bluuebunny/crossref_metadata_2025 huggingface dataset:
A generalized numerical model for clonal growth in scleractinian coral colonies
Authors: Llabrés Eva , Re Eleonora , Pluma Naira , Sintes Tomàs , Duarte Carlos M.
Published: September 2024

Coral reefs, vital ecosystems supporting diverse marine life, are primarily shaped by the clonal expansion of coral colonies. Although the principles of coral clonal growth, involving polyp division for spatial extension, are well-understood, numerical modelling efforts are notably scarce in the literature. In this article, we present a parsimonious numerical model based on the cloning of polyps, using five key parameters to simulate a range of coral shapes. The model is agent-based, where each polyp represents an individual. The colony’s surface expansion is dictated by the growth mode parameter (
s
), guiding the preferred growth direction. Varying
s
facilitates the emulation of diverse coral shapes, including massive, branching, cauliflower, columnar and tabular colonies. Additionally, we introduce a novel approach for self-regulatory branching, inspired by the intricate mesh-like canal system and internode regularity observed in
Acropora
species. Through a comprehensive sensitivity analysis, we demonstrate the robustness of our model, paving the way for future applications that incorporate environmental factors, such as light and water flow. Coral colonies are known for their high plasticity, and understanding how individual polyps interact with each other and their surroundings to create the reef structure has been a longstanding question in the field. This model offers a powerful framework for studying these interactions, enabling a future implementation of environmental factors and the possibility of identifying the key mechanisms influencing coral colonies’ morphogenesis.
Comparative genome analyses of Staphylococcus aureus from platelet concentrates reveal rearrangements involving loss of type VII secretion genes
Authors: Ighem Chi Sylvia , Flint Annika , Weedmark Kelly , Pagotto Franco , Ramirez-Arcos Sandra
Published: September 2024

Staphylococcus aureushas been involved in transfusion-transmitted fatalities associated with platelet concentrates (PCs) due to its heightened pathogenicity enhanced by genome-encoded virulence and antibiotic resistance genes. This may be facilitated by mobile genetic elements (MGEs) that can cause rearrangements. Several factors contribute toS. aureusvirulence, including the type VII secretion system (T7SS), composed of six core genes conserved acrossS. aureusstrains. In this study, we conducted comparative genome analyses of fiveS. aureusisolates from PCs (CI/BAC/25/13 /W, PS/BAC/169/17 /W and PS/BAC/317/16 /W were detected during PCs screening with the BACT/ALERT automated culture system, and ATR-20003 and CBS2016-05 were missed during screening and caused septic transfusion reactions). Multiple alignments of the genomes revealed evidence of rearrangements involving phage Sa3int in PS/BAC/169/17 /W and PS/BAC/317/16 /W. While the former had undergone translocation of its immune evasion cluster (IEC), the latter had lost part of the phage, leaving behind the IEC. This observation highlightsS. aureusgenome plasticity. Unexpectedly, strain CBS2016-05 was found to encode a pseudo-type VII secretion system (T7SS) that had lost five of the conserved core genes (esxA,esaA, essA, esaBandessB) and contained a 5′ truncatedessC. Since these genes are essential for the function of the T7SS protein transport machinery, which plays a key role inS. aureusvirulence, CBS2016-05 probably compensates by recruiting other export mechanisms and/or alternative virulence factors, such as neu-tralizing immunity proteins. This study unravels genome rearrangements inS. aureusisolated from PCs and reports the firstS. aureusisolate lacking conserved T7SS core genes.
Neural Dynamics Underlying False Alarms in Extrastriate Cortex
Authors: Sahoo Bikash , Snyder Adam C.
Published: September 2024

The unfolding of neural population activity can be approximated as a dynamical system. Stability in the latent dynamics that characterize neural population activity has been linked with consistency in animal behavior, such as motor control or value-based decision-making. However, whether similar dynamics characterize perceptual activity and decision-making in the visual cortex is not well understood. To test this, we recorded V4 populations in monkeys engaged in a non-match-to-sample visual change-detection task that required sustained engagement. We measured how the stability in the latent dynamics in V4 might affect monkeys’ perceptual behavior. Specifically, we reasoned that unstable sensory neural activity around dynamic attractor boundaries may make animals susceptible to taking incorrect actions when withholding action would have been correct (“false alarms”). We made three key discoveries: 1) greater stability was associated with longer trial sequences; 2) false alarm rate decreased (and reaction times slowed) when neural dynamics were more stable; and, 3) low stability predicted false alarms on a single-trial level, and this relationship depended on the elapsed time during the trial, consistent with the latent neural state approaching an attractor boundary. Our results suggest the same outward false alarm behavior can be attributed to two different potential strategies that can be disambiguated by examining neural stability: 1) premeditated false alarms that might lead to greater stability in population dynamics and faster reaction time and 2) false alarms due to unstable sensory activity consistent with misperception.
PSMA-specific CAR-engineered macrophages for therapy of prostate cancer
Authors: Xu Yangli , Xie Duoli , Cao Chunhao , Ju Yue , Chen Xinxin , Guan Lili , Li Xuelong , Zhang Luo , Liang Chao , Yin Xiushan
Published: September 2024

