bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential prediction performance between Caribbean- and Mainland-subgroups using state-of-the-art polygenic risk scores for coronary heart disease: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Hutten Christina G. , Boehm Frederick J. , Smith Jennifer A. , Spitzer Brian W. , Wassertheil-Smoller Sylvia , Isasi Carmen R , Cai Jianwen , Unkart Jonathan T , Sun Jiehuan , Persky Victoria , Daviglus Martha L , Sofer Tamar , Argos Maria
Published: September 2024

Background

Coronary heart disease (CHD) is a leading cause of death for Hispanic/Latino populations in the United States. We evaluated polygenic risk scores (PRS) with incident myocardial infarction (MI) in a Hispanic/Latino study sample.

Methods

We leveraged data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to assess four CHD-PRS from the PGS catalog, derived using multiple methods (LDpred, AnnoPred, stacked clumping and thresholding, and LDPred2). We evaluated associations between each standardized PRS and time to adjudicated incident MI, adjusted for age, sex, first 5 principal components, and weighted for survey design. Concordance statistics (c-index) compared predictive accuracy of each PRS with, and in addition to, traditional risk factors (TRF) for CHD (obesity, hypercholesterolemia, hypertension, diabetes, and smoking). Analyses were stratified by self-reported Caribbean- (Puerto Rican, Dominican or Cuban) and Mainland- (those of Mexican, Central American, or South American) heritage subgroups.

Results

After 11 years follow-up, for 9055 participants (mean age (SD) 47.6(13.1), 62.2% female), the incidence of MI was 1.0% (n = 95). Each PRS was more strongly associated with MI among Mainland participants. LDPred2 + TRF performed best among the Mainland subgroup; HR=2.69, 95% CI [1.71, 4.20], c-index = 0.897, 95% CI [0.848, 0.946]; a modest increase over TRF alone, c-index = 0.880, 95% CI [0.827, 0.933]. AnnoPred + TRF performed best among the Caribbean sample; c-index = 0.721, 95% CI [0.647, 0.795]; however, was not significantly associated with rate of MI (HR=1.14, 95% CI [0.82, 1.60]).

Conclusion

PRS performance for CHD is lacking for Hispanics/Latinos of Caribbean origin who have substantial proportions of African genetic ancestry, risking increased health disparities. AnnoPred, using functional annotations, outperformed other PRS in the Caribbean subgroup, suggesting a potential strategy for PRS construction in diverse populations. These results underscore the need to optimize cumulative genetic risk prediction of CHD in diverse Hispanic/Latino populations.
NXPE1alters the sialoglycome by acetylating sialic acids in the human colon
Authors: Lee Bum Seok , Cook Ashley , Sur Surojit , Dobbyn Laura , Popoli Maria , Khalili Sana , Zhou Shibin , Bettegowda Chetan , Papadopoulos Nickolas , Gabrielson Kathy , Buckhaults Phillip , Vogelstein Bert , Kinzler Kenneth W , Wyhs Nicolas
Published: September 2024

Mild periodic acid Schiff staining (mPAS) of human colonic tissue has been used to answer a variety of fundamental questions in germline and somatic genetics. mPAS staining is known to reflect sialic acid O-acetylation, but a full accounting of the genes contributing to sialoglycome diversity is incomplete. Using haplotypes derived from whole genome sequencing, we identified a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, onlyNXPE1haplotypes correlated perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis suggested that one common allele ofNXPE1, with a single base pair substitution in its promoter region, greatly reduces expression of the gene. Genetic manipulation ofNXPE1expression confirmed this conclusion and caused changes to modified sialic acid levels. Finally, high-performance liquid chromatography (HPLC) confirms that enzymatically active NXPE1 is capable of transferring an acetyl group from acetyl coenzyme A to sialic acidin vitro. These findings suggest thatNXPE1is the long-sought gene responsible for differences in colon mPAS staining and may be the prototype of a new family of sialic acid O-acetylation-modifying genes.
Effect of chronic upregulation of endocannabinoid signalingin vivowith JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice
Authors: Sepers Marja D. , Woodard Cameron L. , Ramandi Daniel , Vecchiarelli Haley A. , Hill Matthew N. , Raymond Lynn A.
Published: September 2024

Synaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Here, we tested the effects of JZL184 administeredin vivoto YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.
Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations
Authors: Pierro Elysa W. , Cottam Matthew A. , An Hanbing , Lehmann Brian D. , Pietenpol Jennifer A. , Wellen Kathryn E. , Makowski Liza , Rathmell Jeffrey C. , Fingleton Barbara , Hasty Alyssa H.
Published: September 2024

