bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-platform proteomics signatures of extreme old age
Authors: Reed Eric R , Chandler Kevin B , Lopez Prisma , Costello Catherine E , Andersen Stacy L , Perls Thomas T , Li Mengze , Bae Harold , Soerensen Mette , Monti Stefano , Sebastiani Paola
Published: April 2024

In previous work we used a Somalogic platform targeting approximately 5000 proteins to generate a serum protein signature of centenarians that we validated in independent studies that used the same technology. We set here to validate and possibly expand the results by profiling the serum proteome of a subset of individuals included in the original study using liquid chromatography tandem mass spectrometry (LC-MS/MS). Following pre-processing, the LC-MS/MS data provided quantification of 398 proteins, with only 266 proteins shared by both platforms. At 1% FDR statistical significance threshold, the analysis of LC-MS/MS data detected 44 proteins associated with extreme old age, including 23 of the original analysis. To identify proteins for which associations between expression and extreme-old age were conserved across platforms, we performed inter-study conservation testing of the 266 proteins quantified by both platforms using a method that accounts for the correlation between the results. From these tests, a total of 80 proteins reached 5% FDR statistical significance, and 26 of these proteins had concordant pattern of gene expression in whole blood. This signature of 80 proteins points to blood coagulation, IGF signaling, extracellular matrix (ECM) organization, and complement cascade as important pathways whose protein level changes provide evidence for age-related adjustments that distinguish centenarians from younger individuals.
Sapling: Inferring and Summarizing Tumor Phylogenies from Bulk Data using Backbone Trees
Authors: Qi Yuanyuan , El-Kebir Mohammed
Published: April 2024

Cancer phylogenies are key to understanding tumor evolution. There exists many important downstream analyses that takes as input a single or small number of trees. However, due to uncertainty, one typically infers many, equally-plausible phylogenies from bulk DNA sequencing data of tumors. We introduce Sapling, a heuristic method to solve the Backbone Tree Inference from Reads problem, which seeks a small set of backbone trees on a smaller subset of mutations that collectively summarize the entire solution space. Sapling also includes a greedy algorithm to solve the Backbone Tree Expansion from Reads problem, which aims to expand an inferred backbone tree into a full tree. We prove that both problems are NP-hard. On simulated and real data, we demonstrate that Sapling is capable of inferring high-quality backbone trees that adequately summarize the solution space and that can expanded into full trees.
Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways
Authors: Tumurkhuu Gantsetseg , Moore Richard , Perri Graziela , Huo Lihong , Kumar Arati Naveen , de los Santos Gabriela , Gibb David , Carriere Jessica , Yu Jeong Min , Abuav Rachel , Wallace Daniel J. , Ishimori Mariko , Shon Wonwoo , Dortfleutner Andrea , Stehlik Christian , Jefferies Caroline A.
Published: April 2024

Background

Exposure of systemic lupus erythematosus (SLE) patients to ultraviolet light B (UVB) triggers local and systemic inflammation, with cytosolic DNA sensing and induction of type I interferons (IFNs) known to play a role. We previously identified TRIM21 as a negative regulator of DNA sensing and IFN expression.Here we explore the role of TRIM21 in regulating local and systemic responses following UVB exposure.

Methods

WT (C57BL/6) andTrim21-/-mice were irradiated with UVB (100mJ/cm2) daily for 1 and 3 weeks, and UVB-induced inflammation in skin, blood, and spleen were analyzed by qPCR, histology, RNA sequencing and flow cytometry. Mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) from WT andTrim21-/-mice, andTRIM21-/-THP-1 cells.

Results

Infiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice, howeverTrim21-/-mice developed splenomegaly, enhanced total IgG levels and IFN-stimulated genes (ISG) in the blood and spleen. Enhanced basal and UVB-dependentIfnb1expression was observed inTrim21-/-BMDMs and MDFs, which was dependent on the cytosolic DNA sensing cGAS-STING pathway. Mechanistically, we found both degradation of DDX41 and STING levels were impaired in stimulatedTrim21-/-BMDMs.