Chimeric antigen receptor (CAR)-modified macrophages (CAR-Ms) are a promising approach for the treatment of solid tumors due to its high infiltration and immune-regulation activity. Prostate cancer is a typical solid tumor associated with highly immunosuppressive microenvironment. To date, the potential application of CAR-M cell therapy in prostate cancer has been infrequently explored. The prostate-specific membrane antigen (PSMA) functions as a specific biomarker for prostate cancer. In this study, we assessed the antitumor efficacy of PSMA-targeted CAR-Ms in preclinical models. CAR-Ms were engineered to express a PSMA-specific single-chain variable fragment (scFv) and co-stimulatory domains. In vitro data demonstrated specific cytotoxicity of CAR-Ms against PSMA-expressing prostate cancer cells, which was further supported by transcriptome analysis demonstrating the pro-inflammatory phenotypes of CAR-Ms. In vivo studies using xenograft mouse models confirmed significant tumor regression after administration of PSMA-targeted CAR-Ms compared to controls. Histopathological analysis showed infiltration of CAR-Ms into tumor tissues without off-target toxicity. These results highlight the strong antitumor activity and safety of PSMA-targeted CAR-Ms, supporting their potential as a new immunotherapy for prostate cancer.
Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model
Authors: Dharavath Ravinder N. , Bernardo Ashley M. , Marceau-Linhares Cassandra , Marcotte Michael , Wong Kayla , Pina-Leblanc Celeste , Bouchet Adrien , Sharmin Dishary , Pandey Kamal P. , Cook James M. , Prevot Thomas D. , Sibille Etienne L.
Published: September 2024

Background

Dysregulated tau phosphorylation is one of the hallmarks of Alzheimer’s disease (AD), and it results in cognitive impairments, neuronal atrophy, and neurofibrillary tangle accumulation. Evidence shows that impaired somatostatin (SST) expression, particularly in SST-expressing GABAergic neurons, significantly contributes to AD-related pathophysiology and may increase cognitive burden. Additionally, SST+ interneurons in cortical layers and the hippocampus inhibit the dendrites of excitatory neurons, primarily through α5-GABAA receptors involved in cognitive regulation. Leveraging the potential of a newly developed small molecule that targets the α5-GABAA receptors via positive allosteric modulation (α5-PAM), we aim to assess its effects on tau phosphorylation-related neuronal morphology, cognitive deficits and protein expression.

Methods

In the PS19 transgenic mouse mode, we administered the α5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months. We assessed spatial working memory using the Y-maze. Golgi staining analyzed dendritic morphology in chronically exposed mice to α5-PAM. Western blotting was used to quantify p-Tau and Tau expression.

Results

α5-PAM effectively reverses spatial working memory deficits induced by tau phosphorylation both acutely and chronically. Chronic treatment at 3and 6 months mitigates tau-induced loss of spine density. However, α5-PAM does not directly influence p-Tau levels, suggesting cognitive and neurotrophic benefits of GL-II-73s are independent of Tau burden.

Conclusions

These results demonstrate the potential for both symptomatic and disease-modifying effects, highlighting the promise of α5-GABAA receptor positive allosteric modulation as a novel therapeutic strategy for addressing cognitive deficits associated with tau phosphorylation in AD pathology.
ElixirSeeker: A Machine Learning Framework Utilizing Attention-Driven Fusion of Molecular Fingerprints for the Discovery of Anti-Aging Compounds
Authors: Pan Yan , Cai Hongxia , Ye Fang , Xu Wentao , Huang Zhihang , Zhu Jingyuan , Gong Yiwen , Li Yutong , Ezemaduka Anastasia Ngozi , Gao Shan , Liu Shunqi , Li Guojun , Li Hao , Yang Jing , Ning Junyu , Xian Bo
Published: September 2024

