bluuebunny/crossref_metadata_2025 huggingface dataset:
Avian influenza virus circulation and immunity in a wild urban duck population prior to and during a highly pathogenic H5N1 outbreak
Authors: Wight Jordan , Rahman Ishraq , Wallace Hannah L. , Cunningham Joshua T. , Roul Sheena , Robertson Gregory J. , Russell Rodney S. , Xu Wanhong , Zhmendak Dmytro , Alkie Tamiru N. , Berhane Yohannes , Hargan Kathryn E. , Lang Andrew S.
Published: February 2024

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses were first detected in St. John’s, Newfoundland, Canada in late 2021, with the virus rapidly spreading across the western hemisphere over the next year. To investigate the patterns of avian influenza virus (AIV) infection and immune responses subsequent to the arrival of H5N1, we sampled the wild urban duck population in St. John’s for a period of 16 months after the start of the outbreak and compared these findings to archived samples. Antibody seroprevalence was relatively stable before the outbreak (2011-2014) at 27.6% and 3.9% for anti-AIV (i.e., NP) and H5-specific antibodies, respectively. During the winter of 2022, AIV-NP and H5-specific antibody seroprevalence both reached 100%, signifying a population-wide infection event. As expected, population-level immunity waned over time, and we found that ducks were seropositive for anti- AIV-NP antibodies for around twice as long as for H5-specific antibodies. The population was H5 seronegative to the latter approximately six months after the initial H5N1 incursion. In late February 2023, H5N1 clade 2.3.4.4b viruses were again detected in the duck population as a result of a second incursion into Newfoundland from Eurasia, which resulted in a second population-wide infection event. We observed a clear relationship of increasing antibody levels with decreasing viral RNA loads that allowed for interpretation of the course of infection and immune response in infected individuals and applied these findings to two cases of resampled ducks to infer infection history. Our study highlights the significance of applying both AIV surveillance and seroprevalence monitoring to provide a better understanding of AIV dynamics in wild populations, which may be crucial following the arrival of 2.3.4.4b H5Nx subtypes to assess the threats they pose to both wild and domestic animals, and to humans.
Access to community-based eye services in Meru, Kenya: a cross-sectional equity analysis
Authors: Allen Luke , Karanja Sarah , Gichangi Michael , Bunywera Cosmas , Rono Hillary , Mcleod David , Kim Min J , Tlhajoane Malebogo , Burton Matthew J , Ramke Jacqueline , Bolster Nigel M. , Bastawrous Andrew
Published: February 2024

Background: Over 80% of blindness in Kenya is due to curable or preventable causes, with an estimated 7.5 million Kenyans in need of quality eye care services. Embedding sociodemographic data collection into the national eye screening programme could help identify the groups facing systematic barriers to care. We aimed to determine the sociodemographic characteristics that are associated with access among patients diagnosed with an eye problem and referred for treatment in the national eye screening programme. Method: We used an embedded, pragmatic, cross-sectional study design. A list of sociodemographic questions was developed with input from researchers, community members, policymakers, and programme implementers. After five rounds of iteration, the final sociodemographic question set included the following domains: age, gender, religion, marital status, disability, education, occupation, income, housing, assets, and health insurance. These were integrated into an app that is used to screen, refer, and check-in (register) participants within a major eye screening programme. We gathered data from 4,240 people who screened positive during community screening and were referred to a local outreach treatment clinic in Meru County. We used logistic regression to identify groups for whom services were inaccessible. Findings: Only 46% of those who were referred to local treatment outreach clinics were able to access care. In our fully adjusted model, at the 0.05 level there were no statistically significant differences in the odds of attendance within the domains of disability, health insurance, housing, income, or religion. Strong evidence (p<0.001) was found of an association between access and age, gender, and occupation, with males, younger adults, and those working in sales, services and manual jobs being the least likely to access care. Conclusions: Less than half of those identified with an eye need and referred to free local clinics were able to access care in Meru. Younger people are being left behind, with less than a third of those aged 18-44 receiving care. Future work should explore the barriers and potential solutions to equitably improve access to care for this group.
Characterizing the skeletal muscle immune microenvironment for sarcopenia using transcriptome analysis and histological validation
Authors: Shen Linhui , Zong Yuan , Zhao Jiawen , Yang Yi , Li Lei , Li Ning , Gao Yiming , Xie Xianfei , Bao Qiyuan , Jiang Liting , Hu Weiguo
Published: February 2024

