bluuebunny/crossref_metadata_2025_split huggingface dataset:
A sterility–mortality tolerance trade-off leads to within-population variation in host tolerance
Authors: Singh Prerna , Best Alex 
Published: November 2022

AbstractWhile experimental studies have demonstrated within-population variation in host tolerance to parasitism, theoretical studies rarely predict for polymorphism to arise. However, most theoretical models do not consider the crucial distinction between tolerance to the effects of infection-induced deaths (mortality tolerance) and tolerance to the parasite-induced reduction in the reproduction of infected hosts (sterility tolerance). While some studies have examined trade-offs between host tolerance and resistance mechanisms, none has considered a correlation within different tolerance mechanisms. We assume that sterility tolerance and mortality tolerance are directly traded-off in a host population subjected to a pathogen and use adaptive dynamics to study their evolutionary behaviour. We find that such a trade-off between the two tolerance strategies can drive the host population to branch into dimorphic strains, leading to coexistence of strains with sterile hosts that have low mortality and fully fertile with high mortality rates. Further, we find a wider range of trade-off shapes allows branching at intermediate or high infected population size. Our other significant finding is that sterility tolerance is maximised (and mortality tolerance minimised) at an intermediate disease-induced mortality rate. Additionally, evolution entirely reverses the disease prevalence pattern corresponding to the recovery rate, compared to when no strategies evolve. We provide novel predictions on the evolutionary behaviour of two tolerance strategies concerning such a trade-off.
G Protein-Coupled Receptor Kinase-2 (GRK-2) controls exploration through neuropeptide signaling inCaenorhabditis elegans
Authors: Davis Kristen , Mitchell Christo , Weissenfels Olivia , Bai Jihong , Raizen David M. , Ailion Michael , Topalidou Irini 
Published: November 2022

AbstractAnimals alter their behavior in manners that depend on environmental conditions as well as their developmental and metabolic states. For example,C. elegansis quiescent during larval molts or during conditions of satiety. By contrast, worms enter an exploration state when removed from food. Sensory perception influences movement quiescence (defined as a lack of body movement), as well as the expression of additional locomotor states inC. elegansthat are associated with increased or reduced locomotion activity, such as roaming (exploration behavior) and dwelling (local search). Here we find that movement quiescence is enhanced, and exploration behavior is reduced in G protein-coupled receptor kinasegrk-2mutant animals.grk-2was previously shown to act in chemosensation, locomotion, and egg-laying behaviors. Using neuron-specific rescuing experiments, we show that GRK-2 acts in multiple ciliated chemosensory neurons to control exploration behavior.grk-2acts in opposite ways from the cGMP-dependent protein kinase geneegl-4to control movement quiescence and exploration behavior. Analysis of mutants with defects in ciliated sensory neurons indicates thatgrk-2and the cilium-structure mutants act in the same pathway to control exploration behavior. We find that GRK-2 controls exploration behavior in an opposite manner from the neuropeptide receptor NPR-1 and the neuropeptides FLP-1 and FLP-18. Finally, we show that secretion of the FLP-1 neuropeptide is negatively regulated by GRK-2 and that overexpression of FLP-1 reduces exploration behavior. These results define neurons and molecular pathways that modulate movement quiescence and exploration behavior.Author summaryMany modulatory neurotransmitters affect behavior by binding to G protein-coupled receptors (GPCRs) and initiating signals that modify neuronal activity. GPCRs are regulated by G protein-coupled receptor kinases (GRKs). GRKs phosphorylate and promote the inactivation of GPCRs. Here we identify GRK-2 as a regulator of distinct locomotor states inC. elegans. We find that GRK-2 acts in olfactory sensory neurons to promote exploration and suppress movement quiescence. Additionally, we show that GRK-2 acts in opposition to a neuropeptide signaling pathway that acts in interneurons. Thus, this study demonstrates critical roles for GRK-2 in regulating neuromodulatory signaling and locomotor behavior.
Deciphering tumor ecosystems at super-resolution from spatial transcriptomics with TESLA
Authors: Hu Jian , Coleman Kyle , Lee Edward B. , Kadara Humam , Wang Linghua , Li Mingyao 
Published: November 2022

