bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain-wide Disruptions of Anatomical Connectivity in Antipsychotic-Naïve First Episode Psychosis
Authors: Chopra Sidhant , Levi Priscila T. , Holmes Alexander , Orchard Edwina R. , Segal Ashlea , Francey Shona M. , O’Donoghue Brian , Cropley Vanessa L. , Nelson Barnaby , Graham Jessica , Baldwin Lara , Yuen Hok Pan , Allott Kelly , Alvarez-Jimenez Mario , Harrigan Susy , Pantelis Christos , Wood Stephen J , McGorry Patrick , Fornito Alex
Published: November 2023

OBJECTIVE

Disruptions of axonal connectivity are thought to be a core pathophysiological feature of psychotic illness, but whether they are present early in the illness, prior to antipsychotic exposure, and whether they can predict clinical outcome remains unknown.

METHODS

We acquired diffusion-weighted MRI to map axonal connectivity between each pair of 319 parcellated brain regions in 61 antipsychotic-naive individuals with First Episode Psychosis (FEP; 15-25 years, 46% female) and a demographically matched sample of 27 control participants, along with clinical follow-up data in patients 3 months and 12 months after the scan. We used connectome-wide analyses to map disruptions of inter-regional pairwise connectivity coupled with connectome-based predictive modelling to predict longitudinal change in symptoms and functioning.

RESULTS

Individuals with FEP showed disrupted connectivity in a brain-wide network linking all brain regions when compared with controls (pFWE=.03). Baseline structural connectivity significantly predicted change in functioning over 12 months (r =.44;pFWE=.041), such that lower connectivity within fronto-striato-thalamic systems predicted worse functional outcomes.

CONCLUSIONS

Brain-wide reductions of structural connectivity exist during the early stages of psychotic illness and cannot be attributed to antipsychotic medication. Moreover, baseline measures of structural connectivity can predict change in patient functional outcomes up to one year after engagement with treatment services.
Multi-voxel neuro-reinforcement changes resting-state functional connectivity: A pilot study
Authors: Wang Shawn , Cushing Cody A. , Lau Hakwan , Craske Michelle G. , Taschereau-Dumouchel Vincent
Published: November 2023

Background

Multi-voxel neuro-reinforcement has been shown to selectively reduce amygdala reactivity in response to feared stimuli, but the precise mechanisms supporting these effects are still unknown. The current pilot study seeks to identify potential intermediaries of change using functional brain connectivity at rest.

Methods

Individuals (N = 11) diagnosed with at least two animal subtype specific phobias took part in a double-blind multi-voxel neuro-reinforcement clinical trial targeting one of two phobic animals, with the untargeted animal as placebo control. Changes in whole-brain resting state functional connectivity from pre-treatment to post-treatment were measured using group ICA. These changes were tested to see if they predicted the previously observed decreases in amygdala reactivity in response to images of target phobic animals.

Results

A common functional connectivity network overlapping with the visual network was identified in resting state data pre-treatment and post-treatment. Significant increases in functional connectivity in this network from pre-treatment to post-treatment were found in higher level visual and cognitive processing regions of the brain. Increases in functional connectivity in these regions also significantly predicted decreases in task-based amygdala reactivity to targeted phobic animals following multi-voxel neuro-reinforcement. Specifically, greater increases of functional connectivity pre-treatment to post-treatment were associated with greater decreases of amygdala reactivity to target phobic stimuli pre-treatment to post-treatment.

Conclusions

These findings provide preliminary evidence that multi-voxel neuro-reinforcement can induce persisting functional connectivity changes in the brain. Moreover, these changes in functional connectivity were not limited to the direct area of neuro-reinforcement, suggesting neuro-reinforcement may change how the targeted region interacts with other brain regions. Identification of these brain regions represent a first step towards explaining the underlying mechanisms of change in previous multi-voxel neuro-reinforcement studies. Future research should seek to replicate these effects in a larger sample size to further assess their role in the effects observed from multi-voxel neuro-reinforcement.
Fetal sexual dimorphism and preeclampsia among twin pregnancies
Authors: Brown Rebekah E. , Noah Akaninyene I. , Hill Ashley V. , Taylor Brandie DePaoli
Published: November 2023

Background

In singleton pregnancies, fetal sexual dimorphism has been observed in hypertensive disorders of pregnancy (HDP), particularly preeclampsia, a morbid syndrome that increases risk of adult onset cardiovascular disease for mothers and their offspring. However, few studies have explored the effect of fetal sex on HDP among twin pregnancies.

Methods

We conducted a retrospective cohort study of 1,032 twin pregnancies between 2011 - 2022 using data from a perinatal database that recruits participants from three hospitals in Houston, TX. We categorized pregnancies based on fetal sex pairings into female/female, male/male, and female/male. Pregnancies with a female/female fetal sex were used as our reference group. Our primary outcomes included gestational hypertension, preeclampsia, superimposed preeclampsia, and preeclampsia subtyped by gestational age of delivery. A modified Poisson regression model with robust error variance was used to calculate the relative risk (RR) and 95% confidence interval (CI) for the association between fetal sex pairs and HDP.