Sarcopenia is a condition characterized by the age-related loss of skeletal muscle mass and function. The pathogenesis of the disease is influenced by chronic low-grade inflammation. However, the specific changes in the immune landscape changes of sarcopenic muscle are not yet fully understood. To gain insights into the immune cell composition and interactions, we combined single-nuclei RNA sequencing data, bulk RNA sequencing datasets, and comprehensive bioinformatic analyses on skeletal muscle samples from young, aged, and sarcopenic individuals. Histological staining was then performed on skeletal muscles to validate the distribution of immune cells in clinical samples. Overall, we analyzed the transcriptomes of 101,862 single nuclei, revealing a total of 10 major cell types and 6 subclusters of immune cell types within the human skeletal muscle tissues. Among the immune cells, macrophages constituted the largest immune fraction. A specific marker gene LYVE1 for skeletal muscle macrophages was further identified. Cellular subclasses included four distinct groups of resident macrophages, which play a different role in physiological or non-physiological conditions. Using bulk RNA sequencing data, we identified strong enrichment for a macrophage-rich inflammation in sarcopenia. Our findings demonstrate age-related changes in the composition and cross-talk of immune cells, which contribute to chronic inflammation. Furthermore, macrophages emerge as a potential therapeutic target, thus advancing our understanding of the pathogenesis of sarcopenia.
Arg18 substitutions reveal the capacity of the HIV-1 capsid protein for non-fullerene assembly
Authors: Schirra Randall T. , Santos Nayara F. B. dos , Ganser-Pornillos Barbie K. , Pornillos Owen
Published: February 2024

In the fullerene cone HIV-1 capsid, the central channels of the hexameric and pentameric capsomers each contain a ring of arginine (Arg18) residues that perform essential roles in capsid assembly and function. In both the hexamer and pentamer, the Arg18 rings coordinate inositol hexakisphosphate, an assembly and stability factor for the capsid. Previously, it was shown that amino-acid substitutions of Arg18 can promote pentamer incorporation into capsid-like particles (CLPs) that spontaneously assemble in vitro under high salt conditions. Here, we show that these Arg18 mutant CLPs contain a non-canonical pentamer conformation and distinct lattice characteristics that do not follow the fullerene geometry of retroviral capsids. The Arg18 mutant pentamers resemble the hexamer in intra-oligomeric contacts, and forms a unique tetramer-of-pentamers that allows for incorporation of an octahedral vertex with a cross-shaped opening in the hexagonal capsid lattice. Our findings highlight an unexpected degree of structural plasticity in HIV-1 capsid assembly.
PLK1-Mediated Phosphorylation Cascade Activates the Mis18 Complex to Ensure Centromere Inheritance
Authors: Parashara Pragya , Medina-Pritchard Bethan , Abad Maria Alba , Sotelo-Parrilla Paula , Thamkachy Reshma , Grundei David , Zou Juan , Das Vimal , Yan Zhaoyue , Kelly David A. , McHugh Toni , Rappsilber Juri , Jeyaprakash A. Arockia
Published: February 2024

Accurate chromosome segregation requires the attachment of spindle microtubules to centromeres, which are epigenetically defined by the enrichment of CENP-A nucleosomes. During DNA replication, existing CENP-A nucleosomes undergo dilution as they get redistributed among the two DNA strands. To preserve centromere identity, CENP-A levels must be restored in a cell-cycle controlled manner orchestrated by the Mis18 complex. Here we provide a comprehensive mechanistic basis for PLK1-mediated licensing of CENP-A loading. We demonstrate that PLK1 interacts with Mis18α and Mis18BP1 subunits of the Mis18 complex by recognising self-primed phosphorylations of Mis18α (S54) and Mis18BP1 (T78 and S93) through its Polo-box binding domain. Disrupting these PLK1 phosphorylations perturbed the centromere recruitment of HJURP and new CENP-A loading. Biochemical and functional analyses show that phosphorylation of Mis18α and subsequent PLK1 binding is required to activate the Mis18α/β complex for robust Mis18α/β-HJURP interaction. Thus, our study reveals key molecular events underpinning the licensing role of PLK1 in ensuring accurate centromere inheritance.

One-Sentence Summary

PLK1 phosphorylation cascade licenses CENP-A loading by facilitating HJURP centromere recruitment via Mis18α/β activation.
Detecting phenotype-specific tumor microenvironment by merging bulk and single cell expression data to spatial transcriptomics
Authors: Zhu Wencan , Tang Hui , Zeng Tao
Published: February 2024

In addressing the limitations of current multimodal analysis methods that largely ignore phenotypic data, leading to a lack of biological interpretability at the phenotypic level, we developed the Single-Cell and Tissue Phenotype prediction (SCTP), a deep-learning-based multimodal fusion framework. SCTP can simultaneously detect phenotype-specific cells and characterize the tumor microenvironment of pathological tissue by integrating essential information from the bulk sample phenotype, the composition of individual cells, and the spatial distribution of cells. Upon evaluating SCTP’s efficiency and robustness against traditional analytical methods, we developed a specialized model, SCTP-CRC, tailored for colorectal cancer (CRC). This model integrates RNA-seq, scRNA-seq, and spatial transcriptomic data to offer a better understanding of CRC. SCTP-CRC has proven effective in accurately identifying tumor-associated cells and clusters and continuously defines boundary regions as well as the spatial organization of the entire tumor microenvironment. This enables a detailed depiction of cellular communication networks, capturing the dynamic shifts that occur during tumor progression. Furthermore, SCTP-CRC extends to the identification of abnormal sub-regions in the early state of CRC and uncovers potential early-warning signature genes such as MMP2, IGKC, and PIGR. These biomarkers are not only important in recognizing the onset of CRC but may also play a crucial role in differentiating between CRC-derived liver metastases and primary liver tumors. SCTP stands as a transformative framework, offering a deeper understanding of the tumor microenvironment through its ability to quantitatively characterize cancer’s fundamental traits and dissect the intricate molecular and cellular interactions at play. This comprehensive insight supports the early diagnosis and enables personalized treatment strategies, marking a significant stride toward improving patient outcomes and tailoring therapies to individual disease profiles.
A series of spontaneously blinking dyes for super-resolution microscopy
Authors: Holland Katie L. , Plutkis Sarah E. , Daugird Timothy A. , Sau Abhishek , Grimm Jonathan B. , English Brian P. , Zheng Qinsi , Dave Sandeep , Rahman Fariha , Xie Liangqi , Dong Peng , Tkachuk Ariana N. , Brown Timothy A. , Singer Robert H. , Liu Zhe , Galbraith Catherine G. , Musser Siegfried M. , Legant Wesley R. , Lavis Luke D.
Published: February 2024

