bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Effects of Slow-Paced Breathing on Measures of HRV in Hospitalized Patients With Bilateral COVID-19 Pneumonia: A Secondary Analysis of a Randomized Clinical Trial
Authors: Balint Elisabeth Maria , Grüner Beate , Gündel Harald , Haase Sophia , Kaw-Geppert Mandakini , Thayer Julian , Weimer Katja , Jarczok Marc N.
Published: December 2024

Objective

Slow-paced breathing (SPB) with prolonged exhalation is assumed to stimulate vagal reflexes, which is represented by increased heart rate variability (HRV) values. However, most trials were conducted in healthy participants. We sought to evaluate the feasibility of SPB in hospitalized patients with confirmed bilateral COVID-19 pneumonia with major respiratory impairment and to investigate if SPB shows acute increasing effects on HRV measures in these severely ill patients with distinctly reduced vagal tone.

Methods

This single-center randomized controlled clinical trial enrolled 23 patients in the intervention (4-second inhalation, 6-second exhalation for 20 minutes 3× daily) and 23 patients in the control group (IG/CG). The effects of SPB on HRV were calculated using post-hoc likelihood ratio tests. Baseline HRV measures between the groups over time were compared using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age.

Results

HRV values at baseline were significantly decreased in all patients. During SPB, HRV parameters increased significantly (ln(SDNN), ln(LF), ln(TP); all p < .001). Higher breathing rate at baseline correlated with lower LF during SPB (p < .045). IL-6 morning levels were associated with lower HRV measures (p < .001). Resting HRV measures as well as subjective health increased over hospitalization time with no differences between IG and CG (comparing random slope with random slope interaction models: all LR χ
2(5) < 4.5; p > .48).

Conclusion

SPB is feasible and safe in patients with bilateral COVID-19 pneumonia and appears to be an effective self-performed intervention to acutely increase HRV measures. This observation was independent of comorbidities and comedication. Further trials should corroborate these findings and extend it to other severely ill populations.

Registration

German Clinical Trials Register under ID DRKS00023971 (https://drks.de/search/en/trial/DRKS00023971), with a Universal Trial Number (UTN) U1111-1263-8658
The Implementation of Perioperative Geriatric Management Could Decrease the Incidence of Postoperative Delirium in the Elderly Undergoing Major Orthopedic Surgeries
Authors: Zou Yan , Deng Tingzhi , Xu Yu , Zheng Qing , Wu Yuan , Hui Shan , Liu Cuizhong , Wei An
Published: December 2024

Objectives:

This study aimed to explore the association of perioperative geriatric management (PGM) in major orthopedic surgeries.

Methods:

One hundred seventy-five participants aged 75 and older were in-hospital patients who underwent major orthopedic surgery from September 2020 to September 2021, and they received PGM and necessary treatment for indicators with abnormal value (the PGM group). Another 175 participants in the control group only received the evaluation part of the PGM, recruited by filtering in the electronic medical record system from March 2016 to March 2017. The treatment included joint intervention of psychiatrists and rehabilitation physicians. For example, for patients at risk for falling, evaluation of inadequate blood volume, delirium, abnormal gait, and visual impairment should be performed. The logistic regression analysis was adopted to determine the association of PGM and postoperative delirium.

Results:

The prevalence of postoperative delirium among participants was 13.71%. Compared with the empirical treatment group, the postoperative delirium was significantly decreased (7.43% versus 14.29%) (P<0.05). Compared with the control group, participants were in the PGM group were at lower risk of postoperative delirium, mainly attributed to these following factors: Charlson comorbidity index <5 [odds ratio (OR)=0.620; 95% CI: 0.010-0.623], mini cog >2 (OR=0.224; 95% CI: 0.061-0.824), Confusion Assessment Method score indicating low risk (OR=0.079; 95% CI: 0.010-0.623), nutritional risk screening scale <3 (OR=0.306; 95% CI: 0.095-0.989), and major adverse cardiovascular events <3 (OR=0.253; 95% CI: 0.073-0.720). After adjusting for the length of hospital stay and reason for hospitalization, the association between the parameters above and postoperative delirium is still significant (P<0.05).

Conclusions:

The implementation of the PGM could decrease the incidence of postoperative delirium significantly, which might contribute to improving the overall prognosis in elderly patients who underwent major orthopedic surgeries.
Automated Computerized-Based Intervention to Identify Hypomagnesemia in Primary Care Patients With Arrhythmia
Authors: López-Garrigós Maite , Ahumada Miguel , Leiva-Salinas María , Blasco Alvaro , Flores Emilio , Leiva-Salinas Carlos ,   On behalf of the PRIMary Care-LABoratory (PRIMLAB) working group
Published: December 2024

Objectives:

Hypomagnesemia early diagnosis and consequently early, timely magnesium supplementation is of utmost benefit, but it often goes underdiagnosed. The objective was to show and monitor an intervention to identify hypomagnesemia in patients with arrhythmia.

Methods:

A cross-sectional study was designed in the laboratory. In primary care patients, the Laboratory Information System would automatically add a serum magnesium test when sample availability is present in any request when a diagnosis of arrhythmia is made. We counted the number of detected patients with hypomagnesemia (serum magnesium <1.7 mg/dL, <0.7 mmol/L), and calculated the cost in reagent of each identified case.