Despite the growing interest in anti-aging drug development, high cost and low success rate pose a significant challenge. We present ElixirSeeker, a new machine-learning framework designed to help speed up the discovery of potential anti-aging compounds by utilizing the attention-driven fusion of molecular fingerprints. Our approach integrates molecular fingerprints generated by different algorithms and utilizes XGBoost to select optimal fingerprint lengths. Subsequently, we assign weights to the molecular fingerprints and employ Kernel Principal Component Analysis (KPCA) to reduce dimensionality, integrating different attention-driven methods. We trained the algorithm using DrugAge database. Our comprehensive analyses demonstrate that 64-bit Attention-ElixirFP maintains high predictive accuracy and F1 score while minimizing computational cost. Using ElixirSeeker to screen external compound databases, we identified a number of promising candidate anti-aging drugs. We tested top 6 hits and found that 4 of these compounds extend the lifespan of Caenorhabditis elegans, including Polyphyllin Ⅵ, Medrysone, Thymoquinone and Medrysone. This study illustrates that attention-driven fusion of fingerprints maximizes the learning of molecular activity features, providing a novel approach for high-throughput machine learning discovery of anti-aging molecules.
Binocular integration of prey stimuli in the zebrafish visual system
Authors: Tian Guangnan , Chung Lam Thomas Ka , Yan Gewei , He Yingzhu , Khan Biswadeep , Qu Jianan Y. , Semmelhack Julie L.
Published: September 2024

Most animals with two eyes combine the inputs to achieve binocular vision, which can serve numerous functions, and is particularly useful in hunting prey. However, the mechanisms by which visual information from the two eyes are combined remain largely unknown. Here, we designed a device to reversibly occlude the eyes of a head-fixed zebrafish larva, and used large-scale volumetric two-photon imaging to identify binocular neurons that respond to prey stimuli. We found these binocular prey-responsive neurons (bino-PRNs) were primarily located in three areas, the pretectum, thalamus, and nucleus isthmi. We then characterized the bino-PRNs’ functional properties, and found that their left and right eye receptive fields are offset to varying degrees, which would correspond to objects at naturalistic hunting distances for a larva with converged eyes. We also found that bino-PRNs have a significantly greater response in hunting trials, which could be the result of an eye convergence-related corollary discharge. We then optogenetically induced prey capture eye and tail movements, and found that this hunting command activates prey responsive neurons in the pretectum, thalamus, and nucleus isthmi. These findings indicate that bino-PRNs receive visual and motor input that would allow them to encode prey position in three dimensions.
IL-1β-mediated Immunometabolic Adaptation in Corneal Epithelial Cells
Authors: Sanches Jose Marcos , Ramachandra Rajalakshmy Ayilam , Mussi Natalia , Baniasadi Hamid , Robertson Danielle M.
Published: September 2024

Purpose

As an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1β, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1β have been associated with corneal disease, the effects of IL-1β on mitochondrial function in corneal epithelial cells (CECs) is unknown.

Methods

To investigate the effects of IL-1β on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1β for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy.

Results

Short term exposure to IL-1β triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin andde novotriacylglyceride biosynthesis, along with increasing numbers of lipid droplets.

Conclusion

Prolonged exposure to IL-1β induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.
Sequential ATR and PARP Inhibition Overcomes Acquired DNA Damaging Agent Resistance in Pancreatic Ductal Adenocarcinoma
Authors: Herbert Katharine J , Upstill-Goddard Rosie , Dreyer Stephan B , Rebus Selma ,   Australian Pancreatic Cancer Genome Initiative, Pilarsky Christian , Mukhopadhyay Debabrata , Lord Christopher J. ,   Genomics Innovation Alliance, Biankin Andrew V , Froeling Fieke E.M. , Chang David K
Published: September 2024

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer and will soon be the second most common cause of cancer related death. While regimens containing DNA damaging agents such as FOLFIRINOX and PARP inhibitors have derived clinical benefits for some patients, their efficacy invariably fails over time. This presents a significant clinical challenge, and thus there is an urgent need for novel therapeutic strategies which are able to overcome the acquisition of resistance in PDAC. Clinically relevant models of treatment resistance were generated from patient-derived cell lines by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity assays, flow cytometry, immunofluorescence and transcriptomic analysis were used to investigate the efficacy of combined ATR and PARP inhibition in re-sensitising resistant PDAC to treatment. Acquisition of resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death and the replication stress response. Additionally, combined treatment with the ATR inhibitor (ceralasertib), and the PARP inhibitor (olaparib) was synergistic in all models of acquired resistance. Sequential treatment using ceralasertib prior to olaparib was highly effective at low dose for DDR proficient cell lines, whereas DDR deficient models responded better when treated with olaparib first. We provide in vitro evidence of a novel therapeutic strategy to overcome acquired PARP inhibitor and platinum resistance in PDAC by using sequential exposure to ceralasertib and olaparib. A sequential regimen may be more tolerable and should be investigated clinically to circumvent dose limiting toxicity in concurrent combinations.
G3BP1 Maintains Vascular Endothelial Barrier Integrity by Negatively Regulating the MYD88-ARNO-ARF6 Signaling Pathway
Authors: Sun Weiyue , Wu Haoran , He Yuxi , Chen Huiqiao , Meng Yuanhui , Tang Guofang , Zhu Jinshun , Wen Zhengwang , Wu Rongzhou , Wu Guowei , Zhang Chunxiang , Chu Maoping , Wen Bin
Published: September 2024

Endothelial permeability is essential for vascular function. This process is regulated by intercellular junctions, including adherens junctions (AJs) and tight junctions (TJs), which form the endothelial barrier and dynamically connect adjacent cells. However, the mechanisms that control endothelial permeability are not fully understood.

