bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting intestinal healing by exclusive enteral nutrition with TGF-β in a mouse model of colitis
Authors: Boumessid Kawthar , Lacroix Vickie , Ovtchinnikova Ekaterina , Quaranta Nicaise Muriel , Roy Maryline , Dumay Anne , Thenet Sophie , Carriere Marie , Mas Emmanuel , Barreau Frédérick
Published: September 2023

Background and aims

Exclusive Enteral Nutrition (EEN) is the first line of treatment for pediatric Crohn’s disease (CD), but its mechanisms of action remain poorly understood. We studied EEN nutritional composition and TGF-β effect in a mouse model of colitis, as well as the role of intestinal microbiota.

Methods

Mice were treated with Dextran Sulfate Sodium (DSS) during 5 days to induce colitis, until the inflammatory peak (day 7) or gut restitution (day 14). After DSS treatment, some of them received EEN formula such as Modulen IBD® (DM mice) or Infatrini Peptisorb® (DINF mice), with TGF-β supplementation or neutralization, and clinical inflammation was evaluated. After sacrifice, macroscopic and microscopic inflammation were analyzed, as well as intestinal permeability (IP). The composition of mucosal colonic microbiota was analyzed and fecal microbiota transplantation was performed to evaluate its capacity to mediate anti-inflammatory and pro-regenerative effect. Colonic crypts from DSS and EEN mice were cultured as 3D organoids and cellular properties were analyzed.

Results

DSS mice developed colitis, as evidenced by the weight loss and clinical inflammation. It was accompanied by macroscopic inflammation such as colon thickness and edemas, and an elevated IP. In contrast, EEN mice with TGF-β formula present faster weight recovery and decreased inflammatory parameters, with a normalized IP, suggesting gut restitution and functionality. These functional improvements were not obtained for EEN mice without TGF-β formula. Moreover, EEN with Modulen IBD® (DM mice) modified the microbiota in comparison to DSS condition and attenuated inflammation. In addition, the organoids from DM mice colonic crypts treated had an enhanced survival, and re-epithelialization capacity.

Conclusions

Both EEN formula have anti-inflammatory properties, certainly by the nutritional composition. However, TGF-β plays a significant role in intestinal restitution and restoring barrier function. These beneficial effects are partly mediated by the microbiota to maintain gut homeostasis.
Methods for tagging an ectoparasite, the salmon louseLepeophtheirus salmonis
Authors: Folk Alexius , Mennerat Adèle
Published: September 2023

ABSTRACT

Monitoring individuals within populations is a cornerstone in evolutionary ecology, yet individual tracking of invertebrates and particularly parasitic organisms remains rare. To address this gap, we describe here a method for attaching radio frequency identification (RFID) tags to individual adult females of a marine ectoparasite, the salmon louseLepeophtheirus salmonis. Comparing two alternative types of glue, we found that one of them (2-octyl cyanoacrylate,2oc) gave a significantly higher tag retention rate than the other (ethyl 2-cyanoacrylate,e2c). This glue comparison test also resulted in a higher loss rate of adult ectoparasites from the population where tagging was done using2oc, but this included males not tagged and thus could also suggest a mere tank effect. Corroborating this, a more extensive analysis using data collected over two years showed no significant difference in mortality after repeated exposure to the2ocglue, nor did it show any significant effect of the tagging procedure on the reproduction of female salmon lice. The proportion of RFID-tagged individuals followed a negative exponential decline, with tag retention among the living female population generally high. The projected retention was found to be about 88% after 30 days or 80% after 60 days, although one of the four batches of glue used, purchased from a different supplier, appeared to give significantly lower tag retention and with greater initial loss (74% and 60% respectively). Overall, we find that RFID tagging is a simple and effective technology that enables documenting individual life histories for invertebrates of a suitable size, including marine and parasitic species, and that it can be used over long periods of study.
Motor neuron activity induces proteomic stress in the target muscle
Authors: Srivastav Saurabh , van der Graaf Kevin , Jonnalagadda Prisha C. , Thawani Maanvi , McNew James A. , Stern Michael
Published: September 2023

Several lines of evidence demonstrate that increased neuronal excitability can enhance proteomic stress. For example, epilepsy can enhance the proteomic stress caused by the expression of certain aggregation-prone proteins implicated in neurodegeneration. However, unanswered questions remain concerning the mechanisms by which increased neuronal excitability accomplishes this enhancement. Here we test whether increasing neuronal excitability at a particular identified glutamatergic synapse, the Drosophila larval neuromuscular junction, can enhance the proteomic stress caused by mutations in the ER fusion geneatlastin(atl). It was previously shown that larval muscle from theatl2null mutant is defective in autophagy and accumulates protein aggregates containing ubiquitin (poly-UB aggregates). To determine if increased neuronal excitability might enhance the increased proteomic stress caused byatl2, we activated theTrpA1-encoded excitability channel within neurons. We found that TrpA1 activation had no effect on poly-UB aggregate accumulation in wildtype muscle, but significantly increased poly-UB aggregate number inatl2muscle. Previous work has shown thatatlloss from either neuron or muscle increases muscle poly-UB aggregate number. We found that neuronal TrpA1 activation enhanced poly-UB aggregate number whenatlwas removed from muscle, but not from neuron. Neuronal TrpA1 activation enhanced other phenotypes conferred by muscleatlloss, such as decreased pupal size and decreased viability. Taken together, these results indicate that the proteomic stress caused by muscleatlloss is enhanced by increasing neuronal excitability.
SpyMask Enables Combinatorial Assembly of Bispecific Binders
Authors: Driscoll Claudia L. , Keeble Anthony H. , Howarth Mark
Published: September 2023

