bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of novel plasma proteomic biomarkers of Dupuytren Disease
Authors: Hummer Blake , Sebastiani Paola , Leshchyk Anastasia , Gurinovich Anastasia , Bager Cecilie , Karsdal Morten , Nielsen Signe , Eaton Charles 
Published: December 2024

ABSTRACTDupuytren Disease (DD) is a chronic progressive disease that can cause disabling hand deformities. The most common treatments have high rates of complications and early recurrence. Dupuytren lacks a staging biomarker profile to develop preventive therapeutics to improve long-term outcomes. This multi-omic study aimed to create a DD blood proteomic biomarker profile by comparing DD plasma to a healthy control group. We measured circulating collagen metabolism peptides and found normal Collagen I synthesis but impaired Collagen I degradation in DD. We measured 6995 serum protein aptamers and identified 68 proteins with statistically significant differences from the control group. We developed two Diagnostic Proteomic Risk Scores (DPRS) based on hypothesis-free and hypothesis-based analyses. In independent data, our hypothesis-free and the hypothesis-based DPRS distinguished Dupuytren from control subjects with 76.5% and 70.6% accuracy, respectively. Our hypothesis- based DPRS also distinguished DD subjects with different disease progression rates based on subject age at the time of their first corrective procedure (p=0.0018). This pilot study is the first to provide evidence that Collagen I accumulation in DD is due to impaired degradation rather than increased collagen synthesis. It also describes novel DPRS that have potential use as diagnostic and staging biomarker panels for Dupuytren disease.
Limited durability of protection conferred by XBB.1.5 vaccines against Omicron-associated severe outcomes among community-dwelling adults aged ≥50 years, Ontario, Canada, September 2023 to June 2024
Authors: Lee Nelson , Nguyen Lena , Nasreen Sharifa , Austin Peter C. , Brown Kevin A. , Buchan Sarah A , Grewal Ramandip , Schwartz Kevin L , Tadrous Mina , Wilson Kumanan , Wilson Sarah E , Kwong Jeffrey C 
Published: December 2024

ABSTRACTWe estimated XBB.1.5 vaccine effectiveness against hospitalization/death among adults aged ≥50 years. Compared with non-XBB.1.5 vaccinees, the initial protection of 64% (95%CI, 57%−69%) was reduced when JN/KP-sublineages became predominant, and quickly declined. No significant protection was observed >6 months post-vaccination. Short durability of protection poses unique challenges for COVID-19 vaccination.
Differences between meeting 24-hour movement guidelines and physical fitness levels among Japanese elementary school children
Authors: Naito Takashi , Aoyagi Kenryu , Oka Koichiro , Ishii Kaori 
Published: December 2024

AbstractCurrent physical fitness levels in Japanese children are lower than that in the 1980s. Investigating the specific relationship between adherence to 24-hour movement guidelines (24-h MG, MVPA: moderate-to-vigorous physical activity; ScT: screen time; Sleep: sleep duration) and physical fitness is crucial to improve children’s fitness levels. Overall physical fitness and eight physical fitness component scores (handgrip strength, sit-up, sit-and-reach, repeated side jump, 20-meter shuttle run, 50-meter sprint, standing long jump, and softball throw) were measured using standardized tests in Japanese elementary schools. Associations between compliance with 24-h MG, overall physical fitness, and each physical fitness component score were analyzed by analysis of covariance. A total of 307 participants (41.4% male) were included in the analysis. Overall fitness scores were significantly higher in children who met only MVPA (P < 0.01), MVPA and ScT (P < 0.01), MVPA and Sleep (P < 0.001), and all three criteria (P < 0.05), than in those who did not. Children meeting only MVPA, MVPA and ScT, and MVPA and Sleep criteria, had higher scores for physical fitness components than those who did not. Children who met one or both of ScT and Sleep criteria, did not differ significantly for overall fitness or its components scores compared to those who did not meet. Handgrip strength and flexibility were not associated with any 24-h MG pattern. Furthermore, compliance with MVPA combined with other behaviors (ScT and Sleep) demonstrated a trend towards greater overall fitness, muscle strength in lower extremities, cardiorespiratory fitness, agility, and dexterity.
Phoretic mites as benign passengers: no influence on mate choice in the burying beetleNicrophorus nepalensis
Authors: Lan Brendan , Malik Tanzil Gaffar , Tsai Mu-Tzu , Wu Yi-Ta , Sun Syuan-Jyun 
Published: December 2024