Results

Adjusted models of female/male fetal sex pairs were associated with preterm preeclampsia (RR 2.01, 95% CI 1.15-3.53) relative to those with female/female fetuses. No associations with other HDP were observed among pregnancies with male/male fetal sex compared to those with female/female fetal sex pairs.

Conclusions

We found some evidence of sexual dimorphism for preterm preeclampsia among female/male twin pairs. Additional research is needed to understand what biological mechanisms could explain these findings.
E2F transcription factors promote tumorigenicity in pancreatic ductal adenocarcinoma
Authors: Bertonnier-Brouty Ludivine , Andersson Jonas , Kaprio Tuomas , Hagström Jaana , Bsharat Sara , Asplund Olof , Hatem Gad , Haglund Caj , Seppänen Hanna , Prasad Rashmi B , Artner Isabella
Published: November 2023

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we identified embryonic signalling pathways that were reinitiated during tumor formation and expansion. Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. In conclusion, our findings show that E2F1 and E2F8 transcription factors regulate cell proliferation, survival, and migration during pancreatic carcinogenesis.
Holistic in silico developability assessment of novel classes of small proteins using publicly available sequence-based predictors
Authors: Pais Daniel A. M. , Mayer Jan-Peter A. , Felderer Karin , Batalha Maria B. , Eichner Timo , Santos Sofia T. , Kumar Raman , Silva Sandra D. , Kaufmann Hitto
Published: November 2023

The development of novel therapeutic proteins is a lengthy and costly process, with an average attrition rate of 91% (Thomas et al., 2021). To increase the probability of success and ensure robust drug supply beyond approval, it is essential to assess the developability profile of new potential drug candidates as early and broadly as possible in development (Jain et al., 2023). Predicting these propertiesin silicois expected to be the next leap in innovation as it would enable significantly reduced development timelines combined with broader screens at lower costs. However, developing predictive algorithms typically requires substantial datasets generated under very defined conditions, a limiting factor especially for new classes of therapeutic proteins that hold immense clinical promise.

Here we describe a strategy for assessing the developability of a novel class of small therapeutic Anticalin® proteins using machine learning in conjunction with a knowledge-driven approach. The knowledge-driven approach considers developability attributes such as aggregation propensity, charge variants, immunogenicity, specificity, thermal stability, hydrophobicity, and potential post-translational modifications, to calculate a holistic developability score. Based on sequence-derived descriptors as input parameters we established novel statistical models designed to predict the developability scores for Anticalin proteins. The best models yielded low root mean square errors across the entire dataset and were further validated by removing input data from individual screening campaigns and predicting developability scores for those drug candidates.

The adoption of the described workflow will enable significantly streamlined preclinical development of Anticalin drug candidates and could potentially be applied to other therapeutic protein scaffolds.
Lateral inhibition in V1 controls neural & perceptual contrast sensitivity
Authors: Del Rosario Joseph , Coletta Stefano , Kim Soon Ho , Mobille Zach , Peelman Kayla , Williams Brice , Otsuki Alan J , Del Castillo Valerio Alejandra , Worden Kendell , Blanpain Lou T. , Lovell Lyndah , Choi Hannah , Haider Bilal
Published: November 2023

Lateral inhibition is a central principle for sensory system function. It is thought to operate by the activation of inhibitory neurons that restrict the spatial spread of sensory excitation. Much work on the role of inhibition in sensory systems has focused on visual cortex; however, the neurons, computations, and mechanisms underlying cortical lateral inhibition remain debated, and its importance for visual perception remains unknown. Here, we tested how lateral inhibition from PV or SST neurons in mouse primary visual cortex (V1) modulates neural and perceptual sensitivity to stimulus contrast. Lateral inhibition from PV neurons reduced neural and perceptual sensitivity to visual contrast in a uniform subtractive manner, whereas lateral inhibition from SST neurons more effectively changed the slope (or gain) of neural and perceptual contrast sensitivity. A neural circuit model identified spatially extensive lateral projections from SST neurons as the key factor, and we confirmed this with anatomy and direct subthreshold measurements of a larger spatial footprint for SST versus PV lateral inhibition. Together, these results define cell-type specific computational roles for lateral inhibition in V1, and establish their unique consequences on sensitivity to contrast, a fundamental aspect of the visual world.
In vivo evaluation of a novel compliance-matching vascular graft
Authors: Rovas G. , Reymond P. , van Steenberghe M. , Diaper J. , Bikia V. , Cikirikcioglu M. , Habre W. , Huber C. , Stergiopulos N.
Published: November 2023

Background

The mismatch of elastic properties between the arterial tissue and the vascular grafts, commonly called compliance mismatch, is responsible for many deleterious post-operative complications. Currently, there is an absence of prostheses that conform with the compliance of healthy aortas.

