bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data-independent acquisition coupled with electron-activated dissociation for in-depth structure elucidation of fatty acid ester of hydroxy fatty acids
Authors: Kurizaki Yuto , Matsuzawa Yuki , Takahashi Mikiko , Takeda Hiroaki , Hasegawa Mayu , Arita Makoto , Miyamoto Junki , Tsugawa Hiroshi 
Published: December 2024

ABSTRACTFatty acid esters of hydroxy fatty acid (FAHFAs) are a biologically important class of lipids known for their anti-inflammatory and anti-diabetic effects in animals. The physiological activity of FAHFAs varies depending on the length of the carbon chain, number and position of double bonds (DBs), and the position of the hydroxyl (OH) group. Moreover, gut bacteria produce FAHFAs with more diverse structures than those produced by the host, which necessitates a FAHFA-lipidomics approach grasping their diverse structures to fully understand the physiological and metabolic significance of FAHFAs. In this study, we developed a methodology for in-depth structural elucidation of FAHFAs. First, FAHFAs were enriched using a solid-phase extraction (SPE) system coated with titanium and zirconium dioxide, which separated these analytes from neutral lipids and phospholipids. The fractionated metabolites were then derivatized usingN,N-dimethylethylenediamine (DMED) to facilitate FAHFA detection in the positive ion mode of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. A data-independent acquisition technique known as sequential window acquisition of all theoretical mass spectra (SWATH-DIA) was used to collect sequential MS/MS spectra of the DMED-derivatized fatty acid metabolites. Structural elucidation was based on the fragment ions generated by electron-activated dissociation (EAD). DMED-FAHFAs were annotated using the newly updated MS-DIAL program, and FAHFA isomers were quantified using the MRMPROBS program, which quantifies lipids based on SWATH-MS/MS chromatograms. This procedure was applied to profile the FAHFAs present in mouse fecal samples, characterizing seven structures at the molecular species level, 63 structures at the OH position-resolved level, and 15 structures at both the DB and OH position-resolved levels using the MS-DIAL program. In the MRMPROBS analysis, 2OH and 3OH hydroxy fatty acids with more than 20 carbon atoms were predominantly expressed, while 5OH–13OH hydroxy fatty acids with 16 or 18 carbon atoms were the major components, abundant at positions 5, 7, 9, and 10. Furthermore, age-related changes in FAHFA isomers were also observed, where FAHFA 4:0/2O(FA 26:0) and FAHFA 16:0/10O(FA 16:0) significantly increased with age. In conclusion, our study offers a novel LC-SWATH-EAD-MS/MS technique with the updates of computational MS to facilitate in-depth structural lipidomics of FAHFAs.TOC graphics
Impact of dopamine deficiency and REM sleep behavior disorder on cognition in early neuronal synuclein disease with hyposmia
Authors: Weintraub Daniel , Nair Anuprita R , Kurth Ryan , Brumm Michael C. , York Michele K. , Dobkin Roseanne , Marek Kenneth , Tanner Caroline , Simuni Tanya , Siderowf Andrew , Galasko Douglas , Chahine Lana M. , Coffey Christopher , Merchant Kalpana , Poston Kathleen L. , Foroud Tatiana , Mollenhauer Brit , Brown Ethan G. , Kieburtz Karl , Frasier Mark , Sherer Todd , Chowdhury Sohini , Alcalay Roy N. , Videnovic Aleksandar ,   the Parkinson’s Progression Markers Initiative
Published: December 2024

ABSTRACTObjectivesTo determine the impact of dopamine deficiency and isolated REM sleep behavior disorder (iRBD) on cognitive performance in early neuronal alpha-synuclein disease (NSD) with hyposmia.MethodsUsing Parkinson’s Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) developed by applying regression-based internal norms derived from a robust healthy control (HC) group. Performance was examined for participants with hyposmia classified as NSD-Integrated Staging System (NSD-ISS) Stage 2, either Stage 2A (CSF alpha-synuclein seed amplification assay [SAA]+, SPECT dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).ResultsParticipants were Stage 2A (N=101), Stage 2B (N=227) and HCs (N=158). Although Stage 2 overall had intact Montreal Cognitive Assessment scores (mean (SD) =27.0 (2.3)), Stage 2A had a numerically worse CSS (z-score mean difference =0.05, p-value NS; effect size=0.09) and Stage 2B had a statistically worse CSS (z-score mean difference =0.23, p-value <0.05; effect size=0.40) compared with HCs. In Stage 2A participants with hyposmia alone had normal cognition, but presence of comorbid iRBD was associated with significantly worse cognition (z-score mean difference =0.33, p-value <0.05, effect size =0.50). In Stage 2B participants with hyposmia had abnormal cognition (z-score mean difference =0.18, p-value =.0078, effect size =0.29), and superimposed iRBD had a non-statistically significant additive effect.InterpretationUsing a CSS, early NSD with hyposmia is associated with measurable cognitive deficits compared with robust HCs, particularly in presence of dopamine system impairment or comorbid iRBD, highlighting the importance of focusing on cognition in early-stage synuclein disease.
H2B.W2, a Spermatocytes-specific Histone Variant, disrupts nucleosome stability and reduces chromatin compaction
Authors: Nguyen Thi Thuy , Ding Dongbo , Bai Xingpeng , Pang Matthew Y.H. , Deng Mingxi , Liu Yue , Jin Tingyu , Xu Zhichun , Zhang Yingyi , Zhai Yuanliang , Yan Yan , Ishibashi Toyotaka 
Published: December 2024

