leshinskaya Anna , Nguyen Mitchell , Ranganath Charan
Published: November 2022

We investigated how the human brain integrates experiences of specific events to build general knowledge about typical event structure. We examined an episodic area important for temporal relations, anterior-lateral entorhinal cortex (alEC), and a semantic area important for action concepts, middle temporal gyrus (MTG). Participants underwent fMRI while watching sequences of novel events and recalling their temporal relations over two sessions one week apart. Across different contexts, the roles of these events could either be consistent, or conflict; integrative representations should weaken in the conflicting condition. We found integrative representations that emerged quickly in alEC, and only subsequently in MTG, which showed a significant change across sessions. Thus, alEC is important in building integrative representations early in learning and may be a gateway to semantic knowledge in MTG. We suggest that both episodic and semantic systems participate in integrating new information when it is aligned with their content specializations.
Adaptive coding across visual features during free-viewing and fixation conditions
Authors: Nigam Sunny , Milton Russell , Pojoga Sorin , Dragoi Valentin
Published: November 2022

Theoretical studies have long proposed that adaptation allows the brain to effectively use the limited response range of sensory neurons to encode widely varying natural inputs. However, despite this influential view, experimental studies have exclusively focused on how the neural code adapts to a range of stimuli lying along a single feature axis, such as orientation or contrast. Here, we performed electrical recordings in macaque visual cortex (area V4) to reveal significant adaptive changes in the neural code of single cells and populations across multiple feature axes. Both during free viewing and passive fixation, populations of cells improved their ability to encode image features after rapid exposure to stimuli lying on orthogonal feature axes even in the absence of initial tuning to these stimuli. These results reveal a remarkable adaptive capacity of visual cortical populations to improve network computations relevant for natural viewing despite the modularity of the functional cortical architecture.
Semaphorin7A patterns neural circuitry in the lateral line of the zebrafish
Authors: Dasgupta Agnik , Reagor Caleb C. , Paik Sang P. , Snow Lauren M. , Jacobo Adrian , Hudspeth A. J.
Published: November 2022

In a developing nervous system, axonal arbors often undergo complex rearrangements before neural circuits attain their final innervation topology. In the lateral line sensory system of the zebrafish, developing sensory axons reorganize their terminal arborization patterns to establish precise neural microcircuits around the mechanosensory hair cells. However, a quantitative understanding of the changes in the sensory arbor morphology and the regulators behind the microcircuit assembly remain enigmatic. Here, we report that Semaphorin7A (Sema7A) acts as an important mediator of these processes. Utilizing a semi-automated three-dimensional neurite tracing methodology and computational techniques, we have identified and quantitatively analyzed distinct topological features that shape the network in wild-type and Sema7A loss-of-function mutants. In contrast to those of wild-type animals, the sensory axons in Sema7A mutants display aberrant arborizations with disorganized network topology and diminished contacts to hair cells. Moreover, ectopic expression of a secreted form of Sema7A by non-hair cells induces chemotropic guidance of sensory axons. Our findings propose that Sema7A likely functions both as a juxtracrine and as a secreted cue to pattern neural circuitry during sensory organ development.
Esr1+ hypothalamic-habenula neurons shape aversive states
Authors: Calvigioni Daniela , Fuzik Janos , Le Merre Pierre , Slashcheva Marina , Jung Felix , Ortiz Cantin , Lentini Antonio , Csillag Veronika , Graziano Marta , Nikolakopoulou Ifigeneia , Weglage Moritz , Lazaridis Iakovos , Kim Hoseok , Lenzi Irene , Park Hyunsoo , Reinius Björn , Carlén Marie , Meletis Konstantinos
Published: November 2022

Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA-LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex-specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity.
Rab11 is essential to pancreas morphogenesis, lumen formation and endocrine mass
Authors: Barlow Haley R. , Htike Yadanar , Fassetta Luke , Ahuja Neha , Bierschenk Tyler , Azizoglu D. Berfin , Flores Juan , Gao Nan , Marciano Denise , Cleaver Ondine
Published: November 2022

The molecular links between tissue-level morphogenesis and the differentiation of cell lineages in the pancreas remain elusive despite a decade of studies. We previously showed that in pancreas both these processes depend on proper lumenogenesis. The Rab GTPase Rab11 has been shown to be essential to epithelial lumen formationin vitro, however few studies have addressed its functionsin vivoand none have tested its requirement in pancreas. Here, we show that Rab11 is critical to proper pancreas development. Co-deletion of the Rab11 isoformsRab11AandRab11Bin the developing pancreatic epithelium (Rab11pancDKO) results in ~50% neonatal lethality, and surviving adult Rab11pancDKOmice exhibit defective endocrine function. Loss of Rab11 in the embryonic pancreas results in morphogenetic defects of the epithelium linked to defective lumen formation and interconnection. In contrast to wildtype cells, Rab11pancDKOcells attempt to form multiple lumens, resulting in a failure to coordinate a single apical membrane initiation site (AMIS) between groups of cells. We show that these defects are due to failures in vesicle trafficking, as apical components remain trapped within Rab11pancDKOcells. Together, these observations suggest Rab11 directly regulates epithelial lumen formation and morphogenesis. Our report links intracellular trafficking to organ morphogenesisin vivo, and presents a novel framework for decoding pancreatic development.

