bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial FABP4 constitutes the majority of basal circulating hormone levels and regulates lipolysis-driven insulin secretion
Authors: Inouye Karen E. , Prentice Kacey J. , Lee Alexandra , Dominguez-Gonzalez Carla , Chen Mu Xian , Lee Grace Yankun , Hotamışlıgil Gökhan S. 
Published: October 2022

AbstractFatty acid binding protein 4 (FABP4) is a lipid chaperone secreted from adipocytes upon stimulation of lipolysis. Circulating FABP4 levels strongly correlate with body mass index and obesity-related pathologies in experimental models and humans. While adipocytes have been presumed to be the major source of hormonal FABP4, this question has not been addressed definitivelyin vivo. We generated mice with FABP4 deletion in cells known to express the gene; adipocytes (Adipo-KO), endothelial cells (Endo-KO), myeloid cells (Myeloid-KO), and the whole body (Total-KO) to examine the contribution of these cell types to basal and stimulated plasma FABP4 levels. Unexpectedly, baseline plasma FABP4 was only reduced by ∼25% in Adipo-KO mice, whereas Endo-KO mice showed ∼75% decreases compared to wildtype controls. In contrast, Adipo-KO mice exhibited ∼62% reduction in FABP4 responses to lipolysis, while there was minimal reduction in Endo-KO mice, indicating that adipocytes are the main FABP4 source in lipolysis. We did not detect any myeloid cell contribution to circulating FABP4. Surprisingly, despite the nearly intact FABP4 responses, Endo-KO mice showed blunted lipolysis-induced insulin secretion, identical to Total-KO mice. We conclude that the endothelium is the major source of baseline hormonal FABP4 and is required for the insulin response to lipolysis.
Are under-studied proteins under-represented? How to fairly evaluate link prediction algorithms in network biology
Authors: Yılmaz Serhan , Yorgancioglu Kaan , Koyutürk Mehmet 
Published: October 2022

AbstractFor biomedical applications, new link prediction algorithms are continuously being developed and these algorithms are typically evaluated computationally, using test sets generated by sampling the edges uniformly at random. However, as we demonstrate, this evaluation approach introduces a bias towards “rich nodes”, i.e., those with higher degrees in the network. More concerningly, this bias persists even when different network snapshots are used for evaluation, as recommended in the machine learning community. This creates a cycle in research where newly developed algorithms generate more knowledge on well-studied biological entities while under-studied entities are commonly overlooked. To overcome this issue, we propose a weighted validation setting specifically focusing on under-studied entities and present AWARE strategies to facilitate bias-aware training and evaluation of link prediction algorithms. These strategies can help researchers gain better insights from computational evaluations and promote the development of new algorithms focusing on novel findings and under-studied proteins.TeaserSystematically characterizes and mitigates bias toward well-studied proteins in the evaluation pipeline for machine learning.Code and data availabilityAll materials (code and data) to reproduce the analyses and figures in the paper is available in figshare (doi:10.6084/m9.figshare.21330429). The code for the evaluation framework implementing the proposed strategies is available at github†. We provide a web tool‡to assess the bias in benchmarking data and to generate bias-adjusted test sets.
Decoding Fear or Safety and Approach or Avoidance by Brain-Wide Network Dynamics
Authors: Marques Danilo Benette , Rossignoli Matheus Teixeira , Mesquita Bruno de Avó , Prizon Tamiris , Zacharias Leonardo Rakauskas , Ruggiero Rafael Naime , Leite João Pereira 
Published: October 2022