Abstract

Obesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association − and the potential benefits of weight loss − have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function (Trem2+/+andTrem2-/-) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably,Trem2deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed that tumors of leanTrem2-/-mice exhibited a shift in clonal CD8+T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4+Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adjof the same mouse. Finally, an immune checkpoint study demonstrated that αPD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.
Particular sequence characteristics induce bias in the detection of polymorphic transposable element insertions
Authors: Verneret Marie , Le Van Anthony , Faraut Thomas , Turpin Jocelyn , Lerat Emmanuelle
Published: September 2024

Transposable elements (TEs) have an important role in genome evolution but are challenging for bioinformatics detection due to their repetitive nature and ability to move and replicate within genomes. New sequencing technologies now enable the characterization of nucleotide and structural variations within species. Among them, TE polymorphism is critical to identify as it may influence species adaptation or trigger diseases. Despite the development of numerous bioinformatic programs, identifying the most effective tool is challenging due to non-overlapping results and varying efficiency across studies. Benchmarking efforts have highlighted the limitations of these tools, often evaluated on either real or simulated data. However, real data may be incomplete or contain unannotated TEs, while simulated data may not accurately reflect real genomes. This study introduces a simulation method generating data based on real genomes to control all genomic parameters. Evaluating several TE polymorphic detection tools using data fromDrosophila melanogasterandArabidopsis thaliana, our study investigates factors like copy size, sequence divergence, and GC content that influence detection efficiency. Our results indicate that only a few programs perform satisfactorily and that all are sensitive to TE and genomic characteristics, that may differ according to the species considered. UsingBos tauruspopulation data as a case study to identify polymorphic LTR-retrotransposon insertions, we found low-frequency insertions particularly challenging to detect due to a high number of false positives. Increased sequencing coverage improved sensitivity but reduced precision. Our work underscores the importance of selecting appropriate tools and thresholds according to the specific research questions.
Single molecule spectrum dynamics imaging with 3D target-locking tracking
Authors: Sha Hao , Wu Yu , Zhang Yongbing , Feng Xiaochen , Li Haoyang , Wang Zhong , Zhang Xiufeng , Hou Shangguo
Published: September 2024

Fluorescence spectrum can provide rich physicochemical insights into molecular environments and interactions. However, imaging the dynamic fluorescence spectrum of rapidly moving biomolecules, along with their positional dynamics, remains a significant challenge. Here, we report a three-dimensional (3D) target-locking tracking-based single molecule fluorescence Spectrum Dynamics Imaging Microscopy (3D-SpecDIM), which is capable of simultaneously capturing both the rapid 3D positional dynamics and the physicochemical parameters changing dynamics of the biomolecules with enhanced spectral accuracy, high spectral acquisition speed, single-molecule sensitivity, and high 3D spatiotemporal localization precision. As a demonstration, 3D-SpecDIM is applied to real-time spectral imaging of the mitophagy process, showing its enhanced ratiometric fluorescence imaging capability. Additionally, 3D-SpecDIM is used to perform multi-resolution imaging, which provides valuable contextual information on the mitophagy process. Furthermore, we demonstrated the quantitative imaging capability of 3D-SpecDIM by imaging the cellular blebbing process. By continuously monitoring the physicochemical parameter dynamics of biomolecular environments through spectral information, coupled with 3D positional dynamics imaging, 3D-SpecDIM offers a versatile platform for concurrently acquiring multiparameter dynamics, providing comprehensive insights unattainable through conventional imaging techniques. 3D-SpecDIM represents a substantial advancement in single-molecule spectral dynamics imaging techniques.
Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy
Authors: Shorer Ofir , Pinhasi Asaf , Yizhak Keren
Published: September 2024

Despite the crucial role of T cell clones in the anti-tumor activity, their characterization and association with clinical outcome following immune checkpoint inhibitors (ICI) is lacking. Here we analyzed paired single-cell RNA-sequencing/T-cell receptor sequencing of 767,606 T cells from 460 samples spanning 6 cancer types. We found a robust signature of response based on expanded CD8+clones that differentiates between responders and non-responders. Analysis of persistent clones showed transcriptional changes that are differentially induced by therapy in the different response groups, suggesting an improved reinvigoration capacity in responding patients. Moreover, a gene trajectory analysis revealed changes in the pseudo-temporal state of de-novo clones that are associated with response to therapy. Lastly, we found that clones shared between tumor and blood are more abundant in non-responders and execute distinct transcriptional programs. Overall, our results highlight differences in clonal transcriptional states that are linked to patient response, offering valuable insights into the mechanisms driving effective anti-tumor immunity.

