bluuebunny/crossref_metadata_2025 huggingface dataset:
KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability inDrosophila
Authors: Rogers Michael F , Marshall Owen J , Secombe Julie
Published: May 2023

The precise coordination of gene expression is critical for developmental programs, and histone modifying proteins play important, conserved roles in fine-tuning transcription for these processes. One such family of proteins are KDM5 enzymes that interact with chromatin through demethylating H3K4me3 as well as demethylase-independent mechanisms that remain less understood. The singlekdm5ortholog inDrosophilais an essential gene that has crucial developmental roles in a neuroendocrine tissue, the prothoracic gland. To characterize the regulatory functions of KDM5, we examined its role in coordinating gene expression programs critical to cellular homeostasis and organismal viability in larval prothoracic gland cells. Utilizing targeted genetic experiments, we analyzed the relationship between critical cell signaling pathways, particularly MAPK, and the lethality caused by loss ofkdm5. Integrating KDM5 genome binding and transcriptomic data revealed conserved and tissue-specific transcriptional programs regulated by KDM5. These experiments highlighted a role for KDM5 in regulating the expression of a set of genes critical for the function and maintenance of mitochondria. This gene expression program is key to the essential functions of KDM5, as expression of the mitochondrial biogenesis transcription factor Ets97D/Delg, theDrosophilahomolog of GABPα, in prothoracic gland cells suppressed the lethality ofkdm5null animals. Consistent with this, we observed morphological changes to mitochondria in the prothoracic gland ofkdm5null mutant animals. Together, these data establish KDM5-mediated cellular functions that are both important for normal development and could also contribute to KDM5-linked disorders when dysregulated.
sncRNAP: Prediction and profiling of full sncRNA repertoires from sRNAseq data
Authors: Gibriel Hesham A. Y. , Baindoor Sharada , Slack Ruth S. , Prehn Jochen H. M.
Published: May 2023

Motivation

Non-coding RNAs (ncRNAs), which include long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs), have been shown to play essential roles in various biological processes. Over the past few years, a group of sncRNA identification tools have been developed but none has shown the capacity to fully profile and accurately identify those that are differentially expressed in control vs treated samples. Therefore, a tool that fully profiles and identifies differentially expressed sncRNAs in group comparisons is required.

Results

We developed sncRNAP, a Nextflow pipeline for the profiling and identification of differentially abundant sncRNAs from sRNAseq datasets. sncRNAP primary use case is the comparison of multiple small RNA-seq datasets belonging to two conditions such as the comparison of treatment (T) and control (C) cohorts. sncRNAP can be used to analyze human, mouse, and rat datasets. The pipeline carries out all the steps required to assess raw sequencing data, performs differential gene expression (DE) analysis, profiles sncRNAs in each sample, and outputs TXT, PDF, CSV, and interactive HTML files for the quality score and the top identified sncRNA candidates. We verified sncRNAP on publicly available sRNAseq datasets in chronic hepatitis-infected liver tissue and pancreatic ductal adenocarcinoma (PDAC) datasets. Our results support the identification of Val[C/A]AC in hepatitis patients and miR135b in PDAC as potential disease biomarkers. Furthermore, we applied sncRNAP on mouse samples from control and Opa1 mouse mutants and identified AspGTC, ValAAC, SerTGA, and AspGTC as the top DE tsRNAs. In addition, sncRNAP identified mmu-miR-136-5p, mmu-miR-10b-5p, mmu-miR-351-5p, and mmu-miR-6390 as the top DE miRNA candidates.
Modulation of functional phosphorylation sites by basic residues in the Unique domain of c-Src
Authors: Lang Andras , Fernández Alejandro , Diaz-Lobo Mireia , Vilanova Mar , Cárdenas Francisco , Gairí Margarida , Pons Miquel
Published: May 2023

In contrast to the well-studied canonical regulatory mechanisms, the way by which the recently discovered Src N-terminal regulatory element (SNRE) modulates Src activity is not yet well understood. Phosphorylation of serine and threonine residues modulate the charge distribution along the disordered region of the SNRE and may affect a fuzzy complex with the SH3 domain that is believed to act as an information transduction element. The preexisting positively charged sites can interact with the newly introduced phosphate groups by modulating their acidity, introducing local conformational restrictions, or coupling various phosphosites into a functional unit. In this paper we use pH dependent NMR measurements combined with single point mutations to identify the interactions of basic residues with physiologically important phosphorylated residues and to characterize the effect of these interactions in neighbor residues, thus providing insight on the electrostatic network in the isolated disordered regions and in the entire SNRE. From a methodological point of view, the linear relationship observed between the mutation induced pKa changes of the phosphate groups of phosphoserine and phosphothreonine and the pH induced chemical shifts of the NH groups of these residues provides a very convenient alternative to identify interacting phosphate groups without the need to introduce point mutations on specific basic residues.
Variation in Dental Tissues: Using Bayesian Multilevel Modelling to Explore Intra- and Inter-Individual Dental Variation
Authors: Fernee Christianne , Zakzewski Sonia , Robson Brown Kate
Published: May 2023

Objectives

Dental variation within populations and, even more so, within individuals is far less well understood than variation between populations. This is problematic as a single tooth type is often used as a representative of the whole dentition, despite a lack of understanding of intra-tooth type relationships. This research investigates the variation of dental tissues and proportions within and between individuals.