AbstractRecent advances in spatial transcriptomics (ST) have enabled the comprehensive characterization of gene expression in tumor microenvironment. However, ST only measures expression in discrete spots, which limits their usefulness in studying the detailed structure of TME. Here we present TESLA, a machine learning framework for multi-level tissue annotation in ST. TESLA integrates histological information with gene expression to annotate heterogeneous immune and tumor cells directly on the histology image, and further detects tertiary lymphoid structures and differential transcriptome programs between the edge and core of a tumor. TESLA provides a powerful tool for understanding the spatial architecture of the TME.
Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer
Authors: Mah Chui Yan , Nguyen An Dieu Trang , Niijima Takuto , Helm Madison , Dehairs Jonas , Ryan Feargal J , Ryan Natalie , Mills Ian G , Swinnen Johannes V , Lynn David J , Nassar Zeyad D , Butler Lisa M 
Published: November 2022

ABSTRACTPeroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferationin vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.
MethylSeqLogo: DNA methylation smart sequence logos
Authors: Hsu Fei-Man , Horton Paul 
Published: November 2022

AbstractBackgroundSequence logos can effectively visualize position specific base preferences evident in a collection of binding sites of some transcription factor. But those preferences usually fall far short of fully explaining binding specificity. Interestingly, some transcription factors bind sites of potentially methylated DNA. For example, MYC bindsCpGsites. This may increase binding specificity as such sites are 1) highly under-represented in the genome, and 2) offer additional, tissue specific information in the form of hypo- or hyper-methylation. Fortunately, bisulfite sequencing data suitable to investigate this possibility is readily available.MethodWe developed MethylSeqLogo, an extension of sequence logos which adds DNA methylation information to sequence logos. MethylSeqLogo includes new elements to indicate DNA methylation and under-represented dimers in each position of a set of aligned binding sites. Our method displays information from both DNA strands, and takes into account the sequence context (CpGor other) and genome region (promoter versus whole genome) appropriate to properly assess the expected background dimer frequency and level of methylation.When designing MethylSeqLogo, we took care to preserve the usual sequence logo meaning of heights; in which the relative height of nucleotides within a column represents their proportion in the binding sites, while the absolute height of each column represents information (relative entropy) and the height of all columns added together represents total information.ResultsWe present several figures illustrating the utility of using MethylSeqLogo to summarize data fromCpGbinding transcription factors. The logos show that unmethylatedCpGbinding sites are a feature of transcription factors such as MYC and ZBTB33, while some otherCpGbinding transcription factors, such as CEBPB, appear methylation neutral. We also compare MethylSeqLogo with two previously reported ways to create methylation aware sequence logos.ConclusionsOur freely available software enables users to explore large-scale bisulfite and ChIP sequencing data sets — and in the process obtain publication quality figures.
Adipocyte lipolysis protects the host againstTrypanosoma bruceiinfection
Authors: Machado Henrique , Hofer Peter , Zechner Rudolf , Figueiredo Luísa M. 
Published: November 2022

AbstractTrypanosoma brucei, an etiological agent of African trypanosomiasis, colonizes the interstitial spaces of the adipose tissue in disproportionately high numbers, inducing a robust local immune response. Loss of body weight, including loss of adipose mass, is a hallmark symptom of African trypanosomiasis. Nevertheless, it is unclear which molecular mechanisms drive this loss of adipose mass and in turn whether it contributes to pathology. Here we show that lipolysis is activated early in infection in adipose tissue ofT. brucei-infected mice. This activation is dependent on immune activation, as mice deficient for both B and T lymphocytes failed to upregulated adipocyte lipolysis upon infection and retained higher fat mass. Genetic ablation of the rate limiting adipose triglyceride lipase specifically from adipocytes in mice (AdipoqCre/+-Atglfl/fl) prevented the upregulation of adipocyte lipolysis during infection, leading to reduced loss of fat mass and adipocyte volume. Surprisingly infectedAdipoqCre/+-Atglfl/flmice succumbed earlier to infection and presented a higher parasite burden in the gonadal adipose tissue, indicating that lipolysis limits the growth of the parasite population. Collectively, this work provides molecular mechanistic insight into the loss of fat mass in African trypanosomiasis and identifies adipocyte lipolysis as a host-protective mechanism during aT. bruceiinfection.
WarpSTR: Determining tandem repeat lengths using raw nanopore signals
Authors: Sitarčík Jozef , Vinař Tomáš , Brejová Broňa , Krampl Werner , Budiš Jaroslav , Radvánszky Ján , Lucká Mária 
Published: November 2022