Graphical abstract
Transcription-dependent swelling of a transplanted chromosome in an artificial cell
Authors: Greiss Ferdinand , Daube Shirley S. , Noireaux Vincent , Bar-Ziv Roy
Published: September 2024

Transplanting chromosomes from living to artificial cells would impact our understanding of chromosome organization and DNA transactions, with implications for autonomous biological systems. Here, we transplantedEscherichia colichromosomes into artificial cells, enabling real-time labeling, manipulation, and steady-state gene expression down to the single-molecule limit. Chromosomes stripped of native proteins transitioned from a swollen to compacted state induced by transcription inhibition, in contrast to protein-bound chromosomes retaining an organization with blobs. In a cell-free expression reaction, RNA polymerases were uniformly distributed along the entire chromosome and rapidly detached, consistent with a global transcriptional activity. We used tailored surfaces to capture and count 20 nascent proteins per hour from a single gene on the chromosome. We mapped stably bound condensins to the blobs, supporting a model where swelling by transcription is counterbalanced by condensin-mediated compaction. Our data suggest transplanted chromosomes as active gels organized by molecular machines.
CCR5 antagonists as cerebroprotective and stroke recovery enhancing agents: a preclinical systematic review and meta-analysis
Authors: Sharif Ayni , Jeffers Matthew S. , Fergusson Dean A. , Bapuji Raj , Nicholls Stuart G. , Humphrey John , Johnston Warren , Mitchell Ed , Speirs Mary-Ann , Stronghill Laura , Vuckovic Michele , Wulf Susan , Shorr Risa , Dowlatshahi Dar , Corbett Dale , Lalu Manoj M.
Published: September 2024

Background

C-C chemokine receptor type 5 (CCR5) antagonists may improve both acute stroke outcome and long-term recovery. Despite their evaluation in ongoing clinical trials, gaps remain in the evidence supporting their use.

Methods

With a panel of patients with lived experiences of stroke, we performed a systematic review of animal models of stroke that administered a CCR5 antagonist and assessed infarct size or behavioural outcomes. MEDLINE, Web of Science, and Embase were searched. Article screening and data extraction were completed in duplicate. We pooled outcomes using random effects meta-analyses. We assessed risk of bias using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool and alignment with the Stroke Treatment Academic Industry Roundtable (STAIR) and Stroke Recovery and Rehabilitation Roundtable (SRRR) recommendations.

Results

Five studies representing 10 experiments were included. CCR5 antagonists reduced infarct volume (standard mean difference −1.02; 95% confidence interval −1.58 to −0.46) when compared to stroke-only controls. Varied timing of CCR5 administration (pre- or post-stroke induction) produced similar benefit. CCR5 antagonists significantly improved 11 of 16 behavioural outcomes reported. High risk of bias was present in all studies and critical knowledge gaps in the preclinical evidence were identified using STAIR/SRRR.

Conclusions

CCR5 antagonists demonstrate promise; however, rigorously designed preclinical studies that better align with STAIR/SRRR recommendations and downstream clinical trials are warranted.

Registration

Prospective Register of Systematic Reviews (PROSPERO CRD42023393438)
Antimicrobial Resistance and Virulence-Associated Genes ofPasteurella multocidaandMannheimia haemolyticaIsolated from Polish Dairy Calves with Symptoms of Bovine Respiratory Disease
Authors: Lachowicz-Wolak Agnieszka , Chmielina Aleksandra , Przychodniak Iwona , Karwańska Magdalena , Siedlecka Magdalena , Klimowicz-Bodys Małgorzata , Dyba Kamil , Rypuła Krzysztof
Published: September 2024

Background

Bovine respiratory disease causes significant economic losses in cattle farming due to mortality, treatment costs, and reduced productivity. It involves viral and bacterial infections, withPasteurella multocida(P. multocida) andMannheimia haemolytica(M. haemolytica) as key bacterial pathogens. These bacteria contribute to severe pneumonia and are often found together. A total of 70 bacterial strains were analysed: 48P. multocidaand 22M. haemolytica, collected from deep nasal swabs or lung and bronchial swabs from affected calves. The bacterial species were confirmed molecularly using PCR, which was also employed to detect antimicrobial resistance and virulence-associated genes. Antimicrobial susceptibility was determined using the broth microdilution method.

Results

Antimicrobial resistance varied between the two bacterial species studied. The highest resistance inP. multocidawas observed to chlortetracycline 79.2% and oxytetracycline 81.3%, whileM. haemolyticashowed 63.6% resistance to penicillin and tilmicosin. Multidrug resistance amongP. multocidawas 27.1%, while amongM. haemolyticait reached 40.9%. The most commonly observed phenotypic resistance patterns were ‘chlortetracycline, oxytetracycline’ in 37.5% ofP. multocidaand ‘ceftiofur, chlortetracycline, oxytetracycline, penicillin, tilmicosin, tulathromycin’ in 18.2% ofM. haemolytica. The highest susceptibility was found for fluoroquinolones:P. multocidademonstrated 91.7% susceptibility to enrofloxacin, while 77.3% ofM. haemolyticawere susceptible to both enrofloxacin and danofloxacin. Multidrug resistance was detected in 31.4% of all tested strains. MIC50and MIC90determinations were performed for all tested antimicrobials. AllM. haemolyticacontained thelkt, gs60, andgcpgenes.P. multocidacarried thesodAgene, while thehgbBandompHgenes were present in 37.5% and 20.8% of strains, respectively. ThetetHandtetRgenes were observed only inP. multocida, at frequencies of 20.8% and 16.7%, respectively. Both species carried themphEandmsrEgenes, though at lower frequencies between 6.3% and 14.6%.