Bispecific antibodies are a successful and expanding therapeutic class, bridging two cell-types or engaging two different molecules on the same cell. Bispecifics unlock avenues towards synergy, resistance evasion, and signaling bias. Standard approaches to generate bispecifics are complicated by the need for disulfide reduction/oxidation or cloning of each binder molecule in two different formats. Here we present a modular approach to bispecifics using SpyTag/SpyCatcher spontaneous amidation, where all binders are cloned in the same format, bearing a SpyTag. Two SpyTag-fused antigen-binding modules can be precisely conjugated onto DoubleCatcher, a tandem SpyCatcher where the second Catcher is unreactive until unveiling of reactivity using site-specific protease. Assembly on DoubleCatcher is efficient in phosphate-buffered saline at 37 °C, with half-times less than 5 min for both SpyCatcher arms and over 97% bispecific homogeneity. We engineer a panel of DoubleCatchers, locked through disulfide bonds to direct binders to project in different directions from the hub. We establish a generalized methodology for one-pot assembly and purification of bispecifics in 96-well plate format. A panel of Fab, affibody or nanobody binders recognizing different sites on HER2 were coupled to DoubleCatcher, revealing unexpected combinations with anti-proliferative or pro-proliferative activity on HER2-addicted cancer cells. Bispecific activity depended sensitively on both the order of the binders within the assembly and the geometry of DoubleCatcher scaffolds. These findings support the need for straightforward assembly in different formats. SpyMask provides a simple and scalable tool to discover synergy in bispecific activity, through modulating receptor organization and geometry.
A Stochastic Programming Approach to the Antibiotics Time Machine Problem
Authors: Mesüm Oğuz , Atilgan Ali Rana , Kocuk Burak
Published: September 2023

Antibiotics Time Machine is an important problem to understand antibiotic resistance and how it can be reversed. Mathematically, it can be modelled as follows: Consider a set of genotypes, each of which contain a set of mutated and unmutated genes. Suppose that a set of growth rate measurements of each genotype under a set of antibiotics are given. The transition probabilities of a ‘realization’ of a Markov chain associated with each arc under each antibiotic are computable via a predefined function given the growth rate realizations. The aim is to maximize the expected probability of reaching to the genotype with all unmutated genes given the initial genotype in a predetermined number of transitions, considering the following two sources of uncertainties: i) the randomness in growth rates, ii) the randomness in transition probabilities, which are functions of growth rates. We develop stochastic mixed-integer linear programming and dynamic programming approaches to solve static and dynamic versions of the Antibiotics Time Machine Problem under the aforementioned uncertainties. We adapt a Sample Average Approximation approach that exploits the special structure of the problem and provide accurate solutions that perform very well in an out-of-sample analysis.
Hmgb2 improves astrocyte to neuron conversion by increasing the chromatin accessibility of genes associated with neuronal maturation in a proneuronal factor-dependent manner
Authors: Maddhesiya Priya , Lepko Tjasa , Steiner-Mezzardi Andrea , Schwarz Veronika , Merl-Pham Juliane , Berger Finja , Hauck Stefanie M. , Ronfani Lorenza , Bianchi Marco , Masserdotti Giacomo , Götz Magdalena , Ninkovic Jovica
Published: September 2023

Background

Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding the influence of the injury-induced neuroinflammatory environment and released growth factors on the direct conversion process.

Results

We established a newin vitroculture system of postnatal astrocytes without epidermal growth factor that reflects the direct conversion rate in the injured, neuroinflammatory environmentin vivo. We demonstrated that the growth factor combination corresponding to the injured environment defines the ability of glia to be directly converted to neurons. Using this culture system, we showed that chromatin structural protein high mobility group box 2 (HMGB2) regulates the direct conversion rate downstream of the growth factor combination. We further demonstrated that Hmgb2 cooperates with neurogenic fate determinants, such as Neurog2, in opening chromatin at the loci of genes regulating neuronal maturation and synapse formation. Consequently, early chromatin rearrangements occur during direct fate conversion and are necessary for full fate conversion.