Materials and Methods

Upper and lower first incisor to second premolar tooth rows were obtained from 30 individuals (n=300), from 3 archaeological samples. The teeth were micro-CT scanned and surface area and volumetric measurements were obtained from the surface meshes extracted. Dental variation of these measurements on a tooth and individual level was studied using Bayesian Multilevel Modelling.

Results

The individual and tooth level variation differed by dental measurement, ranging between 9.5%-47.5% and 52.6-90.5% respectively. Enamel volume had the highest degree of individual-level variation in contrast to coronal dentine volume that had the lowest of individual-level variation. Tooth type, isomere, and position in field all showed a significant effect on the dental measurements examined in this study.

Discussion

Tooth selection and sampling strategies should consider individual and tooth-level variation, with at least one tooth from each type and isomere included in analyses. This will ensure that any population-level differences are not masked by variability between teeth. The low level of coronal dentine volume individual variation indicates that it is particularly useful in studies with small sample sizes.
Building the vector in? Construction practices contribute to the invasion and persistence ofAnopheles stephensiin Jigjiga, Ethiopia
Authors: Yared Solomon , Gebresilassie Araya , Aklilu Esayas , Abdulahi Elyas , Kirstein Oscar D. , Gonzalez-Olvera Gabriela , Che-Mendoza Azael , Bibiano-Marin Wilbert , Waymire Elizabeth , Lines Jo , Lenhart Audrey , Kitron Uriel , Carter Tamar , Manrique-Saide Pablo , Vazquez-Prokopec Gonzalo M.
Published: May 2023

Anopheles stephensiis a major vector of malaria in Asia and the Arabian Peninsula, and its recent invasion into Africa poses a significant threat to malaria control and elimination efforts on the continent. The mosquito is well-adapted to urban environments, and its presence in Africa could potentially lead to an increase in malaria transmission in cities. Most of the knowledge aboutAn. stephensiecology in Africa has been generated from studies conducted during the rainy season, when vectors are most abundant. Here, we provide evidence from the peak of the dry season in the city of Jigjiga, Ethiopia, and report the finding ofAn. stephensiimmature stages infesting predominantly water reservoirs made to support construction operations (in construction sites or associated with brick manufacturing businesses). Political and economic changes in Ethiopia (and particularly the Somali Region) have fueled an unprecedented construction boom since 2018 that, in our opinion, has been instrumental in the establishment, persistence and propagation ofAn. stephensivia the year-round availability of perennial larval habitats associated with construction. We argue that larval source management during the dry season may provide a unique opportunity for focused control ofAn. stephensiin Jigjiga and similar areas.
Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer
Authors: Cárdenas Emilio L. , O’Rourke Rachel L. , Menon Arya , Meagher Jennifer , Stuckey Jeanne , Garner Amanda L.
Published: May 2023

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m7GpppX-cap at the 5′ terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis among other cancerous phenotypes. eIF4E is the rate-limiting translation factor and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance. These findings have established eIF4E as a translational oncogene and promising, albeit challenging, anti-cancer therapeutic target. Although significant effort has been put forth towards inhibiting eIF4E, the design of cell-permeable, cap-competitive inhibitors remains a challenge. Herein, we describe our work towards solving this long-standing challenge. By employing an acyclic nucleoside phosphonate prodrug strategy, we report the synthesis of cell-permeable inhibitors of eIF4E binding to capped mRNA to inhibit cap-dependent translation.
Mifepristone decreases nicotine intake in dependent and non-dependent adult rats
Authors: Chellian Ranjithkumar , Behnood-Rod Azin , Bruijnzeel Adriaan W.
Published: May 2023

Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. The aim of these studies was to investigate if glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent (3 days per week) or daily access (7 days per week) for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine if the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access, but only the rats with daily access to nicotine showed signs of dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the total distance traveled and rearing in the open field test and operant responding for food pellets. These findings indicate that mifepristone decreases the reinforcing effects of nicotine and food, but it might also be somewhat sedative.
Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway
Authors: Koumoundourou Artemis , Rannap Märt , Bruyckere Elodie De , Nestel Sigrun , Reißner Carsten , Egorov Alexei V. , Liu Pentao , Missler Markus , Heimrich Bernd , Draguhn Andreas , Britsch Stefan
Published: May 2023