Results:

In 430 patients with arrhythmia, serum magnesium was measured, and 41 (9.5%) had hypomagnesemia results. One patient showed severe hypomagnesemia values (<1.2 mg/dL and <0.49 mmol/L). Patients with a deficit were significantly (P<0.01) older than the total group of patients with normal magnesium values (66.3±13.2 versus 61.6±12.5). Each case represented a cost of 3.15€ in reagent.

Conclusions:

The automated computer-based intervention to identify patients with hypomagnesemia was useful and affordable, given the cost per detected case.
Modified Infrabrow Blepharoplasty for Periorbital Rejuvenation in Asia Women
Authors: Luo Mengmeng , Zhao Qingfang , Liu Wenjing , Xu Jinghong , He Zhigang
Published: December 2024

Objective:

The infrabrow blepharoplasty is a common surgical operation indicated in Asians for periorbital rejuvenation. This operation alone is difficult to achieve the correction of crow’s feet. Therefore, the authors elucidate the authors' experiences of applying infrabrow blepharoplasty combined with the subcutaneous undermining of the lateral periorbital region to treat upper eyelid dermatochalasis with lateral hooding deformity and alleviate crow’s feet, including its indications, operative procedures, and postoperative outcomes.

Methods:

Retrospective review of patients undergoing infrabrow blepharoplasty incorporated with subcutaneous undermining of the lateral periorbital region between January 2019 and December 2023. Thirty-nine patients who were well followed up were retrospectively reviewed. The surgical procedure is described in depth. Frontal and lateral view photographs were obtained to evaluate the curative effect. The following data were collected preoperatively and at postoperative 6 months: distance between the pupil centre and the supratarsal fold, distance between the pupil centre and lower margin of eyebrow, distance between the lateral canthus and the supratarsal fold, distance between the lateral canthus and lower margin of eyebrow, the rating of Crow’s Feet Grading Scale (CFGS) at rest and at a maximum smile.

Results:

The study included 78 eyelids of 39 patients ranging in age from 37 to 56 years, with a mean age of 46.25 years. The mean follow-up for the patients was 6.7 months. Compared with the postoperation with the preoperation, distance between the pupil centre and the supratarsal fold increased from 5.45 ± 1.31 to 5.98 ± 1.62 mm, distance between the lateral canthus and the supratarsal fold increased from 3.93 ± 1.24 to 6.13 ± 1.87 mm, no evidence of significant changes in distance between the pupil centre and lower margin of eyebrow and distance between the lateral canthus and lower margin of eyebrow. The average change in the rating of CFGS was -0.62 ± 0.11 at maximum contraction and -0.24 ± 0.08 at rest. No significant complications occurred in any patient postoperatively.

Conclusion:

The combination of infrabrow blepharoplasty with the subcutaneous undermining of the lateral periorbital region was effective in addressing moderate dermatochalasis with lateral hooding and improve crow’s feet in middle-aged Chinese patients, resulting in a rejuvenated periorbital area and flattening of the eyebrow is not noted at the same time. The anthropometric measurement of the upper eyelid and CFGS facilitate operation outcome assessment.
ED Nurse-Led Code Sepsis to Reduce Time to Antibiotics
Authors: Gomez Leslie , LeClair Kelli , Jenkins Danisha , David Mary Ann , Downing Jillian , Graham Julie
Published: December 2024

Background: Delays in sepsis recognition contribute to delays in antibiotic administration, which lead to increased morbidity and mortality in patients with sepsis. Our objective was to create an Emergency Department (ED) Code Sepsis Nurse-led team to reduce the time to antibiotics and mortality in patients with sepsis. Methods: This initiative was implemented at a community hospital in Southern California in response to previous undesirable sepsis outcomes. In fiscal year 2021, the ED Sepsis Nursing Team was launched with the goal of improving sepsis-related outcomes. The following interventions were implemented: First, a group of dedicated Sepsis Nurses with training specific to sepsis recognition was created, and an electronic ED-sepsis screening tool was developed and implemented. Next, the dedicated sepsis nurses designed and educated to a “Code Sepsis” activation process. The code triggered a multidisciplinary response and implementation of standing orders for blood cultures, lactate, complete blood count, complete metabolic panel, and chest x-ray or urinalysis if indicated. Finally, the Sepsis Team Registered Nurse (RN) Captain led house-wide monthly Sepsis Task Force meetings to improve unit-level engagement and to allow the team to have ownership over sharing wins and losses. Results: By Quarter 4 (Q4) of Fiscal Year 2021, door-to-antibiotic time for sepsis patients dropped from 196.7 min (Q1) to 144.7 (Q4). Additionally, mortality dropped below the health system average (10.4% vs. 13.5%), and Fiscal Year 2021 surpassed the readmissions benchmark of <1.0 at a rate of 0.5. Conclusion: An RN-led, interprofessional response to accepted sepsis identification criteria enhanced staff and physician engagement and improved sepsis outcomes for patient mortality and hospital reporting outcomes. The process was adopted with very few obstacles that were easily overcome as the understanding of the role and its significance was realized.
Anin vitroinvestigation into the survival ofTropilaelaps mercedesaeon a range of matrices
Authors: Gill Maggie C , Chuttong Bajaree , Davies Paul , Earl Avril , Tonge George , Etheridge Dan
Published: December 2024