Conclusions

Our data demonstrate novel growth factor-controlled regulation of gene expression during direct fate conversion. This regulation is crucial for proper maturation of induced neurons and could be targeted to improve the repair process.
Population-Level Genetic Variation Shapes Generative Brain Mechanisms
Authors: Monaghan Alicja , Akarca Danyal , Astle Duncan E.
Published: September 2023

The structural organisation of the human brain emerges probabilistically as we develop. Due to the inherent complexity of the human brain, understanding the forces that shape this probabilistic emergence remains one of the central challenges of systems theory and neuroscience. Across 2153 children (9-11 years old) we used a computational model to simulate the formation of structural brain connectivity, conceptualised as a trade-off between the cost of new connections η and their topological value γ. We then triangulated this population-level neuroimaging and computational modelling with genomics. For each participant we assessed their genetic propensity for cognitive ability by calculating polygenic scores. Modelled parameters differed systematically for participants depending upon their genetic propensity. Those with the highest genetic propensity had a significantly weaker η term – put simply, their networks emerged with a weaker distance penalty. Strikingly, this softer distance penalty produces more stochastic, diverse, and efficient networks. Furthermore, across the sample, overlapping biological and cellular pathways between polygenic scores and each child’s optimal η-γ trade-off emerged. This application of computational modelling demonstrates a converging genomic basis for structural brain development and cognitive ability across the population, providing a mechanistic explanation of how and why characteristic network topologies emerge from children at the extreme distributions of polygenic scores, and why they might predict cognitive ability.
Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms
Authors: Alcala Nicolas , Voegele Catherine , Mangiante Lise , Sexton-Oates Alexandra , Clevers Hans , Fernandez-Cuesta Lynnette , Dayton Talya L. , Foll Matthieu
Published: September 2023

Background

Organoids are three-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types.

Results

We have generated the first multi-omic dataset (whole-genome sequencing, WGS, and RNA-sequencing, RNA-seq) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n= 12; 6 grade 1, 6 grade 2), and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n= 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n= 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time-points), for a total ofn= 47 RNA-seq andn= 33 WGS. We here provide quality control for each technique, and provide the raw and processed data as well as all scripts for genomic analyses to ensure an optimal re-use of the data. In addition, we report somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random-forest classifier to detect variants in tumor-only RNA-seq.

Conclusions

This dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases.
Automatic Ploidy Prediction and Quality Assessment of Human Blastocyst Using Time-Lapse Imaging
Authors: Rajendran Suraj , Brendel Matthew , Barnes Josue , Zhan Qiansheng , Malmsten Jonas E. , Zisimopoulos Pantelis , Sigaras Alexandros , Ofori-Atta Kwabena , Meseguer Marcos , Miller Kathleen A , Hoffman David , Rosenwaks Zev , Elemento Olivier , Zaninovic Nikica , Hajirasouliha Iman
Published: September 2023

Assessing fertilized human embryos is crucial for in vitro-fertilization (IVF), a task being revolutionized by artificial intelligence and deep learning. Existing models used for embryo quality assessment and chromosomal abnormality (ploidy) detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we developed and compared various embryo ploidy status prediction models across distinct embryo development stages. We present BELA (Blastocyst Evaluation Learning Algorithm), a state-of-the-art ploidy prediction model surpassing previous image- and video-based models, without necessitating subjective input from embryologists. BELA uses multitask learning to predict quality scores that are used downstream to predict ploidy status. By achieving an AUC of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists’ manual scores. While not a replacement for preimplantation genetic testing for aneuploidy (PGT-A), BELA exemplifies how such models can streamline the embryo evaluation process, reducing time and effort required by embryologists.
Sexually discordant selection is associated with trait specific morphological changes and a complex genomic response
Authors: Audet Tyler , Krol Joelle , Pelletier Katie , Stewart Andrew D. , Dworkin Ian
Published: September 2023

Sexes often have differing fitness optima, potentially generating intra-locus sexual conflict, as each sex bears a genetic ‘load’ of alleles beneficial to the other sex. One strategy to evaluate conflict in the genome is to artificially select populations discordantly, against established sexual dimorphism, reintroducing attenuated conflict. We investigate a long-term artificial selection experiment reversing sexual size dimorphism inDrosophila melanogasterduring ∼350 generations of sexually discordant selection. We explore morphological and genomic changes to identify loci under selection between the sexes in discordantly and concordantly size selected treatments. Despite substantial changes to overall size, concordant selection maintained ancestral sexual dimorphism. However, discordant selection altered size dimorphism in a trait-specific manner. We observe multiple, possible soft selective sweeps in the genome, with size related genes showing signs of selection. Patterns of genomic differentiation between the sexes within lineages identified potential sites maintained by sexual conflict. One discordant selection lineage shows a pattern of elevated genomic differentiation on chromosome 3L, consistent with the maintenance of sexual conflict. Our results suggest measurable signs of conflict and differentially segregating alleles between the sexes due to discordant selection.
Electrophoresis-Based Approach for Characterizing Dendrimer-Protein Interactions: A Proof-of-Concept Study
Authors: Douglas-Green Simone A. , Aleman Juan A. , Hammond Paula T.
Published: September 2023