Spontaneously blinking fluorophores permit the detection and localization of individual molecules without reducing buffers or caging groups, thus simplifying single-molecule localization microscopy (SMLM). The intrinsic blinking properties of such dyes are dictated by molecular structure and modulated by environment, which can limit utility. We report a series of tuned spontaneously blinking dyes with duty cycles that span two orders of magnitude, allowing facile SMLM in cells and dense biomolecular structures.
Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation
Authors: Bellotti Paolo , Ladd Zachary , Leroy Victoria , Su Gang , Sharma Shiven , Hartman Joseph B. , Krebs Jonathan , Viscardi Chelsea , Maile Robert , Moldawer Lyle L. , Efron Phillip , Sharma Ashish K. , Upchurch Gilbert R.
Published: February 2024

Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized proresolving lipid mediators, via G-protein coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption and increased smooth muscle cell α-actin expression as well as increased TGF-β2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-β2 and IL-10 secretions that mitigated smooth muscle cell activation in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling via this intercellular crosstalk. Collectively, this study demonstrates RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, and activates GPR18-dependent signaling to enhance TGF-β2 and IL-10 secretion that contributes to resolution of aortic inflammation and remodeling during AAA formation.
Criticalcis-parameters influence STructure Assisted RNA Translation (START) initiation on non-AUG codons in eukaryotes
Authors: Tidu Antonin , Alghoul Fatima , Despons Laurence , Eriani Gilbert , Martin Franck
Published: February 2024

In eukaryotes, translation initiation is a highly regulated process, which combinescis-regulatory sequences located on the messenger RNA along withtrans-acting factors like eukaryotic initiation factors (eIF). One critical step of translation initiation is the start codon recognition by the scanning 43S particle, which leads to ribosome assembly and protein synthesis. In this study, we investigated the involvement of secondary structures downstream the initiation codon in the so-called START (Structure-Assisted RNA translation) mechanism on AUG and non-AUG translation initiation. The results demonstrate that downstream secondary structures can efficiently promote non-AUG translation initiation provided that they are stable enough to stall a scanning 43S particle and that they are located at an optimal distance from this non-AUG codon to trigger and stabilize the codon-anticodon base-pairing in the P site. The required stability of the downstream structure for efficient translation initiation varies in distinct cell types. We extended this study to genome-wide analysis of theHomo sapiensalternative translation initiation sites and discovered 556 of them starting with an AUG and 506 starting with a non-AUG that contained a downstream RNA structure at an optimal distance and with a predicted stability of at least -15 kcal/mol. We validated the impact of these structures on translation initiation for several selected uORFs.
HippoMaps: Multiscale cartography of the human hippocampal formation
Authors: DeKraker Jordan , Cabalo Donna Gift , Royer Jessica , Ngo Alexander , Khan Ali R. , Karat Bradley , Benkarim Oualid , Rodriguez-Cruces Raul , Frauscher Birgit , Pana Raluca , Hansen Justine Y. , Misic Bratislav , Valk Sofie L. , Lau Jonathan C. , Kirschner Matthias , Bernasconi Andrea , Bernasconi Neda , Muenzing Sascha , Axer Markus , Amunts Katrin , Evans Alan C. , Bernhardt Boris C.
Published: February 2024