AbstractMate choice is a fundamental aspect of sexual selection where the ‘chooser’ chooses a ‘courter’ by assessing a variety of traits that communicate potential fitness. However, the influence of interspecific interactions, such as symbiosis, on mate choice remains underexplored. We addressed this shortcoming with experiments on burying beetleNicrophorus nepalensisand their interactions with phoretic mitesPoecilochirus carabi. The mites can act either as mutualists or parasites depending on the presence of competitors and mite densities, thus potentially influencing mate choice. In a laboratory experiment, we presented femaleN. nepalensiswith a range of natural mite densities: 0, 5, 10, or 20, with males carrying either 0 or 10 mites in an olfactory-based mate choice assay. Subsequently we allowed females to breed with their chosen male and all their mites before evaluating the fitness effects of the varying mite densities. We found that females across all mite densities had no preference for males with or without mites. In line with this, the mite densities had no effect on the brood size or the averaged larva mass. However, the mite densities per breeding cohort did positively affect the number of mite offspring. Our results suggest that mites act as benign passengers, not directly affecting mate choice or fitness.
An activation-based high throughput screen identifies caspase-10 inhibitors
Authors: Castellón José O. , Yuen Constance , Han Brandon , Andrews Katrina H. , Ofori Samuel , Julio Ashley R. , Boatner Lisa M. , Palafox Maria F. , Perumal Nithesh , Damoiseaux Robert , Backus Keriann M. 
Published: December 2024

ABSTRACTCaspases are a family of highly homologous cysteine proteases that play critical roles in inflammation and apoptosis. Small molecule inhibitors are useful tools for studying caspase biology, complementary to genetic approaches. However, achieving inhibitor selectivity for individual members of this highly homologous enzyme family remains a major challenge in developing such tool compounds. Prior studies have revealed that one strategy to tackle this selectivity gap is to target the precursor or zymogen forms of individual caspases, which share reduced structural homology when compared to active proteases. To establish a screening assay that favors the discovery of zymogen-directed caspase-10 selective inhibitors, we engineered a low-background and high-activitytobacco etchvirus (TEV)--activated caspase-10 protein. We then subjected this turn-on protease to a high-throughput screen of approximately 100,000 compounds, with an average Z’ value of 0.58 across all plates analyzed. Counter screening, including against TEV protease, delineated bona fide procaspase-10 inhibitors. Confirmatory studies identified a class of low-pH activatable caspase-10 inhibitors. In parallel, mode-of-action studies revealed that pifithrin-µ (PFTµ), a reported TP53 inhibitor, also functions as a promiscuous caspase inhibitor. Both inhibitor classes showed preferential zymogen inhibition. Given the generalized utility of activation assays, we expect our screening platform to have widespread applications in identifying state-specific protease inhibitors.
Deep learning-based prediction of chemical accumulation in a pathogenic mycobacterium
Authors: Sullivan Mark R. , Rubin Eric J. 
Published: December 2024

AbstractDrugs must accumulate at their target site to be effective, and inadequate uptake of drugs is a substantial barrier to the design of potent therapies. This is particularly true in the development of antibiotics, as bacteria possess numerous barriers to prevent chemical uptake. Designing compounds that circumvent bacterial barriers and accumulate to high levels in cells could dramatically improve the success rate of antibiotic candidates. However, a comprehensive understanding of which chemical structures promote or prevent drug uptake is currently lacking. Here we use liquid chromatography-mass spectrometry to measure accumulation of 1528 approved drugs inMycobacterium abscessus, a highly drug-resistant, opportunistic pathogen. We find that simple chemical properties fail to effectively predict drug accumulation in mycobacteria. Instead, we use our data to train deep learning models that predict drug accumulation inM. abscessuswith high accuracy, including for chemically diverse compounds not included in our original drug library. We find that differential drug uptake is a critical determinant of the efficacy of drugs currently in development and can identify compounds which accumulate well and have antibacterial activity inM. abscessus. These predictive algorithms can be an important complement to chemical synthesis and accumulation assays in the evaluation of drug candidates.
Obesity-related brain atrophy occurs through mechanisms independent of Alzheimer’s disease pathology
Authors: Morys Filip , Liu Lang , Senkevich Konstantin , Gan-Or Ziv , Dagher Alain 
Published: December 2024