Improving the clinical translation of nanomedicine requires better knowledge about how nanoparticles interact with biological environments. As researchers are recognizing the importance of understanding the protein corona and characterizing how nanocarriers respond in biological systems, new tools and techniques are needed to analyze nanocarrier-protein interactions, especially for smaller-size (<10nm) nanoparticles like polyamidoamine (PAMAM) dendrimers. Here we developed a streamlined, semi-quantitative approach to assess dendrimer-protein interactions using a non-denaturing electrophoresis technique combined with mass spectrometry. With this protocol, we detect fluorescently tagged dendrimers and proteins simultaneously, enabling us to analyze when dendrimers migrate with proteins. We found PAMAM dendrimers mostly interact with complement proteins, particularly C3 and C4a, which aligns with previously published data, verifying our approach can be used to isolate and identify dendrimer-protein interactions.

Abstract Figure
Recording neural reward signals in the real-world using mobile-EEG and augmented reality
Authors: Stringfellow Jaleesa , Liran Omer , Lin Mei-Heng , Baker Travis E.
Published: September 2023

The electrophysiological response to rewards recorded during laboratory-based tasks has been well documented over the past two decades, yet little is known about the neural response patterns in ‘real-world’ settings. To address this issue, we combined a mobile-EEG system with an augmented reality headset (which blends high definition “holograms” within the real-world) to record event-related brain potentials (ERP) while participants navigated an operant chamber to find rewards. 25 participants (age = 18-43, Male=6, Female=19) were asked to choose between two floating holograms marking a west or east goal-location in a large room, and once participants reached the goal location, the hologram would turn into a reward (5 cents) or no-reward (0 cents) cue. Following the feedback cue, participants were required to return to a hologram marking the start location, and once standing in it, a 3 second counter hologram would initiate the next trial. This sequence was repeated until participants completed 200 trials. Consistent with previous research, reward feedback evoked the reward positivity, an ERP component believed to index the sensitivity of the anterior cingulate cortex to reward prediction error signals. The reward positivity peaked around 235ms post-feedback with a maximal at channel FCz (M=-2.60μV, SD=1.73μV) and was significantly different than zero (p < 0.01). At a behavioral level, participants took approximately 3.38 seconds to reach the goal-location and exhibited a general lose-shift (68.3% ± 3.5) response strategy and were slightly slower to return to the start location following negative feedback (2.43 sec) compared to positive feedback (2.38 sec), evidence of post-error slowing. Overall, these findings provide the first evidence that combining mobile-EEG with augmented reality technology is a feasible solution to enhance the ecological validity of human electrophysiological studies of goal-directed behavior and a step towards a new era of human cognitive neuroscience research that blurs the line between laboratory and reality.
Identifying residues in unfolded whole proteins with a nanopore: a theoretical model based on linear inequalities
Authors: Sampath G.
Published: September 2023

A theoretical model is proposed for the identification of individual amino acids (AAs) in an unfolded whole protein’s primary sequence. It is based in part on a recent report (Nat. Biotech. 41, 1130–1139, 2023) that describes the unfolding and translocation of whole proteins at constant speed through a biological nanopore (alpha-Hemolysin) of length 5 nm with a residue dwell time inside the pore of ∼10 μs. Here current blockade levels in the pore due to the translocating protein are assumed to be measured with a limited precision of 70 nm3and a bandwidth of 20 KHz for measurement with a low-bandwidth detector. Exclusion volumes in two pores of slightly different lengths are used as a computational proxy for the blockade signal; subsequence exclusion volume differences along the protein sequence are computed from the sampled translocation signals in the two pores relatively shifted multiple times. These are then converted into a system of linear inequalities that can be solved with linear programming and related methods; residues are coarsely identified as belonging to one of 4 subsets of the 20 standard AAs. To obtain the exact identity of a residue an artifice analogous to the use of base-specific tags for DNA sequencing with a nanopore (PNAS113, 5233–5238, 2016) is used. Conjugates that add volume are attached to a given AA type, this biases the set of inequalities toward the volume of the conjugated AA, from this biased set the position of occurrence of every residue of the AA type in the whole sequence is extracted. By applying this step separately to each of the 20 standard AAs the full sequence can be obtained. The procedure is illustrated with a protein in the human proteome (Uniprot id UP000005640_9606).
Whole organ volumetric sensing Ultrasound Localization Microscopy for characterization of kidney structure
Authors: Chabouh Georges , Denis Louise , Bodard Sylvain , Lager Franck , Renault Gilles , chavignon arthur , couture olivier
Published: September 2023