Conclusion

Taken together, our results indicate that TRIM21 protects against IFN induction at local and systemic levels through restricting STING signaling. Our finding that reduced levels of TRIM21 are observed in SLE patients with cutaneous involvement indicates a potential role for TRIM21 in guarding against systemic flare in SLE patients.
The promise and challenge of spatial inference with the full ancestral recombination graph under Brownian motion
Authors: Deraje Puneeth , Kitchens James , Coop Graham , Osmond Matthew M.
Published: April 2024

Spatial patterns of genetic relatedness among samples reflect the past movements of their ancestors. Our ability to untangle this history has the potential to improve dramatically given that we can now infer the ultimate description of genetic relatedness, the ancestral recombination graph (ARG). By extending spatial theory previously applied to trees, we generalize the common model of Brownian motion to full ARGs, thereby accounting for correlations in trees along a chromosome while efficiently computing likelihood-based estimates of dispersal rate and genetic ancestor locations, with associated uncertainties. We evaluate this model’s ability to reconstruct spatial histories using individual-based simulations and unfortunately find a clear bias in the estimates of dispersal rate and ancestor locations. We investigate the causes of this bias, pinpointing a discrepancy between the model and the true spatial process at recombination events. This highlights a key hurdle in extending the ubiquitous and analytically-tractable model of Brownian motion from trees to ARGs, which otherwise has the potential to provide an efficient method for spatial inference, with uncertainties, using all the information available in the full ARG.
Circadian rhythms tied to changes in brain morphology in a densely-sampled male
Authors: Murata Elle M. , Pritschet Laura , Grotzinger Hannah , Taylor Caitlin M. , Jacobs Emily G.
Published: April 2024

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

Significance Statement

Though rhythmic changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species, this relationship has not been well characterized in humans. In this precision neuroimaging study, we found that global and regional brain morphology and steroid hormone levels exhibit tandem circadian rhythms. These findings provide high-resolution insight into the anatomical signature of diurnal changes in brain morphology and steroid hormone production in a human male and reveal the metronomic regularity of these rhythms over time.
A quantitative tumor–wide analysis of morphological heterogeneity of colorectal adenocarcinoma
Authors: Dragomir Mihnea P. , Popovici Vlad , Schallenberg Simon , Čarnogurská Martina , Horst David , Nenutil Rudolf , Bosman Fred , Budinská Eva
Published: April 2024

Morphologic heterogeneity of colorectal adenocarcinoma (CRC) is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes, and showed that these patterns have distinct molecular motifs (Budinská et al., 2023). Here, we evaluated the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four different tissue blocks per tumor in a pilot set of 22 CRCs (n=88). An artificial intelligence (AI) image analysis tool was trained using the pathologist-rated tumors to assess the morphologic heterogeneity on an expanded set of 161 CRCs (644 images). Heterogeneity was expressed as a combination of morphology patterns (morphotypes) across slides and normalized Shannon’s index (NSI). All pathologists agreed that the majority of tumors had 2-3 different dominant morphotypes, and that the complex tubular (CT) morphotype was the most common. AI analysis confirmed these observations in the full set. CT morphotype combined with all other dominant morphotypes within a tumor. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) was most often combined with solid/trabecular (TB) and papillary (PP). Most tumors showed medium or high NSI, but without clinical consequence. The proportion of DE morphotype was associated with higher T-stage, N-stage, metastasis, AJCC-stage, and shorter relapse-free survival, and MU morphotype was associated with higher grade, right side, microsatellite instability, and shorter overall survival. In conclusion, we observed high intratumoral morphological heterogeneity of CRC, and that not heterogeneityper se, but the proportion of certain morphotypes showed associations with clinical outcome. This has implications for molecular profiling of CRC.
Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration
Authors: Nascimento Filipe , Özyurt M. Görkem , Halablab Kareen , Bhumbra Gardave Singh , Caron Guillaume , Bączyk Marcin , Zytnicki Daniel , Manuel Marin , Roselli Francesco , Brownstone Rob , Beato Marco
Published: April 2024

In many neurological conditions, early-stage neural circuit adaption can preserve relatively normal behaviour. In some diseases, spinal motoneurons progressively degenerate yet movement is initially preserved. We therefore investigated whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination ofin vitroandin vivoelectrophysiology and super-resolution microscopy, we found that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific, and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that in motoneuron degenerative conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.
Biophysical Profiling of Red Blood Cells from Thin-film Blood Smears using Deep Learning
Authors: Lamoureux Erik S. , Cheng You , Islamzada Emel , Matthews Kerryn , Duffy Simon P. , Ma Hongshen
Published: April 2024