Conclusions

This study expands the knowledge of the pathogenicity and antimicrobial resistance ofP. multocidaandM. haemolyticain dairy calves.P. multocidaexhibited the highest resistance to tetracyclines,M. haemolyticademonstrated the greatest nonsusceptibility to penicillin. Both bacterial species were found to be susceptible to fluoroquinolones. One third of strains showed multidrug resistance.
AnalyzAIRR: A user-friendly guided workflow for AIRR data analysis
Authors: Mhanna Vanessa , Pires Gabriel , Bohl-Viallefond Grégoire , El Soufi Karim , Tchitchek Nicolas , Klatzmann David , Six Adrien , Pham Hang P. , Mariotti-Ferrandiz Encarnita
Published: September 2024

The analysis of bulk adaptive immune receptor repertoires (AIRR) enables the understanding of immune responses in both normal and pathological conditions. However, the complexity of AIRR calls for advanced, specialized methods to extract meaningful biological insights. These sophisticated approaches often present challenges for researchers with limited bioinformatics expertise, hindering access to comprehensive immune system analysis. To address this challenge, we developed AnalyzAIRR, an AIRR-compliant R package enabling advanced bulk AIRR sequencing data. The tool integrates state-of-the-art statistical and visualization methods applicable at various levels of granularity. It offers a platform for general data exploration, filtering and manipulation, and in-depth cross-comparisons of AIRR datasets, aimed at answering specific biological questions. We illustrate AnalyzAIRR functionalities using of a published murine dataset of 18 T-cell receptor repertoires from three diferrent T cell subsets. We first detected and removed a major contaminant in a group of samples, before proceeding with to the comparative analysis. Subsequent cross-sample analysis revealed differences in repertoire diversity that aligned with the respective cell phenotypes, and in repertoire convergence among the studied subsets. AnalyzAIRR’s set of analytical metrics is integrated into a Shiny web application and complemented with a tutorial to help users in their analytical strategy, making it user-friendly for biologists with little or no background in bioinformatics.
Cisplatin exposure dysregulates pancreatic islet function in male mice
Authors: Basu Lahari , McKay Kelsea S. , Hoyeck Myriam P. , Grieco-St-Pierre Lili , Rick Kayleigh R.C. , Poleo-Giordani Emilia , Fadzeyeva Evgenia , Mulvihill Erin E. , Mennigen Jan A. , Bruin Jennifer E.
Published: September 2024

Cancer survivors have an increased risk of developing new-onset Type 2 diabetes compared to the general population. Moreover, patients treated with cisplatin, a commonly used chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes compared to age- and sex-matched controls. Insulin-secreting beta cells—located within pancreatic islets—are critical for maintaining glucose homeostasis, and dysregulated insulin secretion is central to Type 2 diabetes pathophysiology. Surprisingly, the impact of cisplatin treatment on pancreatic islets has not been reported. In this study, we aimed to determine if murine islet function is adversely affected by direct or systemic exposure to cisplatin.In vitrocisplatin exposure to male mouse islets profoundly dysregulated insulin release, reduced oxygen consumption, and altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family.In vivocisplatin exposure led to sustained hypoinsulinemia and hypoglycemia in male mice. Pancreas tissues from cisplatin-exposed male mice showed increased proinsulin accumulation and expression of DNA-damage markers in beta cells, but no change in average islet size or % insulin+area per islet. Our data suggest both direct and systemic cisplatin exposure cause acute defects in insulin secretion and may have lasting effects on islet health in mice.
Retinotopic coding organizes the interaction between internally and externally oriented brain networks
Authors: Steel Adam , Angeli Peter A. , Silson Edward H. , Robertson Caroline E.
Published: September 2024