Objectives

We proposed a novel compliance-matching graft design, composed of a standard aortic graft surrounded by an optimized Nickel-Titanium compliance-augmenting layer. We aimed to evaluate the in vivo performance of the novel grafts in a swine model and compare it to the native aorta and to gold-standard aortic grafts.

Methods

We replaced the thoracic aorta of six domestic pigs with compliance-matching grafts under cardiopulmonary bypass. We removed the compliance-regulating layer of the compliant grafts, so that gold-standard grafts remained implanted.

Results

The compliance-matching grafts were implanted without surgical complications and without inducing post-operative hypertension by maintaining systolic pressure (11% increase), aortic pulse wave velocity (17% decrease) and aortic distensibility (40% increase) at healthy levels. The gold-standard grafts caused a significant rise in systolic pressure (47%), pulse pressure (126%) and pulse wave velocity (64%).

Conclusions

Our novel compliant grafts could diminish the complications caused by compliance-mismatch and they could surpass the clinical performance of existing prostheses. The proposed grafts comprise a step towards optimized treatment and improved life expectancy of patients subjected to aortic replacement.
A population code for idiothetic representations in the hippocampal-septal circuit
Authors: Etter Guillaume , van der Veldt Suzanne , Mosser Coralie-Anne , Hasselmo Michael E , Williams Sylvain
Published: November 2023

The hippocampus is a higher-order brain structure responsible for encoding new episodic memories and predicting future outcomes. In absence of external stimuli, neurons in the hippocampus express sequential activities which have been proposed to support path integration by tracking elapsed time, distance traveled, and other idiothetic variables. On the other hand, with sufficient external sensory inputs, hippocampal neurons can fire with respect to allocentric cues. Previously, these idiothetic codes have been described in conditions where running speed is clamped experimentally. To this day, the balance of idiothetic and allocentric representations in freely moving conditions remains unclear. Additionally, whether CA1 and CA3 temporal and distance codes are transmitted downstream to the lateral septum has not been established. Here, we develop an unsupervised model trained to compress neural information with minimal loss, and find that we can efficiently decode elapsed time and distance travelled from low-dimensional embeddings of neural activity in freely moving mice. We also developed unbiased information metrics that are minimally sensitive to quantization parameters and enable comparisons across modalities and brain regions. In more than 30,000 CA1 pyramidal neurons, we show that spatiotemporal information is represented as a mixture of self-motion, idiothetic as well as allocentric information, the balance of which is dictated by task demand and environmental conditions. In particular, we find that a subset of CA1 pyramidal neurons encode the spatiotemporal distance relative to rewards. Single cell and population statistics across the hippocampal-septal circuit reveal that idiothetic variables emerge in CA1 and are integrated postsynaptically in the lateral septum. Finally, we implement a computational model trained to replicate real world neural activity, and find that grid cells could provide a plausible input for CA1 representations of time and distance. Altogether, our results suggest that hippocampal CA1 continuously integrates both idiothetic and allocentric signals depending on task demand and available cues, and these high-level representations are effectively transmitted to downstream regions.
CGCom: a framework for inferring Cell-cell Communication based on Graph Neural Network
Authors: Wang Honglin , Zhang Chenyu , Hong Seung-Hyun , Maye Peter , Rowe David , Shin Dong-Guk
Published: November 2023

Cell-cell communication is crucial in maintaining cellular homeostasis, cell survival and various regulatory relationships among interacting cells. Thanks to recent advances of spatial transcriptomics technologies, we can now explore if and how cells’ proximal information available from spatial transcriptomics datasets can be used to infer cell-cell communication. Here we present a cell-cell communication inference framework, called CGCom, which uses a graph neural network (GNN) to learn communication patterns among interacting cells by combining single-cell spatial transcriptomic datasets with publicly available ligand-receptor information and the molecular regulatory information down-stream of the ligand-receptor signaling. To evaluate the performance of CGCom, we applied it to mouse embryo seqFISH datasets. Our results demonstrate that CGCom can not only accurately infer cell communication between individual cell pairs but also generalize its learning to predict communication between different cell types. We compared the performance of CGCom with two existing methods, CellChat and CellPhoneDB, and our comparative study revealed both common and unique communication patterns from the three approaches.

Commonly found communication patterns include three sets of ligand-receptor communication relationships, one between surface ectoderm cells and spinal cord cells, one between gut tube cells and endothelium, and one between neural crest and endothelium, all of which have already been reported in the literature thus offering credibility of all three methods. However, we hypothesize that CGCom is superior in reducing false positives thanks to its use of cell proximal information and its learning between specific cell pairs rather than between cell types. CGCom is a GNN-based solution that can take advantage of spatially resolved single-cell transcriptomic data in predicting cell-cell communication with a higher accuracy.
Insulin and Exercise-induced Phosphoproteomics of Human Skeletal Muscle Identify REPS1 as a New Regulator of Muscle Glucose Uptake
Authors: Kjærgaard Larsen Jeppe , Lindqvist Cecilie B. , Jessen Søren , García-Ureña Mario , Ehrlich Amy M. , Schlabs Farina , Quesada Júlia Prats , Schmalbruch Johann H. , Small Lewin , Thomassen Martin , Lemminger Anders Krogh , Eibye Kasper , Gonzalez-Franquesa Alba , Stidsen Jacob V. , Højlund Kurt , Kilpeläinen Tuomas O. , Bangsbo Jens , Treebak Jonas T. , Hostrup Morten , Deshmukh Atul S.
Published: November 2023