AbstractObesity increases the risk for Alzheimer’s disease (AD) and related dementias, likely through structural brain changes in the same regions as AD. The mechanisms underpinning brain atrophy in AD involve the deposition of misfolded and dysfunctional tau and β-amyloid proteins, but are not well understood in obesity. Here, we tested whether obesity, cerebrovascular disease, and obesity-related metabolic risk score were associated with structural brain and cognitive changes via the same mechanisms as AD or independent of them. We used the microtubule-associated protein tau (MAPT)and apolipoprotein E (APOE)genotypes involved in tau and β-amyloid synthesis, folding, and clearance, as well as AD polygenic risk score (PRS) to define vulnerability to protein deposition. We then tested whether those factors moderated the relationship between obesity, brain structure, and cognition. A significant moderation would imply that obesity may affect brain structure via mechanisms involving tau and β-amyloid deposition. We found thatMAPTandAPOEstatus as well as AD PRS did not moderate the relationship between obesity and brain structure. We also found sparse evidence for the moderation ofMAPTandAPOEof the cerebrovascular disease-brain structure relationship as well as the metabolic risk score-brain structure relationship. We conclude that the mechanisms linking obesity with brain atrophy are most likely independent of the ones governing AD-related brain atrophy and might involve cerebrovascular factors.
Efficacy of Naloxone in reducing hypoxemia and duration of immobility following focal to bilateral tonic-clonic seizures
Authors: Rheims Sylvain , Chorfa Fatima , Michel Véronique , Hirsch Edouard , Maillard Louis , Valton Luc , Bartolomei Fabrice , Derambure Philippe , Navarro Vincent , Biberon Julien , Crespel Arielle , Nica Anca , Martin Martine Lemesle , Mazzola Laure , Petit Jerome , Rossero Vincent , Boulogne Sébastien , Leclercq Mathilde , Bezin Laurent , Mercier Catherine , Roy Pascal , Ryvlin Philippe 
Published: December 2024

ABSTRACTPurposeEvaluating the efficacy of an opioid antagonist, naloxone (NLX), to reduce the severity of post-ictal hypoxemia and immobility after focal to bilateral tonic-clonic seizures (FBTCS).MethodsENALEPSY is a double-blind placebo (PCB)-controlled trial conducted in patients with focal epilepsy undergoing long-term video-EEG monitoring (LTM). Patient with a FBTCS during LTM were randomized 1:1 to receive intravenous NLX or PCB within the 2 minutes following the end of FBTCS. After database lock, a discrepancy between the allocated arm and the received treatment was detected, resulting in a 4:1 NLX:PCB ratio. To further explore the efficacy of NLX, we used historical control (HC) data collected in patients included in the REPO2MSE study whose characteristics matched those of patients randomized in ENALEPSY. Efficacy of NLX was then assessed versus PCB and versus HC. The primary endpoint was the delay between the end of the seizure and recovery of SpO2≥ 90%. Secondary efficacy outcomes included desaturation nadir and duration of the postictal immobility.Results33 patients contributed to the NLX group, 7 to the PCB group and 43 to the HC group. The proportion of FBTCS type 1 or 3 was 84% in NLX, 100% in PCB and 84% in HC. NLX did not improve the delay of recovery of SpO2≥ 90% or the desaturation nadir. In contrast, duration of the postictal immobility differed across groups. The time to mobility recovery within the first 5 minutes post-ictal was very similar in PCB (200.3±215.8 seconds) and HC (194.4±192.0 second) groups, and significantly shorter in the NLX group (128.9±151.1 seconds) when compared to HC (Hazard Ratio, 1.84; 95% CI, 1.11 to 3.05; p=0.021).ConclusionNLX did not prevent postictal respiratory dysfunction but might reduce the duration of postictal immobility. Confirmation of this effect and its impact on SUDEP risk will require additional studiesKEY BULLET POINTS–ENALEPSY trial evaluated the efficacy of intravenous naloxone to reduce the severity of post-ictal complications after focal to bilateral tonic-clonic seizures.–Naloxone did not improve the delay of recovery of SpO2≥ 90% or the desaturation nadir–The time to mobility recovery was significantly shorter in the NLX group when compared to historical control–Impact of these results on SUDEP prevention will require additional studies
SL/Kh Pre-B Lymphomas Originate in the Thymus and are a Model for Primary Mediastinal (Thymic) Large B-Cell Lymphoma
Authors: Thomae Tami L. , Tan Si Hui , Akagi Keiko , Ward Jerrold M. , Copeland Neal G. , Jenkins Nancy A. 
Published: December 2024