AbstractMotivationShort tandem repeats (STRs) are regions of a genome containing many consecutive copies of the same short motif, possibly with small variations. Analysis of STRs has many clinical uses, but is limited by technology mainly due to STRs surpassing the used read length. Nanopore sequencing, as one of long read sequencing technologies, produces very long reads, thus offering more possibilities to study and analyze STRs. Basecalling of nanopore reads is however particularly unreliable in repeating regions, and therefore direct analysis from raw nanopore data is required.ResultsHere we present WarpSTR, a novel method for characterizing both simple and complex tandem repeats directly from raw nanopore signals using a finite-state automaton and a search algorithm analogous to dynamic time warping. By applying this approach to determine the lengths of 241 STRs, we demonstrate that our approach decreases the mean absolute error of the STR length estimate compared to basecalling and STRique.AvailabilityWarpSTR is freely available athttps://github.com/fmfi-compbio/warpstrContactjozef.sitarcik@uniba.sk
WITHDRAWN: Mimicry promotes morphological diversification but not speciation in mimetic swallowtail butterflies
Authors: Kizhakke Athulya Girish , Kunte Krushnamegh 
Published: November 2022

Withdrawal statementThis manuscript has been withdrawn after a formal notification from the National Centre for Biological Sciences (Bengaluru, India) as it was submitted without listing all contributing authors. Therefore, this work should not be cited as reference for the project.
Meta-analytic evidence for a novel hierarchical model of conceptual processing
Authors: Kuhnke Philipp , Beaupain Marie C. , Arola Johannes , Kiefer Markus , Hartwigsen Gesa 
Published: November 2022

AbstractConceptual knowledge plays a pivotal role in human cognition. Grounded cognition theories propose that concepts consist of perceptual-motor features represented in modality-specific perceptual-motor cortices. However, it is unclear whether conceptual processing consistently engages modality-specific areas. Here, we performed an activation likelihood estimation (ALE) meta-analysis across 212 neuroimaging experiments on conceptual processing related to 7 perceptual-motor modalities (action, sound, visual shape, motion, color, olfaction-gustation, and emotion). We found that conceptual processing consistently engages brain regions also activated during real perceptual-motor experience of the same modalities. In addition, we identified multimodal convergence zones that are recruited for multiple modalities. In particular, the left inferior parietal lobe (IPL) and posterior middle temporal gyrus (pMTG) are engaged for three modalities: action, motion, and sound. These “trimodal” regions are surrounded by “bimodal” regions engaged for two modalities. Our findings support a novel model of the conceptual system, according to which conceptual processing relies on a hierarchical neural architecture from modality-specific to multimodal areas up to an amodal hub.
Obsessive-Compulsive Disorder (OCD) is Associated with Increased Engagement of Frontal Brain Regions Across Multiple Event Related Potentials
Authors: Perera M. Prabhavi N. , Mallawaarachchi Sudaraka , Bailey Neil W. , Murphy Oscar W. , Fitzgerald Paul B. 
Published: November 2022

ABSTRACTBackgroundObsessive-Compulsive Disorder (OCD) is a psychiatric condition leading to significant distress and poor quality of life. Successful treatment of OCD is restricted by the limited knowledge about its pathophysiology. This study aimed to investigate the pathophysiology of OCD using electroencephalographic (EEG) event related potentials (ERP), elicited from multiple tasks to characterise disorder-related differences in underlying brain activity across multiple neural processes.MethodsERP data were obtained from 25 OCD patients and 27 age- and sex-matched healthy controls (HC) by recording EEG during Flanker and Go/Nogo tasks. Error-related negativity (ERN) was elicited by the Flanker task, while N200 and P300 were generated using the Go/Nogo task. Primary comparisons of the neural response amplitudes and the topographical distribution of neural activity were conducted using scalp field differences across all time points and electrodes.ResultsCompared to HC, the OCD group showed altered ERP distributions. Contrasting with the previous literature on ERN and N200 topographies in OCD where fronto-central negative voltages were reported, we detected positive voltages. Additionally, the P300 was found to be less negative in the frontal regions. None of these ERP findings were associated with OCD symptom severity.ConclusionsThese results indicate that individuals with OCD show altered frontal neural activity across multiple executive function related processes, supporting the frontal dysfunction theory of OCD. Furthermore, due to the lack of association between altered ERPs and OCD symptom severity, they may be considered potential candidate endophenotypes for OCD.
Deep Learning-based Feature Extraction with MRI Data in Neuroimaging Genetics for Alzheimer’s Disease
Authors: Chakraborty Dipnil , Zhuang Zhong , Xue Haoran , Fiecas Mark , Shen Xiaotong ,   Alzheimer’s Disease Neuroimaging Initiative, Pan Wei 
Published: November 2022