Tropilaelapsspp. are a parasitic mite that feed and reproduce within honey bee brood (Apisspp.) and cause significant damage and mortality toApis melliferacolonies.T. mercedesaeis found outside the range of its natural hostA. dorsataand was recently detected in Europe for the first time in 2024. It is widely believed thatTropilaelapsspp. are unable to survive without brood. However, studies have demonstrated thatT. mercedesaecan survive during broodless periods while parasitisingA. dorsataand without brood in overwintering colonies ofA. melliferain temperate climates. This study sought to examine the survival ofT. mercedesaeon a range of matrices and found that mites could survive for more than 96 hours on live adultA. melliferaand more than 144 hours and 168 hours on decomposingA. melliferapupae and adults respectively. These findings could indicate one possible mechanism which allowsT. mercedesaeto survive without brood. These findings also have implications towards better understanding possible transmission routes forTropilaelaps. Previously bee sales in the form of queens and packages and used beekeeping equipment were considered a relatively low risk for transmittingTropilaelapsspp. due to the absence of live brood. This study demonstratesTropilaelaps’ability to survive in these scenarios and the increased potential for it to spread globally.
Tissue-specific apparent mtDNA heteroplasmy and its relationship with ageing and mtDNA gene expression
Authors: Wengert Simon , Giannoulis Xenofon , Kreitmaier Peter , Kautz Pauline , Ludwig Leif S. , Prokisch Holger , Casale Francesco Paolo , Heinig Matthias , Cai Na
Published: December 2024

Heteroplasmy in the mitochondrial DNA (mtDNA) accumulates with age, but how much it occurs in tissues and how it affects function and physiology is not well-studied. Here we present a comprehensive tissue-specific map of mtDNA heteroplasmy and mtRNA modifications, and their relationships with age and mitochondrial gene expression. We propose a robust variant calling pipeline for mtDNA heteroplasmy and mtRNA modifications using bulk RNAseq data from 49 tissues in GTEx, and a calibrated phenotype association framework for both types of variants. We identify 109 associations between them and donor age, and 784 associations with tissue-specific mtDNA gene expression. Of these, 7 and 18 show cell-type specificity within tissue. In addition, we find 9 instances where these variations mediate donor age effects on mtDNA gene expression. Finally, we confirm previously identified relationships between mt-tRNA modifications and gene expression on their 5’, but read- and gene-level investigations reveal previously unmodeled complexities.
Updating Beliefs using New Evidence from a Diagnostic Decision-Support Aid in a Nurse-Led First-Seizure Clinic
Authors: Tittensor Phil , Batterham Alan M , Rowe Jacqui-Dawn , Russell Daniel , Steward Danielle , Schnabel Elizabeth , Meiklejohn Kay , Mainstone Milaana , Wellburn Shaun , Terry John R , Woldman Wessel
Published: December 2024

Recent studies using computational and mathematical interrogation of background EEG have revealed eight biomarkers that inform a diagnostic decision-support tool called BioEP. To assess the utility of BioEP for aiding clinical decision making, we conducted a prospective single-site diagnostic belief updating study (NCT05764252). Eighty-six adults with suspected seizures attended a nurse-led, first-seizure clinic. Using a 7-point scale ranging from ‘virtually certain’ to ‘exceptionally unlikely’, two clinicians independently rated the probability of having another epileptic seizure before and after reviewing BioEP scores. Recruitment took place over 1 year. The probability ratings changed (beliefs updated) by at least one category in 35/86 participants for Reviewer 1 (41%; 95% confidence interval: 30-51%) and in 58/86 people for Reviewer 2 (67%; 58 to 77%). The impact of the presentation of new evidence from the BioEP score on reviewer beliefs was substantial and bidirectional. For Reviewer 1 n=20 lower and n=15 higher probability, with n=37 lower and n=21 higher probability for Reviewer 2. Future research will explore the impact of these biomarkers on long-term diagnostic decision making and examine robustness and generalisability in multi-site settings.
NOTE ON A SMALL FRUIT-EATING BAT FROM THE MIDDLE HOLOCENE OF LAGOA SANTA, EASTERN BRAZIL
Authors: Chahud Artur
Published: December 2024

Bats represent the second most diverse order of mammals; however, their fossil and subfossil remains are still relatively understudied. In Brazil, numerous living species have been identified in cave deposits, although few fossils have been dated, with none originating from the Holocene. This study presents a specimen from the Middle Holocene, collected from Cuvieri Cave. The fossil consists of an incomplete, U-shaped mandible that includes the first molars. The specimen was identified asArtibeussp., a genus of fruit-eating bats that is currently widespread across Brazilian territory. This specimen dates to a poorly understood period in the Lagoa Santa region, when human populations had abandoned the area (referred to as the Archaic Gap)and during which the faunal population of Cervidae experienced a notable decline in the number of fossil records. The genusArtibeusis widely distributed in tropical regions and is commonly found in environments ranging from semi-arid regions to savannas and dense forests. It is not considered a paleoenvironmental indicator.
PERK Signaling Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation
Authors: Zheng Manxi , Peng Qinlu , Kropp Erin M , Shen Zhejuan , Liu Suxuan , Yin Zhengyou , Matono Sho , Iwawaki Takao , Wang Xiang , Inoki Ken , Mei Yang , Li Qing , Liu Lu
Published: December 2024