We investigated the role of the RNA-binding protein G3BP1 in regulating endothelial permeability. We examined the effects of Loss of g3bp1 in conditional knockout mice and primary human HUVEC cells. We analyzed endothelial barrier integrity and permeability, focusing on AJ and TJ expression, under both normal and LPS-induced inflammatory conditions.

Loss of g3bp1 in vascular endothelial cells decreased AJ and TJ expression, compromised barrier integrity, and increased permeability. These effects were exacerbated under LPS-induced inflammatory conditions. Loss of g3bp1 also increased the expression of MYD88, ARNO, and ARF6, and enhanced ARF6 activity. Mechanistically, G3BP1 bound to and stabilized MYD88 mRNA, negatively regulating the MYD88-ARNO-ARF6 signaling pathway. Inhibiting this pathway by reducing MYD88 or ARF6 expression, or inhibiting ARNO activity, restored AJ/TJ expression and barrier function in G3BP1-deficient models.

Our findings identify G3BP1 as a novel regulator of vascular endothelial permeability. G3BP1 acts by negatively regulating the MYD88-ARNO-ARF6 signaling pathway. Targeting G3BP1 may be a potential therapeutic strategy for diseases associated with endothelial barrier dysfunction.
Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions
Authors: Vattathil Selina M , Gerasimov Ekaterina S , Canon Se Min , Lori Adriana , Tan Sarah Sze Min , Kim Paul J , Liu Yue , Lai Eric C , Bennett David A C. , Wingo Thomas S , Wingo Aliza P
Published: September 2024

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.
An integrated stress response-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation
Authors: Roman-Trufero Monica , Kleijn Istvan T , Blighe Kevin , Zhou Jinglin , Saavedra-Garcia Paula , Gaffar Abigail , Christoforou Marilena , Bellotti Axel , Abrahams Joel , Atrih Abdelmadjid , Lamont Douglas J , Gierlinski Marek , Jayaprakash Pooja , Michel Audrey M , Aboagye Eric , Yuneva Mariia , Masson Glenn R , Shahrezaei Vahid , Auner Holger W
Published: September 2024

The Integrated Stress Response (ISR) is a corrective physiological program to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omic approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations define an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.
Context- and sex-dependent links between sire sexual success and offspring pathogen resistance
Authors: Liao Aijuan , Kawecki Tadeusz J.
Published: September 2024

Sexual selection has been proposed to promote genetic variants that improve resistance to pathogens (a special case of the "good genes" hypothesis). Yet, experimental tests of this hypothesis are scarce and equivocal. It is often assumed that additive genetic correlation between sexual traits and pathogen resistance is generated by their shared dependence on genetically variable "condition" of the organism. However, an alternative scenario posits condition-independent genetic variation in pathogen resistance; individuals more resistant to currently prevalent pathogens remain healthier and can invest more in sexual traits, but this advantage disappears in the absence of pathogens. Here, we tested whether Drosophila melanogaster males that are more sexually competitive (in terms of paternity share) sire offspring that are more resistant to the fungal pathogen Metarhizium brunneum. Furthermore, to investigate the importance of epidemiological context, we exposed sires to either an infection or a sham treatment before mating, to test whether the sire-offspring relationship depends on the presence of pathogens during sexual selection. We found that the relationship between sires sexual success and offspring pathogen resistance not only depended on sires exposure to the pathogen, but also on offspring sex. Sires that were more sexually successful in the absence of the pathogen had less resistant offspring whereas no relationship was detected for sires that competed for paternity after pathogen exposure. For daughters, the relationship tended to be negative irrespective of sire pathogen exposure. In no case was a positive correlation predicted by the "good genes" hypothesis detected. Thus, while sexual selection may act on genes affecting resistance in a context- and sex-dependent manner, we found no circumstances under which it promoted resistance.
Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumourigenesis
Authors: Lim Bryce , Kamal Aryan , Gomez Ramos Borja , Adrian Segarra Juan , Ibarra Ignacio , Dignas Lennart , Kindinger Tim , Volz Kai , Rahbari Mohammad , Rahbari Nuh , Poisel Eric , Kafetzopoulou Kanela , Bose Lio , Breinig Marco , Heide Danijela , Gallage Suchira , Barragan Avila Jose , Wiethoff Hendrik , Berest Ivan , Schnabellehner Sarah , Schneider Martin , Becker Jonas , Helm Dominic , Grimm Dirk , Makinen Taija , Tschaharganeh Darjus , Heikenwalder Mathias , Zaugg Judith B , Mall Moritz
Published: September 2024

Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and acted as a tumour suppressor in multiple liver cancer models. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo, and promoted transition of hepatocellular carcinoma to cholangiocarcinoma, conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.
A genome-wide association screen for genes affecting leaf trichome development and epidermal metal accumulation in Arabidopsis
Authors: Bezvoda Radek , Landeo-Ríos Yazmín Mónica , Kubátová Zdeňka , Kollárová Eva , Kulich Ivan , Busch Wolfgang , Žárský Viktor , Cvrčková Fatima
Published: September 2024

To identify novel genes engaged in plant epidermal development, we characterized the phenotypic variability of rosette leaf epidermis of 310 sequencedArabidopsis thalianaaccessions, focusing on trichome shape and distribution, compositional characteristics of the trichome cell wall, and histologically detectable metal ion distribution. Some of these traits correlated with climate parameters of ourq accession’s locations of origin, suggesting environmental selection. A novel metal deposition pattern in stomatal guard cells was observed in some accessions. Subsequent GWAS analysis identified 1546 loci with protein sequence-altering SNPs associated with one or more traits, including 5 genes with previously reported relevant mutant phenotypes and 80 additional genes with known or predicted roles in relevant developmental and cellular processes. Some candidates, including GFS9/TT9, exhibited environmentally correlated allele distribution. Several large gene families, namely DUF674, DUF784, DUF1262, DUF1985, DUF3741, cytochrome P450, receptor-like kinases, Cys/His-rich C1 domain proteins and formins were overrepresented among the candidates for various traits, suggesting epidermal development-related functions. A possible participation of formins in guard cell metal deposition was supported by observations in available loss of function mutants. Screening of candidate gene lists against the STRING interactome database uncovered several predominantly nuclear protein interaction networks with possible novel roles in epidermal development.
LM11a-31 Inhibits p75 Neurotrophin Receptor (p75NTR) Cleavage and is Neuroprotective in a Cell Culture Model of Parkinson’s Disease
Authors: Pokharel Poshan V. , Newchurch Aaron M. , Overby Sunny C. , Spease Cassidy A. , Darzi Lorelei G. , Kraemer Bradley R.
Published: September 2024

The p75 Neurotrophin Receptor (p75NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75NTRsignaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75NTRin this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson’s disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75NTRsignaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75NTRby promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75NTRfrom the cell surface. This activation of p75NTRsignaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75NTRprocessing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75NTRcleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75NTRin response to oxidative stress, underscore a key role for p75NTRin dopaminergic neurodegeneration, and highlight p75NTRas a potential therapeutic target for reducing neurodegeneration in PD.
Whole genome sequencing of hepatitis B virus (HBV) using tiled amplicon (HEP-TILE) and probe-based enrichment on Illumina and Nanopore platforms
Authors: Lumley Sheila F , Kent Chris , Jennings Daisy , Chai Haiting , Airey George , Waddilove Elizabeth , Delphin Marion , Trebes Amy , McNaughton Anna L , Mohammed Khadija Said , Wilkinson Sam , Wu Yanxia , MacIntyre-Cockett George , Kimono Beatrice , Kwizera Moses , Ojambo Kevin , Maponga Tongai G , de Lara Catherine , Martin Jacqueline , Campbell James , Van Schalkwyk Marije , Goedhals Dominique , Newton Robert , Barnes Eleanor , Loman Nicholas J , Piazza Paolo , Quick Joshua , Ansari M Azim , Matthews Philippa C
Published: September 2024