Glomeruli are the filtration units of the kidney and their function relies heavily on their microcirculation. Despite its obvious diagnostic importance, an accurate estimation of blood flow in the capillary bundle within glomeruli defies the resolution of conventional imaging modalities. Ultrasound Localization Microscopy (ULM) has demonstrated its ability to image in-vivo deep organs in the body. Recently, the concept of sensing ULM or sULM was introduced to classify individual microbubble behavior based on the expected physiological conditions at the micrometric scale. In the kidney of both rats and humans, it revealed glomerular structures in 2D but was severely limited by planar projection. In this work, we aim to extend sULM in 3D to image the whole organ and in order to perform an accurate characterization of the entire kidney structure. The extension of sULM into the 3D domain allows better localization and more robust tracking. The 3D metrics of velocity and pathway angular shift made glomerular mask possible. This approach facilitated the quantification of glomerular physiological parameter such as an interior traveled distance of approximately 7.5 microns within the glomerulus. This study introduces a technique that characterize the complete kidney phisiology which can serve as a method to facilite pathology assessment. Furthermore, its potential for clinical relevance could serve as a bridge between research and practical application, leading to innovative diagnostics and improved patient care.
Neuronal acid-sensing ion channel 1a regulates neuron-to-glioma synapses
Authors: Park Gyeongah , Jin Zhen , Ge Qian , Pan Yuan , Du Jianyang
Published: September 2023

Neuronal activity promotes high-grade glioma progression via secreted proteins and neuron-to-glioma synapses, and glioma cells boost neuronal activity to further reinforce the malignant cycle. Whereas strong evidence supports that the activity of neuron-to-glioma synapses accelerates tumor progression, the molecular mechanisms that modulate the formation and function of neuron-to-glioma synapses remain largely unknown. Our recent findings suggest that a proton (H+) signaling pathway actively mediates neuron-to-glioma synaptic communications by activating neuronal acid-sensing ion channel 1a (Asic1a), a predominant H+receptor in the central nervous system (CNS). Supporting this idea, our preliminary data revealed that local acid puff on neurons in high-grade glioma-bearing brain slices induces postsynaptic currents of glioma cells. Stimulating Asic1a knockout (Asic1a-/-) neurons results in lower AMPA receptor-dependent excitatory postsynaptic currents (EPSCs) in glioma cells than stimulating wild-type (WT) neurons. Moreover, glioma-bearing Asic1a-/-mice exhibited reduced tumor size and survived longer than the glioma-bearing WT mice. Finally, pharmacologically targeting brain Asic1a inhibited high-grade glioma progression. In conclusion, our findings suggest that the neuronal H+-Asic1a axis plays a key role in regulating the neuron-glioma synapse. The outcomes of this study will greatly expand our understanding of how this deadly tumor integrates into the neuronal microenvironment.
Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation
Authors: Ni Qin , Ge Zhuoxu , Li Yizeng , Shatkin Gabriel , Fu Jinyu , Bera Kaustav , Yang Yuhang , Wang Yichen , Sen Anindya , Wu Yufei , Vasconcelos Ana Carina Nogueira , Feinberg Andrew P. , Konstantopoulos Konstantinos , Sun Sean X.
Published: September 2023

Mammalian cells can rapidly respond to osmotic and hydrostatic pressure imbalances during an environmental change, generating large fluxes of water and ions that alter cell volume within minutes. While the role of ion pump and leak in cell volume regulation has been well-established, the potential contribution of the actomyosin cytoskeleton and its interplay with ion transporters is unclear. We discovered a cell volume regulation system that is controlled by cytoskeletal activation of ion transporters. After a hypotonic shock, normal-like cells (NIH-3T3, MCF-10A, and others) display a slow secondary volume increase (SVI) following the immediate regulatory volume decrease. We show that SVI is initiated by hypotonic stress induced Ca2+influx through stretch activated channel Piezo1, which subsequently triggers actomyosin remodeling. The actomyosin network further activates NHE1 through their synergistic linker ezrin, inducing SVI after the initial volume recovery. We find that SVI is absent in cancer cell lines such as HT1080 and MDA-MB-231, where volume regulation is dominated by intrinsic response of ion transporters. A similar cytoskeletal activation of NHE1 can also be achieved by mechanical stretching. On compliant substrates where cytoskeletal contractility is attenuated, SVI generation is abolished. Moreover, cytoskeletal activation of NHE1 during SVI triggers nuclear deformation, leading to a significant, immediate transcriptomic change in 3T3 cells, a phenomenon that is again absent in HT1080 cells. While hypotonic shock hinders ERK-dependent cell growth, cells deficient in SVI are unresponsive to such inhibitory effects. Overall, our findings reveal the critical role of Ca2+and actomyosin-mediated mechanosensation in the regulation of ion transport, cell volume, transcriptomics, and cell proliferation.
The eyelid and pupil dynamics underlying stress levels in awake mice
Authors: Zeng Hang
Published: September 2023

