bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneity of novel APOER2 isoforms specific to Alzheimer’s disease impact cellular and synaptic states
Authors: Gallo Christina M. , Kistler Sabrina , Natrakul Anna , Labadorf Adam T. , Beffert Uwe , Ho Angela
Published: January 2023

Apolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimer’s disease (AD) related risk factor, APOE. Splicing of single exons in mouseApoer2regulates neuronal function and synaptic plasticity. However, the splicing landscape and function of human APOER2 isoforms in physiological and AD conditions remains unclear. Here, we identified over 200 unique humanAPOER2isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specificAPOER2isoforms suggestingAPOER2splicing is spatially regulated and altered in AD. We tested whether the AD-specificAPOER2transcripts have distinct functional properties, and demonstrated AD-specific APOER2 variants have altered cell surface expression, APOE-mediated receptor processing and synaptic changes which could contribute to neuronal dysfunction associated with AD pathogenesis.
Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease
Authors: Umerenkov Dmitry , Herbert Alan , Konovalov Dmitrii , Danilova Anna , Beknazarov Nazar , Kokh Vladimir , Fedorov Aleksandr , Poptsova Maria
Published: January 2023

Identifying roles for Z-flipons remains challenging given their dynamic nature. Here we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified Z-DNA sequences. We show Z-flipons are enriched in promoters and telomeres and overlap quantitative trait loci for RNA expression, RNA editing, splicing and disease associated variants. Surprisingly, many effects are mediated through Z-RNA formation. We describe Z-RNA motifs present in SCARF2, SMAD1 and CACNA1 transcripts and others in non-coding RNAs. We also provide evidence for another Z-RNA motif that likely enables an adaptive anti-viral intracellular defense through alternative splicing of KRAB domain zinc finger proteins. An analysis of OMIM and gnomAD predicted loss-of-function datasets reveals an overlap of predicted and experimentally validated Z-flipons with disease causing variants in 8.6% and 2.9% of mendelian disease genes respectively, with frameshift variants present in 22% of cases. The work greatly extends the number of phenotypes mapped to Z-flipon variants.
A Real-Time Analysis of Protein Transport via the Twin Arginine Translocation Pathway in Response to Different Components of the Protonmotive Forcein vivo
Authors: Zhou Wenjie , Hao Binhan , Bricker Terry M. , Theg Steven M.
Published: January 2023

The twin arginine translocation (Tat) pathway transports folded protein across the cytoplasmic membrane in bacteria, archaea, and across the thylakoid membrane in plants as well as the inner membrane in some mitochondria. In plant chloroplasts, the Tat pathway utilizes the protonmotive force (PMF) to drive protein translocation. However, in bacteria, it has been shown that Tat transport depends only on the Δψ component of PMFin vitro. To investigate the comprehensive PMF requirement inEscherichia coli, we have developed the first real-time assay to monitor Tat transport utilizing the NanoLuc Binary Technology (NanoBiT) inE. colispheroplasts. This luminescence assay allows for continuous monitoring of Tat transport with high-resolution, making it possible to observe subtle changes in transport in response to different treatments. By applying the NanoLuc assay, we report that, under acidic conditions, ΔpH, in addition to Δψ, contributes energetically to Tat transportin vivoinE. colispheroplasts. These results provide novel insight into the mechanism of energy utilization by the Tat pathway.
Injured worker outcomes after compensation system overhaul: an interrupted time series study
Authors: Lane Tyler J , Donato Michael Di , Collie Alex
Published: January 2023

Objective

In 2015, South Australia replaced its workers’ compensation system with the aim of improving return to work rates. We tested whether time off work among injured workers changed under the new system, as well as indicators of potential mechanisms.

Methods

We conducted a controlled interrupted time series using workers’ compensation claims data. The primary outcome was mean weeks of compensated disability duration. Secondary outcomes tested explanatory mechanisms: 1) claim volumes to determine whether the new system changed the makeup of claimants, and 2) mean employer report and insurer decision times to evaluate whether there had been changes in claim processing. Outcomes were aggregated into monthly units. South Australia was compared to six other Australian workers’ compensation systems. To test for moderation by condition type, disease claims were compared to injury claims and mental health claims to physical health claims.

Results

Disability duration and insurer decision time steadily declined before the RTW Act came into effect, but flatlined afterwards. Claim volumes did not change significantly. Employer report time initially increased but gradually decreased until it was lower than the counterfactual. There were non-significant increases in disability durations among injury claims compared to disease claims, and mental health claims compared to physical claims.