Skeletal muscle regulates glucose uptake in response to insulin and exercise which is critical for maintaining metabolic health. We conducted a comprehensive phosphoproteomic analysis of skeletal muscle from healthy people in response to an acute bout of exercise or insulin stimulation by a hyperinsulinemic euglycemic clamp. Our analysis revealed 233 phosphosites regulated by both exercise and insulin of which most phosphosites were regulated in opposite directions. However, 71 phosphosites on 55 proteins displayed regulation in the same direction, indicating a potential convergence of signaling pathways. We identified the vesicle-associated protein, REPS1, to be phosphorylated at Ser709 in response to both insulin and exercise. REPS1 protein level and Ser709 phosphorylation were closely related to insulin-stimulated glucose uptake in skeletal muscle and required for maximal insulin-stimulated glucose uptake. Furthermore, we observed that insulin triggered phosphorylation of REPS1 Ser709 via P90S6 kinase (RSK) and is impaired in mice and humans with insulin resistance. Collectively, REPS1 is a convergence point for insulin and exercise signaling and a promising therapeutic target in insulin resistance.
Larval swimming in the sea anemoneNematostella vectensisis sensitive to a broad light spectrum and exhibits a wavelength-dependent behavioral switch
Authors: Payne Meghan , Lilly Emma , Sharkey Camilla R , McCulloch Kyle J
Published: November 2023

In nearly all animals, light sensing mediated by opsin visual pigments is important for survival and reproduction. Eyeless light-sensing systems, though vital for many animals, have received relatively less attention than forms with charismatic or complex eyes. Despite no single light sensing organ, the sea anemoneNematostella vectensis, has 29 opsin genes and multiple light-mediated behaviors throughout development and reproduction, suggesting a deceptively complex light-sensing system. To characterize one aspect of this light-sensing system, we analyzed larval swimming behavior at high wavelength resolution across the ultraviolet and visual spectrum.N. vectensislarvae respond to light at least from 315 to 650 nm, which is a broad sensitivity range even compared to many animals with complex eyes. Swimming in the water column is induced by ultraviolet (UV) and violet wavelengths until 420 nm. Between 420 and 430 nm a behavioral switch occurs where at wavelengths longer than 430 nm, larvae respond to light by swimming down. Swimming down toward the substrate is distinct from light avoidance, as animals do not exhibit positive or negative phototaxis at any wavelength tested. At wavelengths longer than 575 nm, animals in the water column take increasingly longer to respond and this behavior is more variable until 650 nm where larval response is no different from the dark, suggesting these longer wavelengths lie outside of their sensitivity range. Larval swimming is the only motile stage in the life history ofN. vectensis, and increased swimming activity in the water column could lead to greater dispersal range in potentially damaging shallow environments with short-wavelength light exposure. Longer wavelength environments may indicate more suitable substrates for metamorphosis into the polyp stage, where the individual will remain for the rest of its life. Future work will test whether this robust behavior is mediated by multiple opsins.
Acetylcholine esterase ofDrosophila melanogaster: a laboratory model to explore applications of insecticide susceptibility gene drives
Authors: Hernandes Natalia , Qi Xiaomeng Mollyann , Bhide Soumitra , Brown Courtney , Camm Benjamin J. , Baxter Simon W. , Robin Charles
Published: November 2023

BACKGROUND

One of the proposed applications of gene drives has been to revert pesticide resistant mutations back to the ancestral susceptible state. Insecticides that have become ineffective because of the rise of resistance could have reinvigorated utility and be used to suppress pest populations again, perhaps at lower application doses.

RESULTS

We have created a laboratory model for susceptibility gene drives that replaces field-selected resistant variants of the acetylcholine esterase (Ace) locus ofDrosophila melanogasterwith ancestral susceptible variants. We constructed a CRISPR/Cas9 homing drive and found that homing occurred in many genetic backgrounds with varying efficiencies. While the drive itself could not be homozygosed, it converted resistant alleles into susceptible ones and produced recessive lethal alleles that could suppress populations. Our studies provided evidence for two distinct classes of Gene Drive Resistance (GDR): rather than being mediated by the conventional Non-Homologous End-joining (NHEJ) pathway, one seemed to involve short homologous repair and the other was defined by genetic background.

Additionally, we used simulations to explore a distinct application of susceptibility drives; the use of chemicals to prevent the spread of synthetic gene drives into protected areas.