Microscopic inspection of thin-film blood smears is widely used to identify red blood cell (RBC) pathologies, including malaria parasitism and hemoglobinopathies, such as sickle cell disease and thalassemia. Emerging research indicates that non-pathologic changes in RBCs can also be detected in images, such as deformability and morphological changes resulting from the storage lesion. In transfusion medicine, cell deformability is a potential biomarker for the quality of donated RBCs. However, a major impediment to the clinical translation of this biomarker is the difficulty associated with performing this measurement. To address this challenge, we developed an approach for biophysical profiling of RBCs based on cell images in thin-film blood smears. We hypothesize that subtle cellular changes are evident in blood smear images, but this information is currently undetectable by human cognition. To test this hypothesis, we developed a deep learning strategy to analyze Giemsa-stained blood smears to assess the subtle morphologies indicative of RBC deformability and storage-based degradation. Specifically, we prepared thin-film blood smears from 27 RBC samples (9 donors evaluated at 3 storage timepoints) and imaged them using high-resolution microscopy. Using this dataset, we trained a convolutional neural network to evaluate image-based morphological features related to cell deformability. The prediction of donor deformability is strongly correlated to the microfluidic scores and can be used to categorize images into specific deformability groups with high accuracy. We also used this model to evaluates differences in RBC morphology resulting from cold storage. Together, our results demonstrate that deep learning models can exceed the limits of human cognition to detect subtle cellular differences in morphology resulting from deformability and cold storage. This result suggests the potential to assess donor blood quality from thin-film blood smears, which can be acquired ubiquitously in clinical workflows.
The relationship between event boundary strength and pattern shifts across the cortical hierarchy during naturalistic movie-viewing
Authors: Lee Yoonjung , Chen Janice
Published: April 2024

Our continuous experience is spontaneously segmented by the brain into discrete events. However, the beginning of a new event (an event boundary) is not always sharply identifiable: phenomenologically, event boundaries vary in salience. How are the response profiles of cortical areas at event boundaries modulated by boundary strength during complex, naturalistic movie-viewing? Do cortical responses scale in a graded manner with boundary strength, or do they merely detect boundaries in a binary fashion? We measured “cortical boundary shifts” as transient changes in multi-voxel patterns at event boundaries with different strengths (weak, moderate, and strong), determined by across-subject agreement. Cortical regions with different processing timescales were examined. In auditory areas, which have short timescales, cortical boundary shifts exhibited a clearly graded profile both in group-level and individual-level analyses. In cortical areas with long timescales, including the default mode network, boundary strength modulated pattern shift magnitude at the individual subject level. We also observed a positive relationship between boundary strength and the extent of temporal alignment of boundary shifts across different levels of the cortical hierarchy. Additionally, hippocampal activity was highest at event boundaries for which cortical boundary shifts were most aligned across hierarchical levels. Overall, we found that event boundary strength modulated cortical pattern shifts strongly in sensory areas and more weakly in higher-level areas, and that stronger boundaries were associated with greater alignment of these shifts across the cortical hierarchy.
Water Diffusion in the Live Human Brain is Gaussian at the Mesoscale
Authors: Magdoom Kulam Najmudeen , Avram Alexandru V. , Witzel Thomas E. , Huang Susie Y. , Basser Peter J.
Published: April 2024

Imaging the live human brain at the mesoscopic scale is a desideratum in basic and clinical neurosciences. Despite the promise of diffusion MRI, the lack of an accurate model relating the measured signal and the associated microstructure has hampered its success. The widely used diffusion tensor MRI (DTI) model assumes an anisotropic Gaussian diffusion process in each voxel, but lacks the ability to capture intravoxel heterogeneity. This study explores the extension of the DTI model to mesoscopic length scales by use of the diffusion tensor distribution (DTD) model, which assumes a Gaussian diffusion process in each subvoxel. DTD MRI has shown promise in addressing some limitations of DTI, particularly in distinguishing among different types of brain cancers and elucidating multiple fiber populations within a voxel. However, its validity in live brain tissue has never been established. Here, multiple diffusion-encoded (MDE) data were acquired in the living human brain using a 3 Tesla MRI scanner with large diffusion weighting factors. Two different diffusion times (Δ = 37, 74 ms) were employed, with other scanning parameters fixed to assess signal decay differences. In vivo diffusion-weighted signals in gray and white matter were nearly identical at the two diffusion times. Fitting the signals to the DTD model yielded indistinguishable results, except in the cerebrospinal fluid (CSF)-filled voxels likely due to pulsatile flow. Overall, the study supports the time invariance of water diffusion at the mesoscopic scale in live brain parenchyma, extending the validity of the anisotropic Gaussian diffusion model in clinical brain imaging.
Genomic epidemiology ofPlasmodium knowlesireveals putative genetic drivers of adaptation in Malaysia
Authors: Westaway Jacob A F , Diez Benavente Ernest , Auburn Sarah , Kucharski Michal , Aranciaga Nicolas , Nayak Sourav , William Timothy , Rajahram Giri S , Piera Kim A , Braima Kamil , Tan Angelica F , Alaza Danshy , Barber Bridget E , Drakeley Chris , Amato Roberto , Sutanto Edwin , Trimarsanto Hidayat , Anstey Nicholas M , Bozdech Zbynek , Field Matthew , Grigg Matthew J
Published: April 2024