Conclusions

The increase in disability duration after the RTW Act took effect may be attributable to the disruption of implementing a new compensation system or the elimination of provisional liability entitlements that incentivised early decision making and provided early intervention.

KEY MESSAGES

What is already known on this topic

Workers’ compensation systems are a major determinant of injured worker recovery.

However, the specific mechanisms of how the compensation system influences outcomes are often opaque, which impedes the design of effective systems.

What this study adds

This interrupted time series study evaluates the effect of a new workers’ compensation system in South Australia, which was designed specifically to improve return to work rates.

Time off work increased relative to the counterfactual, which paralleled trends in the time for insurers to decide on liability.

How this study might affect research, practice, or policy

The findings highlight the importance of understanding how compensation systems influence injured workers outcomes and considering the entire claims process when designing new systems.
Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation
Authors: Courraud Julie , Russo Francesco , Themudo Gonçalo Espregueira , Laursen Susan Svane , Hougaard David M. , Cohen Arieh S. , Werge Thomas , Ernst Madeleine
Published: January 2023

Background

Large deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes.

Methods

Here, we used targeted metabolomics to compare neonatal dried blood spot samples from individuals clinically identified as carriers of a 3MB deletion at the chromosome 22q11.2 with unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers.

Results

We found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%) and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength.

Conclusions

Targeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis.
Deep learning-based algorithm versus physician judgement for diagnosis of myopathy and neuropathy from needle electromyography
Authors: Yoo Ilhan , Yoo Jaesung , Kim Dongmin , Youn Ina , Kim Hyodong , Youn Michelle , Won Jun Hee , Cho Woosup , Myong Youho , Kim Sehoon , Yu Ri , Kim Sung-Min , Kim Kwangsoo , Lee Seung-Bo , Kim Keewon
Published: January 2023

Electromyography is a valuable diagnostic procedure for diagnosing patients with neuromuscular diseases; however, it has some drawbacks. First, diagnosis using electromyography is subjective, and in some cases, there is the potential for inter-individual discrepancies. Second, it is a time- and effort-intensive process that requires expertise to yield accurate results. Recently, a deep learning algorithm shows effectiveness for the analysis of waveform data such as electrocardiography. To overcome limitations of electromyography, we developed a deep learning-based electromyography classification system and compared the performance of our deep learning model with that of six physicians. This study included 58 subjects who underwent electromyography and were finally confirmed as having myopathy or neuropathy, or to be in a normal state between June 2015 and July 2020 at Seoul National University Hospital. We developed a one-dimensional convolutional neural network algorithm and divide-and-vote system for diagnosing subjects. Diagnosis results with our deep learning model were compared with those of six physicians with experience in performing and interpreting electromyography. The accuracy, sensitivity, specificity, and positive predictive value of the deep learning model for diagnosis as to whether subjects have myopathy or neuropathy or normal were 0.875, 0.820, 0.904, and 0.820, respectively, whereas those for the physicians were 0.694, 0.537, 0.773, and 0.524, respectively. The area under the receiver operating characteristic curves of the deep learning model for predicting myopathy, neuropathy, and normal states was better than the averaged results of six physicians. Our study showed that deep learning could play a key role in reading electromyography and diagnosing patients with neuromuscular diseases. In the future, large prospective cohort studies incorporating diverse neuromuscular diseases can enable deep learning-based electrodiagnosis on behalf of physicians.
Single-cell Genome-and-Transcriptome sequencing without upfront whole-genome amplification reveals cell state plasticity of melanoma subclones
Authors: Theunis Koen , Vanuytven Sebastiaan , Rambow Florian , Brown Daniel , Van Der Haegen Michiel , Marin-Bejar Oskar , Rogiers Aljosja , Van Raemdonck Nina , Leucci Eleonora , Demeulemeester Jonas , Sifrim Alejandro , Marine Jean-Christophe , Voet Thierry
Published: January 2023