The human brain seamlessly integrates internally generated thoughts with incoming sensory information, yet the networks supporting internal (default network, DN) and external (dorsal attention network, dATN) processing are traditionally viewed as antagonistic. This raises a crucial question: how does the brain integrate information between these seemingly opposed systems? Here, using precision neuroimaging methods, we show that these internal/external networks are not as dissociated as traditionally thought. Using densely-sampled 7T fMRI data, we defined individualized whole-brain networks from participants at rest and calculated the retinotopic preferences of individual voxels within these networks during an visual mapping task. We show that while the overall network activity between the DN and dATN is independent at rest, considering a latent retinotopic code reveals a complex, voxel-scale interaction stratified by visual responsiveness. Specifically, the interaction between the DN and dATN at rest is structured at the voxel-level by each voxel’s retinotopic preferences, such that the spontaneous activity of voxels preferring similar visual field locations is more anti-correlated than that of voxels preferring different visual field locations. Further, this retinotopic scaffold integrates with the domain-specific preferences of subregions within these networks, enabling efficient, parallel processing of retinotopic and domain-specific information. Thus, DN and dATN are not independent at rest: voxel-scale interaction between these networks preserves and encodes information in both positive and negative BOLD responses, even in the absence of visual input or task demands. These findings suggest that retinotopic coding may serve as a fundamental organizing principle for brain-wide communication, providing a new framework for understanding how the brain balances and integrates internal cognition with external perception.
Suicide Death Predictive Models using Electronic Health Record Data
Authors: Srikanth Shweta , Montoya Lina M. , Turnure Matthew M. , Pence Brian W. , Fulcher Naoko , Gaynes Bradley N. , Goldston David B. , Carey Timothy S. , Ranapurwala Shabbar I.
Published: September 2024

In the realm of medical research, particularly in the study of suicide risk assessment, the integration of machine learning techniques with traditional statistics methods has become increasingly prevalent. This paper used data from the UNC EHR system from 2006 to 2020 to build models to predict suicide-related death. The dataset, with 1021 cases and 10185 controls consisted of demographic variables and short-term informa-tion, on the subject’s prior diagnosis and healthcare utilization. We examined the efficacy of the super learner ensemble method in predicting suicide-related death lever-aging its capability to combine multiple predictive algorithms without the necessity of pre-selecting a single model. The study compared the performance of the super learner against five base models, demonstrating its superiority in terms of cross-validated neg-ative log-likelihood scores. The super learner improved upon the best algorithm by 60% and the worst algorithm by 97.5%. We also compared the cross-validated AUC’s of the models optimized to have the best AUC to highlight the importance of the choice of risk function. The results highlight the potential of the super learner in complex predictive tasks in medical research, although considerations of computational expense and model complexity must be carefully managed.
Detection of diphtheria toxin-producingCorynebacterium ramoniiin wounds of an urban, inner-city population in Vancouver, Canada, 2019-2023
Authors: Lowe Christopher F. , Ritchie Gordon , Crestani Chiara , Imperial Miguel , Matic Nancy , Payne Michael , Stefanovic Aleksandra , Whellams Diana , Brisse Sylvain , Romney Marc G.
Published: September 2024

We conducted a retrospective chart review and whole-genome sequencing of specimens with presumptiveCorynebacterium ulceransin Vancouver from July 2019 to July 2023. WGS confirmed 8/14 wound culture isolates asC. ramonii. Two distinct clusters ofC. ramoniiwere identified with clinical presentations similar to cutaneousC. diphtheriae.

Article Summary

Two distinct clusters of C. ramonii were identified in Vancouver, BC with clinical presentations similar to cutaneous C. diphtheriae.
Not like other conifers: evaluation of phenotypic diversity in British common juniper,Juniperus communis, indicates genetic isolation and local adaptations among remnant populations
Authors: Baker J. , Cottrell J. , Ennos R. , Perry A. , Green S. , Cavers S.
Published: September 2024

Habitat fragmentation and genetic isolation pose threats to the genetic diversity and resilience of natural populations. Protecting the genetic diversity of populations, and the processes that sustain it, optimises their ability to adapt to changing conditions and new threats: conservation efforts with this specific goal are known as “dynamic conservation.” The common juniper,Juniperus communis, is a keystone species that provides habitat and resources for many plants and animals. It is a highly polymorphic species, and across its natural range it grows in a variety of habitats and growth forms. Juniper populations have been shrinking and becoming increasingly fragmented for over a century in the UK and elsewhere in Europe, raising concerns about the genetic diversity present in juniper populations and their ability to adapt to changing conditions, or their adaptive potential. This paper presents an analysis of the partitioning of phenotypic diversity among regions, populations and families from 16 UK populations assessed in a common garden trial. Our findings suggest high phenotypic variation among populations compared to the variation among families within populations, indicating barriers to gene flow between juniper populations, relatively homogenous populations and, consequently, potentially reduced adaptive potential. This information is a useful baseline for conservation managers and can also help to infer the genetic diversity and adaptive potential of populations.
Enzymatic access to the rare ΔUA (1→4) Glc 3, 6, N-sulfated heparin disaccharide, implications for heparin quality control
Authors: Kandola T. K. , Mycroft-West C. J. , Andrade De Lima M. L. , Turner A. , Gardini C. , Urso E. , Miller G.J. , Bisio A. , Yates E. A. , Guerrini M. , Wu L. , Skidmore M. A.
Published: September 2024