The integrity of the hematopoietic stem cell (HSC) pool relies on efficient long-term self-renewal and the timely removal of damaged or differentiation-prone HSCs. Previous studies have demonstrated the PERK branch of the unfolded protein response (UPR) drives specific programmed cell death programs to maintain HSC pool integrity in response to ER stress. However, the role of PERK in regulating HSC fatein vivoremains unclear. Here, we demonstrate that PERK is dispensable for normal hematopoiesis and HSC self-renewal under steady-state conditions. In contrast, PERK is activated to promote HSC proliferation and depletion in response to ER stress induced by the inactivation of ER-associated degradation (ERAD), via the knockout of key components of ERAD Sel1L or Hrd1. Inhibition of PERK, either through genetic knockout or knock-in of a point mutation that eliminates PERK kinase activity, significantly restores the HSC defects induced by Sel1L or Hrd1 knockout. Mechanistic studies reveal that ERAD deficiency does not lead to HSC death or ROS accumulation. Instead, PERK promotes the activation of mTOR signaling and drives abnormal proliferation of HSCs, impairing their self-renewal potential. This process removes stressed HSCs, thereby maintaining HSC pool integrity. Our study uncovers a PERK-centered strategy employed by HSCs to preserve their pool integrity independently of apoptosis.

Key points

PERK is not required for steady-state hematopoiesis but preserves hematopoietic stem cell pool integrity in response to increased ER stress.

Under ER stress induced by ERAD deficiency, PERK is activated to promote mTOR signaling and HSC hyper-proliferation, depleting damaged HSCs.
Dimorphic Neural Network Architecture Prioritizes Sexual-related Behaviors in Male C.elegans
Authors: Wang Xuebin , Liu Hanzhang , Yang Wenjing , Yang Jingxuan , Sun Xuehong , Liu Qiuhan , Zhu Ying , Sun Yinghao , Liu Chunxiuzi , Shi Guiyuan , Liu Qiang , Zhang Ke , Di Zengru , Yang Wenxing , Liu He
Published: December 2024

Neural network architecture determines its functional output. However, the detailed mechanisms are not well characterized. In this study, we focused on the neural network architectures of male and hermaphrodite C. elegans and the association with sexually dimorphic behaviors. We applied graph theory and computational neuroscience methods to systematically discern the features of these two neural networks. Our findings revealed that a small percentage of sexual-specific neurons exerted dominance throughout the entire male neural net-work, suggesting male’s prioritized sexual-related behavior outputs. Based on the structural and dynamical characteristics of two complete neural networks, sub-networks containing sex-specific neurons and their immediate neighbors, or sub-networks exclusively comprising sex-shared neurons, we predicted dimorphic behavioral outcomes for males and hermaphrodites. To verify the prediction, we performed behavioral and calcium imaging experiments and dissected a circuit that is specific for the increased spontaneous local search in males for mate-searching. Our research sheds light on the neural circuits that underlie sexually dimorphic behaviors in C. elegans, and provides significant insights into the inter-connected relationship between network architecture and functional outcomes at the whole-brain level.
Dairy DigiD ∼ A Deep Learning-Based, Non-Invasive Biometric Identification System for Dairy Cattle Using Detectron2
Authors: Mahato Shubhangi , Bi Hanqing , Neethirajan Suresh
Published: December 2024

Precision livestock farming demands accurate and reliable individual animal identification for optimizing health monitoring, resource allocation, and overall herd productivity. Conventional identification methods—such as ear tagging and wearable sensors—are often invasive, potentially causing animal discomfort and affecting natural behaviors. To address these challenges, we introduce Dairy DigiD, a non-invasive biometric classification system for dairy cattle using facial image analysis. Leveraging deep learning and the Detectron2 framework, Dairy DigiD classifies cattle into four categories—young (<2 years), mature milking, pregnant, and old—using over 2,500 high-resolution facial images. A DenseNet121 model achieved a classification accuracy of 97%, showcasing its strong discriminative capability. Further, Detectron2 attained an average recall of 87% in category identification, an average precision of 96% in cattle detection, and an overall detection accuracy of 93%, demonstrating its robustness and adaptability to varied environmental conditions. Unlike traditional approaches that rely on fixed facial landmarks and can be sensitive to environmental variability, Dairy DigiD’s flexible deep learning architecture enables stable and scalable facial feature extraction. This non-invasive method minimizes animal stress, enhances data integrity, and facilitates improved herd management and welfare monitoring. In comparison to existing convolutional neural network (CNN)-based strategies, Dairy DigiD exhibits superior adaptability to real-world farm conditions, including variable lighting and complex poses. This work highlights the potential of integrating advanced computer vision and deep learning methodologies into precision dairy farming, offering an ethically aligned, efficient, and scalable approach to modern livestock management.
Identification of a Highly Expressed Gene Cluster Likely Coding for Benzene Activation Enzymes in a Methanogenic Enrichment Culture
Authors: Toth Courtney R. A. , Molenda Olivia , Nesbo Camilla L. , Luo Fei , Devine Cheryl E. , Chen Xu Charlie , Wu Kan , Xiao Johnny Zi , Guo Shen , Bawa Nancy , Flick Robert , Edwards Elizabeth Anne
Published: December 2024