HIGHLIGHTS

Rab11Af/f;Rab11B-/-;Pdx1-Cre pancreas displays disruption of epithelial organization and reduction of endocrine cell mass.

Loss of Rab11 results in disruption of pancreatic lumen continuity due to a failure of lumen formation.

Epithelial cells lacking Rab11 display abnormal polarity.
Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium
Authors: Wang Zengtao , Sharda Nidhi , Omtri Rajesh S. , Li Ling , Kandimalla Karunya K.
Published: November 2022

Blood-brain barrier (BBB) is a critical portal regulating the bidirectional transport of amyloid beta (Aβ) proteins between blood and brain. Disrupted trafficking at the BBB may not only promote the build-up of Aβ plaques in the brain parenchyma, but also facilitate Aβ accumulation within the BBB endothelium, which aggravates BBB dysfunction. Soluble Aβ42:Aβ40 ratios in plasma and cerebrospinal fluid have been reported to decrease during Alzheimer’s disease (AD) progression. Our previous publications demonstrated that trafficking of Aβ42 and Aβ40 at the BBB is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aβ40 and Aβ42 have not been clearly elucidated. In this study, we identified mechanisms of fluorescently labeled Aβ (F-Aβ) endocytosis in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers using pharmacological inhibition and siRNA knock-down approaches. Further, intracellular transit of F-Aβ following endocytosis was tracked using live cell imaging. Our studies demonstrated that both F-Aβ peptides were internalized by BBB endothelial cells via energy, dynamin and actin dependent endocytosis. Interestingly, endocytosis of F-Aβ40 is found to be clathrin-mediated, whereas F-Aβ42 endocytosis is caveolae-mediated. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. While Aβ42 was shown to accumulate more in the lysosome which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aβ40 demonstrated robust accumulation in recycling endosomes which may facilitate its transcytosis across the BBB. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aβ40 versus Aβ42. This knowledge contributes to the understanding of molecular pathways underlying Aβ accumulation in the BBB endothelium and associated cerebrovascular dysfunction as well as amyloid deposition in the brain parenchyma which are implicated in AD pathogenesis.
Elimination of Foxo triplets following glucocorticoid incubation dampened metabolic stress and enhanced anti-viral response targets based on transcriptomic analysis
Authors: Puthanveetil Prasanth , Rafferty Daniel , Gan Boyi , Bolch Charlotte A.
Published: November 2022

Glucocorticoids, both endogenous and exogenous, are known anti-inflammatory agents with associated adverse effects when administered chronically or in excess. Foxo family members, specifically Foxo1, Foxo3 and Foxo4 have demonstrated to be major regulators of metabolic complications following glucocorticoid action. We employed mouse embryonic fibroblasts as model system and using tamoxifen induced Cre+ recombinase activation, we achieved deletion of the Foxo triplets- Foxo1, Foxo3, and Foxo4. Following incubation of dexamethasone in both wild type and Foxo triplet deleted group, RNA sequencing was performed to reveal the transcriptome. Interestingly, the transcripts involved in initiating metabolic stress like PDK4 and 11 Beta HSD1 were downregulated, whereas transcripts involved in anti-viral response were upregulated following Foxo triplet deletion. The anti-inflammatory property of glucocorticoids was kept intact based on transcripts evaluated including GILZ and COX2. In summary, our study reveals a unique phenomenon where we will be able to manipulate glucocorticoid action by deleting Foxo triplets eliminating the metabolic stress components but enhancing anti-viral response and maintaining their clinical use as an anti-inflammatory agent. This work will lay foundation for a paradigm shift in clinical use of glucocorticoids according to therapeutic advantage with lesser adverse effects
Heart Rate Assessment in a Pediatric ICU with Non-Contact Infrared Thermography and Machine Learning
Authors: Kaur Amandeep , Prajapati Samyak , Singh Pradeep , Nagori Aditya , Lodha Rakesh , Sethi Tavpritesh
Published: November 2022