Sabah, Malaysia, has amongst the highest burden of humanPlasmodium knowlesiinfection in the country, associated with increasing encroachment on the parasite’s macaque host habitat. However, the genomic make-up ofP. knowlesiin Sabah was previously poorly understood. To inform on local patterns of transmission and putative adaptive drivers, we conduct population-level genetic analyses ofP. knowlesihuman infections using 52 new whole genomes from Sabah, Malaysia, in combination with publicly available data. We identify the emergence of distinct geographical subpopulations within the macaque-associated clusters using IBD-based connectivity analysis. Secondly, we report on introgression events between the clusters, which may be linked to differentiation of the subpopulations, and that overlap genes critical for survival in human and mosquito hosts. Using village-level locations fromP. knowlesiinfections, we also identify associations between several introgressed regions and both intact forest perimeter-area ratio and mosquito vector habitat suitability. Our findings provide further evidence of the complex role of changing ecosystems and sympatric macaque hosts in Malaysia driving distinct genetic changes seen inP. knowlesipopulations. Future expanded analyses of evolvingP. knowlesigenetics and environmental drivers of transmission will be important to guide public health surveillance and control strategies.

Author Summary

The zoonoticP. knowlesiparasite is an emerging, yet understudied, cause of malaria in Southeast Asia. Sabah, Malaysia, has amongst the highest burden of human P. knowlesi infection in the country, however, the region is currently understudied. Thus, we produced a collection of high-qualityP. knowlesigenomes from Sabah, and in combination with publicly available data, performed an extensive population genetics analysis. Our work contributes novel insights forPlasmodium knowlesipopulation genetics and genetic epidemiology.
Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease
Authors: Mendiratta Mohini , Mendiratta Meenakshi , Ganguly Shuvadeep , Rai Sandeep , Gupta Ritu , Kumar Lalit , Bakhshi Sameer , Dadhwal Vatsla , Pushpam Deepam , Malik Prabhat Singh , Pramanik Raja , Aggarwal Mukul , Gupta Aditya Kumar , Dhawan Rishi , Seth Tulika , Mahapatra Manoranjan , Nayak Baibaswata , Singh Thoudam Debraj , Singla Sachin Kumar , Singh Mayank , Prasad Chandra Prakash , Prakash Hridayesh , Mohanty Sujata , Sahoo Ranjit Kumar
Published: April 2024

Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. In this context, we here demonstrate that hypoxia preconditioned apoptotic MSCs [bone marrow (BM), Wharton’s Jelly (WJ)] bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). To this purpose, we programmed MSCs by exposing them to hypoxia and inducing apoptosis both sequentially as well as simultaneously. Our findings demonstrated that WJ MSCs that were conditioned with indicated approaches simultaneously induced the differentiation of CD4+T-cell towards Tregs, enhanced Th2 effector, and concomitantly mitigated Th1 and Th17, with polarization of M1 effector macrophages towards their M2 phenotype, and more interestingly enhanced efferocytosis by macrophages indicated Th2 programming ability of MSCs programmed by conjunctional approaches Overall, our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD and underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.

GRAPHICAL ABSTRACT
Distinct communities of Bacteria and unicellular eukaryotes in the different water masses of Cretan Passage water column (Eastern Mediterranean Sea)
Authors: Charalampous Georgia , Kormas Konstantinos A. , Antoniou Eleftheria , Kalogerakis Nicolas , Gontikaki Evangelia
Published: April 2024

Understanding the diversity and dynamics of marine microbiota holds significant importance due to their role in maintaining vital ecosystem functions and services including climate regulation and bioremediation. Here, we studied the diversity and associations between Bacteria and unicellular eukaryotes in the different water masses of the Cretan Passage water column in the Eastern Mediterranean Sea (EMS). Samples were collected from two stations in the Hellenic Exclusive Economic Zone (EEZ) at various depths down to 1000 m during two sampling expeditions in August 2019 and February 2020. Through high-throughput 16S and 18S rRNA gene analysis, we unveiled vertical variations in both bacterial and unicellular eukaryotes diversity respectively. Additionally, interspecies co-occurrence patterns were evaluated between the top and bottom water masses. Our results revealed species fluctuations indicative of seasonality in the surface water mass while the deepest water layers were enriched in heterotrophic taxa and grazers related to organic matter degradation and nutrient cycling. Finally, we found a higher number of microbial associations in surface waters indicating abundant ecological niches compared to the deepest layer, possibly related to the lack of bottom-up resources in the oligotrophic deep ocean.
Proteomic profile analysis of plasma and aqueous humor from glaucoma and non-glaucomatous patients
Authors: Pessuti Carmen L. , Huang Chia Ling , Banks Angela , Vo Nhi , Jennings Lori , Loureiro Joseph , Ribeiro Kleber S. , Costa Deise Fialho , Nascimento Heloisa , Muccioli Cristina , Tavares Ivan Maynart , Commodaro Alessandra G. , Belfort Rubens , Wilson Christopher W. , Chen Amy , Prasanna Ganesh , Raghunathan VijayKrishna
Published: April 2024