AbstractThe prognosis and treatment of the patients suffering from Alzheimer’s disease (AD) have been one of the most important and challenging problems over the last few decades. To better understand the mechanism of AD, it is of great interest to identify genetic variants associated with brain atrophy. Commonly in these analyses, neuroimaging features are extracted based on one of many possible brain atlases with FreeSurf and other popular softwares, which however may lose important information due to our incomplete knowledge about brain function embedded in these suboptimal atlases. To address the issue, we propose convolutional neural network (CNN) models applied to three-dimensional MRI data for the whole brain or multiple divided brain regions to perform completely data-driven and automatic feature extraction. These image-derived features are then used as endophenotypes in Genome-Wide Association Studies (GWAS) to identify associated genetic variants. When applied to the ADNI data, we identified several associated SNPs which have been previously shown to be related to several neurodegenerative/mental disorders such as AD, depression and schizophrenia. Code and supplementary materials are available athttps://github.com/Dipnil07. The codes have been implemented using Python, R and Plink softwares.
Strategies for increasing the depth and throughput of protein analysis by plexDIA
Authors: Derks Jason , Slavov Nikolai 
Published: November 2022

AbstractAccurate protein quantification is key to identifying protein markers, regulatory relationships between proteins, and pathophysiological mechanisms. Realizing this potential requires sensitive and deep protein analysis of a large number of samples. Toward this goal, proteomics throughput can be increased by parallelizing the analysis of both precursors and samples using multiplexed data independent acquisition (DIA) implemented by the plexDIA framework:https://plexDIA.slavovlab.net. Here we demonstrate the improved precisions of RT estimates within plexDIA and how this enables more accurate protein quantification. plexDIA has demonstrated multiplicative gains in throughput, and these gains may be substantially amplified by improving the multiplexing reagents, data acquisition and interpretation. We discuss future directions for advancing plexDIA, which include engineering optimized mass-tags for high-plexDIA, introducing isotopologous carriers, and developing algorithms that utilize the regular structures of plexDIA data to improve sensitivity, proteome coverage and quantitative accuracy. These advances in plexDIA will increase the throughput of functional proteomic assays, including quantifying protein conformations, turnover dynamics, modifications states and activities. The sensitivity of these assays will extend to single-cell analysis, thus enabling functional single-cell protein analysis.Abstract Figure
Repurposing clemastine to target glioblastoma cell stemness
Authors: Sun Michael A. , Yang Rui , Liu Heng , Wang Wenzhe , Song Xiao , Hu Bo , Reynolds Nathan , Roso Kristen , Chen Lee H. , Greer Paula K. , Keir Stephen T. , McLendon Roger E. , Cheng Shi-Yuan , Bigner Darell D. , Ashley David M. , Pirozzi Christopher J. , He Yiping 
Published: November 2022

AbstractBrain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearingPDGFRAamplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that Emopamil binding protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment.
Reducing mitochondrial ribosomal gene expression does not alter metabolic health or lifespan in mice
Authors: Reid Kim , Daniels Eileen G. , Vasam Goutham , Kamble Rashmi , Janssens Georges E. , Hu Man , Green Alexander E. , Houtkooper Riekelt H. , Menzies Keir J. 
Published: November 2022

ABSTRACTMaintaining mitochondrial function is critical to an improved health span and lifespan. Introducing mild stress by inhibiting mitochondrial translation invokes the mitochondrial unfolded protein response (UPRmt) and increases lifespan in several animal models. Notably, lower mitochondrial ribosomal protein (MRP) expression also correlates with increased lifespan in a reference population of mice. In this study, we tested whether partially reducing the expression of a critical MRP,Mrpl54, reduced mitochondrial DNA-encoded protein content, induced the UPRmt, and affected lifespan or metabolic health using germline heterozygousMrpl54mice. Despite reducedMrpl54expression in multiple organs and a reduction in mitochondrial-encoded protein expression in myoblasts, we identified few significant differences between male or femaleMrpl54+/-and wild type mice in initial body composition, respiratory parameters, energy intake and expenditure, or ambulatory motion. We also observed no differences in glucose or insulin tolerance, treadmill endurance, cold tolerance, heart rate, or blood pressure. There were no differences in median life expectancy or maximum lifespan. Overall, we demonstrate that genetic manipulation ofMrpl54expression reduces mitochondrial-encoded protein content but is not sufficient to improve healthspan in otherwise healthy and unstressed mice.