CONCLUSIONS

Insecticide susceptibility gene drives could be useful tools to control pest insects however problems associated with particularities of the target loci and GDR will need to be overcome for them to be effective. Furthermore, realistic patterns of pest dispersal and high insecticide exposure rates would be required if susceptibility were to be useful as a ‘safety-switch’ to prevent the unwanted spread of gene drives.
Malaria parasite resistance to azithromycin is not readily transmitted by mosquitoes
Authors: Buchanan Hayley D. , McConville Robyn , Yeoh Lee M. , Duffy Michael F. , Boddey Justin A. , McFadden Geoffrey I. , Goodman Christopher D.
Published: November 2023

Antimalarials are now used in combination with partner drugs to stem parasite drug resistance. Partners are often older, safe, cheap drugs, but resistance is already circulating for many, which raises the risk of selecting for multidrug resistance. If the partner drug(s) could be refractory to the spread of resistance, better resistance control could be implemented. We tested whether resistance to the antibiotic azithromycin, which kills malaria parasites by perturbing prokaryote-like protein synthesis in the apicoplast (relict plastid), had fitness costs to the spread of parasites via mosquitoes where parasites are not under drug pressure. Azithromycin resistance mutations in both rodent and human malaria parasites had a negative impact on the ability of resistant parasites to transmit from one vertebrate host to another via mosquitoes. Azithromycin resistance will therefore be less likely to spread geographically, making it an attractive option as a perennial partner compound to protect appropriate frontline antimalarials.
Digital Voice-Based Biomarker for Monitoring Respiratory Quality of Life: Findings from the Colive Voice Study
Authors: Despotovic Vladimir , Elbéji Abir , Fünfgeld Kevser , Pizzimenti Mégane , Ayadi Hanin , Nazarov Petr V. , Fagherazzi Guy
Published: November 2023

Regular monitoring of respiratory quality of life (RQoL) is essential in respiratory healthcare, facilitating prompt diagnosis and tailored treatment for chronic respiratory diseases. Voice alterations resulting from respiratory conditions create unique audio signatures that can potentially be utilized for disease screening or monitoring. Analyzing data from 1908 participants from the Colive Voice study, which collects standardized voice recordings alongside comprehensive demographic, epidemiological, and patient-reported outcome data, we evaluated various strategies to estimate RQoL from voice, including handcrafted acoustic features, standard acoustic feature sets, and advanced deep audio embeddings derived from pretrained convolutional neural networks. We compared models using clinical features alone, voice features alone, and a combination of both. The multimodal model combining clinical and voice features demonstrated the best performance, achieving an accuracy of 70.34% and an area under the receiver operating characteristic curve (AUROC) of 0.77; an improvement of 5% in terms of accuracy and 7% in terms of AUROC compared to model utilizing voice features alone. Incorporating vocal biomarkers significantly enhanced the predictive capacity of clinical variables across all acoustic feature types, with a net classification improvement (NRI) of up to 0.19. Our digital voice-based biomarker is capable of accurately predicting RQoL, either as an alternative to or in conjunction with clinical measures, and could be used to facilitate rapid screening and remote monitoring of respiratory health status.
Interleaved TMS/fMRI shows that threat decreases dlPFC-mediated top-down regulation of emotion processing
Authors: Patel Milan , Teferi Marta , Casalvera Abigail , Lynch Kevin , Nitchie Frederick , Makhoul Walid , Oathes Desmond J , Sheline Yvette , Balderston Nicholas L
Published: November 2023

Background

The right dorsolateral prefrontal cortex (dlPFC) has been indicated to be a key region in the cognitive regulation of emotion by many previous neuromodulation and neuroimaging studies. However, there is little direct causal evidence supporting this top-down regulation hypothesis. Furthermore, it is unclear whether contextual threat impacts this top-down regulation. By combining TMS/fMRI, this study aimed to uncover the impact of unpredictable threat on TMS-evoked BOLD response in dlPFC-regulated emotional networks. Based on the previous findings linking the dlPFC to the downregulation of emotional network activity, we hypothesized TMS pulses would deactivate activity in anxiety expression regions, and that threat would reduce this top-down regulation.

Methods

44 healthy controls (no current or history of psychiatric disorders) were recruited to take part in a broader study. Subjects completed the neutral, predictable, and unpredictable (NPU) threat task while receiving TMS pulses to either the right dlPFC or a control region. dlPFC targeting was based on data from a separate targeting session, where subjects completed the Sternberg working memory (WM) task inside the MRI scanner.

Results

When compared to safe conditions, subjects reported significantly higher levels of anxiety under threat conditions. Additionally, TMS-evoked responses in the left insula (LI), right sensory/motor cortex (RSM), and a region encompassing the bilateral SMA regions (BSMA) differed significantly between safe and threat conditions. There was a significant TMS-evoked deactivation in safe periods that was significantly attenuated in threat periods across all 3 regions.