Single-cell multi-omics methods are enabling the study of cell state diversity, which is largely determined by the interplay of the genome, epigenome, and transcriptome. Here, we describe Gtag&T-seq, a genome-and-transcriptome sequencing (G&T-seq) protocol of the same single cells that omits whole-genome amplification (WGA) by using direct genomic tagmentation (Gtag). Gtag drastically decreases the cost and improves coverage uniformity at both the single-cell and pseudo-bulk level when compared to WGA-based G&T-seq. We also show that transcriptome-based DNA copy number inference has limited resolution and accuracy, underlining the importance of affordable multi-omic approaches. Moreover, applying Gtag&T-seq to a melanoma xenograft model before treatment and at minimal residual disease revealed differential cell state plasticity and treatment response between cancer subclones. In summary, Gtag&T-seq is a low-cost and accurate single-cell multi-omics method enabling the exploration of genetic alterations and their functional consequences in single cells at scale.
The junctional mechanosensor AmotL2 regulates YAP promotor accessibility
Authors: Mannion Aarren J. , Zhao Honglei , Zhang Yuanyuan , von Wright Ylva , Bergman Otto , Björck Hanna M. , Saharinen Pipsa , Holmgren Lars
Published: January 2023

Endothelial cells (ECs) are constantly exposed to mechanical forces in the form of fluid shear stress, extracellular stiffness, and cyclic strain. How these forces are sensed by ECs remains an understudied aspect in the homeostatic regulation of the circulatory system. Angiomotin-like 2 (AmotL2) is localised to EC junctions and is required for alignment and actin reorganisation under conditions of high shear stress. Here we show that AmotL2 crucially regulates transcription and promotor activity of the YAP gene. Functionally, density-dependent proliferation of ECsin vitroand proliferation of a subpopulation of ECs within the inner aortic arch, were both reliant on AmotL2 and Yap/Taz endothelial expressionin vivo. Mechanistically, depletion of AmotL2 led to altered nuclear morphology, chromatin accessibility and suppression of YAP-promotor activity through increased H3K27me3 mediated by the polycromb repressive complex component EZH2. Our data describe a previously unknown role for junctional mechanotransduction in shaping the epigenetic landscape and transcriptional regulation of YAP in vascular homeostasis.
The mitochondrial multi-omic response to exercise training across tissues
Authors: Amar David , Gay Nicole R , Jimenez-Morales David , Jean Beltran Pierre M , Ramaker Megan E , Raja Archana Natarajan , Zhao Bingqing , Sun Yifei , Marwaha Shruti , Gaul David , Hershman Steven G , Xia Ashley , Lanza Ian , Fernandez Facundo M , Montgomery Stephen B. , Hevener Andrea L. , Ashley Euan A. , Walsh Martin J , Sparks Lauren M , Burant Charles F , Rector R Scott , Thyfault John , Wheeler Matthew T. , Goodpaster Bret H. , Coen Paul M. , Schenk Simon , Bodine Sue C , Lindholm Maléne E. ,   the MoTrPAC Study Group
Published: January 2023

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.
Micromotion derived fluid shear stress mediates peri-electrode gliosis through mechanosensitive ion channels
Authors: Trotier Alexandre , Bagnoli Enrico , Walski Tomasz , Evers Judith , Pugliese Eugenia , Lowry Madeleine , Kilcoyne Michelle , Fitzgerald Una , Biggs Manus
Published: January 2023

Clinical applications for neural implant technologies are steadily advancing. Yet, despite clinical successes, neuroelectrode-based therapies require invasive neurosurgery and can subject local soft-tissues to micro-motion induced mechanical shear, leading to the development of peri-implant scaring. This reactive glial tissue creates a physical barrier to electrical signal propagation, leading to loss of device function. Although peri-electrode gliosis is a well described contributor to neuroelectrode failure, the mechanistic basis behind the initiation and progression of glial scarring remains poorly understood.

Here, we develop anin silicomodel of electrode-induced shear stress to evaluate the evolution of the peri-electrode fluid-filled void, encompassing a solid and viscoelastic liquid/solid interface. This model was subsequently used to inform anin vitroparallel-plate flow model of micromotion mediated peri-electrode fluid shear stress.

Ventral mesencephalic E14 rat embryonicin vitrocultures exposed to physiologically relevant fluid shear exhibited upregulation of gliosis-associated proteins and the overexpression of two mechanosensitive ion channel receptors, PIEZO1 and TRPA1, confirmedin vivoin a neural probe induced rat glial scar model. Finally, it was shownin vitrothat chemical inhibition/activation of PIEZO1 could exacerbate or attenuate astrocyte reactivity as induced by fluid shear stress and that this was mitochondrial dependant.

Together, our results suggests that mechanosensitive ion channels play a major role in the development of the neuroelectrode micromotion induced glial scar and that the modulation of PIEZO1 and TRPA1 through chemical agonist/antagonist may promote chronic electrode stabilityin vivo.