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapsesin vivoandin vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.
Quantitative Geometric Modeling of Blood Cells from X-ray Histotomograms of Whole Zebrafish Larvae
Authors: Yakovlev Maksim A. , Liang Ke , Zaino Carolyn R. , Vanselow Daniel J. , Sugarman Andrew L. , Lin Alex Y. , La Riviere Patrick J. , Zheng Yuxi , Silverman Justin D. , Leichty John C. , Huang Sharon X. , Cheng Keith C.
Published: May 2023

Tissue phenotyping is foundational to understanding and assessing the cellular aspects of disease in organismal context and an important adjunct to molecular studies in the dissection of gene function, chemical effects, and disease. As a first step toward computational tissue phenotyping, we explore the potential of cellular phenotyping from 3-Dimensional (3D), 0.74 µm isotropic voxel resolution, whole zebrafish larval images derived from X-ray histotomography, a form of micro-CT customized for histopathology. As proof of principle towards computational tissue phenotyping of cells, we created a semi-automated mechanism for the segmentation of blood cells in the vascular spaces of zebrafish larvae, followed by modeling and extraction of quantitative geometric parameters. Manually segmented cells were used to train a random forest classifier for blood cells, enabling the use of a generalized cellular segmentation algorithm for the accurate segmentation of blood cells. These models were used to create an automated data segmentation and analysis pipeline to guide the steps in a 3D workflow including blood cell region prediction, cell boundary extraction, and statistical characterization of 3D geometric and cytological features. We were able to distinguish blood cells at two stages in development (4- and 5-days-post-fertilization) and wild-type vs.polA2 huli hutu(hht) mutants. The application of geometric modeling across cell types to and across organisms and sample types may comprise a valuable foundation for computational phenotyping that is more open, informative, rapid, objective, and reproducible.
A single cell transcriptomic fingerprint of stressed premature, imbalanced differentiation of embryonic stem cells
Authors: Ruden Ximena , Singh Aditi , Marben Teya , Tang Wen , Awonuga Awoniyi , Ruden Douglas M. , Puscheck Elizabeth , Feng Hao , Rappolee Daniel
Published: May 2023

Cultured naïve pluripotent ESC differentiate into first lineage, XEN or second lineage, formative pluripotency. Hyperosmotic stress (sorbitol), like retinoic acid, decreases naive pluripotency and increases XEN in two ESC lines, as reported by bulk and scRNAseq, analyzed by UMAP. Sorbitol overrides pluripotency in two ESC lines as reported by bulk and scRNAseq, analyzed by UMAP. UMAP analyzed the effects of 5 stimuli - three stressed (200-300mM sorbitol with leukemia inhibitory factor +LIF) and two unstressed (+LIF, normal stemness-NS and -LIF, normal differentiation-ND). Sorbitol and RA decrease naive pluripotency and increase subpopulations of 2-cell embryo-like and XEN sub-lineages; primitive, parietal, and visceral endoderm (VE). Between the naïve pluripotency and primitive endoderm clusters is a stress-induced cluster with transient intermediate cells with higher LIF receptor signaling, with increased Stat3, Klf4, and Tbx3 expression. Sorbitol, like RA, also suppresses formative pluripotency, increasing lineage imbalance. Although bulk RNAseq and gene ontology group analyses suggest that stress induces head organizer and placental markers, scRNAseq reveals few cells. But VE and placental markers/cells were in adjacent clusters, like recent reports. UMAPs show that dose-dependent stress overrides stemness to force premature lineage imbalance. Hyperosmotic stress induces lineage imbalance, and other toxicological stresses, like drugs with RA, may cause lineage imbalance, resulting in miscarriages or birth defects.
Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer’s Disease mice
Authors: Hafycz Jennifer M. , Strus Ewa , Naidoo Nirinjini N.
Published: May 2023

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that is pervasive among the aging population. Two distinct phenotypes of AD are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock-in mouse model of AD and several protein chaperone supplementation paradigms, including a late-stage intervention. We show that supplementing protein chaperones systemically and locally in the hippocampus reduces PERK signaling and increases XBP1s, which is associated with increased ADAM10 and decreased Aβ42. Importantly, chaperone treatment improves cognition which is correlated with increased CREB phosphorylation and BDNF. Together, this data suggests that chaperone treatment restores proteostasis in a mouse model of AD and that this restoration is associated with improved cognition and reduced pathology.

