bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of risk prediction models for preterm delivery in a rural setting in Ethiopia
Authors: Pons-Duran Clara , Wilder Bryan , Hunegnaw Bezawit Mesfin , Haneuse Sebastien , Goddard Frederick G. B. , Bekele Delayehu , Chan Grace J.
Published: November 2022

Background

Preterm birth complications are the leading causes of death among children under five years. A key practical challenge, however, is the inability to accurately identify pregnancies that are at high risk of preterm delivery, especially in resource-limited settings where there is limited availability of biomarkers assessment.

Methods

We evaluated whether risk of preterm delivery can be predicted using available data from a pregnancy and birth cohort in Amhara region, Ethiopia. All participants were enrolled in the cohort between December 2018 and March 2020. The study outcome was preterm delivery, defined as any delivery occurring before week 37 of gestation regardless of vital status of the fetus or neonate. A range of sociodemographic, clinical, environmental, and pregnancy-related factors were considered as potential inputs. Cox and accelerated failure time models, and decision tree ensembles were used to predict risk of preterm delivery. Model discrimination was estimated using the area-under-the-curve (AUC). Additionally, the conditional distributions of cervical length (CL) and fetal fibronectin (FFN) were simulated to ascertain whether those factors could improve model performance.

Results

A total of 2493 pregnancies were included. Of those, 138 women were censored due to loss-to-follow-up before delivery. Overall, predictive performance of models was poor. The AUC was highest for the tree ensemble classifier (0.60, 95%CI [0.57, 0.63]). When models were calibrated so that 90% of women who experienced a preterm delivery were classified as high risk, at least 75% of those classified as high risk did not experience the outcome. The simulation of CL and FFN distributions did not significantly improve models’ performance.

Conclusions

Prediction of preterm delivery remains a major challenge. In resource-limited settings, predicting high-risk deliveries would not only save lives, but also inform resource allocation. It may not be possible to accurately predict risk of preterm delivery without investing in novel technologies to identify genetic factors, immunological biomarkers or the expression of specific proteins.
Global transmission suitability maps for dengue virus transmitted byAedes aegyptifrom 1981 to 2019
Authors: Nakase Taishi , Giovanetti Marta , Obolski Uri , Lourenço José
Published: November 2022

Mosquito-borne viruses increasingly threaten human populations due to accelerating changes in climate, human and mosquito migration, and land use practices. Over the last three decades, the global distribution of dengue has rapidly expanded, causing detrimental health and economic problems in many areas of the world. To develop effective disease control measures and plan for future epidemics, there is an urgent need to map the current and future transmission potential of dengue across both endemic and emerging areas. Expanding and applying Index P, a previously developed mosquito-borne viral suitability measure, we map the global climate-driven transmission potential of dengue virus transmitted byAedes aegyptimosquitoes from 1981 to 2019. This database of dengue transmission suitability maps and an R package for Index P estimations are offered to the public health community as resources towards the identification of past, current and future transmission hotspots. These resources and the studies they facilitate can contribute to the planning of disease control and prevention strategies, especially in areas where surveillance is unreliable or non-existent.
Wearable-Derived Maternal Heart Rate Variability As A Novel Digital Biomarker of Preterm Birth
Authors: Jasinski Summer R. , Rowan Shon , Presby David M. , Claydon Elizabeth A. , Capodilupo Emily R.
Published: November 2022