Graphical abstract

Highlights

Peri-electrode void progression is mediated by fluid flow shear stress

Oscillatory fluid flow shear stress replicates neuroelectrode glial scarring in vitro

Astrocyte PIEZO1 and TRPA1 are upregulated at the peri-electrode region in response to electrode micromotion

PIEZO1 pharmaceutical activation diminishes shear stress-induced gliosis

PIEZO1 chemical inhibition exacerbates gliosis and reduces mitochondrial functions
Spatio-temporal remodeling of extracellular matrix orients epithelial sheet folding
Authors: Tsuboi Alice , Fujimoto Koichi , Kondo Takefumi
Published: January 2023

Biological systems are inherently noisy; however, they produce highly stereotyped tissue morphology.Drosophilapupal wings show a highly stereotypic folding through uniform expansion and subsequent buckling of wing epithelium within a surrounding cuticle sac. The folding pattern produced by buckling is generally stochastic; it is thus unclear how buckling leads to stereotypic tissue folding of the wings. We found that the extracellular matrix (ECM) protein, Dumpy, guides the position and direction of buckling-induced folds. Dumpy anchors the wing epithelium to the overlying cuticle at specific tissue positions. Tissue-wide alterations of Dumpy deposition and degradation yielded different buckling patterns. In summary, we propose that spatio-temporal ECM remodeling shapes stereotyped tissue folding through dynamic interactions between the epithelium and its external structures.

One-Sentence Summary

Remodeling of extracellular matrix protein, Dumpy, guides epithelial tissue folding duringDrosophilawing development.
Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils
Authors: Li Jiang , Ruggiero-Ruff Rebecca E. , He Yuxin , Qiu Xinru , Lainez Nancy M. , Villa Pedro A. , Godzik Adam , Coss Djurdjica , Nair Meera G.
Published: January 2023

Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high fat diet-induced obesity. Compared to male mice, RELMα levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELMα treatment and eosinophil transfer rescued this phenotype. Single cell RNA-sequencing of the adipose stromal vascular fraction was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.
Oxygen-induced chromophore degradation in the photoswitchable red fluorescent protein rsCherry
Authors: Bui Thi Yen Hang , De Zitter Elke , Moeyaert Benjamien , Pecqueur Ludovic , Srinivasu Bindu Y , Economou Anastassios , Fontecave Marc , Van Meervelt Luc , Dedecker Peter , Pedre Brandán
Published: January 2023

Reversibly switchable monomeric Cherry (rsCherry) is a photoswitchable variant of the red fluorescent protein mCherry. We report that this protein gradually and irreversibly loses its red fluorescence in the dark over a period of months at 4°C and a few days at 37°C. We also find that its ancestor, mCherry, undergoes a similar fluorescence loss but at a slower rate. X-ray crystallography and mass spectrometry reveal that this is caused by the cleavage of thep-hydroxyphenyl ring from the chromophore and the formation of two novel types of cyclic structures at the remaining chromophore moiety. Overall, our work sheds light on a new process occurring within fluorescent proteins, further adding to the chemical diversity and versatility of these molecules.
Automated staging of zebrafish embryos with deep learning
Authors: Jones Rebecca A. , Renshaw Matthew J. , Devenport Danelle , Barry David J.
Published: January 2023

The zebrafish (Danio rerio), is an important biomedical model organism used in many disciplines. The phenomenon of developmental delay in zebrafish embryos has been widely reported as part of a mutant or treatment-induced phenotype. However, the detection and quantification of these delays is often achieved through manual observation with reference to staging guides, which is both time-consuming and subjective. We recently reported a machine learning-based classifier, capable of quantifying the developmental delay between two populations of zebrafish embryos. Here, we build on that work by introducing a deep learning-based model (KimmelNet) that has been trained to predict the age (hours post fertilisation) of populations of zebrafish embryos. We show that when KimmelNet is tested on 2D brightfield images of zebrafish embryos, the predictions generated agree closely with those expected from established approaches to staging. Random sampling of the test data demonstrate that KimmelNet can be used to detect developmental delay between two populations with high confidence based on as few as 100 images of each population. Finally, we show that KimmelNet generalises to previously unseen data, with limited transfer learning improving this performance significantly. With the ability to analyse tens of thousands of standard brightfield microscopy images on a timescale of minutes, we envisage that KimmelNet will be a valuable resource for the developmental biology community. Furthermore, the approach we have used could easily be adapted to generate models for other organisms.
DMRT1is a testis determining gene in rabbits and is also essential for female fertility
Authors: Dujardin Emilie , André Marjolaine , Dewaele Aurélie , Mandon-Pépin Béatrice , Poulat Francis , Frambourg Anne , Thépot Dominique , Jouneau Luc , Jolivet Geneviève , Pailhoux Eric , Pannetier Maëlle
Published: January 2023

DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, whereSRYis the testis-determining gene, remains ambiguous. So far, DMRT1 loss of function has been described in two mammalian species and induces different phenotypes: disorders of sex development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XYDMRT1-/-rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of theSOX9gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XYDMRT1-/-ovaries did not undergo meiosis and folliculogenesis. XXDMRT1-/-adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement ofDMRT1mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.
Prion-like characteristics of Hepatitis E virus ORF3 protein are associated with virus release and pathogenesis
Authors: Wang Yajing , Tian Houlu , Shi Na , Wu Chunyan , Huang Yaowei , Yang Yongling , Ding Qiang , Zheng Xu , Zhao Qin , Tuite Mick F. , Chen Hongying , Nan Yuchen
Published: January 2023

Hepatitis E virus (HEV) is a common causative agent of acute hepatitis. Due to the shortage of efficient in vitro model, the viral assembly and release processes are still poorly understood. In this study, we found that ORF3, an HEV structural protein showed prion-like properties. The prion domain (PrD) of yeast prion Sup35 could be functionally replaced by HEV-ORF3 and its candidate PrD (cPrD). A single amino acid substitution in the cPrD reduced the aggregation propensity of ORF3 and blocked the function of ORF3 in enhancing the stability of microtubules in HEV-infected cells, thus blocking virion release from the infected cells and resulting in reduced HEV pathogenicity in Mongolian gerbils. These data suggest that HEV-ORF3 is a novel functional prion-like protein which assembles into a filamentous structure for virion release, supporting the hypothesis that the self-propagating properties of prion proteins are widely exploited as epigenetic information carriers in nature.
Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex
Authors: Leech Robert , De Wael Reinder Vos , Vasa Frantisek , Xu Ting , Benn R. Austin , Scholz Robert , Braga Rodrigo M. , Milham Michael , Royer Jessica , Bernhardt Boris , Jones Emily , Jefferies Elizabeth , Margulies Daniel , Smallwood Jonathan
Published: January 2023

Recent theories of cortical organisation maintain that important features of brain function emerge through the spatial arrangement of regions of cortex. For example, areas of association cortex are located in regions of cortex furthest from sensory and motor cortex. Association cortex is also ‘interdigitated’ since adjacent regions can have relatively different patterns of functional connectivity. It is assumed that topographic properties such as distance between cortical regions constrain their functions. For example, large distances between association and sensory and motor systems may enable these areas of cortex to maintain differentiable neural patterns, while an interdigitated organisation may enable association cortex to contain many functional systems in a relatively compact space. We currently lack a formal understanding of how spatial organisation impacts brain function, limiting the ability to leverage cortical topography to facilitate better interpretations of a regions function. Here we use variograms, a quantification of spatial autocorrelation, to develop a cortex-wide profile of how functional similarity changes as a function of the distance between regions. We establish that function changes gradually within sensory and motor cortex as the distance between regions increases, while in association cortex function changes rapidly over shorter distances. Subsequent analysis suggests these differential classes of spatial dependency are related to variation in intracortical myelin between sensory motor and association cortex. Our study suggests primary and association cortex are differentiated by the degree to which function varies over space, emphasising the need to formally account for spatial properties when estimating a system’s contribution to cognition and behaviour.

Significance statement

The spatial arrangements of regions in the human brain are hypothesised to underpin important features of a brain regions function. Currently, however, we lack a formal understanding of how topography shapes brain function, limiting our ability to leverage topographical perspectives to inform better theories of brain function. Here we use a formal mathematical approach to establish that in regions of association cortex function varies across the cortex more rapidly than in sensory and motor cortex, a phenomenon linked to levels of intracortical myelin. This result highlights how topographical features distinguish between cortical regions with different functional profiles and provides a formal account of how spatial differences support different features of brain function.
Transplantation-based screen uncovers inducers of muscle progenitor cell engraftment across vertebrate species
Authors: Tavakoli Sahar , Adatto Isaac , Kakhki Sara Ashrafi , Chan Victoria S , Fotowat Haleh , Gähwiler Eric , Manning Margot E , Messemer Kathleen A , Rangan Apoorva , Yang Song , Wagers Amy J , Zon Leonard I
Published: January 2023

Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited due to the deleterious effects of cell expansionin vitroand consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small molecule screening platform employing zebrafish and mouse, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to identify those that could increase myogenic engraftmentin vivoin zebrafish and mice. Two lipids, lysophosphatidic acid (LPA) and niflumic acid (NFA), are linked to activation of intracellular calcium ion flux, which showed conserved, dose-dependent and synergistic effects in promoting muscle engraftment across these vertebrate species.
Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Authors: Podolsky Michael J. , Kheyfets Benjamin , Pandey Monika , Beigh Afaq H. , Yang Christopher D. , Valenzuela Carlos Lizama , Datta Ritwik , Wolters Paul J. , McManus Michael T. , Qi Ling , Atabai Kamran
Published: January 2023

Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, we executed unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discovered a previously unappreciated mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism is dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of SEL1L. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus cell-autonomous, rheostatic collagen clearance is a previously unidentified pathway of tissue homeostasis.
Sex-biased expression is associated with chromatin state inD. melanogasterandD. simulans
Authors: Nanni Adalena V. , Martinez Natalie , Graze Rita , Morse Alison , Newman Jeremy R. B. , Jain Vaibhav , Vlaho Srna , Signor Sarah , Nuzhdin Sergey V. , Renne Rolf , McIntyre Lauren M.
Published: January 2023

We propose a new model for the association of chromatin state and sex-bias in expression. We hypothesize enrichment of open chromatin in the sex where we see expression bias (OS) and closed chromatin in the opposite sex (CO). In this study ofD. melanogasterandD. simulanshead tissue, sex-bias in expression is associated with H3K4me3 (open mark) in males for male-biased genes and in females for female-biased genes in both species. Sex-bias in expression is also largely conserved in direction and magnitude between the two species on the X and autosomes. In male-biased orthologs, the sex-bias ratio is more divergent between species if both species have H3K27me2me3 marks in females compared to when either or neither species has H3K27me2me3 in females. H3K27me2me3 marks in females are associated with male-bias in expression on the autosomes in both species, but on the X only inD. melanogaster. In female-biased orthologs the relationship between the species for the sex-bias ratio is similar regardless of the H3K27me2me3 marks in males. Female-biased orthologs are more similar in the ratio of sex-bias than male-biased orthologs and there is an excess of male-bias in expression in orthologs that gain/lose sex-bias. There is an excess of male-bias in sex-limited expression in both species suggesting excess male-bias is due to rapid evolution between the species. The X chromosome has an enrichment in male-limited H3K4me3 in both species and an enrichment of sex-bias in expression compared to the autosomes.
Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin2G protein-coupled receptor
Authors: Babin Katie M. , Karim Jordan A. , Gordon Peyton H. , Lennon James , Dickson Alex , Pioszak Augen A.
Published: January 2023

The signaling peptides adrenomedullin 2/intermedin (AM2/IMD), adrenomedullin (AM), and CGRP have overlapping and distinct functions in the cardiovascular, lymphatic, and nervous systems by activating three shared receptors comprised of the class B GPCR CLR in complex with a RAMP1, −2, or −3 modulatory subunit. Here, we report that AM2/IMD, which is thought to be a non-selective agonist, is kinetically selective for CLR-RAMP3, known as the AM2R. AM2/IMD-AM2R elicited substantially longer duration cAMP signaling than the eight other peptide-receptor combinations due to AM2/IMD slow off-rate binding kinetics. The regions responsible for the slow off-rate were mapped to the AM2/IMD mid-region and the RAMP3 extracellular domain. MD simulations revealed how these bestow enhanced stability to the complex. Our results uncover AM2/IMD-AM2R as a cognate pair with unique temporal features, define the mechanism of kinetic selectivity, and explain how AM2/IMD and RAMP3 collaborate to shape the signaling output of a clinically important GPCR.
Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas
Authors: Marley Andrew R. , Williams Kyle B. , Tibbitts Justin , Moertel Christopher L. , Johnson Kimberly J. , Linden Michael A. , Largaespada David A. , Marcotte Erin L.
Published: January 2023

Objective

In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model.