The Oil Refinery (OR) consortium is a model methanogenic enrichment culture for studying anaerobic benzene degradation. Over 50% of the culture′s bacterial community is comprised of two closely related strains of benzene-fermenting Desulfobacterota (designated ORM2a and ORM2b) whose mechanism of benzene degradation is unknown. Two new metagenomes, including a complete circularized metagenome-assembled genome (MAG) for ORM2a, enabled a thorough investigation of this culture′s proteome. Among the proteins identified were Bam-like subunits of an ATP-independent benzoyl-CoA degradation pathway and associated downstream beta-oxidation proteins producing acetyl-CoA. The most abundant proteins identified mapped to two ORM2a gene clusters of unknown function. Syntenic gene clusters were identified in two other known benzene degrader, ORM2b and Pelotomaculum candidate BPL, and in nine contigs assembled from hydrothermal vent metagenomes. Extensive searches against reference sequence and structural databases indicate that the first (″Magic″) gene cluster likely catalyzes the chemically difficult benzene activation step. The second (″Nanopod″) gene cluster is predicted to code for an efflux system that may pump excess benzene out of cells to mitigate toxicity. Phylogenomic analyses place ORM2a and ORM2b within a novel genus of benzene-degrading specialists which we propose naming ″Candidatus Benzenivorax″.
Emergence and Dynamics of Usutu and West Nile Viruses in the Netherlands, 2016-2022
Authors: Münger Emmanuelle , Atama Nnomzie , van Irsel Jurrian , Blom Rody , Krol Louie , van den Berg Tijs J , Braks Marieta , de Vries Ankje , van der Linden Anne , Chestakova Irina , Boter Marjan , Chandler Felicity D , Kohl Robert , Nieuwenhuijse David F , Uiterwijk Mathilde , Fouchier Ron A M , Sprong Hein , Gröne Andrea , Koenraadt Constantianus J M , Schrama Maarten , Reusken Chantal B E M , Stroo Arjan , van den Brand Judith M A , van der Jeugd Henk P , Oude Munnink Bas B , Sikkema Reina S , Koopmans Marion P G
Published: December 2024

Background

Mosquito-borne arboviruses, including Usutu virus (USUV) and West Nile virus (WNV), are emerging threats in Europe, with changes in climate, land use, and increased travel and trade influencing their dynamics. Understanding the emergence and establishment of these viruses in new regions is critical for informing targeted mitigation of drivers of emergence and enhancing public and wildlife health preparedness.

Methods

Seven years (2016-2022) of interconnected studies were conducted in the Netherlands. Live birds were sampled by volunteer bird ringers, dead birds were referred for sampling by citizen-scientists and zoological institutions, and mosquitoes were trapped. Samples were tested for USUV and WNV using RT-PCR and screened forOrthoflavivirusantibodies using protein microarray and neutralization assays. Sequencing and phylogenetic analyses were performed.

Findings

USUV was first detected in the Netherlands in 2016, caused large outbreaks in birds until 2018, and resurged in 2022. One dominant, enzootic lineage, co-circulated alongside several limited introductions of a second lineage. A localized WNV lineage 2 outbreak occurred in live birds and mosquitoes in 2020, with another positive bird in 2022 and serological evidence of continued circulation.

Interpretation

We provide the first comprehensive, multi-year documentation of two emerging arboviruses in the Netherlands. USUV was enzootically maintained over seven years and was associated with substantial bird mortality. WNV is in an early stage of establishment with no bird mortality observed. Our integrated wildlife sampling was crucial in detecting a human WNV outbreak, bringing this emerging threat to public health attention.

Funding

ZonMw, Dutch Research Council (NWO), European Union, Government of the Netherlands
A protein cage system for producing bioactive peptides inEscherichia coli
Authors: Harding Maxim D. , Jackson Mark A. , Gilding Edward K. , Yap Kuok , Craik David J. , Sainsbury Frank , Lawrence Nicole
Published: December 2024

New therapeutics are urgently needed to curb the spread of drug-resistant diseases. Bioactive peptides (BAPs), including antimicrobial peptides, are emerging as an exciting new class of compounds with advantages over current drug modalities, especially small molecule drugs that are prone to resistance development. However, production of BAPs currently relies heavily on chemical synthesis, which is environmentally and economically costly. To address this limitation, we developed a platform that enables the biosynthetic production of BAPs via encapsulation within self-assembling protein cages in the cytoplasm ofEscherichia coli. Using bacteriophage P22 virus-like particles (VLPs), we assessed the encapsulation of three structurally distinct classes of BAPs with activities against bacteria, cancer, and malaria. We demonstrated that encapsulation within P22 VLPs enables successful production of BAPs that are otherwise recalcitrant to recombinant expression. This approach is especially attractive for positively charged BAPs and we observed an increase in packaging efficiency within P22 VLPs that corresponded to an increase in overall positive charge. Both cyclic and linear BAPs were recovered following a simple downstream processing pipeline that involved VLP disassembly, then extraction of BAPs via enzymatic processing. This work demonstrates that encapsulation of BAPs within P22 VLPs is an effective method for biosynthetic production of BAPs inE. coli. By providing an alternative to chemical synthesis, this approach has the potential to increase accessibility and reduce the cost and burden of chemical waste for producing therapeutically valuable BAPs.
CD24-Fc resolves inflammation and rescues CD8 T cells with polyfunctionality in humanized mice infected with HIV-1 under cART
Authors: Li Guangming , Ma Jianping , Yu Haisheng , Tsahouridis Ourania , Lou Yaoxian , He Xiuting , Funaki Masaya , Mathur Poonam , Kottilil Shyamasundaran , Zheng Pan , Liu Yang , Su Lishan
Published: December 2024