One-sentence summary

Chaperone therapy in a mouse model of Alzheimer’s disease improves cognition by reducing chronic UPR activity
Theoretical framework and experimental solution for the air-water interface adsorption problem in cryoEM
Authors: Kang Joon S. , Zhou Xueting , Liu Yun-Tao , Wang Kaituo , Zhou Z. Hong
Published: May 2023

As cryogenic electron microscopy (cryoEM) gains traction in the structural biology community as a method of choice for determining atomic structures of biological complexes, it has been increasingly recognized that many complexes that behave well under conventional negative-stain electron microscopy tend to have preferential orientation, aggregate or simply mysteriously “disappear” on cryoEM grids, but the reasons for such misbehavior are not well understood, limiting systematic approaches to solving the problem. Here, we have developed a theoretical formulation that explains these observations. Our formulation predicts that all particles migrate to the air-water interface (AWI) to lower the total potential surface energy — rationalizing the use of surfactant, which is a direct solution to reducing the surface tension of the aqueous solution. By conducting cryogenic electron tomography (cryoET) with the widely-tested sample, GroEL, we demonstrate that, in a standard buffer solution, nearly all particles migrate to the AWI. Gradual reduction of the surface tension by introducing surfactants decreased the percentage of particles exposed to the surface. By conducting single-particle cryoEM, we confirm that applicable surfactants do not damage the biological complex, thus suggesting that they might offer a practical, simple, and general solution to the problem for high-resolution cryoEM. Application of this solution to a real-world AWI adsorption problem with a more challenging membrane protein, namely, the ClC-1 channel, has led to its first near-atomic structure using cryoEM.
HNF4α mediated QPRT expression in the kidney facilitates resilience against acute kidney injury
Authors: Clark Amanda J. , Saade Marie Christelle , Vemireddy Vamsidhara , Vu Kyle Q. , Flores Brenda Mendoza , Etzrodt Valerie , Ciampa Erin J. , Huang Huihui , Takakura Ayumi , Zandi-Nejad Kambiz , Zsengellér Zsuzsanna K. , Parikh Samir M.
Published: May 2023

Nicotinamide adenine dinucleotide (NAD+) levels decline in experimental models of acute kidney injury (AKI). Attenuated enzymatic conversion of tryptophan to NAD+ in tubular epithelium may contribute to adverse cellular and physiological outcomes. Mechanisms underlying defense of tryptophan-dependent NAD+ production are incompletely understood. Here we show that regulation of a bottleneck enzyme in this pathway, quinolinate phosphoribosyltransferase (QPRT) may contribute to kidney resilience. Expression of QPRT declined in two unrelated models of AKI. Haploinsufficient mice developed worse outcomes compared to littermate controls whereas novel, conditional gain-of-function mice were protected from injury. Applying these findings, we then identified hepatocyte nuclear factor 4 alpha (HNF4α) as a candidate transcription factor regulating QPRT expression downstream of the mitochondrial biogenesis regulator and NAD+ biosynthesis inducer PPARgamma coactivator-1-alpha (PGC1α). This was verified by chromatin immunoprecipitation. A PGC1a-HNF4α -QPRT axis controlled NAD+ levels across cellular compartments and modulated cellular ATP. These results propose that tryptophan-dependent NAD+ biosynthesis via QPRT and induced by HNF4α may be a critical determinant of kidney resilience to noxious stressors.
Differential Contribution of Sensorimotor Cortex and Subthalamic Nucleus to Unimanual and Bimanual Hand Movements
Authors: Merrick Christina M. , Doyle Owen N. , Gallegos Natali E. , Irwin Zachary T. , Olson Joseph W. , Gonzalez Christopher L. , Knight Robert T. , Ivry Richard B. , Walker Harrison C.
Published: May 2023

Why does unilateral subthalamic nucleus deep brain stimulation improve motor function bilaterally? To address this clinical observation, we collected parallel neural recordings from sensorimotor cortex and the subthalamic nucleus during repetitive ipsilateral, contralateral, and bilateral hand movements in patients with Parkinson’s disease undergoing subthalamic nucleus deep brain stimulation. We used a cross-validated electrode-wise encoding model to map EMG data to the neural signals. Electrodes in the subthalamic nucleus encoded movement in a comparable manner for both hands during unimanual and bimanual movements, whereas sensorimotor cortex electrodes displayed a strong contralateral bias. To examine representational overlap in encoding across the two hands, we trained the model with data from one condition (contralateral hand) and used the trained weights to predict neural activity for movements produced with the other hand (ipsilateral hand). Overall, between-hand generalization was poor and this limitation was evident in both SMC and STN. A similar method was used to probe representational overlap across different task contexts (unimanual vs. bimanual). Task context was more important for the STN compared to the SMC indicating that neural activity in the STN showed greater divergence between the unimanual and bimanual conditions. These results indicate that whereas SMC activity is strongly lateralized and relatively context-free, STN integrates contextual information with the ongoing behavior.