Results

We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days,P=0.56) or supplemented (177 days,P=0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P=0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P=0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.
The TNFΔAREmouse as a model of intestinal fibrosis
Authors: Steiner Calen A , Koch Samuel D , Evanoff Tamara , Welch Nichole , Kostelecky Rachael , Callahan Rosemary , Murphy Emily M , Hall Caroline H T , Lu Sizhao , Weiser-Evans Mary CM , Cartwright Ian M , Colgan Sean P
Published: January 2023

Background & Aims

Crohn’s disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis. This is in part due to lack of high-fidelity biomimetic models to enhance understanding and drug development. There is a need to developin vivomodels of inflammatory bowel disease-related intestinal fibrosis. We sought to determine if the TNFΔAREmouse, a model of ileal inflammation, may also develop intestinal fibrosis.

Methods

Several clinically relevant outcomes were studied including features of structural fibrosis, histological fibrosis, and gene expression. These include the use of a luminal casting technique we developed, traditional histological outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNFΔAREmice as well as in cohorts of numerous ages.

Results

At ages of 24+ weeks, TNFΔAREmice develop structural, histological, and genetic changes of ileal fibrosis. Genetic expression profiles have changes as early as six weeks, followed by histological changes occurring as early as 14-15 weeks, and overt structural fibrosis delayed until after 24 weeks.

Discussion

The TNFΔAREmouse is a viable and highly tractable model of intestinal fibrosis. This model and the techniques employed can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.
Active compensation for changes inTDH3expression mediated by direct regulators ofTDH3inSaccharomyces cerevisiae
Authors: Vande Zande Pétra , Wittkopp Patricia J.
Published: January 2023

Genetic networks are surprisingly robust to perturbations caused by new mutations. This robustness is conferred in part by compensation for loss of a gene’s activity by genes with overlapping functions, such as paralogs. Compensation occurs passively when the normal activity of one paralog can compensate for the loss of the other, or actively when a change in one paralog’s expression, localization, or activity is required to compensate for loss of the other. The mechanisms of active compensation remain poorly understood in most cases. Here we investigate active compensation for the loss or reduction in expression of theSaccharomyces cerevisiaegeneTDH3by its paralogsTDH1andTDH2. TDH1andTDH2are upregulated in a dose-dependent manner in response to reductions inTDH3by a mechanism requiring the shared transcriptional regulators Gcr1p and Rap1p. Other glycolytic genes regulated by Rap1p and Gcr1p show changes in expression similar toTDH2, suggesting that the active compensation byTDH3paralogs is part of a broader homeostatic response mediated by shared transcriptional regulators.
Draft Genome Sequence ofPedococcussp. Strain 5OH_020 Isolated from California Grassland Soil
Authors: Green Myka A. , Alvarez-Aponte Zoila I. , Trotter Valentine V. , Taga Michiko E.
Published: January 2023

The draft genome sequence of the soil bacteriumPedococcussp. 5OH_020, isolated on a natural vitamin B12analog, contains 4.4 Mbp with 4,108 protein-coding genes. Its genome encodes B12-dependent enzymes including methionine synthase and class II ribonucleotide reductase. Taxonomic analysis suggests it is a novel species within the genusPedococcus.
Cuticular profiling of insecticide resistantAedes aegypti
Authors: Jacobs Ella , Chrissian Christine , Rankin-Turner Stephanie , Wear Maggie , Camacho Emma , Scott Jeff G. , Broderick Nichole A. , McMeniman Conor J. , Stark Ruth E. , Casadevall Arturo
Published: January 2023

Insecticides have made great strides in reducing the global burden of vector-borne disease. Nonetheless, serious public health concerns remain because insecticide-resistant vector populations continue to spread globally. To circumvent insecticide resistance, it is essential to understand all contributing mechanisms. Contact-based insecticides are absorbed through the insect cuticle, which is comprised mainly of chitin polysaccharides, cuticular proteins, hydrocarbons, and phenolic biopolymers sclerotin and melanin. Cuticle interface alterations can slow or prevent insecticide penetration in a phenomenon referred to as cuticular resistance. Cuticular resistance characterization of the yellow fever mosquito,Aedes aegypti, is lacking. In the current study, we utilized solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy, gas chromatography/mass spectrometry (GC-MS), and transmission electron microscopy (TEM) to gain insights into the cuticle composition of congenic cytochrome P450 monooxygenase insecticide resistant and susceptibleAe. aegypti. No differences in cuticular hydrocarbon content or phenolic biopolymer deposition were found. In contrast, we observed cuticle thickness of insecticide resistantAe. aegyptiincreased over time and exhibited higher polysaccharide abundance. Moreover, we found these local cuticular changes correlated with global metabolic differences in the whole mosquito, suggesting the existence of novel cuticular resistance mechanisms in this major disease vector.
Biophysical modeling with variational autoencoders for bimodal, single-cell RNA sequencing data
Authors: Carilli Maria , Gorin Gennady , Choi Yongin , Chari Tara , Pachter Lior
Published: January 2023