The sulfated glycosaminoglycan heparin is the most commonly used pharmaceutical anticoagulant worldwide. Heparin, which is extracted primarily from porcine sources, has a complex heterogeneous structure, resulting in a highly variable pharmaceutical product susceptible to contamination. As a by-product of the food industry, heparin is also limited by production capacity, giving rise to concerns that demand will outstrip supply. The anticoagulant activity of heparin derives principally from the AGA*IA pentasaccharide sequence, containing a rare 3-O-sulfated glucosamine, which binds and activates antithrombin. Analytical heparin digestion by the widely usedPedobacter heparinuslyases has limited activity in regions of 3-O-sulfation, rendering these enzymes poorly suited to study anticoagulant sequences. Here, we provide structural and functional characterization of aBacteroides eggerthiilyase that exhibits highly efficient heparin depolymerization, with specificity distinct toP. heparinus. Using a panel of biophysical and structural techniques, we demonstrate thatB. eggerthiilyase effectively liberates the rare GA* disaccharide, a key indicator of anticoagulant potential, from the defined heparin pentasaccharide fondaparinux. We envision superior cleavage byB. eggerthiilyases will enable the future quantitative, direct detection of anticoagulant relevant 3-O-sulfated sequences, delivering complementary structural information to existing analytical methods, with clear utility for pharmaceutical quality control workflows.
Bridging Glucose Metabolism and Intrinsic Functional Organization of the Human Cortex
Authors: Wan Bin , Riedl Valentin , Castrillon Gabriel , Kirschner Matthias , Valk Sofie L.
Published: September 2024

The human brain requires a continuous supply of energy to function effectively. Here, we investigated how the low-dimensional organization of intrinsic functional connectivity patterns based on resting-state functional magnetic resonance imaging relates to brain energy expenditure measured by fluorodeoxyglucose positron emission tomography. By incrementally adding more dimensions of brain organization (via functional gradients), we were able to show that increasing amounts of variance in the map of brain energy expenditure could be accounted for. In particular, the brain organization dimensions that explained a large amount of the variance in intrinsic brain function also explained a large amount of the regional variance in the energy expenditure maps. This was particularly true for brain organization maps based on the strongest connections, suggesting that "weak" connections may not explain as much energy variance. Notably, our topological model was more effective than random brain organization configurations, suggesting that brain organization may be specifically associated with energy optimization. Finally, using brain asymmetry as a model for metabolic efficiency, we found that optimizing energy expenditure independently in each hemisphere outperformed non-independent optimization. This supports the concept of hemispheric competition rather than lateralization in energy allocation. Our results demonstrate how the spatial organization of functional connections is systematically linked to optimized energy expenditure in the human brain, providing new insights into the metabolic basis of brain function.
Distinct modulation of Ihby synaptic potentiation in excitatory and inhibitory neurons
Authors: Herstel Lotte J. , Wierenga Corette J.
Published: September 2024

Selective modifications in the expression or function of dendritic ion channels regulate the propagation of synaptic inputs and determine the intrinsic excitability of a neuron. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open upon membrane hyperpolarization and conduct a depolarizing inward current (Ih). HCN channels are enriched in the dendrites of hippocampal pyramidal neurons where they regulate the integration of synaptic inputs. Synaptic plasticity can bidirectionally modify dendritic HCN channels in excitatory neurons depending on the strength of synaptic potentiation. In inhibitory neurons, however, the dendritic expression and modulation of HCN channels is largely unknown. In this study, we systematically compared the modulation of Ihby synaptic potentiation in hippocampal CA1 pyramidal neurons andstratum Radiatum (sRad)interneurons. Ihproperties were similar in inhibitory and excitatory neurons and contributed to resting membrane potential and action potential firing. We found that insRadinterneurons, HCN channels were downregulated after synaptic plasticity, irrespective of the strength of synaptic potentiation. This suggest differential regulation of Ihin excitatory and inhibitory neurons, possibly signifying their distinct role in network activity.

Significance statement

Learning reflects a change in the way information is processed in neuronal circuits. This occurs via changes in synaptic connections and via alterations of intrinsic excitability of neurons. Here we examined how synaptic changes affect properties of HCN channels, which are important ion channels for intrinsic excitability. We found that strong synaptic potentiation leads to opposite changes in HCN channels in CA1 pyramidal neurons andsRadinterneurons. We speculate that this reflects their differential role in the CA1 network. An upregulation of HCN channels in pyramidal neurons results in a decrease in their excitability, which limits overall network excitation. In contrast,sRadinterneurons show downregulation of Ih, and therefore an increased excitability after strong synaptic activation, which will strengthen feedforward inhibition and sharpen activity patterns.
Endosomal Microautophagy is Activated by Specific Cellular Stresses in Trout Hepatocytes
Authors: Vélez Emilio J. , Véron Vincent , Gouis Jeanne , Reji Steffi , Dias Karine , Herpin Amaury , Beaumatin Florian , Seiliez Iban
Published: September 2024