The hippocampus has a unique microarchitecture, is situated at the nexus of multiple macroscale functional networks, contributes to numerous cognitive as well as affective processes, and is highly susceptible to brain pathology across common disorders. These features make the hippocampus a model to understand how brain structure covaries with function, in both health and disease. Here, we introduce HippoMaps, an open access toolbox and online data warehouse for the mapping and contextualization of hippocampal data in the human brain (http://hippomaps.readthedocs.io). HippoMaps capitalizes on a novel hippocampal unfolding approach as well as shape intrinsic registration capabilities to allow for cross-subject and cross-modal data aggregation. We initialize this repository with data spanning 3D post-mortem histology, ex-vivo 9.4 Tesla MRI, as well as in-vivo structural MRI and resting-state functional MRI (rsfMRI) obtained at 3 and 7 Tesla, together with intracranial encephalography (iEEG) recordings in epilepsy patients. HippoMaps also contains validated tools for spatial map association analysis in the hippocampus that correct for autocorrelation. All code and data are compliant with community standards, and comprehensive online tutorials facilitate broad adoption. Applications of this work span methodologies and modalities, spatial scales, as well as clinical and basic research contexts, and we encourage community feedback and contributions in the spirit of open and iterative scientific resource development.
PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in aDictyosteliumchemorepulsion pathway
Authors: Consalvo Kristen M. , Rijal Ramesh , Beruvides Steven L. , Mitchell Ryan , Beauchemin Karissa , Collins Danni , Scoggin Jack , Scott Jerome , Gomer Richard H.
Published: February 2024

The directed movement of eukaryotic cells is crucial for processes such as embryogenesis and immune cell trafficking. The enzyme Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] to phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2].Dictyostelium discoideumcells require both PTEN and the PTEN-like phosphatase CnrN to locally inhibit Ras activation to induce biased movement of cells away from the secreted chemorepellent protein AprA. Both PTEN and CnrN decrease basal levels of PI(3,4,5)P3and increase basal numbers of macropinosomes, and AprA prevents this increase. AprA requires both PTEN and CnrN to increase PI(4,5)P2levels, decrease PI(3,4,5)P3levels, inhibit proliferation, decrease myosin II phosphorylation, and increase filopod sizes. AprA causes PTEN, similar to CnrN, to localize to the side of the cell towards AprA in an AprA gradient. However, PTEN and CnrN also have distinct roles in some signaling pathways. PTEN, but not CnrN, decreases basal levels of PI(4,5)P2, AprA requires PTEN, but not CnrN, to induce cell roundness, and CnrN and PTEN have different effects on the number of filopods and pseudopods, and the sizes of filopods. Together, our results suggest that CnrN and PTEN play unique roles inD. discoideumsignaling pathways, and possibly dephosphorylate PI(3,4,5)P3in different membrane domains, to mediate chemorepulsion away from AprA.
Influenza A Viral Burst Size from Thousands of Infected Single Cells Using Droplet Quantitative PCR (dqPCR)
Authors: Zath Geoffrey K. , Thomas Mallory M. , Loveday Emma Kate , Bikos Dimitri A. , Sanche Steven , Ke Ruian , Brooke Christopher B. , Chang Connie B.
Published: February 2024

An important aspect of how viruses spread and infect is the viral burst size, or the number of new viruses produced by each infected cell. Surprisingly, this value remains poorly characterized for influenza A virus (IAV), commonly known as the flu. In this study, we screened tens of thousands of cells using a microfluidic method called droplet quantitative PCR (dqPCR). The high-throughput capability of dqPCR enabled the measurement of a large population of infected cells producing progeny virus. By measuring the fully assembled and successfully released viruses from these infected cells, we discover that the viral burst sizes for both the seasonal H3N2 and the 2009 pandemic H1N1 strains vary significantly, with H3N2 ranging from 101to 104viruses per cell, and H1N1 ranging from 101to 103viruses per cell. Some infected cells produce average numbers of new viruses, while others generate extensive number of viruses. In fact, we find that only 10% of the single-cell infections are responsible for creating a significant portion of all the viruses. This small fraction produced approximately 60% of new viruses for H3N2 and 40% for H1N1. On average, each infected cell of the H3N2 flu strain produced 709 new viruses, whereas for H1N1, each infected cell produced 358 viruses. This novel method reveals insights into the flu virus and can lead to improved strategies for managing and preventing the spread of viruses.

Author summary

Viruses infect and exploit host cells to reproduce and spread. The viral burst size, or the number of viral particles released from an infected cell, plays a critical role in understanding infection dynamics and overall viral fitness. However, accurately determining burst size for many single cells using conventional laboratory methods can be challenging. Here, we introduce dqPCR, a droplet microfluidic method for the rapid measurement of influenza virus numbers produced by thousands of individual cells. Our findings revealed that only a small proportion of infected cells are responsible for producing a significant portion of the total viral population. By utilizing this method in future studies, we can gain a deeper understanding of the role of diversity in rapidly evolving viruses.
Chlorpromazine inhibits EAG1 channels by altering the coupling between the PAS, CNBH and pore domains
Authors: Ghorbani Mahdi , Wang Ze-Jun , Chen Xi , Tiwari Purushottam B. , Klauda Jeffery B. , Brelidze Tinatin I.
Published: February 2024