We motivate and presentbiVI, which combines the variational autoencoder framework ofscVIwith biophysically motivated, bivariate models for nascent and mature RNA distributions. While previous approaches to integrate bimodal data via the variational autoencoder framework ignore the causal relationship between measurements,biVImodels the biophysical processes that give rise to observations. We demonstrate through simulated benchmarking thatbiVIcaptures cell type structure in a low-dimensional space and accurately recapitulates parameter values and copy number distributions. On biological data,biVIprovides a scalable route for identifying the biophysical mechanisms underlying gene expression. This analytical approach outlines a generalizable strateg for treating multimodal datasets generated by high-throughput, single-cell genomic assays.
Coupling During Collective Cell Migration is Controlled by a Vinculin Mechanochemical Switch
Authors: Shoyer T. Curtis , Gates Evan M. , Cabe Jolene I. , Conway Daniel E. , Hoffman Brenton D.
Published: January 2023

Collective cell migration (CCM) plays important roles in development, physiological, and pathological processes. A key feature of CCM is the dynamic mechanical coupling between cells, which enables both long-range coordination and local rearrangements. This coupling requires the ability of cell adhesions to adapt to forces. Recent efforts have identified key proteins and implicated cellular-scale mechanical properties, but how key proteins give rise to these larger-scale mechanical processes is unclear. Using force-sensitive biosensors, cell migration assays, and molecular clutch models, we sought a molecular understanding of adhesion strengthening that could bridge this gap. We found that the mechanical linker protein vinculin bears substantial loads at AJs, FAs, and in the cytoplasm during epithelial sheet migration, and we identified a switch-like residue on vinculin that regulates its conformation and loading at the AJs during CCM. In vinculin KO-rescue, this switch jointly controlled the speed and coupling length-scale of CCM, which suggested changes in adhesion-based friction. To test this, we developed molecularly detailed friction clutch models of the FA and AJ. They show that open, loaded vinculin increases friction in adhesive structures, with larger affects observed in AJs. Thus, this work elucidates how load-bearing linker proteins can be regulated to alter mechanical properties of cells and enable rapid tuning of mechanical coupling in CCM.
The exon junction complex component EIF4A3 is essential for mouse and human cortical progenitor mitosis and neurogenesis
Authors: Lupan Bianca M. , Solecki Rachel A. , Musso Camila Manso , Alsina Fernando C. , Silver Debra L.
Published: January 2023

Mutations in components of the exon junction complex (EJC) are associated with neurodevelopment and disease. In particular, reduced levels of the RNA helicaseEIF4A3cause Richieri-Costa-Pereira Syndrome (RCPS) and CNVs are linked to intellectual disability. Consistent with this,Eif4a3haploinsufficient mice are microcephalic. Altogether, this implicates EIF4A3 in cortical development; however, the underlying mechanisms are poorly understood. Here, we use mouse and human models to demonstrate that EIF4A3 promotes cortical development by controlling progenitor mitosis, cell fate, and survival.Eif4a3haploinsufficiency in mice causes extensive cell death and impairs neurogenesis. UsingEif4a3;p53compound mice, we show that apoptosis is most impactful for early neurogenesis, while additional p53-independent mechanisms contribute to later stages. Live imaging of mouse and human neural progenitors revealsEif4a3controls mitosis length, which influences progeny fate and viability. These phenotypes are conserved as cortical organoids derived from RCPS iPSCs exhibit aberrant neurogenesis. Finally, using rescue experiments we show that EIF4A3 controls neuron generation via the EJC. Altogether, our study demonstrates that EIF4A3 mediates neurogenesis by controlling mitosis duration and cell survival, implicating new mechanisms underlying EJC-mediated disorders.

Summary statement

This study shows that EIF4A3 mediates neurogenesis by controlling mitosis duration in both mouse and human neural progenitors, implicating new mechanisms underlying neurodevelopmental disorders.