Endosomal microautophagy (eMI) is a recently discovered autophagic process where cytosolic proteins are selectively captured in late endosome/multivesicular bodies (LE/MVB). This pathway, similar to chaperone-mediated autophagy (CMA), involves the recognition of KFERQ-like motif containing proteins by HSC70. While CMA targets substrates to lysosomes via the receptor LAMP2A, eMI involves internalization into intraluminal vesicles within LE/MVB through interactions with ESCRT machinery. Although the same proteins could be targeted by either pathway, eMI’s role in cellular homeostasis is less understood. Our research identified an eMI-like process in rainbow trout hepatocytes, triggered by oxidative stress, high-glucose, DNA damage, and nutrient deprivation, but not serum deprivation. This finding suggests eMI’s stimulus-specific induction and its potential compensatory role when CMA is impaired. Our study provides new insights into eMI and offers novel model organisms for exploring its interactions with CMA, enhancing our understanding of cellular stress responses.
The coronavirus nsp14 exoribonuclease interface with the cofactor nsp10 is essential for efficient virus replication and enzymatic activity
Authors: Grimes Samantha L. , Heaton Brook E. , Anderson Mackenzie L. , Burke Katie , Stevens Laura , Lu Xiaotao , Heaton Nicholas S. , Denison Mark R. , Anderson-Daniels Jordan
Published: September 2024

Coronaviruses (CoVs) encode nonstructural proteins (nsps) 1-16, which assemble to form replication-transcription complexes that function in viral RNA synthesis. All CoVs encode a proofreading 3’-5’ exoribonuclease (ExoN) in nsp14 (nsp14-ExoN) that mediates proofreading and high-fidelity replication and is critical for other roles in replication and pathogenesis. Thein vitroenzymatic activity of nsp14 ExoN is enhanced in the presence of the cofactor nsp10. We introduced alanine substitutions in nsp14 of murine hepatitis virus (MHV) at the nsp14-10 interface and recovered mutant viruses with a range of impairments in replication andin vitrobiochemical exonuclease activity. Two of these substitutions, nsp14 K7A and D8A, had impairments intermediate between WT-MHV nsp14 and the known ExoN(-) D89A/E91A nsp14 catalytic inactivation mutant. All introduced nsp14-10 interface alanine substitutions impairedin vitroexonuclease activity. Passage of the K7A and D8A mutant viruses selected second-site non-synonymous mutations in nsp14 associated with improved mutant virus replication and exonuclease activity. These results confirm the essential role of the nsp14-nsp10 interaction for efficient enzymatic activity and virus replication, identify proximal and long-distance determinants of nsp14-nsp10 interaction, and support targeting the nsp14-10 interface for viral inhibition and attenuation.

IMPORTANCE

Coronavirus replication requires assembly of a replication transcription complex composed of nonstructural proteins (nsp), including polymerase, helicase, exonuclease, capping enzymes, and non-enzymatic cofactors. The coronavirus nsp14 exoribonuclease mediates several functions in the viral life cycle including genomic and subgenomic RNA synthesis, RNA recombination, RNA proofreading and high-fidelity replication, and native resistance to many nucleoside analogs. The nsp-14 exonuclease activityin vitrorequires the non-enzymatic co-factor nsp10, but the determinants and importance the nsp14-10 interactions during viral replication have not been defined. Here we show that for the coronavirus murine hepatitis virus, nsp14 residues at the nsp14-10 interface are essential for efficient viral replication andin vitroexonuclease activity. These results shed new light on the requirements for protein interactions within the coronavirus replication transcription complex, and they may reveal novel non active-site targets for virus inhibition and attenuation.
Modified homotopy approach for diffractive production in the saturation region
Authors: Contreras Carlos , Garrido José , Levin Eugene , Meneses Rodrigo
Published: September 2024

In this paper we continue to develop the homotopy method for solving of the nonlinear evolution equation for the diffractive production in deep inelastic scattering. We introduce part of the nonlinear corrections as a first step of this approach. This simplified nonlinear evolution equation is solved analytically taking into account the initial and boundary conditions for the process. At the second step of our approach we demonstrated that the perturbative procedure can be used for the remaining parts of the nonlinear corrections. It turns out that these corrections are small and can be estimated in the regular iterative procedure.