Hepatitis B virus (HBV) whole genome sequencing (WGS) is currently limited as the DNA viral loads (VL) of many clinical samples are below the threshold required to generate full genomes using current sequencing methods. We developed two pan-genotypic viral enrichment methods, using probe-based capture and tiled amplicon PCR (HEP-TILE) for HBV WGS. We demonstrate using mock samples that both enrichment methods are pan-genotypic (genotypes A-J). Using clinical samples, we demonstrate that HEP-TILE amplification successfully amplifies full genomes at the lowest HBV VL tested (30 IU/ml), and the PCR products can be sequenced using both Nanopore and Illumina platforms. Probe-based capture with Illumina sequencing required VL >300,000 IU/ml to generate full length HBV genomes. The capture-Illumina and HEP-TILE-Nanopore pipelines had consensus sequencing accuracy of 100% in mock samples with known DNA sequences. Together, these protocols will facilitate the generation of HBV sequence data, enabling a more accurate and representative picture of HBV molecular epidemiology, cast light on persistence and pathogenesis, and enhance understanding of the outcomes of infection and its treatment.
Rising prevalence ofPlasmodium falciparumartemisinin resistance mutations in Ethiopia
Authors: Brhane Bokretsion G. , Fola Abebe A. , Nigussie Helen , Leonetti Alec , Kassa Moges , Hailgiorgis Henok , Wuletaw Yonas , Abera Adugna , Mohammed Hussein , Sime Heven , G/Tsadik Abeba , Assefa Gudissa , Solomon Hiwot , Tasew Geremew , Tollera Getachew , Hailu Mesay , Juliano Jonathan J. , Assefa Ashenafi , Parr Jonathan B. , Bailey Jeffrey A.
Published: September 2024

Ethiopia is striving to eliminate local malaria transmission by 2030, despite a recent resurgence of malaria cases due to multiple factors. A significant contributor to this resurgence could be drug resistance, particularly the emergence of partial resistance to artemisinin (ArtR) in Ethiopia and other regions of Eastern Africa. This situation highlights the necessity for genomic surveillance to monitor relevant drug resistance markers. This study reports sentinel site-based genomic surveillance results forP. falciparumantimalarial drug resistance mutations. From 2019 to 2022, dried blood spots (DBS) were collected from febrile outpatients ≥1 year of age with microscopically confirmed falciparum malaria at 12 sentinel sites across 5 regions. Molecular inversion probe (MIP) sequencing targeted mutations associated with artemisinin and partner drug resistance, includingk13,mdr1, crt, dhfr,anddhpsgenes, along with genome-wide markers to assess the complexity of infection (COI) and parasite relatedness. A total of 1,199 falciparum-positive patients were assessed, with a median age of 20 years (IQR: 14-30) and including 463 (38.6%) females. The WHO-validated K13 R622I mutation had a high but regionally variable prevalence (15.7%, range 0-58.8%). The validated K13 A675V mutation was detected for the first time in Ethiopia in the Gambella Region (4.5%), as well as P441L and P574L mutations were detected at low frequencies in Southern and Oromia Regions, respectively. Several partner drug resistance markers were identified, with mutations in MDR1(184F), DHPS, DHFR, and CRT nearly fixed across the country. Most samples (87.2%) were monogenic infections (COI=1) and showed high genetic relatedness, particularly within the health facilities. Principal component analysis revealed regional clustering of parasites, particularly in Gambella. The prevalence of K13 R622I across the country and the presence of multiple additional ArtR markers emphasizes the urgent need for rigorous monitoring of artemisinin combination therapy (ACT) efficacy to detect partner drug resistance and ACT failure early and its impact on malaria resurgence in Ethiopia.
How does date-rounding affect phylodynamic inference for public health?
Authors: Featherstone Leo A. , Ingle Danielle J. , Wirth Wytamma , Duchene Sebastian
Published: September 2024

Phylodynamic analyses enable the inference of epidemiological parameters from pathogen genome sequences for enhanced genomic surveillance in public health. Pathogen genome sequences and their associated sampling times are the essential data in every analysis. However, sampling times are usually associated with hospitalisation or testing dates and can sometimes be used to identify individual patients, posing a threat to patient confidentiality. To lower this risk, sampling times are often given with reduced date-resolution to the month or year, which can potentially bias inference of epidemiological parameters. Here, we characterise the extent to which reduced date-resolution biases phylodynamic analyses across a diverse range of empirical and simulated datasets. We develop a practical guideline on when date-rounding biases phylodynamic inference and we show that this bias is both unpredictable in its direction and compounds with decreasing date-resolution, higher substitution rates, and shorter sampling intervals. We conclude by discussing future solutions that prioritise patient confidentiality and propose a method for safer sharing of sampling dates by translating them uniformly by a random number.
Anatomically distinct regions in the inferior frontal cortex are modulated by task and reading skill
Authors: Stone Hannah L , Mitchell Jamie L , Fuentes-Jimenez Mia , Tran Jasmine E , Yeatman Jason D , Yablonski Maya
Published: September 2024