Significance Statement

Unilateral subthalamic nucleus deep brain stimulation (DBS) improves both contralateral and ipsilateral motor symptoms of Parkinson’s disease. To explore mechanisms for bilateral improvement, parallel neural recordings from the sensorimotor cortex (SMC) and subthalamic nucleus (STN) were recorded in patients with Parkinson’s disease undergoing DBS. Neural activity and muscle activity from the hands were collected while patients performed unimanual and bimanual repetitive hand movements. Activity in SMC primarily encoded contralateral movements and was relatively context-free. In contrast, STN encoded movements in a comparable manner for both hands and was sensitive to the behavioral context.
Structural Visualization of HECT-E3 Ufd4 accepting and transferring Ubiquitin to Form K29/K48-branched Polyubiquitination on N-degron
Authors: Mao Junxiong , Ai Huasong , Wu Xiangwei , Zheng Qingyun , Cai Hongyi , Liang Lujun , Tong Zebin , Pan Man , Liu Lei
Published: May 2023

Proteins with destabilizing N-terminal residues are degraded via K48-linked ubiquitination-dependent N-degron pathway, during which the HECT-type E3 ligase Ufd4 can further augment polyubiquitination events on these proteins to accelerate their degradation. How Ufd4 increase polyubiquitination on ubiquitinated N-degrons remains unclear. Here, we biochemically determined that Ufd4 preferentially ubiquitinates the proximal ubiquitin in K48-linked ubiquitin chain in K29-linkage specific manner and revealed high-resolution cryo-EM structures of Ufd4 accepting (E2-to-E3 state, 3.52 Å) and transferring ubiquitin-thioester (E3-to-substrate state, 3.31 Å), respectively. The N-terminal ARM region and HECT domain C-lobe of Ufd4 were identified and characterized as key structural elements that together recruit K48-linked diUb and orient Lys29 of its proximal Ub to the active cysteine of Ufd4 for K29-linked branched ubiquitination. These structures not only provide mechanistic insights into the architecture of the Ufd4 complex but also show the full picture of the Ub transferring cascades of HECT-type E3 ligase.
Study protocol for a randomised controlled trial investigating the effects of Mindfulness Based Stress Reduction on stress regulation and associated neurocognitive mechanisms in stressed university students: The MindRest study
Authors: Kogias Nikos , Geurts Dirk E. M. , Krause Florian , Speckens Anne E. M. , Hermans Erno J.
Published: May 2023

Background:

Stress-related disorders are a growing public health concern. While stress is a natural and adaptive process, chronic exposure to stressors can lead to dysregulation and take a cumulative toll on physical and mental well-being. One approach to coping with stress and building resilience is through Mindfulness-Based Stress Reduction (MBSR). By understanding the neural mechanisms of MBSR, we can gain insight into how it reduces stress and what drives individual differences in treatment outcomes. This study aims to establish the clinical effects of MBSR on stress regulation in a population that is susceptible to develop stress-related disorders (i.e., university students with mild to high self-reported stress), to assess the role of large-scale brain networks in stress regulation changes induced by MBSR, and to identify who may benefit most from MBSR.

Methods:

This study is a longitudinal two-arm randomised, wait-list controlled trial to investigate the effects of MBSR on a preselected, Dutch university student population with elevated stress levels. Clinical symptoms are measured at baseline, post-treatment, and three months after training. Our primary clinical symptom is perceived stress, with additional measures of depressive and anxiety symptoms, alcohol use, stress resilience, positive mental health, and stress reactivity in daily life. We investigate the effects of MBSR on stress regulation in terms of behaviour, self- report measures, physiology, and brain activity. Repetitive negative thinking, cognitive reactivity, emotional allowance, mindfulness skills, and self-compassion will be tested as potential mediating factors for the clinical effects of MBSR. Childhood trauma, personality traits and baseline brain activity patterns will be tested as potential moderators of the clinical outcomes.

Discussion

This study aims to provide valuable insights into the effectiveness of MBSR in reducing stress-related symptoms in a susceptible student population and crucially, to investigate its effects on stress regulation, and to identify who may benefit most from the intervention.

Trial registration

Registered on September 15, 2022, at clinicaltrials.gov,NCT05541263.https://clinicaltrials.gov/ct2/show/study/NCT05541263
SifiNet: A robust and accurate method to identify feature gene sets and annotate cells
Authors: Gao Qi , Ji Zhicheng , Wang Liuyang , Owzar Kouros , Li Qi-Jing , Chan Cliburn , Xie Jichun
Published: May 2023

SifiNet is a robust and accurate computational pipeline for identifying distinct gene sets, extracting and annotating cellular subpopulations, and elucidating intrinsic relationships among these subpopulations. Uniquely, SifiNet bypasses the cell clustering stage, commonly integrated into other cellular annotation pipelines, thereby circumventing potential inaccuracies in clustering that may compromise subsequent analyses. Consequently, SifiNet has demonstrated superior performance in multiple experimental datasets compared with other state-of-the-art methods. SifiNet can analyze both single-cell RNA and ATAC sequencing data, thereby rendering comprehensive multiomic cellular profiles. It is conveniently available as an open-source R package.
A combination of convergent extension and differential adhesion explains the shapes of elongating gastruloids
Authors: de Jong Martijn A. , Adegeest Esmée , Bérenger-Currias Noémie M. L. P. , Mircea Maria , Merks Roeland M. H. , Semrau Stefan
Published: May 2023