Purpose

Glaucoma, a multifactorial ocular neuropathic and age associated disease, can lead to irreversible vision loss. Diagnosis involves assessing optic cupping (increased cup-to-disc ratios) and structural changes (like retinal nerve fiber layer thinning) through clinical imaging. Elevated intraocular pressure (IOP) is commonly associated with glaucoma, but not always. However, understanding disease progression is hindered by limited access to donor ocular tissue and consistent clinical data. Our study focuses on live patient samples, analyzing their proteome for potential biomarkers to enhance precise diagnosis and monitor glaucoma progression.

Methods

Aqueous humor (AH) samples were collected from 36 glaucoma patients (17 male, 19 female), and 35 non-glaucomatous control patients (16 male, 19 female) undergoing cataract surgery. The protein profile was compared using the SOMAscan® assay system for proteome profiling. From glaucomatous donors, significant correlations between IOP and cup-to-disc ratios to proteome differences were identified.

Results

Correlations in proteins between plasma and AH were identified. These proteins were enriched in pathways related to vascular integrity, inflammatory response, humoral & adaptive immune response, cell-cell & cell-matrix adhesion, and complement activation. Glaucomatous AH exhibited increased protein levels in general. Neurofilament light chain (NEFL) protein correlated with elevated IOP and inflammatory markers, but not with cup-to-disc ratios.

Conclusions

Together, our data demonstrate that the proteins identified in this study from glaucomatous donors correspond to both markers of neurodegeneration and those that may inhibit cell proliferation or disrupt vascular integrity.

Translational Relevance

Proteome analysis may lead to potential biomarker identification during disease progression.

Precis

Clinical glaucoma diagnosis is by assessing structure-function relationship which doesn’t yield molecular mechanisms underlying disease. Here, we analyzed proteome from aqueous and plasma of glaucomatous patients. Proteins correspond to markers of neurodegeneration, pressure and cup-to-disc-ratios.
Distinguishing microgliosis and tau deposition in the mouse brain using paramagnetic and diamagnetic susceptibility source separation
Authors: Joshi Jayvik , Yao Minmin , Kakazu Aaron , Ouyang Yuxiao , Duan Wenzhen , Aggarwal Manisha
Published: April 2024

Tauopathies, including Alzheimer's disease (AD), are neurodegenerative disorders characterized by hyperphosphorylated tau protein aggregates in the brain. In addition to protein aggregates, microglia-mediated inflammation and iron dyshomeostasis are other pathological features observed in AD and other tauopathies. It is known that these alterations at the subcellular level occur much before the onset of macroscopic tissue atrophy or cognitive deficits. The ability to detect these microstructural changes with MRI therefore has substantive importance for improved characterization of disease pathogenesis. In this study, we demonstrate that quantitative susceptibility mapping (QSM) with paramagnetic and diamagnetic susceptibility source separation has the potential to distinguish neuropathological alterations in a transgenic mouse model of tauopathy. 3D multi-echo gradient echo data were acquired from fixed brains of PS19 (Tau) transgenic mice and age-matched wild-type (WT) mice (n = 5 each) at 11.7 T. The multi-echo data were fit to a 3-pool complex signal model to derive maps of paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS). Group-averaged signal fraction and composite susceptibility maps showed significant region-specific differences between the WT and Tau mouse brains. Significant bilateral increases in PCS and |DCS| were observed in specific hippocampal and cortical sub-regions of the Tau mice relative to WT controls. Comparison with immunohistological staining for microglia (Iba1) and phosphorylated-tau (AT8) further indicated that the PCS and DCS differences corresponded to regional microgliosis and tau deposition in the PS19 mouse brains, respectively. The results demonstrate that quantitative susceptibility source separation may provide sensitive imaging markers to detect distinct pathological alterations in tauopathies.
DeepRBP: A novel deep neural network for inferring splicing regulation
Authors: Sancho Joseba , Ferrer-Bonsoms Juan A. , Olaverri-Mendizabal Danel , Carazo Fernando , Valcárcel Luis V. , Ochoa Idoia
Published: April 2024

Motivation

Alternative splicing plays a pivotal role in various biological processes. In the context of cancer, aberrant splicing patterns can lead to disease progression and treatment resistance. Understanding the regulatory mechanisms underlying alternative splicing is crucial for elucidating disease mechanisms and identifying potential therapeutic targets.