AbstractDiscerning safety from threat and positive or negative outcomes of adversity are fundamental for mental health. Many brain structures have been implicated in both adaptive and maladaptive stress coping, however, how multiple regions function together as a network in the processing of this information is unclear. Here, we recorded local field potentials from seven regions of the mesolimbic-hippocampal-prefrontal cortical network (MLHFC) of male rats during the conditioning of a stimulus (CS) to the absence (safety) and then to the anticipation (fear) of footshocks, and during an approach-avoidance task. We developed a machine learning pipeline to investigate the relevance of specific features of oscillatory activity in the decoding of fear versus safety and approach versus avoidance. We found that decoding performance increased as a function of the number of brain regions included, reaching the best classification if all regions were considered. In addition, the best decoding was obtained from frequencies within the theta range (4-10 Hz). Remarkably, decoder models showed robust generalization within but not between individuals. Nevertheless, we were also able to identify patterns of MLHFC activity that decoded stress coping states from all rats. These patterns were characterized by increased brain-wide theta synchrony during fear and preceding approach. Our results indicate that stress coping information is encoded at the brain-wide level and highlight individual variability in this neural processing. Our findings also suggest that MLHFC network theta activity underlies active stress coping with both aversive and positive motivational valences.SIGNIFICANCE STATEMENTThe appraisal of safety versus threat and positive versus negative valence of adversity are core dimensions of emotional experience and stress coping. We developed a new behavioral protocol that discriminates states of fear, safety, approach, and avoidance in a single subject and a machine learning-based method to investigate how neural oscillations can decode such states. Our work provides evidence that stress coping is processed at multiple regions on a brain-wide level involving network oscillations at the theta frequencies, which especially synchronizes during fear and approach. We highlight the potentials of combining artificial intelligence and multi-site electroencephalography to guide therapeutic decisions in precision psychiatry and theta-boosting stimulation therapies for stress-related disorders, especially related to cognitive and motivational deficits.
Disparate patterns of genetic divergence in three widespread corals across a pan-Pacific environmental gradient highlights species-specific adaptation trajectories
Authors: Hume Benjamin C C , Voolstra Christian R , Armstrong Eric , Mitushasi Guinther , Porro Barbara , Oury Nicolas , Agostini Sylvain , Boissin Emilie , Poulain Julie , Carradec Quentin , Paz-García David A. , Zoccola Didier , Magalon Hélène , Moulin Clémentine , Bourdin Guillaume , Iwankow Guillaume , Romac Sarah , Banaigs Bernard , Boss Emmanuel , Bowler Chris , de Vargas Colomban , Douville Eric , Flores Michel , Furla Paola , Galand Pierre E , Gilson Eric , Lombard Fabien , Pesant Stéphane , Reynaud Stéphanie , Sullivan Matthew B. , Sunagawa Shinichi , Thomas Olivier , Troublé Romain , Thurber Rebecca Vega , Wincker Patrick , Planes Serge , Allemand Denis , Forcioli Didier 
Published: October 2022

ABSTRACTTropical coral reefs are among the worst affected ecosystems by climate change with predictions ranging between a 70-90% loss of reefs in the coming decades. Effective conservation strategies that maximize ecosystem resilience, and potential for recovery, must be informed by the accurate characterization of extant genetic diversity and population structure together with an understanding of the adaptive potential of keystone species. Here, we analyzed samples from theTaraPacific Expedition (2016 to 2018) that completed an 18,000 km longitudinal transect of the Pacific Ocean sampling three widespread corals –Pocillopora meandrina, Porites lobata, andMilleporacf.platyphylla– across 33 sites from 11 islands. Using deep metagenomic sequencing of 269 colonies in conjunction with morphological analyses and climate variability data we can show that the sampled transect encompasses multiple morphologically cryptic species that exhibit disparate biogeographic patterns, and most importantly, distinct evolutionary patterns, despite exposure to identical environmental regimes. Our findings demonstrate on a basin-scale that evolutionary trajectories are species-specific and complex, and can only in part be predicted from the environment. This highlights that conservation strategies must integrate multi-species investigations to consider the distinct genomic footprints shaped by selection as well as the genetic potential for adaptive change.
In silicocomparative RNA-seq analysis reveals varietal-specific intergenic small open reading frames inCucumis sativusL.
Authors: Chieng Gabrielle Shiao Wei , Tan Boon Chin , Teo Chee How 
Published: October 2022