Conclusions

These findings suggest that threat decreases dlPFC-regulated emotional processing by attenuating the top-down control of emotion, like the left insula. Critically, these findings provide support for the use of right dlPFC stimulation as a potential intervention in anxiety disorders.
Examining the Efficacies of Different Machine Learning Algorithms on Predicting Future Potential Death from Heart Failure
Authors: Radi Osama
Published: November 2023

1 in every 5 deaths is from heart failure. If this heart failure was able to be predicted, medical practitioners would be able to issue the proper preventative measures in order to prevent the fatal heart attack. As machine learning is gaining its place in medicine, one of the most commonly asked questions is which machine learning algorithms can be used where. This paper aims to find which machine learning algorithm is most efficacious in predicting future fatal heart disease. Two machine learning algorithms were evaluated in this study; namely linear regression models and k-nearest-neighbors models. The K-Nearest-Neighbors model was found to be most efficacious with an accuracy between 96.67% and 100% in predicting future heart failure. The reliability of this algorithm in predicting death from heart failure will surely prove useful in the future of treating at-risk patients.
Translocations spur population growth but exacerbate inbreeding in an imperiled species
Authors: Linderoth Tyler , Deaner Lauren , Chen Nancy , Bowman Reed , Boughton Raoul , Fitzpatrick Sarah W.
Published: November 2023

Land and natural resource usage that supports human society can pose a risk to the survival of other species, spurring biodiversity loss. In extreme cases, when development threatens the existence of individuals, wildlife managers may perform mitigation translocations, relocating individuals out of harm’s way. We investigated the efficacy of mitigation translocations as a conservation strategy in Federally Threatened Florida Scrub-Jays using a dataset that provided unprecedented resolution into both the demographic and genomic outcomes of translocations. Over the course of seven years, a total of fourteen groups (51 jays) from five subpopulations that had been declining from agriculture and lack-of-fire driven habitat degradation were translocated to a larger site of more contiguous restored habitat with only four family groups, to mitigate for loss of these subpopulations from mining activity. Habitat restoration and translocations established a core population that increased 10-fold in size after only 17 years from the first translocations. Pedigree analyses of this population revealed that a small subset of mostly translocated individuals fueled the demographic expansion, with a single breeding pair responsible for ∼24% of the ancestral genetic contributions since 2008. Genomic comparisons between translocated individuals and individuals from the core population before and after translocations revealed that the high reproductive skew led to increased inbreeding and loss of genetic diversity. This study stresses the importance of demographic and genetic monitoring following translocations, and that subsequent, genetic-rescue-oriented translocations may be necessary in mitigation scenarios to counter the genetic consequences of reproductive skew in fragmented populations.

Significance Statement

There is ongoing debate surrounding the effectiveness of mitigation-driven translocations for conservation, however we show that translocations to mitigate the effects of mining on Federally Threatened Florida Scrub-Jays spurred population growth; a major boon to the viability of this species. We translocated individuals from at-risk subpopulations that were demographic sinks into recently restored habitat, which quickly established a rapidly growing core population. We demonstrate that demographic and genetic recovery do not necessarily go hand-in-hand, as reproduction was highly skewed towards a small subset of mostly translocated individuals, which increased inbreeding and eroded genetic diversity. This stresses the importance of demographic and genetic monitoring for identifying reproductive skew, allowing for adaptive management that addresses inbreeding and achieves broader conservation goals.
Orientation-Independent-DIC imaging reveals that a transient rise in depletion force contributes to mitotic chromosome condensation
Authors: Iida Shiori , Ide Satoru , Tamura Sachiko , Tani Tomomi , Goto Tatsuhiko , Shribak Michael , Maeshima Kazuhiro
Published: November 2023

Genomic information must be faithfully transmitted into two daughter cells during mitosis. To ensure the transmission process, interphase chromatin is further condensed into mitotic chromosomes. Although protein factors like condensins and topoisomerase IIα are involved in the assembly of mitotic chromosomes, the physical bases of the condensation process remain unclear. Depletion force/macromolecular crowding, an effective attractive force that arises between large structures in crowded environments around chromosomes, may contribute to the condensation process. To approach this issue, we investigated the “chromosome milieu” during mitosis of living human cells using orientation-independent-differential interference contrast (OI-DIC) module combined with a confocal laser scanning microscope, which is capable of precisely mapping optical path differences and estimating molecular densities. We found that the molecular density surrounding chromosomes increased with the progression from prometaphase to anaphase, concurring with chromosome condensation. However, the molecular density went down in telophase, when chromosome decondensation began. Changes in the molecular density around chromosomes by hypotonic or hypertonic treatment consistently altered the condensation levels of chromosomes.In vitro, native chromatin was converted into liquid droplets of chromatin in the presence of cations and a macromolecular crowder. Additional crowder made the chromatin droplets stiffer and more solid-like, with further condensation. These results suggest that a transient rise in depletion force, likely triggered by the relocation of macromolecules (proteins, RNAs and others) via nuclear envelope breakdown and also by a subsequent decrease in cell-volumes, contributes to mitotic chromosome condensation, shedding light on a new aspect of the condensation mechanism in living human cells.