The persistence of HIV-1 reservoirs during combination anti-retroviral therapy (cART) leads to chronic immune activation and systemic inflammation in people with HIV (PWH), associating with a suboptimal immune reconstitution as well as an increased risk of non-AIDS events. This highlights the needs to develop novel therapy for HIV-1 related diseases in PWH. In this study, we assessed the therapeutic effect of CD24-Fc, a fusion protein with anti-inflammatory properties that interacts with danger-associated molecular patterns (DAMPs) and siglec-10, in chronic HIV-1 infection model using humanized mice undergoing suppressive cART. Our findings show that CD24-Fc treatment significantly reduced inflammation and immune hyperactivation in vivo when combined with cART. CD24-Fc mediated resolution of inflammation was associated with improved recovery of CD4 T cells, reduced immune activation, restored central memory T cells and reversal of immune cell exhaustion phenotype. Notably, CD24-Fc treatment rescued CXCR5+ CD8 central memory T cell (TCM) which correlated with increased polyfunctionality in HIV-specific T cells in humanized mice and in cultured peripheral blood mononuclear cells (PBMCs) from PWH. This restoration of CXCR5+ memory CD8 T cells was associated with HIV replication inhibition, delayed viral rebound and reduced HIV-1 pathogenesis upon cART cessation. This study suggests that CD24-Fc treatment could represent a promising new therapeutic strategy for managing chronic systemic inflammation and associated diseases in PWH.

Author summary

Combination antiretroviral therapy (cART) cannot block viral gene expression from activated HIV proviral DNA in reservoir cells, contributing to chronic immune activation and inflammation associated diseases in people with HIV (PWH). The therapeutic treatment of anti-inflammatory fusion protein CD24-Fc in humanized mice during suppressive cART (i) resolves inflammation and chronic HIV-1 immune pathogenesis during suppressive cART, (ii) rescues CXCR5-expressing CD8 memory T cells and enhances antiviral response in humanized mice and PWH PBMCs, (iii) delays virus rebound and reduces viral pathogenesis after cART cessation. Thus, CD24-Fc could provide a novel therapeutic strategy for treating chronic systemic inflammation and associated diseases in PWH.
CCGM: a Compound Coarse Grain Model representation for enhanced chemotype exploration, annotation and screening
Authors: Sahni Navriti , Patek Marcel , Rahman Rayees , Ravikumar Balaguru
Published: December 2024

Structurally similar compounds often exhibit similar bioactivity, making similarity estimation an essential step in many cheminformatics workflows. Traditionally, compound similarity has been evaluated using diverse molecular representations, such as molecular fingerprints, compound 3D structural features, and physicochemical properties. These methods have proven effective, particularly during the early stages of drug discovery, where the primary goal is to identify initial hits from large compound libraries. However, these representation and methods often fall short during the hit-to-lead development phase, where modifications to the core scaffold or chemotype are performed and evaluated. To address this limitation, we developed the Compound-Coarse-Grain-Model (CCGM), a framework that represents structural features of a compound as nodes and edges within a simplified graph. This approach augments the pharmacophore and chemotype features of the compound within the graph, enabling the identification of compounds with similar chemotype and pharmacophore features more effectively than conventional methods. CCGM is particularly useful for when screening large libraries to identify compounds with similar chemotypes and for filtering generative designs to retain designs with similar pharmacophore features.
Illuminating the Potential: Light Harvesting and Semiconducting Properties of Bacterial Microcompartment Shell Proteins
Authors: Bedi Silky , Rose S M , Sinha Sharmistha
Published: December 2024

Biomaterials with self-assembly, genetic tunability, self-healing, and biocompatibility hold promise for next-generation electronics. This study explores disc-like shell proteins from bacterial microcompartments as photovoltaic materials. These self-assembling proteins exhibit semiconducting properties, including a low work function and non-linear I-V behavior. Notably, under UV light, they generate significant photocurrent without external voltage, demonstrating efficient electron transfer. Electron conduction occurs via tunneling, enabled by distinct electron-rich surface regions. High responsivity and quantum efficiency outperform prior protein-based systems, emphasizing their potential in photocurrent and light-harvesting applications. Genetic mutations revealed a proton-coupled electron transfer (PCET) mechanism, where tyrosine residues strategically positioned near proton abstraction sites enhance photocurrent generation. This study highlights the innovative capabilities of shell proteins for energy-efficient devices and demonstrates how genetic engineering can further optimize biomaterial performance, paving the way for sustainable electronic applications.
A Conditional Degron Tag for RNA Sensing in Bacteria
Authors: Simons Tyler J. , Hammond Ming C.
Published: December 2024