Despite considerable health consequences from preterm births, their incidence remains unchanged over recent decades, due partially to limited screening methods and limited use of extant methods. Wearable technology offers a novel, noninvasive, and acceptable way to track vital signs, such as maternal heart rate variability (mHRV). Previous research observed that mHRV declines throughout the first 33 weeks of gestation in term, singleton pregnancies, after which it improves. The aim of this study was to explore whether mHRV inflection is a feature of gestational age or an indication of time to delivery. This retrospective case-control study considered term and preterm deliveries. Remote data collection via non-invasive wearable technology enabled diverse participation with subjects representing 42 US states and 16 countries. Participants (N=241) were recruited from the WHOOP (Whoop, Inc.) userbase and wore WHOOP straps during singleton pregnancies between March 2021 and October 2022. Mixed effect spline models by gestational age and time until birth were fit for within-person mHRV, grouped into preterm and term births. For term pregnancies, gestational age (AIC = 26627.6, R2m = 0.0109, R2c= 0.8571) and weeks until birth (AIC =26616.3, R2m = 0.0112, R2c = 0.8576) were representative of mHRV trends, with significantly stronger fit for weeks until birth (relative log-likelihood ratio = 279.5). For preterm pregnancies, gestational age (AIC =1861.9, R2m = 0.0016, R2c = 0.8582) and time until birth (AIC = 1848.0, R2m = 0.0100, R2c = 0.8676) were representative of mHRV trends, with significantly stronger fit for weeks until birth (relative log-likelihood ratio= 859.4). This study suggests that wearable technology, such as the WHOOP strap, may provide a digital biomarker for preterm delivery by screening for changes in nighttime mHRV throughout pregnancy that could in turn alert to the need for further evaluation and intervention.
Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities
Authors: Roider Tobias , Baertsch Marc A. , Fitzgerald Donnacha , Voehringer Harald , Brinkmann Berit J. , Czernilofsky Felix , Knoll Mareike , Llaó-Cid Laura , Bruch Peter-Martin , Liebers Nora , Schürch Christian M. , Passerini Verena , Brobeil Alexander , Mechtersheimer Gunhild , Müller-Tidow Carsten , Weigert Oliver , Seiffert Martina , Nolan Garry P. , Huber Wolfgang , Dietrich Sascha
Published: November 2022

T-cell-engaging immunotherapies have improved the treatment of nodal B-cell lymphoma, but responses vary highly. Future improvements of such therapies require better understanding of the variety of lymphoma-infiltrating T-cells. We employed single-cell RNA and T-cell receptor sequencing alongside quantification of surface proteins, flow cytometry and multiplexed immunofluorescence on 101 lymph nodes from healthy controls, and patients with diffuse large B-cell, mantle cell, follicular, or marginal zone lymphoma. This multimodal resource revealed entity-specific quantitative and spatial aberrations of the T-cell microenvironment. Clonal PD1+TCF7-but not PD1+TCF7+cytotoxic T-cells converged into terminally exhausted T-cells, the proportions of which were variable across entities and linked to inferior prognosis. In follicular and marginal zone lymphoma, we observed expansion of follicular helper and IKZF3+regulatory T-cells, which were clonally related and inversely associated with tumor grading. Overall, we portray lymphoma-infiltrating T-cells with unprecedented comprehensiveness and decipher both beneficial and adverse dimensions of T-cell response.
Improving annotation propagation on molecular networks through random walks: Introducing ChemWalker
Authors: Borelli Tiago C. , Arini Gabriel Santos , Feitosa Luís G. P. , Dorrestein Pieter C. , Lopes Norberto P. , da Silva Ricardo R.
Published: November 2022