Stress is a natural response of the body to perceived threats, and it can have both positive and negative effects on brain hemodynamics. Stress-induced changes in pupil and eyelid size/shape have been used as a biomarker in several fMRI studies. However, there were limited knowledges regarding changes in behavior of pupil and eyelid dynamics, particularly on animal models. In the present study, the pupil and eyelid dynamics were carefully investigated and characterized in a newly developed awake rodent fMRI protocol. Leveraging deep learning techniques, the mouse pupil and eyelid diameters were extracted and analyzed during different training and imaging phases in the present project. Our findings demonstrate a consistent downwards trend in pupil and eyelid dynamics under a meticulously designed training protocol, suggesting that the behaviors of the pupil and eyelid can be served as reliable indicators of stress levels and motion artifacts in awake fMRI studies. The current recording platform not only enables the facilitation of awake animal MRI studies but also highlights its potential applications to numerous other research areas, owing to the non-invasive nature and straightforward implementation.
A response playbook for early detection and population surveillance of new SARS-CoV-2 variants in a regional public health laboratory
Authors: Barbian Hannah J. , Kittner Alyse , Teran Richard , Bobrovska Sofiya , Qiu Xueting , English Kayla , Green Stefan J. , Ghinai Isaac , Pacilli Massimo , Hayden Mary K.
Published: September 2023

Background

Timely genomic surveillance is required to inform public health responses to new SARS-CoV-2 variants. However, the processes involved in local genomic surveillance introduce inherent time constraints. The Regional Innovative Public Health Laboratory in Chicago developed and employed a genomic surveillance response playbook for the early detection and surveillance of emerging SARS-CoV-2 variants.

Methods

The playbook outlines modifications to sampling strategies, laboratory workflows, and communication processes based on the emerging variant’s predicted viral characteristics, observed public health impact in other jurisdictions and local community risk level. The playbook outlines procedures for implementing and reporting enhanced and accelerated genomic surveillance, including supplementing whole genome sequencing (WGS) with variant screening by quantitative PCR (qPCR).

Results

The ability of the playbook to improve the response to an emerging variant was tested for SARS-CoV-2 Omicron BA.1. Increased submission of clinical remnant samples from local hospital laboratories enabled detection of a new variant at 1% prevalence with 95% confidence rather than 2% at baseline. Genotyping qPCR concurred with WGS lineage assignments in 99.9% of 1541 samples with results by both methods, and was more sensitive, providing lineage results in 90.4% of 1833 samples rather than 85.1% for WGS, while reducing the time to lineage result from 27 to 7 days.

Conclusions

The genomic surveillance response playbook provides a structured, stepwise, and data-driven approach to responding to emerging SARS-CoV-2 variants. These pre-defined processes can streamline workflows and expedite the detection and public health response to emerging variants. Based on the processes piloted during the Omicron BA.1 response, this method has been applied to subsequent Omicron subvariants and can be readily applied to future SARS-CoV-2 emerging variants and other public health surveillance activities.
Suriname Cerebral Palsy Register - preliminary data from the first hospital-based surveillance of children with cerebral palsy in Suriname
Authors: Declerck Marlies , Jahan Israt , Lissone Neirude , Walhain Fenna , Chin A Fat Ruby , Fleurkens Marianne , Muradin Sarfaraz , Cruden Rhea , Ortibus Els , Badawi Nadia , Khandaker Gulam
Published: September 2023

Aim: To describe the epidemiology of cerebral palsy (CP) among children and their access to rehabilitation and education in Suriname. Methods: Hospital-based surveillance of children with CP at the Academic Hospital in Suriname between August 2018 and March 2020. Results: Data were collected from 82 children with CP (mean (SD) age: 5y 0mo (3y 10mo)). The median age of diagnosis was 5y 2mo. Spastic CP was predominant (73.2%), 58.8% had gross motor function classification system level III-V. Overall, 42.2% had preterm birth compared to 13.9% reported nationally (p<0.001), 57% had birth-related complications in comparison to 15% reported nationally (p<0.001). Additionally, 39.1% had birth asphyxia, 23.2% had early feeding difficulties. Sixty-two percent were admitted to Neonatal Intensive Care Unit, 54.0% of them required ventilation. Majority (82.5%) had CP acquired pre-or perinatally and 17.5% had CP acquired post-neonatally. Sixteen percent had never received any rehabilitation services, and 31.9% of the school-aged children were not enrolled in any education system. Interpretation: The high burden of known risk factors, substantially delayed diagnosis and severe functional impairment among registered children with CP in Suriname is concerning. Public health interventions targeting early diagnosis and intervention could improve the functional outcome of children with CP in Suriname.
Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders
Authors: Tesfaye Markos , Jaholkowski Piotr , Shadrin Alexey A. , van der Meer Dennis , Hindley Guy F.L. , Holen Børge , Parker Nadine , Parekh Pravesh , Birkenæs Viktoria , Rahman Zillur , Bahrami Shahram , Kutrolli Gleda , Frei Oleksandr , Djurovic Srdjan , Dale Anders M. , Smeland Olav B. , O’Connell Kevin S. , Andreassen Ole A.
Published: September 2023

Background

Anxiety disorders are prevalent and anxiety symptoms co-occur with many psychiatric disorders. We aimed to identify genomic risk loci associated with anxiety, characterize its genetic architecture, and genetic overlap with psychiatric disorders.