Significance Statement

Mitotic chromosome condensation is an essential process to transmit replicated chromosomes into two daughter cells during cell division. To study the underlying physical principles of this process, we focused on depletion force/macromolecular crowding, which is a force that attracts large structures in crowded cell environments. Using newly developed special light microscopy, which can image the molecular density of cellular environments, we found that crowding around chromosomes increases during cell division.In vitro, higher concentrations of macromolecules condense chromatin and make it stiffer and more solid-like. Our results suggest that the rise in depletion force renders chromosomes more rigid, ensuring accurate chromosome transmission during cell division.
eIF3 engages with 3’-UTR termini of highly translated mRNAs
Authors: Mestre-Fos Santi , Ferguson Lucas , Trinidad Marena , Ingolia Nicholas T. , Cate Jamie H. D.
Published: November 2023

Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.
Modelling the transmission and spread of yellow fever in forest landscapes with different spatial configurations
Authors: Medeiros-Sousa Antônio Ralph , Lange Martin , Mucci Luis Filipe , Marrelli Mauro Toledo , Grimm Volker
Published: November 2023

Yellow fever (YF) is a major public health issue in tropical and subtropical areas of Africa and South America. The disease is caused by the yellow fever virus (YFV), an RNA virus transmitted to humans and other animals through the bite of infected mosquitoes (Diptera: Culicidae). In Brazil and other South American countries, YFV is restricted to the sylvatic cycle, with periodic epizootic outbreaks affecting non-human primate (NHP) populations and preceding the emergence of human infections in areas close to forests. In recent epizootic-epidemic waves, the virus has expanded its range and spread across highly fragmented landscapes of the Brazilian Atlantic coast. Empirical evidence has suggested a possible relationship between highly fragmented areas, increased risk of disease in NHP and humans, and easier permeability of YFV through the landscape. Here, we present a hybrid compartmental and network-based model to simulate the transmission and spread of YFV in forest landscapes with different spatial configurations (forest cover and edge densities) and apply the model to test the hypothesis of faster virus percolation in highly fragmented landscapes. The model was parameterized and tested using the pattern- oriented modelling approach. Two different scenarios were simulated to test variations in model outputs, a first where the landscape has no influence on model parameters (default) and a second based on the hypothesis that edge density influences mosquito and dead-end host abundance and dispersal (landscape-dependent). The model was able to reproduce empirical patterns such as the percolation speed of the virus, which presented averages close to 1 km/day, and provided insights into the short persistence time of the virus in the landscape, which was approximately three months on average. When assessing the speed of virus percolation across landscapes, it was found that in the default scenario virus percolation tended to be faster in landscapes with greater forest cover and lower edge density, which contradicts empirical observations. Conversely, in the landscape- dependent scenario, virus percolation was faster in landscapes with high edge density and intermediate forest cover, supporting empirical observations that highly fragmented landscapes favour YFV spread. The proposed model can contribute to the understanding of the dynamics of YFV spread in forested areas, with the potential to be used as an additional tool to support prevention and control measures. The potential applications of the model for YFV and other mosquito-borne diseases are discussed.
Turnover ofPPP1R15AmRNA encoding GADD34 controls the molecular memory of the cellular integrated stress response
Authors: Magg Vera , Manetto Alessandro , Kopp Katja , Wu Chia Ching , Naghizadeh Mohsen , Lindner Doris , Eke Lucy , Welsch Julia , Kallenberger Stefan M. , Schott Johanna , Haucke Volker , Locker Nicolas , Stoecklin Georg , Ruggieri Alessia
Published: November 2023

The integrated stress response (ISR) is a key cellular signaling pathway activated by environmental alterations that represses protein synthesis to restore homeostasis. To prevent sustained damage, the ISR is counteracted by the upregulation of Growth Arrest and DNA Damage inducible 34 (GADD34), a stress-induced regulatory subunit of protein phosphatase 1 that mediates translation reactivation and stress recovery. Here, we uncover a novel ISR regulatory mechanism that post-transcriptionally controls the stability ofPPP1R15AmRNA encoding GADD34. We established that the 3’ untranslated region ofPPP1R15AmRNA contains an active AU-rich element recognized by proteins of the ZFP36 family, promoting its rapid decay under normal conditions and stabilization for efficient expression of GADD34 in response to stress. We identify the tight temporal control ofPPP1R15AmRNA turnover as a key step in establishing the ISR molecular memory, which sets the threshold for cellular responsiveness and mediates adaptation to repeated stress conditions.
Bacterial aggregation triggered by low-level antibiotic-mediated lysis
Authors: Tavaddod Sharareh , Dawson Angela , Allen Rosalind J
Published: November 2023