Annotation of the mass signals is still the biggest bottleneck for the untargeted mass spectrometry analysis of complex mixtures. Molecular networks are being increasingly adopted by the mass spectrometry community as a tool to annotate large scale experiments. We have previously shown that the process of propagating annotations from spectral library matches on molecular networks can be automated using Network Annotation Propagation (NAP). One of the limitations of NAP is that the information for the spectral matches is only propagated locally, to the first neighbor of a spectral match. Here we show that annotation propagation can be expanded to nodes not directly connected to spectral matches using random walks on graphs, introducing the ChemWalker python library. Similarly to NAP, ChemWalker relies on combinatorial in silico fragmentation results, performed by MetFrag, searching biologically relevant databases. Departing from the combination of a spectral network and the structural similarity among candidate structures, we have used MetFusion Scoring function to create a weight function, producing a weighted graph. This graph was subsequently used by the random walk to calculate the probability of ‘walking’ through a set of candidates, departing from seed nodes (represented by spectral library matches). This approach allowed the information propagation to nodes not directly connected to the spectral library match. Compared to NAP, ChemWalker has a series of improvements, on running time, scalability and maintainability and is available as a stand alone python package. ChemWalker is freely available athttps://github.com/computational-chemical-biology/ChemWalker.
CTCF mediates the Activity-by-contact derived cis-regulatory hubs
Authors: Lee Mick , Mangnier Loïc , Padilla Cory C. , Lee Dominic Paul , Tan Wilson , Li Peter Yiqing , Zheng Wen Hao , Gan Louis , Chen Ching Kit , Lim Yee Phong , Qin Wang Rina Miao , Bilodeau Steve , Bureau Alexandre , Foo Roger Sik-Yin , Anene-Nzelu Chukwuemeka George
Published: November 2022

The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modeled by cis-regulatory hubs (CRH) which underscore the local functional interactions between enhancers and promoter regions and differ from other higher order chromatin structures such as topological associated domains (TAD). The Activity-by-contact (ABC) model of enhancer-promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of CTCF on the ABC scores and the consequent impact on CRHs. Here we show that the loss of CTCF leads to a reorganization of the enhancer-promoter interactions resulting in a re-distribution of ABC scores of the putative enhancers in C57/bl6 mouse hearts. The loss of CTCF also leads to a global reduction of the total number of CRHs, and an increase in the size of the CRHs due to increase in the number of elements within each hub. In addition, CTCF loss led to more CRHs that cross TAD boundaries. These results provide another layer of evidence to support the importance of CTCF in the formation of regulatory networks necessary for gene regulation.
GHB degradation via TCA cycle is the major metabolic route inArabidopsis thaliana
Authors: Mekonnen Dereje W.
Published: November 2022

Gamma-hydroxybutyric acid (GHB) is a reduced product of the chemically reactive succinic semi-aldehyde (SSA), which itself is produced from the degradation of GABA. It is regarded as a short chain fatty acid. Despite our understanding of the synthesis of GHB, little is known about its fate. Exogenous application of 0.1 mM GHB topop2 x ssadh, a double mutant incapable of catabolizing GABA, increased the endogenous GHB level by 13-fold compared to the wild type. The GHB dynamic studies by feeding and relieving from treatments showed that GHB is rapidly metabolized in wild type plants compared to thepop2 x ssadhdouble mutant. Although regarded as a short chain fatty acid, GHB level was not altered in mutants of the beta oxidation pathway following exogenous feeding. Therefore, the metabolism back to SSA and then TCA cycle appears to be the major route for GHB degradation. However, the presence of another catabolic route such as secondary modifications cannot be ruled out.
DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex
Authors: Poisel Eric , Zillich Lea , Streit Fabian , Frank Josef , Friske Marion M , Foo Jerome C , Mechawar Naguib , Turecki Gustavo , Hansson Anita C , Nöthen Markus M , Rietschel Marcella , Spanagel Rainer , Witt Stephanie H
Published: November 2022

Cocaine use disorder (CUD) is characterized by a loss of control over drug intake and is associated with structural, functional, and molecular alterations in the brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes as observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue. We investigated epigenome-wide DNA methylation signatures of CUD in human postmortem brain tissue of Brodmann Area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. While no CpG site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identifiedNPFFR2andKALRNfor which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such asCACNA1C, NR3C1, andJUN. In BA9, we observed a trend toward epigenetic age acceleration in individuals with CUD remaining stable even after adjustment for covariates. Results from our study highlight that CUD is associated with epigenome-wide differences in DNA methylation levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex. Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.
The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Authors: Jaime Diego , Fish Lauren A. , Madigan Laura A. , Ewing Madison D. , Fallon Justin R.
Published: November 2022

Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
Single-cell microencapsulation improves lung retention of endothelial colony forming cells after intravascular delivery and unmasks therapeutic benefit in severe pulmonary arterial hypertension
Authors: Cober Nicholas D. , Chaudhary Ketul R. , Deng Yupu , Lee Chyan-Jang , Rowe Katelynn , Courtman David W. , Stewart Duncan J.
Published: November 2022

Background

Pulmonary arterial hypertension (PAH) is triggered by pulmonary vascular endothelial cell apoptosis and microvascular loss; therefore, therapies that can regenerate lost vasculature may offer therapeutic benefit. Endothelial colony forming cells (ECFCs) can directly repair damaged blood vessels and may have therapeutic potential for the treatment of PAH. However, poor retention of ECFCs in the lungs following intravenous delivery greatly limits their therapeutic application. Therefore, we studied whether cellular microencapsulation could enhance ECFCs viability and retention in the lung after systemic delivery and improve therapeutic efficacy of ECFCs in a rat monocrotaline (MCT) PAH model.

Methods

ECFCs were encapsulated by vortex-emulsion using various concentrations of agarose, and capsule size and initial cell viability were assessed. Encapsulated and free ECFCs were transduced with luciferase and administered to Sprague-Dawley rats three days after injection of MCT. ECFCs were trackedin vivoby bioluminescence imaging (BLI) to assess cell persistence and bio-distribution. At end-study, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were assessed for therapeutic efficacy.

Results

Microgel encapsulation using 3.5% agarose improved cells survival and supported cell migration from capsules. At 15 minutes after delivery, BLI radiance were similar for free and microencapsulated ECFCs; however, only encapsulated cells could be detected by BLI at 4 and 24 hours. Transplantation of microencapsulated ECFCs led to significant improvement in RVSP three weeks after delivery compared to non-encapsulated ECFCs.

Conclusion

Together, microencapsulation increased retention of ECFCs within the lungs. Furthermore, even a modest increase in ECFCs persistence over 24 hours can provide an important therapeutic benefit in the rat MCT model of PAH.
A sterility–mortality tolerance trade-off leads to within-population variation in host tolerance
Authors: Singh Prerna , Best Alex
Published: November 2022

While 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

Animals 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 summary

Many 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

Recent 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

Peroxisomes 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

Background

Sequence 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.

Method

We 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.

Results

We 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.

Conclusions

Our 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

Trypanosoma 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

Motivation

Short 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.

Results

Here 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.

Availability

WarpSTR is freely available athttps://github.com/fmfi-compbio/warpstr

Contact

jozef.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 statement

This 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

Conceptual 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

Background

Obsessive-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.

Methods

ERP 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.

Results

Compared 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.

Conclusions

These 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

The 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

Accurate 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

Brain 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

Maintaining 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.
Eccentric cycling involves greater mental demand and cortical activation of the frontoparietal network
Authors: Borot Lénaic , Pageaux Benjamin , Laroche Davy , Vergotte Grégoire , Lepers Ro-muald , Perrey Stéphane
Published: November 2022

Eccentric, compared to concentric exercise, is proposed to involve different neuro-motor processing strategies and a higher level of mental demand. This study compared eccentric and concentric cycling at matched perceived effort and torque for the mental demand and related-cortical activation patterns. Nineteen men (30 ± 6 yrs) performed four different 5-min cycling conditions at 30 RPM on a semi-recumbent isokinetic cycle ergometer: 1) concentric at a moderate perceived effort (23 on the CR100® scale) without torque feedback; 2) concentric and 3) eccentric at the same average torque produced in the first condition; and 4) eccentric at the same moderate perceived effort than the first concentric condition. The conditions 2-4 were randomised. After each condition, mental demand was monitored using the NASA Task Load Index scale. Changes in oxy-(O2Hb) and deoxy-(HHb) haemoglobin during exercise were meas-ured over both prefrontal cortices and the right parietal lobe from a 15-probe layout using a continuous-wave NIRS system. Mental demand was significantly higher during eccentric compared to concentric cycling (+52%,p= .012) and when the exercise intensity was fixed by the torque rather than the perceived effort (+70%,p˂ .001). For both torque- or perceived effort-matched exercises, O2Hb increased significantly (p< .001) in the left and right prefrontal cortices, and right parietal lobe, and HHb decreased in the left, and right, prefrontal cortices during eccentric compared to concentric cycling. This study supports that acute eccentric cycling, compared to concentric cycling, involves a higher mental demand and frontoparietal network activation.
Integration of cell wall synthesis activation and chromosome segregation during cell division inCaulobacter
Authors: Mahone Christopher R. , Yang Xinxing , McCausland Joshua W. , Payne Isaac P. , Xiao Jie , Goley Erin D.
Published: November 2022