EAG1 depolarization-activated potassium selective channels are important targets for treatment of cancer and neurological disorders. EAG1 channels are formed by a tetrameric subunit assembly with each subunit containing an N-terminal Per-Arnt-Sim (PAS) domain and C-terminal cyclic nucleotide-binding homology (CNBH) domain. The PAS and CNBH domains from adjacent subunits interact and form an intracellular tetrameric ring that regulates the EAG1 channel gating, including the movement of the voltage sensor domain (VSD) from closed to open states. Small molecule ligands can inhibit EAG1 channels by binding to their PAS domains. However, the allosteric pathways of this inhibition are not known. Here we show that chlorpromazine, a PAS domain small molecule binder, alters interactions between the PAS and CNBH domains and decreases the coupling between the intracellular tetrameric ring and the pore of the channel, while having little effect on the coupling between the PAS and VSD domains. In addition, chlorpromazine binding to the PAS domain did not alter Cole-Moore shift characteristic of EAG1 channels, further indicating that chlorpromazine has no effect on VSD movement from the deep closed to opened states. Our study provides a framework for understanding global pathways of EAG1 channel regulation by small molecule PAS domain binders.
Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation
Authors: Vassallo Christopher N. , Doering Christopher R. , Laub Michael T.
Published: February 2024

Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacteria that must evade their viral predators known as bacteriophages. Here, we characterize a widely distributed anti-phage defense system, CmdTAC, that provides robust defense against infection by the T-even family of phages. Our results support a model in which CmdC detects infection by sensing viral capsid proteins, ultimately leading to the activation of a toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized capsid protein triggers dissociation of the chaperone CmdC from the CmdTAC complex, leading to destabilization and degradation of the antitoxin CmdA, with consequent liberation of the CmdT ADP-ribosyltransferase. Strikingly, CmdT does not target a protein, DNA, or structured RNA, the known targets of other ADP-ribosyltransferases. Instead, CmdT modifies the N6 position of adenine in GA dinucleotides within single-stranded RNAs leading to arrest of mRNA translation and the inhibition of viral replication. Our work reveals a new mechanism of anti-viral defense and a previously unknown but broadly distributed class of ADP-ribosyltransferases that target mRNA.
Not only ClpC1 but also ClpX are drug targets of Ilamycins
Authors: Gao Yamin , Fang Cuiting , Zhou Biao , Hameed H.M. Adnan , Sun Changli , Tian Xirong , He Jing , Han Xingli , Zhang Han , Li Jun , Ju Jianhua , Chen Xinwen , Zhong Nanshan , Ma Junying , Xiong Xiaoli , Zhang Tianyu
Published: February 2024

The mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. A group of natural cyclic peptides including ilamycins, are traditionally thought to target the ClpC1 component of the ClpC1P1P2 proteasome. However, our study reveals that not only ClpC1 but also ClpX can be targeted by ilamycins. Specifically, ilamycin E (ILE) and ilamycin F (ILF) demonstrated superior delayed mycobactericidal activities compared to other ilamycin components. We identified a unique mutation inclpXand a novel insertion inclpC1, both of which confer resistance to ILE and ILF in mycobacteria, as confirmed through gene editing. Crucially, we found that ILE significantly disrupts the proteolytic functions of both the ClpXP1P2 and ClpC1P1P2 complexes. This is the first report highlighting ClpX as a critical target for mycobacterial killing, alongside ClpC1. Our findings emphasize the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.
Preference for and resistance to a toxic sulfur volatile opens up a unique niche inDrosophila busckii
Authors: Mahadevan Venkatesh Pal , Galagovsky Diego , Knaden Markus , Hansson Bill S.
Published: February 2024

The ability to tolerate otherwise toxic compounds can open up unique niches in nature. Among drosophilid flies few examples of such adaptations are known and then typically from highly host specific species. Here we show that the human commensalDrosophila busckiiuses dimethyldisulfide (DMDS) as a key mediator in its host selection. Despite DMDS’s neurotoxic properties1,D. busckiihas evolved tolerance towards high concentrations and uses the compound as an olfactory cue to pinpoint food and oviposition sites. This adaptability is likely linked to an insensitive cytochrome c oxidase (COX), a DMDS target in other insects. Our findings positionD. busckiias a potential model for studying resistance to toxic gases affecting COX and offer valuable insights into evolutionary adaptations within specific ecological contexts.
Decoding the role of DNA sequence on protein-DNA co-condensation
Authors: Singh Rohit Kumar , Swain Pinaki , Ganji Mahipal , Choubey Sandeep
Published: February 2024

The eukaryotic genome is organized within the cell nucleus through three-dimensional compaction. The physical principles that govern genome organizationin vivoremain less understood. Phase separation of protein and DNA has emerged as an attractive mechanism for reshaping chromatin and compacting the genome.In vitrostudies have shed light on the biophysical principles of protein-DNA condensates driven by protein-protein and protein-DNA interactions. However, the role of DNA sequence and its impact on protein-DNA condensation remains elusive. Guided by experiments, this paper presents a simple polymer-based model of protein-mediated DNA condensation that explicitly incorporates the influence of DNA sequence on protein binding. Using coarse-grained Brownian dynamics simulations, we demonstrate that, in the case of a homogeneous DNA, only one condensate forms in equilibrium. In sharp contrast, DNA sequence heterogeneity can result in the coexistence of multiple condensates, giving rise to the formation of structures resembling pearl-necklaces. Interestingly, we observe that protein binding affinity of interfacial DNA governs the capillary forces arising from the protein-DNA condensates. To demonstrate the usefulness of our modeling framework, we compare the simulation results against published data for co-condensation of Dps, Sox2, and HP1. We find that while Dps exhibits sequence-independent binding, DNA sequence heterogeneity dictates the co-condensation of Sox2 and HP1 with DNA. Overall, the framework developed here can be harnessed to gain mechanistic insights into the role of DNA sequence on protein-DNA co-condensation and pave the way for developing a deeper understanding of genome organisation.
Characterization of the microbiome ofAedes albopictuspopulations in different habitats from Spain and São Tomé: implications for vector control
Authors: Melo Tiago , Sousa Carla Alexandra , Delacour-Estrella Sarah , Bravo-Barriga Daniel , Seixas Gonçalo
Published: February 2024