Published by the American Physical Society
2024
Search for missing symmetry in the Inorganic Crystal Structure Database (ICSD)
Authors: Avdeev Maxim
Published: September 2024

An exhaustive search for missing symmetry was performed for 223 076 entries in the ICSD (2023-2 release). Approximately 0.65% of them can be described with higher symmetry than reported. Out of the identified noncentrosymmetric entries, ∼74% can be described by centrosymmetric space groups; this has implications for compatible physical properties. It is proposed that the information on the correct space group is included in the ICSD.
Determining magnetic structures in GSAS-II using the Bilbao Crystallographic Server tool k-SUBGROUPSMAG
Authors: Von Dreele Robert B. , Elcoro Luis
Published: September 2024

The embedded call to a special version of the web-based Bilbao Crystallographic Server tool k-SUBGROUPSMAG from within GSAS-II to form a list of all possible commensurate magnetic subgroups of a parent magnetic grey group is described. It facilitates the selection and refinement of the best commensurate magnetic structure model by having all the analysis tools including Rietveld refinement in one place as part of GSAS-II. It also provides the chosen magnetic space group as one of the 1421 possible standard Belov–Neronova–Smirnova forms or equivalent non-standard versions.
Development and demonstration of a social sustainability assessment tool for the construction project life cycle
Authors: Kordi Nurul Elma , Belayutham Sheila , Che Ibrahim Che Khairil Izam
Published: September 2024

Purpose

This research paper aims to address the scarcity of social sustainability (SS) in construction by developing a Social Sustainability Assessment Tool (SocSAT), further demonstrating the tool's applicability in measuring SS practices across the construction project life cycle.

Design/methodology/approach

Various research methods were used to establish the assessment criteria, including literature review, focused group discussions and structured interviews. Subsequently, the SocSAT was developed using proprietary spreadsheet software, which was further demonstrated its applicability and validity using ten project case studies.

Findings

The SocSAT was built on 19 indicators for pre-construction, 25 indicators for construction, and 4 indicators for post-construction phases. The SocSAT offers a comprehensive means for practitioners to assess and monitor SS practices across project phases. The findings indicate that the SocSAT is a straightforward and user-friendly assessment tool that enables practitioners to self-diagnose and better comprehend the present SS practices across the project life cycle.

Research limitations/implications

Limitations include the context-specific nature of validating the SocSAT.

Practical implications

SocSAT enables construction practitioners to monitor and improve their SS practices effectively, facilitating informed decision-making and promoting sustainable construction. The tool is a valuable guide for stakeholders to incorporate SS considerations, ensuring transparent communication and project success.

Originality/value

This research fills a gap in SS research within the construction industry. The SocSAT offers theoretical advancements with practical value, providing a standardized approach to objectively measure the SS dimension across construction project life cycles.
Radiative influence on axisymmetric ternary hybrid nanofluid flow with convective boundary conditions over a nonlinearly permeable stretching/shrinking disk
Authors: Jamrus Farah Nadzirah , Ishak Anuar , Waini Iskandar , Khan Umair
Published: September 2024

Purpose

In recent times, ternary hybrid nanofluid has garnered attention from scientist and researchers due to its improved thermal efficiency. This study aims to delve into the examination of ternary hybrid nanofluid (Al2O3–Cu–TiO2/water), particularly concerning axisymmetric flow over a nonlinearly permeable stretching/shrinking disk. In addition, the investigation of convective boundary conditions and thermal radiation effects is also considered within the context of the described flow problem.

Design/methodology/approach

Mathematical formulations representing this problem are reduced into a set of ordinary differential equations (ODEs) using similarity transformation. The MATLAB boundary value problem solver is then used to solve the obtained set of ODEs. The impact of considered physical parameters such as suction parameter, radiation parameter, nonlinear parameter, nanoparticle volumetric concentration and Biot number on the flow profiles as well as the physical quantities is illustrated in graphical form.

Findings

The findings revealed the thermal flux for the nonlinearly shrinking disk is approximately 1.33%, significantly higher when compared to the linearly shrinking disk. Moreover, the existence of dual solutions attributed to the nonlinear stretching/shrinking disk is unveiled, with the first solution being identified as the stable and reliable solution through temporal stability analysis.

Practical implications

Understanding ternary hybrid nanofluid behavior and flow has applications in engineering, energy systems and materials research. This study may help develop and optimize nanofluid systems like heat exchangers and cooling systems.

Originality/value

The study of flow dynamics across nonlinear stretching/shrinking disk gains less attention compared to linear stretching/shrinking geometries. Many natural and industrial processes involve nonlinear changes in boundary shapes or sizes. Understanding flow dynamics over nonlinear shrinking/stretching disks is therefore essential for applications in various fields such as materials processing, biomedical engineering and environmental sciences. Hence, this study highlights the axisymmetric flow over a nonlinear stretching/shrinking disk using ternary hybrid nanofluid composed of alumina (Al2O3), copper (Cu) and titania (TiO2). Besides, this study tackles a complex problem involving multiple factors such as suction, radiation and convective boundary conditions. Analyzing such complex systems can provide valuable insights into real-world phenomena where multiple factors interact.