To divide, bacteria must synthesize and remodel their peptidoglycan (PG) cell wall, a protective meshwork that maintains cell shape. FtsZ, a tubulin homolog, dynamically assembles into a midcell band, recruiting division proteins including the PG synthases FtsW and FtsI. FtsWI are activated to synthesize PG and drive constriction at the appropriate time and place, however their activation pathway remains unresolved. InCaulobacter crescentus, FtsWI activity requires FzlA, an essential FtsZ-binding protein. Through time-lapse imaging and single-molecule tracking ofC. crescentusFtsW and FzlA in perturbed genetic backgrounds, we demonstrate that FzlA is a limiting constriction activation factor that converts inactive, fast-moving FtsW to an active, slow-moving state. We find that FzlA interacts with the DNA translocase FtsK, and place FtsK genetically in a pathway with FzlA and FtsWI. Misregulation of the FzlA-FtsK-FtsWI pathway leads to heightened DNA damage and cell death. We propose that FzlA integrates the FtsZ ring, chromosome segregation, and PG synthesis to ensure robust and timely constriction duringCaulobacterdivision.
Keratin filament mechanics and energy dissipation are determined by metal-like plasticity
Authors: Lorenz Charlotta , Forsting Johanna , Style Robert W. , Klumpp Stefan , Köster Sarah
Published: November 2022

Cell mechanics is determined by an intracellular biopolymer network, including intermediate filaments that are expressed in a cell-type specific manner. A prominent pair of intermediate filaments are keratin and vimentin as the epithelial-to-mesenchymal transition is associated with a switch from keratin to vimentin. The transition coincides with a change in cellular mechanics, and thus dynamic properties of the cells. This observation raises the question of how the mechanical properties already differ on the single filament level. Here we use optical tweezers and a computational model to compare the stretching and dissipation behavior of the two filament types. We find that keratin and vimentin filaments behave in opposite ways: keratin filaments elongate, but retain their stiffness, whereas vimentin filaments soften, but retain their length. This finding is explained by fundamentally different ways to dissipate energy: viscous subunits sliding within keratin filaments and non-equilibriumαhelix unfolding in vimentin filaments.
Large-scale neural dynamics in a shared low-dimensional state space reflect cognitive and attentional dynamics
Authors: Song Hayoung , Shim Won Mok , Rosenberg Monica D.
Published: November 2022

Cognition and attention arise from the adaptive coordination of neural systems in response to external and internal demands. The low-dimensional latent subspace that underlies large-scale neural dynamics and the relationships of these dynamics to cognitive and attentional states, however, are unknown. We conducted functional magnetic resonance imaging as human participants performed attention tasks, watched comedy sitcom episodes and an educational documentary, and rested. Whole-brain dynamics traversed a common set of latent states that spanned canonical gradients of functional brain organization, with global synchrony among functional networks modulating state transitions. Neural state dynamics were synchronized across people during engaging movie watching and aligned to narrative event structures. Neural state dynamics reflected attention fluctuations such that different states indicated engaged attention in task and naturalistic contexts whereas a common state indicated attention lapses in both contexts. Together, these results demonstrate that traversals along large-scale gradients of human brain organization reflect cognitive and attentional dynamics.