Inferior frontal cortex (IFC) is a critical region for reading and language. This part of the cortex is highly heterogeneous in its structural and functional organization and shows high variability across individuals. Despite decades of research, the relationship between specific IFC regions and reading skill remains unclear. To shed light on the function of IFC in reading, we aim to (1) characterize the functional landscape of text-selective responses in the IFC, while accounting for interindividual variability; and (2) examine how text-selective regions in the IFC relate to reading proficiency. To this end, children with a wide range of reading ability (N=66; age 7-14 years, 34 female, 32 male) completed functional MRI scans while performing two tasks on text and non-text visual stimuli. Importantly, both tasks do not explicitly require reading, and can be performed on all visual stimuli. This design allows us to tease apart stimulus-driven responses from task-driven responses and examine where in the IFC task and stimulus interact. We were able to identify three anatomically-distinct, text-selective clusters of activation in the IFC, in the inferior frontal sulcus (IFS), and dorsal and ventral precentral gyrus (PrG). These three regions showed a strong task effect that was highly specific to text. Furthermore, text-selectivity in the IFS and dorsal PrG was associated with reading proficiency, such that better readers showed higher selectivity to text. These findings suggest that text-selective regions in the IFC are sensitive to both stimulus and task, and highlight the importance of this region for proficient reading.
Protein identification using cryo-EM and artificial intelligence guides improved sample purification
Authors: Carr Kenneth D. , Zambrano Dane Evan D. , Weidle Connor , Goodson Alex , Eisenach Helen E. , Pyles Harley , Courbet Alexis , King Neil P. , Borst Andrew J.
Published: September 2024

Protein purification is essential in protein biochemistry, structural biology, and protein design. It enables the determination of protein structures, the study of biological mechanisms, and the biochemical and biophysical characterization of both natural and de novo designed proteins. Despite the broad application of various protein purification protocols, standard strategies can still encounter challenges, such as the unintended co-purification of unknown contaminants alongside the target protein. In particular, co-purification issues pose significant challenges for designed self-assembling protein nanomaterials, as it is difficult to determine whether unexpected observed geometries represent novel assembly states of the designed system, cross-contamination from other assemblies, or native proteins originating from the expression host. In this study, we assessed the ability of an automated structure-to-sequence pipeline to unambiguously identify an unknown co-purifying protein found across several purified designed protein samples. Using cryo-electron microscopy (Cryo-EM), ModelAngelo’s sequence-agnostic automated model-building feature, and the Basic Local Alignment Search Tool (BLAST), we identified the unknown protein as dihydrolipoamide succinyltransferase (DLST). This identification was further confirmed by comparing the cryo-EM data with available DLST structures in the Protein Data Bank (PDB) and AlphaFold 3 predictions from the top BLAST hits. The clear identification of DLST informed our subsequent literature search and led to the rational modification of our protein purification protocol, ultimately enabling the exclusion of the contaminant from preparations of our target nanoparticle. This study demonstrates the successful application of a structure-to-sequence workflow, integrating Cryo-EM, ModelAngelo, protein BLAST, PDB structures, and AlphaFold 3 predictions, to identify and remove an unknown protein from a purified sample. It also highlights the broader potential of integrating Cryo-EM with AI-driven tools for accurate protein identification across various samples and contexts within protein science.

Highlights

An unknown protein was consistently found in multiple de novo designed protein samples.

The protein was identified as dihydrolipoamide succinyltransferase (DLST) using Cryo-EM, ModelAngelo and BLAST, and further verified using AlphaFold 3 and the PDB.

Identification enabled rational modification of the purification protocol to exclude the contaminant.

This method enables accurate protein identification without requiring near-atomic resolution or prior sequence and structural data, making it broadly applicable to various areas of protein science.

Graphical Abstract
The Impacts of Neighborhood Disparities on US Population Health During the COVID-19 Pandemic: A Literature Review and Policy Analysis for Future Response
Authors: White Brianna M. , Brakefield Whitney S. , Olusanya Olufunto A. , Prasad Rameshwari , Kumsa Fekede , Hashtarkhani Soheil , Shaban-Nejad Arash
Published: September 2024

Introduction/Background

The COVID-19 pandemic has disrupted major aspects of daily life since its emergence in late 2019, impacting health and well-being worldwide. Aside from genetic predisposition, numerous external factors play key roles in determining levels of disease susceptibility and overall health status.

Aim/Objectives

This review and policy analysis sought to examine literature focused on the impact of neighborhood environments on population health and well-being during the COVID-19 pandemic period. Examined studies explore the impacts of various aspects of the neighborhood environment (i.e., walkability, transportation, access to healthcare/vaccination, etc.) during the COVID-19 era on population health and well-being.

Methods

Databases were searched for studies published from March 2020 to August 2022. Selected studies examine the impacts of various aspects of the neighborhood environment (i.e., walkability, transportation, access to healthcare/vaccination, climate, crime rates, persistent poverty, the social spread of misinformation, etc.) during the COVID-19 era on population health and well-being.

Results

Findings from our review suggest that those living in less-than-favorable environments were faced with significant challenges, making vulnerable populations more prone to the severity of COVID-19 infection.