AbstractSmall open reading frames (sORFs) have been reported to play important roles in growth, regulation of morphogenesis, and abiotic stress responses in various plant species. However, their sequences and functions remain poorly understood in many plant species includingCucumis sativus. Cucumis sativus(commonly known as cucumber) is Asia’s fourth most important vegetable and the second most important crop in Western Europe. The breeding of climate-resilient cucumbers is of great importance to ensure their sustainability under extreme climate conditions. In this study, we aim to isolate the intergenic sORFs fromC. sativusvar.hardwickiigenome and determine their sequence diversity and expression profiles inC. sativusvar.hardwickiiand different cultivars ofC. sativusvar.sativususing bioinformatics tools. We identified a total of 50,191 coding sORFs with coding potential (coding sORFs) fromC. sativusvar.hardwickiigenome. In addition, 1,311 transcribed sORFs were detected in RNA-seq datasets ofC. sativusvar.hardwickiiand shared homology to sequences deposited in the cucumber EST database, and among these, 91 transcribed sORFs with translation potential were detected. A total of 629 high-confidentC. sativus-specific sORFs were identified in both varieties. Varietal-specific transcribed sORFs were also identified inC. sativusvar.hardwickii(87) andC. sativusvar.sativus(2,906). Furthermore, cultivar- and tissue-specific transcribed sORFs were identified in different cultivars and tissue samples. The findings of this study provide insight into sequence diversity and expression patterns of sORFs inC. sativus, which could help in developing climate-resilient cucumbers.
Tamoxifen, associated to the conservative CKD treatment, promoted additional antifibrotic effect on experimental hypertensive nephrosclerosis
Authors: Fanelli Camilla , Ornellas Felipe M , Celestrino Giovanna A , Carmagnani Danielly N , Francini Ana LR , Noronha Irene L 
Published: October 2022

AbstractCKD progression depends on the activation of an intricate set of hemodynamic and inflammatory mechanisms, promoting renal leukocyte infiltration, inflammation and fibrosis, leading to renal function loss. There are currently no specific drugs to detain fibrogenesis, which is a common end-point for different nephropathies. Clinical therapy for CKD is mostly based on the management of hypertension and proteinuria, partially achieved with renin-angiotensin-aldosterone system (RAAS) blockers, and the control of inflammation by immunosuppressive drugs. The aim of the present study was to verify if the administration of tamoxifen (TAM), an estrogen receptor modulator, clinically employed in the treatment of breast cancer and predicted to exert antifibrotic effects, would promote additional benefits when associated to a currently used therapeutic scheme for the conservative management of experimental CKD. Wistar rats underwent the NAME model of hypertensive nephrosclerosis, obtained by daily oral administration of a nitric oxide synthesis inhibitor, associated to dietary sodium overload. The therapeutic association of TAM to losartan (LOS), and mofetil mycophenolate (MMF) effectively reduced the severe hypertension, marked albuminuria and glomerular damage exhibited by NAME animals. Moreover, the association also succeeded in limiting renal inflammation in this model, and promoted further reduction of ECM interstitial accumulation and renal fibrosis, compared to the monotherapies. According to our results, the association of TAM to the currently used conservative treatment of CKD added significant antifibrotic effects bothin vivoandin vitro, and may represent an alternative to slow the progression of chronic nephropathy.
Modulation of implicitly perceived hand size by visuotactile recalibration
Authors: Fuchs Xaver , Heed Tobias 
Published: October 2022

AbstractWhen concurrent visual and tactile stimuli are repeatedly presented with a spatial offset, even unisensory tactile stimuli are afterwards perceived with a spatial bias towards the previously presented visual stimuli. This so-called visuotactile ventriloquism aftereffect reflects visuotactile recalibration. It is unknown whether this recalibration occurs within a bodily map and interacts with perceived features like shape and size of body parts.Here, we applied tactile stimuli to participants’ hidden left hand and simultaneously presented visual stimuli with spatial offsets that – if integrated with the tactile stimuli – implied an enlarged hand size. We either used a fixed spatial mapping between tactile and visual positions (“congruent”), or a scrambled (“incongruent”) mapping. We assessed implicitly perceived hand size via two independent behavioral assessments: pointing movements to unisensory tactile stimuli and tactile distance judgments. Moreover, we assessed explicitly perceived change in hand size with perceptual self-reports.Especially after congruent recalibration, participants localized unimodal tactile stimuli as if they were aiming at an enlarged hand. They also reported tactile distance as shorter after congruent than incongruent recalibration. These modulations resemble those obtained after using tools that prolong the arm and extend reaching space; they suggest that recalibration affected a common, implicit hand representation that underlies both tasks. In contrast, explicit perceptual self-reports did not differ significantly between congruent and incongruent recalibration.Thus, simple visuotactile stimuli are sufficient to modify implicitly perceived body size, indicating a tight link of low-level multisensory processes such as the visuotactile ventriloquism aftereffect and body representation.
Single and multi-analyte deep learning-based analysis framework for class prediction in biological images
Authors: Krishnan Neeraja M , Kumar Saroj , Kumar Ujjwal , Panda Binay 
Published: October 2022