Gastruloids have emerged as highly usefulin vitromodels of mammalian gastrulation. One of the most striking features of 3D gastruloids is their elongation, which mimics the extension of the embryonic anterior-posterior axis. Although axis extension is crucial for development, the underlying mechanism has not been fully elucidated in mammalian species. Gastruloids provide an opportunity to study this morphogenic processin vitro. Here, we measure and quantify the shapes of elongating gastruloids and show, by Cellular Potts model simulations, that a combination of convergent extension and differential adhesion can explain the observed shapes. We reveal that differential adhesion alone is insufficient and also directly observe hallmarks of convergent extension by time-lapse imaging of gastruloids. Finally, we show that gastruloid elongation can be abrogated by inhibition of the Rho kinase pathway, which is involved in convergent extensionin vivo. All in all, our study demonstrates, how gastruloids can be used to elucidate morphogenic processes in embryonic development.
FuzzyPPI: Human Proteome at Fuzzy Semantic Space
Authors: Halder Anup Kumar , Bandyopadhyay Soumyendu Sekhar , Jedrzejewski Witold , Basu Subhadip , Sroka Jacek
Published: May 2023

Large scale protein-protein interaction (PPI) network of an organism provides key insights into its cellular and molecular functionalities, signaling pathways and underlying disease mechanisms. For any organism the total number of unexplored protein interactions significantly outnumbers all known positive and negative interactions. For Human, all known PPI datasets, contain only ∼ 5.61 million positive and ∼ 0.76 million negative interactions, that together is ∼ 3.1% of potential interactions. Moreover, conventional PPI prediction methods produce binary results. At the same time, recent studies show that protein binding affinities may prove to be effective in detecting protein complexes, disease association analysis, signaling network reconstruction, etc. Keeping these in mind, we present a fuzzy semantic scoring function using the Gene Ontology (GO) graphs to assess the binding affinity between any two proteins at an organism level. We have implemented a distributed algorithm in Apache Spark that computes this function and used it to process a Human PPI network of ∼ 180 million potential interactions resulting from 18 994 reviewed proteins for which GO annotations are available. The quality of the computed scores has been validated with respect to the availablestate-of-the-artmethods on benchmark data sets. The resulting scores are published with a web-server for non-commercial use at:http://fuzzyppi.mimuw.edu.pl/.
Structure of mitoribosome reveals mechanism of mRNA binding, tRNA interactions with L1 stalk, roles of cofactors and rRNA modifications
Authors: Singh Vivek , Itoh Yuzuru , Del’Olio Samuel , Hassan Asem , Naschberger Andreas , Flygaard Rasmus Kock , Nobe Yuko , Izumikawa Keiichi , Aibara Shintaro , Andréll Juni , Whitford Paul C , Barrientos Antoni , Taoka Masato , Amunts Alexey
Published: May 2023

The mitoribosome translates mitochondrial mRNAs and regulates energy conversion that is a signature of aerobic life forms. We present a 2.2 Å resolution structure of human mitoribosome together with validated mitoribosomal RNA (rRNA) modifications, including aminoacylated CP-tRNAVal. The structure shows how mitoribosomal proteins stabilise binding of mRNA and tRNA helping to align it in the decoding center, whereas the GDP-bound mS29 stabilizes intersubunit communication. Comparison between different states, with respect to tRNA position, allowed to characterize a non-canonical L1 stalk, and molecular dynamics simulations revealed how it facilitates tRNA transition in a way that does not require interactions with rRNA. We also report functionally important polyamines that are depleted when cells are subjected to an antibiotic treatment. The structural, biochemical, and computational data illuminate the principal functional components of the translation mechanism in mitochondria and provide the most complete description so far of the structure and function of the human mitoribosome.
Pre-gelation staining expansion microscopy (PS-ExM) for visualization of thePlasmodiumliver stage
Authors: Atchou Kodzo , Berger Bianca Manuela , Heussler Volker , Ochsenreiter Torsten
Published: May 2023