Heart rate is one of the vital signs for monitoring health. Non-invasive, non-contact assessment of heart rate can lead to safe and potentially telemedicine based monitoring. Thermal videos as a modality for capturing heart rate has been underexplored. Regions with large vessels such as the face can capture the pulsatile change in temperature associated with the blood flow. The use of a machine learning-based approach to capture heart rate from continuous thermal videos is currently lacking. Our present clinical investigation comprises the continuous monitoring of heart rate from a smaller number of samples by using a combination of an efficient deep-learning-based segmentation followed by domain-knowledge-based feature calculation for estimating heart rate from 124 thermal imaging videos comprising 3,628,087 frames of 65 patients, admitted to the pediatric intensive care unit at AIIMS, New Delhi. We hypothesized that periodic fluctuations of thermal intensity over the face can capture heart rate. Frequency domain features for thermal time series were extracted followed by supervised learning using a battery of models. A random forest model yielded the best results with a root mean squared error of 24.54 and mean absolute percentage error of 16.129. Clinical profiling of the model showed a wide range of clinical conditions in the admitted children with acceptable model performance. Affordable and commercially available thermal cameras establish the feasibility and cost viability of exploring deployments for patient heart rate estimation in non-invasive and non-contact environments.
Sex-specific neurodevelopmental outcomes in offspring of mothers with SARS-CoV-2 in pregnancy: an electronic health records cohort
Authors: Edlow Andrea G. , Castro Victor M. , Shook Lydia L. , Haneuse Sebastien , Kaimal Anjali J. , Perlis Roy H.
Published: November 2022

Importance

Prior studies using large registries suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific.

Objective

To determine whether in utero exposure to the novel coronavirus SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared to unexposed offspring born during or prior to the pandemic period.

Design

Retrospective cohort.

Participants

Live offspring of all mothers who delivered between March 2018 and May 2021 at any of eight hospitals across two health systems in Massachusetts.

Exposure

PCR evidence of maternal SARS-CoV-2 infection during pregnancy.

Main Outcome and Measures

Electronic health record documentation of ICD-10 diagnostic codes corresponding to neurodevelopmental disorders.

Results

The pandemic cohort included 18,323 live births, including 877 (4.8%) to individuals with SARS-CoV-2 positivity during pregnancy. The cohort included 1806 (9.9%) Asian individuals, 1634 (8.9%) Black individuals, 1711 (9.3%) individuals of another race, and 12,694 (69%) White individuals; 2614 (14%) were of Hispanic ethnicity. Mean maternal age was 33.0 years (IQR 30.0-36.0). In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs. community), maternal age, and preterm status, SARS-CoV-2 positivity was associated with statistically significant elevation in risk for neurodevelopmental diagnoses among male offspring (adjusted OR 1.99, 95% CI 1.19-3.34; p=0.009) but not female offspring (adjusted OR 0.90, 95% CI 0.43-1.88; p=0.8). Similar effects were identified using matched analyses in lieu of regression.

Conclusion and Relevance

SARS-CoV-2 exposure in utero was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring in the 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.

Trial Registration

NA

Key Points

Question

Are rates of neurodevelopmental disorder diagnoses greater among male or female children with COVID-19 exposure in utero compared to those with no such exposure?

Findings

In a cohort of 18,323 infants delivered after February 2020, males but not females born to mothers with a positive SARS-CoV-2 PCR test during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first 12 months after delivery, even after accounting for preterm delivery.

Meaning

These findings suggest that male offspring exposed to COVID-19 in utero may be at increased risk for neurodevelopmental disorders.
Socioeconomic inequalities in sport participation: pattern per sport and time trends
Authors: Richard Viviane , Piumatti Giovanni , Pullen Nick , Lorthe Elsa , Guessous Idris , Cantoreggi Nicola , Stringhini Silvia
Published: November 2022

Background

Sport participation is an important component of a healthy lifestyle and is known to be more common among privileged individuals. However, few studies have examined socio-demographic patterns of participation by type of activity. This study aims at quantifying socio-economic inequalities in sport participation by sport type, and to analyse their trend over 15 years.

Methods

We used 2005-2019 data from the Bus Santé study, a yearly population-based cross-sectional survey of Geneva adults. Sport participation was defined as reporting at least one sporting activity over the previous week; educational level, household income and occupational position were used as indicators of socio-economic position. Socio-economic inequalities in sport participation, and their trend over time, were examined using the relative and slope indexes of inequality (RII/SII).

Results

Out of 7769 participants (50.1% women, mean age 46 years old), 60% participated in a sporting activity. Results showed that the higher the socioeconomic circumstances, the higher the sport participation (RII=1.78; 95% Confidence Interval (CI): 1.64-1.92; SII=0.33; 95%CI: 0.29-0.37 for education). Relative inequalities varied per sport e.g., 0.68 (95%CI: 0.44-1.07) in football participation and 4.25 (95%CI: 2.68-6.75) in tennis/badminton participation for education. Yearly absolute inequalities in sport participation tended to increase between 2005 and 2019 for household income (β=0.01; P-value=0.024).

Conclusion

We observed strong socio-economic inequalities in sport participation in Geneva, with different magnitude depending on the type of sport. These inequalities seemed to increase over the 2005-2019 period. Our results call for tailored measures to promote the participation of socially disadvantaged populations in sporting activities.

KEY MESSAGES

Sport participation is associated with higher socioeconomic conditions. Research on the patterning of inequalities per sport type and on their trend over time remains scarce.

There are high growing socioeconomic inequalities in sport participation in Geneva. Inequalities in sport participation are heterogeneous and lower in sports practised in group.

Tailored sport promotion measures are needed for disadvantaged populations.