AbstractMeasurement of biological analytes, characterizing flavor in fruits, is a cumbersome, expensive and time-consuming process. Fruits with higher concentration of analytes have greater commercial or nutritional values. Here, we tested a deep learning-based framework with fruit images to predict the class (sweet or sour and high or low) of analytes using images from two types of trees in a single and multi-analyte mode. We used fruit images from kinnow (n= 3,451), an edible hybrid mandarin and neem (n= 1,045), a tree with agrochemical and pharmaceutical properties. We measured sweetness in kinnows and five secondary metabolites in neem fruits (azadirachtin or A, deacetyl-salannin or D, salannin or S, nimbin or N and nimbolide or E) using a refractometer and high-performance liquid chromatography, respectively. We trained the models for 300 epochs, before and after hyper-parameters’ evolution, using 300 generations with 50 epochs/generation, estimated the best models and evaluated their performance on 10% of independent images. The validation F1score and test accuracies were 0.79 and 0.77, and 82.55% and 60.8%, respectively for kinnow and neem A analyte. A multi-analyte model enhanced the neem A model’s prediction to ‘high’ class when the D:N:S’s combined class predictions were high:low:high and to ‘low’ class when D:N’s combined class predictions were low:high respectively. The test accuracy increased further to ~70% with a 10-fold cross-validation error of 0.257 across ten randomly split train:validation:test sets proving the potential of a multi-analyte model to enhance the prediction accuracy, especially when the numbers of images are limiting.
Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult
Authors: Hellberg Sanna , Ahmed Osman , Zhang Yuyang , Di Nunzio Giada , Björck Hanna M , Francis Roy , Fagerberg Linn , Gisterå Anton , Zhang Xueming , Metso Jari , Manfé Valentina , Soto Yosdel , Franco-Cereceda Anders , Eriksson Per , Jauhiainen Matti , Olofsson Peder S. , Malin Stephen G. 
Published: October 2022

AbstractApolipoprotein-B (APOB) containing lipoproteins are causative for atherosclerotic cardiovascular disease. Whether the vasculature is the initial responding site or if atherogenic-dyslipidemia effects other organs simultaneously is unknown. We set out to discover how the liver responds to a dyslipidemic insult through the creation of inducible mouse models based on human familial hypercholesterolemia mutations andin vivotracing of APOB. An acute transition to atherogenic APOB-lipoprotein plasma levels resulted in rapid accumulation of triglycerides and cholesterol in the liver. Single cell RNA-seq and flow cytometry disclosed that multiple immune cells have the ability to engulf APOB-lipoproteins. However bulk RNA-seq of the liver revealed an inflammatory Kupffer cell-specific transcriptional program that could not be activated by a western diet alone. Depletion of Kupffer cells through clodronate liposomes or CD8 T cell targeting rapidly raised plasma lipoprotein levels, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting pro-atherosclerotic factors into plasma. Our results place Kupffer cells as a key gateway in organizing systemic responses at the initiation of atherosclerosis.
Arabidopsis Nicotianamine Synthases (NAS) comprise a common core-NAS domain fused to a variable auto-inhibitory C-terminus
Authors: Seebach Hiroyuki , Radow Gabriel , Brunek Michael , Schulz Frank , Piotrowski Markus , Krämer Ute 
Published: October 2022