Methods

We used the GWAS of anxiety symptoms, schizophrenia, bipolar disorder, major depression, and attention deficit hyperactivity disorder (ADHD). We employed MiXeR and LAVA to characterize the genetic architecture and genetic overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of genomic loci associated with anxiety and those shared with psychiatric disorders. Gene annotation and gene set analyses were conducted using OpenTargets and FUMA, respectively.

Results

Anxiety was polygenic with 12.9k estimated genetic risk variants and overlapped extensively with psychiatric disorders (4.1-11.4k variants). MiXeR and LAVA revealed predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 114 novel loci for anxiety by conditioning on the psychiatric disorders. We also identified loci shared between anxiety and major depression (n = 47), bipolar disorder (n = 33), schizophrenia (n = 71), and ADHD (n = 20). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways and differential tissue expression in more diverse tissues than those annotated to the shared loci.

Conclusions

Anxiety is a highly polygenic phenotype with extensive genetic overlap with psychiatric disorders. These genetic overlaps enabled the identification of novel loci for anxiety. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified genetic loci implicate molecular pathways that may lead to potential drug targets.
Brain network changes after the first seizure: an insight into medication response?
Authors: Pedersen Mangor , Pardoe Heath R. , Mito Remika , Sethi Moksh , Vaughan David N. , Carney Patrick W. , Jackson Graeme D.
Published: September 2023

After a first epileptic seizure, anti-seizure medications (ASM) can change the likelihood of having a further event. This prospective study aimed to quantify brain network changes associated with taking ASM monotherapy. We applied graph theoretical network analysis to longitudinal resting-state functional MRI (fMRI) data from 28 participants who had recently experienced their first seizure. Participants were imaged before and during long-term ASM therapy, with a mean inter-scan interval of 6.9 months. After commencing ASM, we observed an increase in the clustering coefficient and a decrease in network path length. Brain changes after ASM treatment were most prominent in the superior frontoparietal and inferior fronto-temporal regions. Participants with recurrent seizures display the most pronounced network changes after ASM treatment. This study shows changes in brain network function after ASM administration, particularly in participants with recurrent seizures. Larger studies that ideally include control cohorts are required to understand further the connection between ASM-related brain network changes and longer-term seizure status.
A One Health approach to pastoral (im)mobility, health, and disease: a qualitative participatory study in Plateau State, Nigeria
Authors: Braam Dorien Hanneke , Bolajoko Muhammad-Bashir , Hammer Charlotte Christiane
Published: September 2023

Abstract/Summary

Background

In Plateau State, pastoralism has historically been a cost effective and resilient economic system well-suited to the ecological context. However, changes in land use and conflict have increasingly changed patterns of mobility. Pastoralist movement is now often associated with zoonotic disease transmission, environmental degradation and conflict, increasingly resulting in forced sedentarisation. Rather than a direct outcome of population movement however, animal, human and zoonotic disease drivers are complex and influenced by a range of socio-economic and environmental factors. The interlinkages of (im)mobility and health requires better understanding of underlying vulnerabilities to disease, which we aim to address in this study.

Methods

Using a multisite case study methodology we investigated pastoralists’ animal and human health concerns and priorities in Plateau State, Nigeria. We deployed participatory tools, including open-ended Focus Group Discussions, transect walks, mapping exercises, calendars and matrices. Data were analysed using a One Health conceptual framework.

Results

We interviewed 105 participants, from transhumance, migratory and sedentary households, dependent on livestock and small-scale crops. While transhumance was often preferred, participants had become sedentary as a result of insecurity, loss in livestock, and household characteristics. Humans and animals suffered from several endemic diseases, including zoonoses, however veterinary and human health services are only available in larger towns, and people mostly rely on community (animal) health workers and self-medication. Both transhumance and sedentary livestock keepers face challenges around forage grazing, regularly blocked by landowners, sometimes escalating into conflict.

Conclusions

While conflict and changes in land use affected animal and human disease patterns, underlying political, social and economic risk factors were important determinants of health. There is a need for more inclusive, transdisciplinary, multilevel approaches to address animal and human disease, based on better contextualization of the challenges, through the participation of affected communities.

Impacts

This study uses participatory approaches to investigate the under researched area of mobility and zoonotic disease dynamics.

We found that animal and human mobility may mitigate or exacerbate zoonotic disease risk, impacting conflict, in turn leading to forced migration.

Conflict and crime related security challenges need to be addressed simultaneously with mitigating structural inequality, through increasing pastoral social and economic capital, increase access to grazing routes and water, secure land tenure arrangements, and the provision of (veterinary) public health to reduce zoonotic disease risks in the region.
Rural trauma team development amongst medical trainees and traffic law enforcement professionals in a low-income country: A protocol for a prospective multi-center interrupted time series of interventional training
Authors: Lule Herman , Mugerwa Michael , SSebuufu Robinson , Kyamanywa Patrick , Posti Jussi P. , Wilson Michael Lowery
Published: September 2023

Background

Road traffic injuries and their resulting mortality disproportionately affect rural communities in low-middle-income countries (LMICs) due to limited human and infrastructural resources for post-crash care. Evidence from high income countries show that trauma team development training could improve the efficiency, care, and outcome of injuries. A paucity of studies has evaluated the feasibility and applicability of this concept in resource constrained settings. The aim of this study protocol is to establish the feasibility of rural trauma team development and training in a cohort of medical trainees and traffic law enforcement professionals in Uganda.