AbstractSL/Kh mice develop a high frequency of retrovirally-induced pre-B lymphomas at 3-6 months of age. They also exhibit an abnormal transient expansion of pre-B cells in the bone marrow, although the relevance of this expansion for lymphomagenesis has remained unclear. Here, we use a dual approach that combines pathology with flow cytometry to more fully characterize the nature and origin of SL/Kh lymphomas. Unexpectedly, our studies showed that SL/Kh lymphomas arise from a rare population of pro/pre-B cells in the thymus. We also identified a 10-fold reduction in Notch1 expression in SL/Kh thymic T cells that is associated with a block in early T cell development, a reduction in the number of thymic T cells with age, and an expansion of thymic pro/pre-B cells. This phenotype is consistent with previous studies showing that Notch1 signaling is essential for lymphoid progenitors to undergo T cell commitment and for suppressing B cell development in the thymus. We propose that this developmental defect provides a niche for early B cells to accumulate in the thymus, which, when combined with subsequent retroviral insertional mutagenesis, results in the induction of pre-B lymphomas that originate in the thymus. This is also consistent with our analysis of the genes insertionally mutated in SL/Kh lymphomas, which shows that many function in signaling pathways such as JAK/STAT and RAS/MAPK/ERK that are commonly deregulated in B-cell lymphomas. Primary human mediastinal large B-cell lymphoma (MLBCL) is another lymphoma that is derived from thymic B cells, although virtually nothing is known about the cause of this rare disease. Our studies provide new insights into an underappreciated class of B-cell lymphomas and a mouse model for the study of MLBCL.
Antibiotics that Kill Gram-negative Bacteria by Restructuring the Outer Membrane Protein BamA
Authors: Modaresi Seyed Majed , Sugiyama Ryosuke , Tram Nhan Dai Thien , Jakob Roman P. , Phan Chin-Soon , Saei Amir Ata , Morishita Yohei , Mühlethaler Tobias , Lim Joel , Ritz Danilo , Long Preston Shi Yang , Lehner Phillipe A , Lim Zhen Heng , Degen Morris , Yao Ziwei , Maier Timm , Hou Yuxin , Lee Jia Ying , Xu Jian , Yeat Andrew Yeo Jung , Koh Kenny Ting Sween , Goh Wei Yang , Ling Sharon Y. H. , Chua Patrina W. L. , Yamazaki Mami , Ee Pui Lai Rachel , Hiller Sebastian , Morinaka Brandon I 
Published: December 2024

SummaryThe essential outer membrane protein insertase BamA has recently emerged as a valid target for killing Gram-negative bacteria. Bamabactins, competitive inhibitors targeting the lateral gate of BamA, disrupt the substrate folding process, compromise the outer membrane integrity, and lead to bacterial cell death. Despite their promise, the full pharmacological potential of bamabactins remains underexploited. We applied phylogenetic genome mining and synthetic biology to identify xenorceptides which selectively killEnterobacteriaceae. Mode of action studies show that xenorceptide A2 integrates itself into BamA as an additional β-strand between β1 and β16 at the lateral gate, inducing a conformation of BamA that has not been observed before. Biological evaluation of xenorceptide A2 shows promising activityin vitroandin vivo, and limited resistance which differentiates it from other bamabactin antibiotics. Our data show that the chemical diversity of bamabactins is far greater than previously recognized and thus an attractive source for antibiotic discovery.
Genetically predicted gene expression effects on changes in red blood cell and plasma polyunsaturated fatty acids
Authors: Khankari Nikhil K. , Su Timothy , Cai Qiuyin , Liu Lili , Jasper Elizabeth A. , Hellwege Jacklyn N. , Murff Harvey J. , Shrubsole Martha J. , Long Jirong , Edwards Todd L. , Zheng Wei 
Published: December 2024

ABSTRACTPolyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows.In vivoconversion of omega-3 and omega-6 PUFAs from short-to long-chain counterparts occurs via a shared metabolic pathway involving fatty acid desaturases and elongase. This analysis leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs, along with expression quantitative trait loci (eQTL) to estimate tissue-specific genetically predicted gene expression effects for delta-5 desaturase (FADS1), delta-6 desaturase (FADS2), and elongase (ELOVL2) on changes in RBC and plasma biomarkers. Using colocalization, we identified shared variants associated with both increased gene expression and changes in RBC PUFA levels in relevant PUFA metabolism tissues (i.e., adipose, liver, muscle, and whole blood). We observed differences in RBC versus plasma PUFA levels for genetically predicted increase inFADS1andFADS2gene expression, primarily for omega-6 PUFAs linoleic acid (LA) and arachidonic acid (AA). The colocalization analysis identified rs102275 to be significantly associated with a 0.69% increase in total RBC membrane-bound LA levels (P=5.4×10-12). Future PUFA genetic studies examining long-term PUFA biomarkers are needed to confirm our results.
Mbd4 and MutSα protect cells from spontaneous deamination of 5-methylcytosine
Authors: Bilardi Rebecca A. , Flensburg Christoffer , Xu Zhen , Derrick Emily B. , Kueh Andrew , Majewski Ian J 
Published: December 2024

Abstract5-Methylcytosine (5mC) is a common source of somatic mutations. Deamination of 5mC to thymine generates a G/T mismatch, which occurs spontaneously and must be repaired prior to DNA replication to avoid mutation. We generated genetically engineered mice and cell lines to define DNA repair pathways that protect against methylation damage. We observed a low background mutation rate in mouse bone marrow or colon, typically 0.2-0.5 CG>TG mutations/genome/day. This increased 3-7 fold in cells lacking the glycosylase Methyl-binding domain 4 (Mbd4), one of the few glycosylases capable of excising thymine from G/T mismatches. We found no role for Thymine DNA glycosylase (Tdg) in methylation damage repair. Instead, our results support cooperation between Mbd4 and the mismatch repair (MMR) complex MutSα (Msh6:Msh2), evident through elevated rates of methylation damage in Msh6-deficient cells; increasing to 2.6-4.8 CG>TG mutations/genome/day in primary cells and up to 13.9 CG>TG mutations/genome/day in cell lines. Our findings support the view that MutSα has DNA repair activity outside of replication. While loss of Mbd4 elevates methylation damage selectively, the broader functionality of MutSα explains why mutational signatures linked to Msh6-deficiency are variable and reflect the replicative history of the cell.
Mechanism of D-type cyclins recognition by the AMBRA1 E3 ligase receptor
Authors: Wang Yang , Liu Ming , Wang Shan , Mai Xinyi , Wang Xi , Teng Fei , Lyu Tianrui , Su Ming-Yuan , Stjepanovic Goran 
Published: December 2024

AbstractAMBRA1 is a tumour suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present the cryo-EM structure of cyclin D1 bound AMBRA1-DDB1 complex at 3.5 Å resolution. The structure reveals a substrate interaction surface on the AMBRA1 WD40 domain that specifically binds to the C-terminal region of D-type cyclins. This interaction is dependent on the phosphorylation of Thr286 residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation followed by a 310helix that promotes its assembly with AMBRA1. Additionally, we show that AMBRA1 mutants, which are defective in cyclin D1 binding, lead to cyclin D1 accumulation and DNA damage. Understanding the AMBRA1-D-type cyclins structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to new therapeutic approaches for cancers linked to abnormal cyclin D activity.