Here we report the development of a conditional degron system for use in bacteria in which a tagged fluorescent protein (FP) reporter, mVenus-S1, is stabilized only in the presence of TAR RNA. The functional design takes advantage of the bipartite nature of the ssrA degron sequence, so that TAR RNA binding to the inserted Tat peptide sequence blocks degron recognition to rescue protein activity. Several fluorescent proteins and a chemiluminescent enzyme can be tagged and activated using this system, and our results reveal that chromophore maturation time correlates with fold change, with up to ∼60-fold turn-on. Finally, we designed a functional biosensor foroxySsRNA and integrated it into a single transcript in which the FP and RNA-based biosensor are encoded on the same mRNA. To our knowledge, this is the first proof-of-concept for a novel biosensor design that expresses both protein and RNA components from a single transcript. The streamlined system is fully genetically encoded, does not require an exogenous fluorophore, and permits both components to be coordinated by expression from the same promoter.
Deep learning-based stride segmentation with wearable sensors: effects of data quantity, sensor location, and task
Authors: Anderson Anthony J. , Gonzalez Michael , Eguren David , Khan Naima , Zuccaroli Isabella , Hirczy Siegfried , Kelly Valerie E. , Muir Brittney C. , Kontson Kimberly
Published: December 2024

Accurate stride segmentation from wearable sensors is foundational for digital gait assessment tools, yet systematic evaluations of deep learning approaches across varied real-world mobility tasks remain limited. We developed and assessed Temporal Convolutional Network (TCN) models for stride segmentation using data from 121 older adults with and without Parkinson’s disease, specifically evaluating how performance varies with model development data quantity, sensor location, and movement complexity. Using a fixed-size test set of 40 participants, we found that lower limb sensors achieved F1 scores above 95% during walking with just 5–10 training participants, but performance declined substantially during more complex movements such as 180° turns. Foot-mounted sensors maintained robust performance across tasks (F1: 99.3% walking, 96.7% turning, 88.4% stationary and transitional movements), while wrist sensors showed marked degradation (F1: 88.4% walking, 72.3% turning, 50.0% stationary and transitional movements). Our findings demonstrate that it is important to tailor performance testing for digital gait assessment tools to both sensor location and use case, as performance achieved during controlled walking may not generalize to complex movements in daily life.
Safety Monitoring of Mpox Vaccines in Adults Aged 18–64 Years during the 2022 Mpox Outbreak in the U.S.
Authors: Gruber Joann F. , Matuska Kathryn , Zelaya Carla E. , Wang Jing , McMahill-Walraven Cheryl N , Peetluk Lauren , Secora Alex , Krishnakumar Shwetha , Hu Mao , Amend Kandace L. , Song Jennifer , Beachler Daniel C. , Lloyd Patricia C. , Chillarige Yoganand , Gwira Jane A. , Tarazi Wafa , Clarke Tainya C. , Djibo Djeneba Audrey , Forshee Richard A. , Shoaibi Azadeh , Anderson Steven A.
Published: December 2024

Two vaccines (JYNNEOS; ACAM2000) were available in the United States to prevent mpox during the 2022 clade II mpox outbreak with the majority of people receiving JYNNEOS. As part of the Biologics Effectiveness and Safety (BEST) Initiative, FDA monitored the safety of JYNNEOS using three commercial health plan claims databases supplemented with local and state Immunization Information System data. We assessed vaccine uptake, described the vaccinated population, monitored rates of 11 potential adverse events (AEs) following vaccination, and compared the observed AE rates to expected background rates. There were 152,001 JYNNEOS doses administered. Of the 92,340 people receiving at least one JYNNEOS dose, most were males (93.1%), aged 25–44 years (63.3%), lived in urban areas (98.7%), and 64.2% received a second dose. AE rates following JYNNEOS doses were similar to expected background rates. Additional safety studies of larger vaccinated populations may be needed to evaluate rare AEs including myocarditis/pericarditis.
Metabolomic profiling reveals grade-specific niacinamide accumulation and its therapeutic Potential via SIRT1-CD38-EMT axis modulation in cervical cancer progression
Authors: Jaiswal Shivani , Mishra Vivek , Majumder Srija , Wangikar Pramod P. , Sengupta Shinjinee
Published: December 2024