The mosquito microbiome significantly influences vector competence, including inAedes albopictus, a globally invasive ectoparasite. Describing the microbiome andWolbachiastrains ofAe. albopictusfrom different regions can guide area-specific control strategies. Mosquito samples from Spain and São Tomé were analyzed using 16S rRNA gene sequencing and metagenomic sequencing.Wolbachiainfection was genotyped, and statistical analysis compared infection patterns by sex and population. Results revealed a dominance of dualWolbachiainfections in the microbiome of both populations ofAe. albopictus, especially among females. The two populations presented a shared microbiome, although 5 and 9 other genera were only present in Spain and São Tomé populations, respectively. Genera likePelomonasandNevskiawere identified for the first time inAedesmosquitoes. This study is the first to describe theAe. albopictusbacteriome in Spain and São Tomé, offering insights for the development of targeted mosquito control strategies.
Code for Collagen Folding Deciphered
Authors: Malcor Jean-Daniel , Ferruz Noelia , Romero-Romero Sergio , Dhingra Surbhi , Sagar Vamika , Jalan Abhishek A.
Published: February 2024

Collagen triple helix folds in two steps: nucleation of three polypeptides at the C-termini followed by zip-chain like propagation. The triple helices found in all domains of life as well as viruses contain upto 6000 amino acids in each polypeptide that are also frequently interrupted with non-helical sequences that disrupt folding and reduce stability. Given the length of polypeptide and the disruptive interruptions, compensating mechanisms that stabilize against local unfolding during propagation and offset the entropic cost of folding the long polypeptides are not fully understood. Here, we show that the information for correct folding of collagen triple helices is encoded in their sequence as interchain electrostatic interactions. In case of humans, disrupting these interactions causes severe to lethal diseases.

Key Result

Collagen triple helices found in all the three domains of life as well as viruses have converged on similar mechanism to fold correctly.
A Prediction Model of PTSD in the Israeli Population in the Aftermath of October 7th, 2023, Terrorist Attack and the Israel-Hamas War
Authors: Katsoty Dana , Greidinger Michal , Neria Yuval , Segev Aviv , Lurie Ido
Published: February 2024

Background

On October 7th, 2023, a mass terror attack was launched by Hamas militants, which was followed by the Israel-Hamas war. These events constitute a nationwide trauma with major ramifications for public mental health. This article presents an evidence-based model for the prediction of the prevalence of posttraumatic stress disorder (PTSD) related to the terrorist attack and the war.

Main body

The creation of the model consisted of several steps. Firstly, the Israeli population was divided into six groups based on the intensity, context, and type of traumatic exposure (direct exposure to terror, close proximity to terror, soldiers in combat and support units, intense exposure to rocket attacks, moderate exposure to rocket attacks, and indirectly affected communities), and the population size of each group was assessed using official national databases. Secondly, an estimation of the expected prevalence of PTSD in each of the exposure groups was based on a review of the relevant literature. A random-effects meta-analysis of the prevalence rates was conducted separately per each exposure group. Finally, the predicted number of PTSD causalities in the population was calculated by multiplying the group size and the PTSD prevalence estimation. Based on population size and estimated PTSD prevalence within each exposure category, the model predicts that approximately 5.3% (N=519,923) of the Israeli population (95% prediction interval, 160,346-879,502), may develop PTSD as a result of the terrorist attack and the war.

Conclusions

The predicted number of individuals with PTSD following mass trauma is expected to be considerable. The presented model can assist policymakers, clinicians, and researchers in preparing and devising adequate interventions for the mental health needs of large populations. Moreover, this model can be applied in other instances of mass-trauma exposure.
Telemedicine’s Impact on Diabetes Care during the COVID-19 Pandemic: A Cohort Study in a Large Integrated Healthcare System
Authors: Patel Reysha , Huang Jie , Hsueh Loretta , Gopalan Anjali , Millman Andrea , Franklin Isabelle , Reed Mary
Published: February 2024

Introduction

To examine if patients exposed to primary care telemedicine (telephone or video) early in the COVID-19 pandemic had higher rates of downstream HbA1cmeasurement and improved HbA1clevels in the second year of the pandemic.

Research Design and Methods

In a cohort of 242, 848 Kaiser Permanente Northern California patients with diabetes, we examined associations between early-pandemic patient-initiated telemedicine visit and downstream HbA1cmonitoring and results during the second year of the pandemic.