Fluorescence and light microscopy are important tools in the history of natural science. However, the resolution of microscopes is limited by the diffraction of light. One possible method to circumvent this physical restriction is the recently developed expansion microscopy (ExM). By physically expanding the sample in a swellable hydrogel, biomolecules are separated in space allowing to image molecules that are otherwise difficult to study due to their size or complexity. Furthermore, the improved resolution is useful to study protein localization and interactions. However, the original ultrastructure ExM (U-ExM) protocol is very time-consuming, and some epitopes are lost during the process. In this study, we developed a shortened pre-gelation staining ExM (PS-ExM) protocol and tested it to investigate thePlasmodiumliver stage. The protocol presented in this study allows expanding pre-stained samples, which results in shorter incubation times, better preservation of some epitopes, and the advantage that non-expanded controls can be performed alongside using the same staining protocol. The protocol applicability was accessed throughout thePlasmodiumliver stage showing isotropic five-fold expansion. Furthermore, we used PS-ExM to visualize the association of lysosomes to the parasitophorous vacuole membrane (PVM) as an example of visualizing host-pathogen interaction. We are convinced that this new tool will be helpful for a deeper understanding of the biology of thePlasmodiumliver stage.
Liver Receptor Homolog-1 (LRH-1/NR5A2) orchestrates hepatic inflammation and TNF-induced cell death
Authors: Lambrecht Rebekka , Eugenia Delgado M. , Gloe Vincent , Schuetz Karina , Plazzo Anna Pia , Franke Barbara , Phan Truong San , Fleming Jennifer , Mayans Olga , Brunner Thomas
Published: May 2023

Liver Receptor Homolog-1 (LRH-1/NR5A2) is a nuclear receptor that has been shown to promote apoptosis resistance in various tissues and disease contexts, however, its role in liver cell death remains unexplored. Deletion of LRH-1 in hepatocytes developed into a mild steatosis and inflammation already under steady-state conditions. Unexpectedly, hepatocyte-specific deletion of LRH-1 also resulted in a profound protection of mice from TNF-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes showed elevated NF-ⲕB activity, while LRH-1 overexpression inhibited NF-ⲕB activity. This inhibition was based on direct physical interaction of the ligand-binding domain of LRH-1 and the Rel homology domain of NF-ⲕB subunit RelA. Mechanistically, we found that increased transcription of anti-apoptotic NF-ⲕB target genes, together with proteasomal degradation of pro-apoptotic BIM via regeneration-driven EGF receptor signaling, prevented mitochondrial apoptosis, ultimately protecting mice from TNF-induced liver damage. Collectively, our study demonstrates that LRH-1 is a critical modulator of cell death and inflammation in the healthy and diseased liver.

Highlights

Hepatic LRH-1 deletion causes mild liver steatosis, fibrosis, and inflammation.

Female LRH-1-deficient mice are protected from TNF-induced liver damage.

LRH-1 interacts with NF-ⲕB and inhibits its activity.

LRH-1 deletion-provoked inflammation causes degradation of pro-apoptotic protein BIM.

Graphical abstract
Investigating the ATP binding pocket of CX3CL1 binding protein 2 usingin silicoapproach
Authors: Kumari Rimjhim , Kaur Satinder , Hora Rachna , Mishra Prakash Chandra
Published: May 2023

Plasmodium falciparum(Pf) causes the most fatal form of malaria owing to its ability to cytoadhere in the microvasculature of various organs in the body. In addition to the Pf erythrocyte membrane protein 1 (PfEMP1) family that binds diverse host receptors, CX3CL1 binding proteins 1 and 2 (CBP1 and 2) also bind the endothelial chemokine ‘CX3CL1’ to effect cytoadhesion of parasite infected erthrocytes. CBP2 is a multifaceted protein that binds nucleic acids, Pf skeleton binding protein (PfSBP1) and ATP. ATP binding to the cytoplasmic domain of CBP2 (cCBP2) induces structural changes in the protein, and hints at its role in cell signaling. In this study, we have attempted to identify the ATP binding pocket of CBP2 using anin silicoapproach. We have also delineated the type of interactions and amino acid residues that are likely to bind ATP. As CX3CL1 binding proteins are central to parasite biology, the obtained information is likely to form the basis for inhibitor and drug design against this molecule.
Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories
Authors: Wuestefeld Anika , Baumeister Hannah , Adams Jenna N. , de Flores Robin , Hodgetts Carl , Mazloum-Farzaghi Negar , Olsen Rosanna K. , Puliyadi Vyash , Tran Tammy T. , Bakker Arnold , Canada Kelsey L. , Dalton Marshall A. , Daugherty Ana M. , Joie Renaud La , Wang Lei , Bedard Madigan , Buendia Esther , Chung Eunice , Denning Amanda , del Mar Arroyo-Jiménez María , Artacho-Pérula Emilio , Irwin David J. , Ittyerah Ranjit , Lee Edward B. , Lim Sydney , del Pilar Marcos-Rabal María , de Onzoño Martin Maria Mercedes Iñiguez , Lopez Monica Munoz , de la Rosa Prieto Carlos , Schuck Theresa , Trotman Winifred , Vela Alicia , Yushkevich Paul , Amunts Katrin , Augustinack Jean C. , Ding Song-Lin , Insausti Ricardo , Kedo Olga , Berron David , Wisse Laura E.M.
Published: May 2023

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer’s disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations.

Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail.

Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually.