AbstractNicotianamine Synthase (NAS) catalyzes the biosynthesis of nicotianamine (NA) from the 2-aminobutyrate moieties of threeS-adenosylmethionine molecules. NA has central roles in metal nutrition and metal homeostasis of flowering plants. Despite the availability of crystal structures of archaeal and bacterial NAS-like proteins that carry out simpler aminobutanoyltransferase reactions, the enzymatic function of NAS remains poorly understood. Here we report amino acids essential for the activity of AtNAS1 based on structural modeling and site-directed mutagenesis. An enzyme-coupled continuous activity assay allowed us to compare differing NAS proteins identified through multiple sequence alignments and phylogenetic analyses. In most class Ia and b NAS proteins of dicotyledonous and monocotyledonous angiosperm plants, respectively, the core-NAS domain is fused to a variable C-terminal domain. Compared to fungal and moss NAS (class III) that consist merely of the core-NAS domain, NA biosynthetic activities of the four paralogous Arabidopsis NAS proteins were far lower. Yet their C-terminally trimmed core-NAS variants exhibited strongly elevated activities. Out of 320 amino acids of AtNAS1, twelve, 287-TRGCMFMPCNCS-298, accounted for the auto-inhibitory effect of the C-terminus, with approximately one third contributed by N296 within a CNCS motif that is conserved in Arabidopsis. No detectable NA biosynthesis was mediated by two representatives of groups of plant NAS proteins that naturally lack the C-terminal domain, class IaArabidopsis halleriNAS5, andMedicago truncatulaNAS2 of class II which is found in dicots and diverged early during the evolution of flowering plants. Our results suggest that NAS activity is under stringent post-translational control in plants.
Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion
Authors: Ko Kyung-Pil , Huang Yuanjian , Zhang Shengzhe , Zou Gengyi , Kim Bongjun , Zhang Jie , Jun Sohee , Martin Cecilia , Dunbar Karen J. , Efe Gizem , Rustgi Anil K. , Nakagawa Hiroshi , Park Jae-Il 
Published: October 2022

AbstractBackground and aimsDespite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown.MethodsUsing CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53,CDKN2A,NOTCH1,NOTCH3,KMT2D,KMT2C,FAT1,FAT4, andAJUBA) in murine esophageal organoids (EOs). Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing (scRNA-seq). Tumorigenicity and immune evasion of organoids were monitored by allograft transplantation. Human ESCC scRNA-seq datasets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion.ResultsWe established 32 genetically engineered EOs and identified key genetic determinants that drive ESCC initiation. A single-cell transcriptomic analysis uncovered thatTrp53,Cdkn2a, andNotch1(PCN) triple-knockout (KO) induces neoplastic features of ESCC by generating cell lineage heterogeneity and high cell plasticity.PCNKO also generates an immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis. Mechanistically,CDKN2Ainactivation transactivatesCCL2via NF-κB. Moreover, comparative single-cell transcriptomic analyses stratified ESCC patients and identified a specific subtype recapitulating the PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1.ConclusionsOur study unveils that loss ofTP53,CDKN2A, andNOTCH1induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable option for targeting PCN-type ESCC.
Automatic mechanistic inference from large families of Boolean models generated by Monte Carlo Tree Search
Authors: Glazer Bryan , Lifferth Jonathan , Lopez Carlos F. 
Published: October 2022

1AbstractMotivationMany important processes in biology, such as signaling and gene regulation, can be described using logic models. These logic models are typically built to behaviorally emulate experimentally observed phenotypes, which are assumed to be steady states of a biological system. Most models are built by hand and therefore researchers are only able to consider one or perhaps a few potential mechanisms. We present a method to automatically synthesize Boolean logic models with a specified set of steady states. Our method, called MC-Boomer, is based on Monte Carlo Tree Search (MCTS), an efficient, parallel search method using reinforcement learning. Our approach enables users to constrain the model search space using prior knowledge or biochemical interaction databases, thus leading to generation of biologically plausible mechanistic hypotheses. Our approach can generate very large numbers of data-consistent models. To help develop mechanistic insight from these models, we developed analytical tools for multi-model inference and model selection. These tools reveal the key sets of interactions that govern the behavior of the models.ResultsWe demonstrate that MC-Boomer works well at reconstructing randomly generated models. Then, using single time point measurements and reasonable biological constraints, our method generates hundreds of thousands of candidate models that match experimentally validatedin-vivobehaviors of theDrosophilasegment polarity network. Finally we outline how our multimodel analysis procedures elucidate potentially novel biological mechanisms and provide opportunities for model-driven experimental validation.AvailabilityCode is available at:www.github.com/bglazer/mcboomer