Suspended bacterial aggregates play a central role in ocean biogeochemistry, industrial processes and probably many clinical infections – yet the factors that trigger aggregation remain poorly understood, as does the relationship between suspended aggregates and surface-attached biofilms. Here we show that very low doses of cell-wall targeting antibiotic, far below the minimal inhibitory concentration, can trigger aggregation ofEscherichia colicells. This occurs when a few cells lyse, releasing extracellular DNA – thus, cell-to-cell variability in antibiotic response leads to population-level aggregation. Although lysis-triggered aggregation echoes known trigger mechanisms for surface-attached biofilms, these aggregates appear to be of a distinct type, since they do not show typical biofilm characteristics such as protection from antibiotics, or increased biofilm-forming potential. Our work contributes to understanding the nature of bacterial aggregates and the factors that trigger their formation, and the consequences of widespread low-dose antibiotic exposure in the environment and in the body.
Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake
Authors: Long Juan , Ma Meng , Chen Yuting , Gong Bo , Zheng Yi , Li Hao , Yang Jing
Published: November 2023

The regulation of cellular metabolism and growth in response to nutrient availability is essential for cell survival and can significantly impact lifespan. Central to the regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this work, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate inS. cerevisiae, as a key gene for regulating lifespan. We performed a systematic analysis to delineate the downstream mechanism underlying the lifespan extension by SUL1 deletion. Surprisingly, we found that the lifespan extending effect of SUL1 deletion is not caused by decreased sulfate transport. SUL1 deletion mutant exhibited decreased PKA signaling, resulting in a range of downstream effects, including increased stress-protective trehalose and glycogen, increased nuclear translocation of MSN2 and elevated expression of general stress response genes, enhanced autophagy, and reduced expression of amino acid biosynthetic and ribosomal genes. We show that the observed increase in lifespan is dependent on MSN2 and autophagy pathways. Our findings exemplify the influence of nutrient signaling, rather than the nutrient itself, on lifespan regulation and further substantiate the pivotal role of the PKA pathway in this process.
Expansion of human centromeric arrays in cells undergoing break-induced replication
Authors: Showman Soyeon , Talbert Paul B. , Xu Yiling , Adeyemi Richard O. , Henikoff Steven
Published: November 2023

Human centromeres are located within α-satellite arrays and evolve rapidly, which can lead to individual variation in array lengths. Proposed mechanisms for such alterations in lengths are unequal cross-over between sister chromatids, gene conversion, and break-induced replication. However, the underlying molecular mechanisms responsible for the massive, complex, and homogeneous organization of centromeric arrays have not been experimentally validated. Here, we use droplet digital PCR assays to demonstrate that centromeric arrays can expand and contract within ~20 somatic cell divisions of a cell line. We find that the frequency of array variation among single-cell-derived subclones ranges from a minimum of ~7% to a maximum of ~100%. Further clonal evolution revealed that centromere expansion is favored over contraction. We find that the homologous recombination protein RAD52 and the helicase PIF1 are required for extensive array change, suggesting that centromere sequence evolution can occur via break-induced replication.
Cell type-specific effects of age and sex on human cortical neurons
Authors: Chien Jo-Fan , Liu Hanqing , Wang Bang-An , Luo Chongyuan , Bartlett Anna , Castanon Rosa , Johnson Nicholas D. , Nery Joseph R. , Osteen Julia , Li Junhao , Altshul Jordan , Kenworthy Mia , Valadon Cynthia , Liem Michelle , Claffey Naomi , O’Connor Caz , Seeker Luise A , Ecker Joseph R. , Behrens M. Margarita , Mukamel Eran A.
Published: November 2023

Excitatory and inhibitory neurons establish specialized identities early in life through cell type-specific patterns of epigenetic regulation and gene expression. Although cell types are largely stable throughout the lifespan, altered transcriptional and epigenetic regulation may contribute to cognitive changes with advanced age. Using single-nucleus multiomic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex samples from young adult and aged donors, we found widespread age- and sex-related variability in specific neuronal cell types. The proportion of GABAergic inhibitory cells, including SST and VIP expressing cells, was reduced in aged donors. On the other hand, excitatory neurons had more profound age-related changes in their gene expression and DNA methylation compared with inhibitory cells. Hundreds of genes involved in synaptic activity were downregulated, while genes located in subtelomeric regions were upregulated with age and anti-correlated with telomere length. We further mapped sex differences in autosomal gene expression and escape from X-inactivation in specific neuron types. Multiomic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.
Discrete synaptic events induce global oscillations in balanced neural networks
Authors: Goldobin Denis S. , di Volo Matteo , Torcini Alessandro
Published: November 2023

Neural dynamics is triggered by discrete synaptic inputs of finite amplitude. However, the neural response is usually obtained within the diffusion approximation (DA) representing the synaptic inputs as Gaussian noise. We derive a mean-field formalism encompassing synaptic shot-noise for sparse balanced networks of spiking neurons. For low (high) external drives (synaptic strenghts) irregular global oscillations emerge via continuous and hysteretic transitions, correctly predicted by our approach, but not from the DA. These oscillations display frequencies in biologically relevant bands.