Conclusion

We argue these results establish cause for the consideration of the effects of neighborhood environments in developing intelligent intervention strategies for both pandemic recovery and preparation for future public health emergencies, especially among vulnerable populations.
Immunological findings of West Caucasian bat virus in an accidental host
Authors: Castellan Martina , Zamperin Gianpiero , Foiani Greta , Zorzan Maira , Priore Maria Francesca , Drzewnioková Petra , Melchiotti Erica , Vascellari Marta , Monne Isabella , Crovella Sergio , Leopardi Stefania , De Benedictis Paola
Published: September 2024

TheLyssavirusgenus includes seventeen neurotropic viral species which are able to cause rabies, an acute and almost invariably fatal encephalomyelitis of mammals. Rabies virus (RABV), the genus prototype, is a multi-host pathogen that undergoes multiple events of host-switching, thus occupying several geographical and ecological niches. In contrast, non-RABV lyssaviruses are mainly confined within a single natural host with rare spillover events never followed by adaptation to new accidental host species. In this scenario, unveiling the mechanisms underlying the host immune response against a virus is crucial to understand the dynamics of infection but also to predict the probability of colonization and adaptation to a new target species. Presently, the host response to lyssaviruses has only been partially explored, with the majority of data inferred from RABV infection, under the assumption that all members of the genus exhibit a similar behavior. Through our study we have investigated the immune response determined by the West Caucasian bat virus (WCBV). Indeed, WCBV has been recently associated with a spillover event to a domestic cat, raising concern about the risks for public health due to the circulation of the virus in its natural host. We selected the Syrian hamster as an animal model representative for an accidental host, and chose the intramuscular route in order to mimic the natural route of infection. In hamsters, WCBV was highly pathogenic, determining 100% lethality and mild encephalitis. In comparison with Duvenhage virus (DUVV) and RABV, we found that WCBV displayed an intermediate ability to promote cellular antiviral response, produce pro-inflammatory cytokines, recruit and activate lymphocytes in the hamsters’ central nervous system.

Author Summary

Viruses belonging to the genus Lyssavirus cause rabies, a zoonotic and almost invariably fatal encephalomyelitis. However, not all lyssaviruses behave in the same way, with Rabies virus (RABV) being a multi-host pathogen and non-RABV ones remaining mostly confined to their natural hosts. Host-pathogen interaction might help to elucidate the mechanisms behind the differences observed among lyssaviruses in terms of disease dynamics and ability to cross the species barrier, adapting to novel hosts. In our study, we have investigated the host immune response triggered by the WCBV strain spilled-over from its host (the bent-winged bat) to a domestic cat in 2020. Our study offers a key to understand and generalize the mechanisms underlying lyssavirus spillover and pathogenicity in accidental hosts. More generally, our work confirms and marshals previous, fragmentary evidence indicating a strong and inverse relationship between lyssavirus pathogenicity and immune response induction.
Caves as species pumps: key innovations, isolation, and periodic introgression drive the world’s largest cavefish radiation in a dynamic karstic landscape
Authors: Mao Tingru , Liu Yewei , Vasconcellos Mariana M. , Zhou Shipeng , Ellepola Gajaba , Yang Jian , Pie Marcio R. , Meegaskumbura Madhava
Published: September 2024

Species diversification is shaped by intricate interactions among biotic drivers, including gene flow, hybridization, and key innovations, and abiotic drivers, such as historical climate change, geological events, and ecological opportunity. However, the relative contributions of these drivers in large radiations remain poorly understood. We investigate the interplay among these factors in the diversification ofSinocyclocheilus, a cavefish radiation comprising 79 species.Sinocyclocheilusinclude typical surface-dwelling forms, with well-developed eyes and pigmentation, to cave-dwelling forms with regressed eyes, reduced pigmentation, and the presence of a horn and a hump. Using reduced representation genomic data (RADseq), we show extensive gene flow events across different species, with introgression playing a key role compared to incomplete lineage sorting in creating phylogenetic discordance and contributing genetic variation for cave adaptation and diversification in this group. Key traits such as eye degeneration, reduced pigmentation, and horn evolved independently multiple times, as adaptations for effectively exploiting cave environments. Furthermore, the uplift of the Tibetan plateau and the late Miocene cooling also significantly impacted speciation rates. Demographic analyses suggest population expansions during the Gonghe Movement and stability during the Last Glacial Maximum, possibly due to cave refugia. Periodic events of introgression promoted by isolation and reconnections due to the changing climate and geological activity, combined with the repeated evolution of key cave-adapted traits, are the primary drivers of this radiation. Our findings underscore the complex interplay of biotic and abiotic factors in the evolution ofSinocyclocheilusfish, offering new insights into the mechanisms of cave adaptation and diversification.