Results

Adjusted HbA1cmeasurement rates were significantly higher among patients with telemedicine exposure in the early-pandemic prior year than those with no visits in the prior year (91.0% testing for patients with video visits, 90.5% for telephone visits, visits, 86.7% for no visits,p< 0.05). Among those with HbA1cmeasured, the rates of having an HbA1c< 8% in the second year of the COVID-19 pandemic were also statistically significantly higher among patients with telemedicine exposure in the early-pandemic prior year than those with no visits in the prior year (68.5% with HbA1c< 8% for video visits, 67.3% for telephone visits, 66.6% for no visits,p< 0.05).

Conclusions

Access to telephone and video telemedicine throughout the early COVID-19 pandemic was associated with patients’ continued engagement in recommended diabetes care. Although our study analyzed telemedicine use during a pandemic, telemedicine visits may continue to support ongoing health care access and positive clinical outcomes.

KEY MESSAGES

The pandemic significantly increased telemedicine adoption, providing an opportunity to maintain health care access for patients with diabetes. Our study investigates the impact of telemedicine, including both telephone and video visits, on diabetes care during the early COVID-19 period. The results demonstrate that patients utilizing telemedicine exhibit higher rates of HbA1cmeasurement and at-goal HbA1c. These findings suggest that telemedicine can be a valuable tool in supporting clinical outcomes in the management of chronic health conditions.
The association of ethnicity and oncologic outcomes for oral cavity squamous cell carcinoma (OSCC)
Authors: Mahboubi Kiana , Nakoneshny Steven C. , Sauro Khara , Roberts Samuel , Hart Rob , Matthews T Wayne , Dort Joseph , Chandarana Shamir P
Published: February 2024

Objective

To compare oncologic outcomes of South Asian (SA) patients treated at a regional cancer centre in Canada, for oral squamous cell carcinoma (OSCC), to the general population.

Methods

Adult patients who underwent primary surgical resection of OSCC +/- adjuvant treatment between 2009 and 2022 (N=697) were included. SA patients were identified using a validated method and compared to non-SA patients. Baseline characteristics, including betel nut consumption, were compared, and disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using Kaplan-Meier methods, with median follow-up time of 36.4 months [SD 31.02]. Cox proportional hazard regression models adjusted for potential confounders. A p-value < 0.05 was considered statistically significant.

Results

SA patients (9% of cohort, n = 64) were significantly younger and had lower rates of smoking and alcohol consumption compared to non-SA patients. There were no differences in tumor characteristics or the use of adjuvant radiation. SA patients had a two-fold higher risk of recurrence and significantly worse disease-specific survival, even after adjusting for stage and high-risk features [RFS: HR 2.01(1.28 - 3.14), DSS: HR 1.79(1.12 - 2.88)]. The consumption of betel nut was not associated with outcomes.

Conclusion

To our knowledge, this study is the first to compare the oncological outcomes of SA patients with OSCC to non-SA patients. SA patients had significantly worse outcomes, even after controlling for known predictors of recurrence and disease-specific survival. These findings can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.
Continuous-Time and Dynamic Suicide Attempt Risk Prediction with Neural Ordinary Differential Equations
Authors: Sheu Yi-han , Simm Jaak , Wang Bo , Lee Hyunjoon , Smoller Jordan W.
Published: February 2024

Suicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB risk assessment methods, whether conducted by clinicians or through machine learning models, treat SRB risk as static and are confined to specific times and locations, such as following a hospital visit. Such a paradigm is unrealistic as SRB risk fluctuates and creates time gaps in the availability of risk scores. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory based on Neural ODEs, an advanced AI model class for time series prediction. As such, these models can estimate changes in risk across the continuum of future time points, even without new observations, and can update these estimations as new data becomes available. We train and validate these models for SRB prediction using a large electronic health records database. Both models demonstrated high discrimination performance for SRB prediction (e.g., AUROC > 0.92 in the full, general cohort), serving as an initial step toward developing novel and comprehensive suicide prevention strategies based on dynamic changes in risk.
Taxonomic distribution of SbmA/BacA and BacA-like antimicrobial peptide transporters suggests independent recruitment and convergent evolution in host-microbe interactions
Authors: Smith Nicholas T. , Boukherissa Amira , Antaya Kiera , Howe Graeme W. , Rodríguez de la Vega Ricardo C , Shykoff Jacqui A. , Alunni Benoît , diCenzo George C.
Published: February 2024