The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.
ESCRT-III-dependent adhesive and mechanical changes are triggered by a mechanism sensing paracellular diffusion barrier alteration inDrosophilaepithelial cells
Authors: de Bournonville Thomas Esmangart , Jaglarz Mariusz K. , Durel Emeline , Le Borgne Roland
Published: May 2023

Barrier functions of proliferative epithelia are constantly challenged by mechanical and chemical constraints. How epithelia respond to and cope with disturbances of the paracellular diffusion barrier to allow tissue integrity maintenance has been poorly characterized. Cellular junctions play an important role in this process and intracellular traffic contribute to their homeostasis. Here, we reveal that, inDrosophilapupal notum, alteration of the bi- or tricellular septate junctions (SJs) triggers a mechanism with two prominent outcomes. On one hand, there is an increase in the levels of E-cadherin, F- Actin and non-muscle myosin II in the plane of adherens junctions. On the other hand, β-integrin/Vinculin-positive cell contacts are reinforced along the lateral and basal membranes. We report that the weakening of SJ integrity, caused by the depletion of bi- or tricellular SJ components, reduces ESCRT-III/Vps32/Shrub-dependent degradation and promotes instead Retromer-dependent recycling of SJ components. The consequence of the reduction in Shrub-dependent degradation extends to other transmembrane protein cargoes. Consequently, this trigger increased levels of β- integrin, Crumbs and the Crumbs effectors β-Heavy Spectrin Karst. We propose a mechanism by which epithelial cells, upon sensing alterations in the paracellular diffusion barrier, target Shrub to adjust the degradation/recycling balance and thereby compensate for barrier defects while maintaining epithelial integrity.
Epigallocatechin Gallate Modulates Microglia Phenotype to Suppress Pro-Inflammatory Signalling Cues and Inhibit Phagocytosis
Authors: Regan Philip , Hole Katriona L , Sero Julia , Williams Robert J
Published: May 2023

Microglia are crucial players in the pathogenesis of late onset Alzheimer’s Disease (AD), with evidence for both deleterious and beneficial effects. Identifying interventions to modulate microglial responsiveness, to promote Amyloid β (Aβ) clearance, disrupt plaque formation or to dampen excessive inflammation has therapeutic potential. Bioavailable flavonoids such as the flavan 3-ols are of interest due to their antioxidant, metal chelating, signalling and anti-inflammatory potential. Primary microglia were treated with a series of structurally related flavanol 3-ols to assess effects on phagocytosis, cytokine release and transcriptional responses by RNA sequencing. Data indicated that the extent of hydroxylation and the presence of the galloyl moiety were strong determinants of flavan 3-ol activity. Epigallocatechin gallate (EGCG) was the most effective flavan-3-ol tested and strongly inhibited phagocytosis of Aβ independent of any metal chelating properties suggesting a more direct modulation of microglia responsiveness. EGCG was broadly anti-inflammatory, reducing cytokine release and downregulating transcription particularly of components of the microglia extracellular matrix such as MMP3 and SerpinB2. Collectively this brings new insight into the actions of flavonoids on microglial responsiveness with potential implications for the therapeutic use of EGCG and structurally related flavanol-3-ols in AD.
Evolutionary conservation of embryonic DNA methylome remodelling in distantly related teleost species
Authors: Ross Samuel E. , Vázquez-Marín Javier , Gert Krista R.B. , González-Rajal Álvaro , Dinger Marcel E. , Pauli Andrea , Martínez-Morales Juan Ramon , Bogdanovic Ozren
Published: May 2023

Methylation of cytosines in the CG context (mCG) is the most abundant DNA modification in vertebrates that plays crucial roles in cellular differentiation and identity. After fertilization, DNA methylation patterns inherited from parental gametes are remodelled into a state compatible with embryogenesis. In mammals, this is achieved through the global erasure and re-establishment of DNA methylation patterns. However, in non-mammalian vertebrates like zebrafish, no global erasure has been observed. To investigate the evolutionary conservation and divergence of DNA methylation remodelling in teleosts, we generated base resolution DNA methylome datasets of developing medaka and medaka-zebrafish hybrid embryos. In contrast to previous reports, we show that medaka display comparable DNA methylome dynamics to zebrafish with high gametic mCG levels (sperm: ∼90%; egg: ∼75%), and adoption of a paternal-like methylome during early embryogenesis, with no signs of prior DNA methylation erasure. We also demonstrate that non-canonical DNA methylation (mCH) reprogramming at TGCT tandem repeats is a conserved feature of teleost embryogenesis. Lastly, we find remarkable evolutionary conservation of DNA methylation remodelling patterns in medaka-zebrafish hybrids, indicative of compatible DNA methylation maintenance machinery in far-related teleost species. Overall, these results suggest strong evolutionary conservation of DNA methylation remodelling pathways in teleosts, which is distinct from the global DNA methylome erasure and reestablishment observed in mammals.