Results

We present DeepRBP, a deep learning (DL) based framework to identify potential RNA-binding proteins (RBP)-Gene regulation pairs for further in-vitro validation. DeepRBP is composed of a DL model that predicts transcript abundance given RBP and gene expression data coupled with an explainability module that computes informative RBP-Gene scores. We show that the proposed framework is able to identify known RBP-Gene regulations, demonstrating its applicability to identify new ones.

Availability and Implementation

DeepRBP is implemented in PyTorch, and all the code and material used in this work is available athttps://github.com/ML4BM-Lab/DeepRBP.

Contact

iochoal@unav.es

Supplementary information

Supplementary data are available atBioinformaticsonline.
Phaeocystisblooms caused carbon drawdown during the Antarctic Cold Reversal from sedimentary ancient DNA
Authors: Weiß Josefine Friederike , Herzschuh Ulrike , Müller Juliane , Liang Jie , Vorrath Maria-Elena , Perfumo Amedea , Stoof-Leichsenring Kathleen R.
Published: April 2024

The Southern Ocean plays a crucial role in the global carbon budget. Modeling studies propose that the atmospheric CO2plateau during the Antarctic Cold Reversal (ACR; 14,700 to 12,700 calibrated years before present (cal yr BP)) is related to increased marine productivity. However, proxy evidence relating environmental conditions as well as primary community composition and productivity to carbon drawdown is missing. Our ancient DNA shotgun metagenomic analysis of marine sediments revealedPhaeocystis antarctica(haptophyte) as a key element of the primary producer community. Independent proxy evidence (blooming-related bacteria, Ba/Fe ratio) from the same sediment record point to high productivity in response to enhanced sea-ice seasonality caused by ACR cooling. Post ACR, abruptPhaeocystiscommunity loss shows how sensitive this ecosystem is to warming, potentially representing a key tipping element that may be further enhanced by thePhaeocystis-related sulfur cycle–climate feedback. As an analogy for present warming, it highlights the importance of regions with high seasonal sea-ice variability andPhaeocystis-dominance, such as the Ross Sea, for stabilizing atmospheric CO2content. Additionally, our shotgun metagenomic data portray complex Holocene ecosystem establishment including key Antarctic taxa such as penguins, whales, and Antarctic fishes with implications for ongoing conservation efforts.
HtDCR-like1regulates the development of structurally coloured cuticle by modulating cuticle chemistry and mechanical properties inHibiscus trionum
Authors: Ferria Jordan , Saladin Siriel , Ponraj Udhaya , Wightman Raymond , Giorio Chiara , Airoldi Chiara A. , Glover Beverley J.
Published: April 2024

Structural colours are a unique trait present in some animals, plants and even bacteria. InHibiscus trionumflowers, they arise from nano-scaled cuticular ridges and may improve pollinator foraging efficiency. These ridges result from the buckling of the cuticle which is thought to be controlled by multiple parameters including anisotropic cell growth, chemical differentiation of the cuticle and formation of two layers of different mechanical properties.

Here we investigate further the molecular and physical mechanisms by which structural colours are achieved inHibiscus trionum. We produced two transgenic lines overexpressingHtDCR-like1, encoding a BAHD acyltransferase involved in cuticle synthesis. Transgenic lines showed impairment of the production of cuticle striations. Cuticle thickness, cuticle chemistry, cell elongation and cuticle stiffness were then investigated to identify the cause of failed buckling.

We found thatHtDCR-like1overexpression leads to modification of cuticle chemistry, including a decrease in detectable C16H32O4(10,16-DHP) and a change to the measured Young’s moduli of the cuticle layers without alteration of the cell growth pattern.

This work demonstrates the mechanisms by which gene regulation may control complex physical phenomena such as cuticle buckling via alteration of material properties of living tissues.
Comparing the effect of imputation reference panel composition in four distinct Latin American cohorts
Authors: French Jennifer N , Pua Victor Borda , Laboulaye Roland , Leal Thiago Peixoto , Olivas Mario Cornejo , Lima-Costa Maria Fernanda , Horta Bernardo L , Barreto Mauricio L , Tarazona-Santos Eduardo , Mata Ignacio , O’Connor Timothy D.
Published: April 2024

Genome-wide association studies have been useful in identifying genetic risk factors for various phenotypes. These studies rely on imputation and many existing panels are largely composed of individuals of European ancestry, resulting in lower levels of imputation quality in underrepresented populations. We aim to analyze how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We compared imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four populations; however, there were differences between chromosomes 7 and X in some cohorts. Excluding Latin Americans from analysis resulted in worse imputation quality in every cohort, while differential effects were seen when excluding Europeans and Africans between and within cohorts and between chromosomes 7 and X. Finally, increasing IA-like admixture proportions in the reference panel increased imputation quality at different levels in different populations. The difference in results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations.
Efficient storage and regression computation for population-scale genome sequencing studies
Authors: Rivas Manuel A. , Chang Christopher
Published: April 2024