Despite the availability of new therapies for cervical cancer, innovative strategies are essential to address challenges related to drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 100 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. The major metabolic alterations included changes in glycolysis, the citric acid cycle, amino acid metabolism, nucleotide metabolism, and nicotinamide metabolism in a grade-dependent manner. Interestingly, metabolic differences between HPV-positive and HPV-negative tumors included elevated arginine and proline metabolism, nicotinamide metabolism, and phosphatidylcholine biosynthesis. We further validated our findings by analyzing transcriptomics datasets from the Gene Expression Omnibus database to understand the expression patterns of the underlying genes involved in the dysregulated pathways. We observed that nicotinamide metabolism exhibits significant effects in lower-grade cervical cancers and specific HPV genotypes. We treated cervical cancer cell lines with niacinamide (NAM), an amide form of niacin, to evaluate its potential therapeutic efficacy. NAM treatment modulated NAD+ metabolism with key players such as CD38, PARP, NAMPT, and SIRT1, promoting apoptosis and inhibiting cell proliferation in cervical cancer cells. Importantly, the metabolic responses differed between the HPV-positive SiHa cells and HPV-negative C33A cells, reflecting distinct NAD+ metabolic adaptations. The study highlights the metabolic adaptation or shifts in cancer progression and provides insights into NAM’s molecular mechanisms and therapeutic potential for precision medicine in cervical cancer.
Eukaryotic composition across seasons and social groups in the gut microbiota of wild baboons
Authors: Chege Mary , Ferretti Pamela , Webb Shasta , Macharia Rosaline W. , Obiero George , Kamau Joseph , Alberts Susan C. , Tung Jenny , Akinyi Mercy Y. , Archie Elizabeth A
Published: December 2024

Background

Animals coexist with complex microbiota, including bacteria, viruses, and eukaryotes (e.g., fungi, protists, and helminths). While the composition of bacterial and viral components of animal microbiota are increasingly well understood, eukaryotic composition remains neglected. Here we characterized eukaryotic diversity in the microbiomes in wild baboons and tested the degree to which eukaryotic community composition was predicted by host social group membership, sex, age, and season of sample collection.

Results

We analyzed a total of 75 fecal samples collected between 2012 and 2014 from 73 wild baboons in the Amboseli ecosystem in Kenya. DNA from these samples was subjected to shotgun metagenomic sequencing, revealing members of the kingdoms Protista, Chromista, and Fungi in 90.7%, 46.7%, and 20.3% of samples, respectively. Social group membership explained 11.2% of the global diversity in gut eukaryotic species composition, but we did not detect statistically significant effect of season, host age, and host sex. Across samples, the most prevalent protists wereEntamoeba coli(74.66% of samples),Enteromonas hominis(53.33% of samples), andBlastocystis subtype3 (38.66% of samples), while the most prevalent fungi includedPichia manshurica(14.66% of samples), andOgataea naganishii(6.66% of samples).

Conclusions

Protista, Chromista, and Fungi are common members of the gut microbiome of wild baboons. More work on eukaryotic members of primate gut microbiota is essential for primate health monitoring and management strategies.
Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3
Authors: Sutton Margie N. , Glazer Sarah E. , Zaki Ajlan Al , Napoli Arianna , Yang Ping , Bhosale Priya , Liu Jinsong , Gammon Seth T. , Piwnica-Worms David
Published: December 2024

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3–6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerizationin cisactivated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01).In vitroandin vivomurine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.
The first comorbidity networks in companion dogs in the Dog Aging Project
Authors: Fang Antoinette , Kumar Lakshin , Creevy Kate E ,   the Dog Aging Project Consortium, Promislow Daniel E.L. , Ma Jing
Published: December 2024

Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n=166) and included only dogs that had at least one of those health conditions (n=26,523). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with blindness and hypertension with chronic kidney disease. In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes occurs before cataracts, which is consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.
Tiled Amplicon Sequencing Enables Culture-free Whole-Genome Sequencing of Pathogenic Bacteria From Clinical Specimens
Authors: Kalinich Chaney C , Gonzalez Freddy L , Osmaston Alice , Breban Mallery I , Distefano Isabel , Leon Candy , Sheen Patricia , Zimic Mirko , Coronel Jorge , Tan Grace , Crudu Valeriu , Ciobanu Nelly , Codreanu Alexandru , Solano Walter , Ráez Jimena , Allicock Orchid M , Chaguza Chrispin , Wyllie Anne L , Brandt Matthew , Weinberger Daniel M , Sobkowiak Benjamin , Cohen Ted , Grandjean Louis , Grubaugh Nathan D , Redmond Seth N
Published: December 2024

Pathogen sequencing is an important tool for disease surveillance and demonstrated its high value during the COVID-19 pandemic. Viral sequencing during the pandemic allowed us to track disease spread, quickly identify new variants, and guide the development of vaccines. Tiled amplicon sequencing, in which a panel of primers is used for multiplex amplification of fragments across an entire genome, was the cornerstone of SARS-CoV-2 sequencing. The speed, reliability, and cost-effectiveness of this method led to its implementation in academic and public health laboratories across the world and adaptation to a broad range of viral pathogens. However, similar methods are not available for larger bacterial genomes, for which whole-genome sequencing typically requiresin vitroculture. This increases costs, error rates and turnaround times. The need to culture poses particular problems for medically important bacteria such asMycobacterium tuberculosis,which are slow to grow and challenging to culture. As a proof of concept, we developed two novel whole-genome amplicon panels forM. tuberculosisandStreptococcus pneumoniae. Applying our amplicon panels to clinical samples, we show the ability to classify pathogen subgroups and to reliably identify markers of drug resistance without culturing. Development of this work in clinical settings has the potential to dramatically reduce the time of diagnosis of drug resistance for multiple drugs in parallel, enabling earlier intervention for high priority pathogens.