Methods

Muti-center interrupted time series of prospective interventional trainings, using the rural trauma team development course (RTTDC) model of the American College of Surgeons. A team of surgeon consultants will execute the training. A prospective cohort of participants will complete a before and after training validated trauma related multiple choice questionnaire (MCQ) during September 2019-November 2023. The difference in mean pre-post training percentage MCQ scores will be compared using ANOVA-test at 95% CI. Time series regression models will be used to test for autocorrelations in performance. Acceptability and relevance of the training will be assessed using 3- and 5-point Likert scales, respectively. All analyses will be performed using Stata 15.0. Ethical approval was obtained from Research and Ethics Committee of Mbarara University of Science and Technology (Ref: MUREC 1/7, 05/05-19) and Uganda National Council for Science and Technology (Ref: SS 5082) prior recruitment. Retrospective registration was accomplished with Research Registry (UIN: researchregistry9490).

Highlights

Injury related mortality significantly impact LMICs.

Rural trauma teams could improve the efficiency of injury care in LMICs.

This study will assess the effect of rural trauma team development training, viewing medical trainees and traffic police as potential human resources for health.

The results could inform the implementation of future trauma teams in rural settings.
Prioritizing Cardiovascular Disease-Associated Variants Altering NKX2-5 Binding through an Integrative Computational Approach
Authors: Peña-Martínez Edwin G. , Pomales-Matos Diego A. , Rivera-Madera Alejandro , Messon-Bird Jean L. , Medina-Feliciano Joshua G. , Sanabria-Alberto Leandro , Barreiro-Rosario Adriana C. , Rodriguez-Rios Jessica M. , Rodríguez-Martínez José A.
Published: September 2023

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are heavily influenced by genetic factors. Genome-wide association studies (GWAS) have mapped > 90% of CVD-associated variants within the non-coding genome, which can alter the function of regulatory proteins, like transcription factors (TFs). However, due to the overwhelming number of GWAS single nucleotide polymorphisms (SNPs) (>500,000), prioritizing variants for in vitro analysis remains challenging. In this work, we implemented a computational approach that considers support vector machine (SVM)-based TF binding site classification and cardiac expression quantitative trait loci (eQTL) analysis to identify and prioritize potential CVD-causing SNPs. We identified 1,535 CVD-associated SNPs that occur within human heart footprints/enhancers and 9,309 variants in linkage disequilibrium (LD) with differential gene expression profiles in cardiac tissue. Using hiPSC-CM ChIP-seq data from NKX2-5 and TBX5, two cardiac TFs essential for proper heart development, we trained a large-scale gapped k-mer SVM

(LS-GKM-SVM) predictive model that can identify binding sites altered by CVD-associated SNPs. The computational predictive model was tested by scoring human heart footprints and enhancers in vitro through electrophoretic mobility shift assay (EMSA). Three variants (rs59310144, rs6715570, and rs61872084) were prioritized for in vitro validation based on their eQTL in cardiac tissue and LS-GKM-SVM prediction to alter NKX2-5 DNA binding. All three variants altered NKX2-5 DNA binding. In summary, we present a bioinformatic approach that considers tissue-specific eQTL analysis and SVM-based TF binding site classification to prioritize CVD-associated variants for in vitro experimental analysis.

Graphical Abstract
Association of Common and Rare Variants with Alzheimer’s Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer’s Disease Sequencing Project
Authors: Lee Wan-Ping , Choi Seung Hoan , Shea Margaret G , Cheng Po-Liang , Dombroski Beth A , Pitsillides Achilleas N , Heard-Costa Nancy L , Wang Hui , Bulekova Katia , Kuzma Amanda B , Leung Yuk Yee , Farrell John J , Lin Honghuang , Naj Adam , Blue Elizabeth E , Nusetor Frederick , Wang Dongyu , Boerwinkle Eric , Bush William S , Zhang Xiaoling , De Jager Philip L , Dupuis Josée , Farrer Lindsay A , Fornage Myriam , Martin Eden , Pericak-Vance Margaret , Seshadri Sudha , Wijsman Ellen M , Wang Li-San , Schellenberg Gerard D , Destefano Anita L , Haines Jonathan L , Peloso Gina M
Published: September 2023

Alzheimer’s Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or nearAPOE, BIN1, andLINC00320significantly associated with AD (p < 5×10-8). Population-specific analyses identified a haplotype on chromosome 14 includingPSEN1associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10-5) of aggregates of rare coding rare variants inABCA7among non-Hispanic Whites (p=5.4×10-6), and rare noncoding variants in the promoter ofTOMM40distinct ofAPOEin pooled-population analyses (p=7.2×10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.