In the era of big data in human genetics, large-scale biobanks aggregating genetic data from diverse populations have emerged as important for advancing our understanding of human health and disease. However, the computational and storage demands of whole genome sequencing (WGS) studies pose significant challenges, especially for researchers from underfunded institutions or developing countries, creating a disparity in research capabilities. We introduce new approaches that significantly enhance computational efficiency and reduce data storage requirements for WGS studies. By developing algorithms for compressed storage of genetic data, focusing particularly on optimizing the representation of rare variants, and designing regression methods tailored for the scale and complexity of WGS data, we significantly lower computational and storage costs. We integrate our approach into PLINK 2.0. The implementation demonstrates considerable reductions in storage space and computational time without compromising analytical accuracy, as evidenced by the application to the AllofUs project data. We optimized the runtime of an exome-wide association analysis involving 19.4 million variants and the body mass index phenotype of 125,077 individuals, reducing it from 695.35 minutes (approximately 11.5 hours) on a single machine to just 1.57 minutes using 30 GB of memory and 50 threads (or 8.67 minutes with 4 threads). Additionally, we extended this approach to support multi-phenotype analyses. We anticipate that our approach will enable researchers across the globe to unlock the potential of population biobanks, accelerating the pace of discoveries that can improve our understanding of human health and disease.
Atypical Pupil-Linked Arousal Induced by Low-Risk Probabilistic Choices, and Intolerance of Uncertainty in Adults with ASD
Authors: Pultsina Kristina I. , Stroganova Tatiana A. , Kozunova Galina L. , Prokofyev Andrey O. , Miasnikova Aleksandra S. , Rytikova Anna M. , Chernyshev Boris V.
Published: April 2024

Adults with autism spectrum disorder (ASD) report stress when acting in a familiar probabilistic environment, but the underlying mechanisms are unclear. Their decision-making may be affected by the uncertainty aversion implicated in ASD, and associated with increased autonomic arousal. Previous studies have shown that in neurotypical (NT) people, decisions with predictably better outcomes are less stressful and elicit smaller pupil-linked arousal than those involving random “trial-and-error” searches or self-imposed risk of exploration. Here, in a sample of 46 high-functioning ASD and NT participants, we explored pupil-linked arousal and behavioral performance in a probabilistic reward learning task with a stable advantage of one choice option over the other. Using mixed-effects model analysis, we contrasted pupil dilation response (PDR) between a preferred frequently rewarded exploitative decision and its explorative alternatives. We observed that subjects with ASD learned the advantageous probabilistic choices at the same rate over time and preferred them to the same degree as NT participants both in terms of choice ratio and decision speed. Despite similar reward prediction abilities, outcome predictability modulated decision-related PDR in ASD in the opposite direction than in NT individuals. Moreover, relatively enhanced PDR elicited by exploitative low-risk decisions predicted a greater degree of self-reported intolerance of uncertainty in everyday life. Our results suggest that in a non-volatile probabilistic environment, objectively good predictive abilities in people with ASD are coupled with elevated physiological stress and subjective uncertainty regarding the decisions with the best possible but still uncertain outcome that contributes to their intolerance of uncertainty.
A Novel Simple ImmunoAssay for Quantification of Blood Anti-NMDAR1 Autoantibodies
Authors: Vaughn Melonie , Powell Susan , Risbrough Victoria , Zhou Xianjin
Published: April 2024

High titers of anti-NMDAR1 autoantibodies in human brain cause anti-NMDAR1 encephalitis, a rare disease that displays a variety of psychiatric symptoms and neurological symptoms. Currently, immunohistochemical staining and cell-based assays are the standard methods for detection and semi-quantification of the anti-NMDAR1 autoantibodies. Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background from less diluted serum/plasma. Development of a new method to quantify these low titers of blood anti-NMDAR1 autoantibodies is necessary to understand their potential impacts on psychiatric symptoms and cognition. Based on our previous One-Step assay, we report the development of a novel simple immunoassay to quantify cross-species blood anti-NMDAR1 autoantibodies, and its validation with immunohistochemistry and cell-based assays in both humans and mice.
Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.
Authors: Qadir Mirza Muhammad Fahd , Elgamal Ruth M. , Song Keijing , Kudtarkar Parul , Sakamuri Siva S.V.P. , Katakam Prasad V. , El-Dahr Samir , Kolls Jay K. , Gaulton Kyle J. , Mauvais-Jarvis Franck
Published: April 2024