Small, antimicrobial peptides are often produced by eukaryotes to control bacterial populations in both pathogenic and mutualistic symbioses. These include proline-rich mammalian immune peptides and cysteine-rich peptides produced by legume plants in symbiosis with rhizobia. The fitness of the bacterial partner is dependent upon their ability to persist in the presence of these antimicrobial peptides. In the case ofEscherichia coliandMycobacterium tuberculosispathogens and nitrogen-fixing legume symbionts (rhizobia), the ability to survive exposure to these peptides depends on peptide transporters called SbmA (also known as BacA) or BclA (for BacA-like). However, how broadly these transporters are distributed amongst bacteria, and their evolutionary history, is poorly understood. Here, we used hidden Markov models, phylogenetic analysis, and sequence similarity networks to examine the distribution of SbmA/BacA and BclA proteins across a representative set of 1,255 species from across the domainBacteria. We identified a total of 71 and 177 SbmA/BacA and BclA proteins, respectively. Phylogenetic and sequence similarity analyses suggest that these protein families likely did not evolve from a common ancestor and that their functional similarity is instead a result of convergent evolution.In vitrosensitivity assays using the legume peptide NCR247 and several of the newly-identified BclA proteins confirmed that transport of antimicrobial peptides is a common feature of this protein family. Analysis of the taxonomic distribution of these proteins showed that SbmA/BacA orthologs were encoded only by species in the phylumPseudomonadotaand that they were primarily identified in just two orders:Hyphomicrobiales(classAlphaproteobacteria) andEnterobacterales(classGammaproteobacteria). BclA orthologs were somewhat more broadly distributed and were found in clusters across four phyla. These included several orders of the phylaPseudomonadotaandCyanobacteriota, as well as the orderMycobacteriales(phylumActinomycetota) and the classNegativicutes(phylumBacillota). Notably, many of the clades enriched for species encoding BacA or BclA orthologs also include many species known to interact with eukaryotic hosts in mutualistic or pathogenic interactions. Collectively, these observations suggest that SbmA/BacA and BclA proteins have been repeatedly co-opted to facilitate both mutualistic and pathogenic associations with eukaryotic hosts by allowing bacteria to cope with host-encoded antimicrobial peptides.
Sleep pressure accumulates in a voltage-gated lipid peroxidation memory
Authors: Rorsman H. Olof , Müller Max A. , Liu Patrick Z. , Sanchez Laura Garmendia , Kempf Anissa , Gerbig Stefanie , Spengler Bernhard , Miesenböck Gero
Published: February 2024

Voltage-gated potassium (KV) channels contain cytoplasmic β-subunits whose aldo-keto reductase activity is required for the homeostatic regulation of sleep. Here we show that Hyperkinetic, the β-subunit of the KV1 channel Shaker inDrosophila, forms a dynamic lipid peroxidation memory. Information is stored in the oxidation state of Hyperkinetic’s nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, which changes when lipid-derived carbonyls, such as 4-oxo-2-nonenal or an endogenous analog generated by illuminating a membrane-bound photosensitizer, abstract an electron pair. NADP+remains locked in the active site of KVβ until membrane depolarization permits its release and replacement with NADPH. Sleep-inducing neurons use this voltage-gated oxidoreductase cycle to encode their recent lipid peroxidation history in the collective binary states of their KVβ-subunits; this biochemical memory influences—and is erased by—spike discharges driving sleep. The presence of a lipid peroxidation sensor at the core of homeostatic sleep control suggests that sleep protects neuronal membranes against oxidative damage. Indeed, brain phospholipids are depleted of vulnerable polyunsaturated fatty acyl chains after enforced waking, and slowing the removal of their carbonylic breakdown products increases the demand for sleep.
Extracellular chemosymbiont populations in a shallow-water thyasirid clam potentially shaped by priority effect
Authors: Li Menggong , Li Yunlong , Mao Shi-Hai , Liu Xu , Wang Hui , Chen Chong , Liu Xiaoshou , Zhuang Guang-Chao , Zhang Weipeng , Sun Jin
Published: February 2024

Chemosymbiosis is a highly successful strategy that evolved in several animal groups, best known for dominating chemosynthetic ecosystems such as deep-sea hot vents and hydrocarbon seeps but also found in other systems such as reducing sediments in shallow water. The symbiont population structure can be determined by the host genetic inheritance, geographic partitions, and environmental factors, among others if the symbionts are acquired horizontally from the environment. Here, we suggest that the earliest colonies can also influence the episymbiont population, known as the “priority effect”, using the thyasirid cleftclamThyasira tokunagai.This species is abundant in reducing sediments in Yellow Sea, hosting an extracellular sulfide-oxidizing symbiont (genusSedimenticola) in the pouch-like structure in the gill. From samples taken across the whole Yellow Sea, complete symbiont genomes revealed only two dominant strains which were also verified by phylogenomic analysis. The two strains share key functional genes but exhibit a single-base difference in the 16S rDNA. We found mutually exclusive communities of these two strains in the 30 individual hosts studied, typically dominated or even monopolized by one strain. Inconsistent phylogenetic relationships between hosts and symbiont indicate the genetic heterogeneity of the holobiont, and the mean fixation indexFSTof each symbiont population within sampling sites showed a lack of correlation with geographic distance and environmental factors, suggesting another driving force. We deduce that the likely scenario is 1) the dominant symbiont strain is determined during initial acquisition; 2) the propagation of this initial strain as the host develops; 3) the continuous but restricted recruitment of the other strain during the adult stage. Overall, our results highlight the importance of “priority effect” in shaping the chemosymbiont population structures even in the horizontally transmitted episymbiont in a whole marginal sea area.