Biological sex affects the pathogenesis of type 2 and type 1 diabetes (T2D, T1D) including the development of β cell failure observed more often in males. The mechanisms that drive sex differences in β cell failure is unknown. Studying sex differences in islet regulation and function represent a unique avenue to understand the sex-specific heterogeneity in β cell failure in diabetes. Here, we examined sex and race differences in human pancreatic islets from up to 52 donors with and without T2D (including 37 donors from the Human Pancreas Analysis Program [HPAP] dataset) using an orthogonal series of experiments including single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), dynamic hormone secretion, and bioenergetics. In cultured islets from nondiabetic (ND) donors, in the absence of the in vivo hormonal environment, sex differences in islet cell type gene accessibility and expression predominantly involved sex chromosomes. Of particular interest were sex differences in the X-linked KDM6A and Y-linked KDM5D chromatin remodelers in female and male islet cells respectively. Islets from T2D donors exhibited similar sex differences in differentially expressed genes (DEGs) from sex chromosomes. However, in contrast to islets from ND donors, islets from T2D donors exhibited major sex differences in DEGs from autosomes. Comparing β cells from T2D and ND donors revealed that females had more DEGs from autosomes compared to male β cells. Gene set enrichment analysis of female β cell DEGs showed a suppression of oxidative phosphorylation and electron transport chain pathways, while male β cell had suppressed insulin secretion pathways. Thus, although sex-specific differences in gene accessibility and expression of cultured ND human islets predominantly affect sex chromosome genes, major differences in autosomal gene expression between sexes appear during the transition to T2D and which highlight mitochondrial failure in female β cells.
Reassessing global historical ℛ0estimates of canine rabies
Authors: Li Michael , Roswell Michael , Hampson Katie , Bolker Benjamin M. , Dushoff Jonathan
Published: April 2024

Rabies spread by domestic dogs continues to cause tens of thousands of human deaths every year in low- and middle-income countries. Nevertheless rabies is often neglected, perhaps because it has already been eliminated from high-income countries through dog vaccination. Estimates of canine rabies’s intrinsic reproductive number (ℛ0), a metric of disease spread, from a wide range of times and locations are relatively low (values<2), with narrow confidence intervals. Given rabies’s persistence, this consistently low and narrow range of estimates is surprising. We combined incidence data from historical outbreaks of canine rabies from around the world with in-depth contact-tracing data from Tanzania to investigate initial growth rates (r0), generation-interval distributions (G), and reproductive numbers (ℛ0). We improved on earlier estimates by choosing outbreak windows algorithmically; fittingr0using a more appropriate statistical method that accounts for decreases through time; and incorporating uncertainty from bothr0andGin our confidence intervals onℛ0. Ourℛ0estimates are larger than previous estimates, with wider confidence intervals. These revisedℛ0estimates suggest that a greater level of vaccination effort will be required to eliminate rabies than previously thought, but that the level of coverage required remains feasible. Our hybrid approach for estimatingℛ0and its uncertainty is applicable to other disease systems where researchers estimateℛ0by combining data-based estimates ofr0andG.
Effects of environmental change on population growth: monitoring time-varying carrying capacity in free-ranging spotted hyenas
Authors: Bailey Liam D. , Höner Oliver P. , Davidian Eve , Dheer Arjun , Radchuk Viktoriia , Walter Leonie F. , White Ella W. , Courtiol Alexandre
Published: April 2024

In conservation, a growing population is often taken as a sign of success. But trends in population size can be misleading. When individuals are long-lived, populations may keep growing—for a time—even as the environment begins to stabilize or deteriorate. Trends in carrying capacity (K) would better reflect the situation that a population finds itself in, yetKis commonly assumed to be static. We developed an individual-based modelling approach to estimate time-varying carrying capacity (Kt) in a population of free-ranging spotted hyenas.Ktnoticeably varied due to events such as disease outbreaks, but not in response to recent conservation interventions. Although the population tripled in size during the 26-year study period, we found no corresponding trend inKt. Rather, population recovery resulted from earlier environmental improvements. Our approach, which can be applied to populations of other species, allows for a faster and more accurate assessment of conservation needs.
Uncovering porphyrin accumulation in the tumor microenvironment
Authors: Adapa Swamy R. , Sami Abdus , Meshram Pravin , Ferreira Gloria C. , Jiang Rays H.Y.
Published: April 2024

Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be exquisitely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed ‘Porphyrin Overdrive’. Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME’s stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no porphyrin accumulation, and CAFs deprived of tumor cease porphyrin overproduction, indicating that both cancer and tumor-stromal porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.