AbstractSpermatogenesis is a highly regulated process that requires precise chromatin remodeling, which includes the incorporation of testis-specific histone variants. While several of these variants have been characterized, the role of H2B.W2, a member of the H2BW family, remains largely unclear. Here, we showed that H2B.W2 expression occurs mainly in spermatocytes, slightly later than its paralog H2B.W1. Cryo-electron microscopy (cryo-EM) analysis of H2B.W2-containing nucleosomes reveals a more relaxed conformation compared to canonical nucleosomes caused by weakened interactions between the outer DNA turn and the histone core. We pinpointed the N-terminal tail and α2 helix of H2B.W2, specifically residues D85 and Q101, as critical for nucleosome destabilization. Furthermore, we identify G73 within the L1 loop as a key residue involved in disrupting higher-order chromatin structure. Our findings suggest that H2B.W2-mediated nucleosome and chromatin destabilization may play a role in regulating gene expression during spermatogenesis, with potential implications for sperm development and function.
A small molecule enhances arrestin-3 binding to the β2-adrenergic receptor
Authors: Kurt Han , Akyol Ali , Son Cagdas Devrim , Zheng Chen , Gado Irene , Meli Massimiliano , Ferrandi Erica Elisa , Bassanini Ivan , Vasile Francesca , Gurevich Vsevolod V. , Nebol Aylin , Cagavi Esra , Morra Giulia , Sensoy Ozge 
Published: December 2024

AbstractG protein-coupled receptor (GPCR) signaling is terminated by arrestin binding to a phosphorylated receptor. Binding propensity has been shown to be modulated by stabilizing the pre-activated state of arrestin through point mutations or C-tail truncation. Here, we hypothesize that pre-activated rotated states can be stabilized by small molecules, and this can promote binding to phosphorylation-deficient receptors, which underly a variety of human disorders. We performed virtual screening on druggable pockets identified on pre-activated conformations in Molecular Dynamics trajectories of arrestin-3, and found a compound targeting an activation switch, the back loop at the inter-domain interface. According to our model, consistent with available biochemical and structural data, the compound destabilized the ionic lock between the finger and the back loop, and enabled transition of the ‘gate loop’ towards the pre-activated state, which stabilizes pre-activated inter-domain rotation. The predicted binding pocket is consistent with saturation-transfer difference NMR data indicating close contact between the piperazine moiety of the compound and C/finger loops. The compound increases in-cell arrestin-3 binding to phosphorylation-deficient and wild-type β2-adrenergic receptor, but not to muscarinic M2 receptor, as verified by FRET and NanoBiT. This study demonstrates that the back loop can be targeted to modulate interaction of arrestin with phosphorylation-deficient GPCRs in a receptor-specific manner.
The Impact of Coiled-Coil Domains on the Phase Behavior of Biomolecular Condensates
Authors: He Zhouyi , Sommer Jens-Uwe , Harmon Tyler S. 
Published: December 2024

AbstractSpatial organization is fundamental to biological systems, with biomolecular condensates as a key subset. Many studies show that folded domains play important roles in condensate formation by facilitating interactions. However, little is known about how the presence of large structured elements impacts condensate formation. Using coarse-grained simulations, we investigated a model system of two multivalent proteins, one containing a coiled-coil domain (CCD), which undergoes liquid-liquid phase separation (LLPS). We found that CCDs promote LLPS by preventing loop-closure defects, enabling protein networking. Replacing the CCD with a flexible linker abolishes LLPS due to formation of oligomeric clusters. There is a critical length of the CCD where the system rapidly changes from no LLPS to LLPS at low concentrations. This highlights their potential in regulating condensate formation and properties. This study provides insights into the phase behavior of biomolecular condensates and offers a framework for designing synthetic condensates with tunable phase behaviors.
Human Hippocampal Theta Oscillations Organise Distance to Goal Coding
Authors: Huang Zimo , Bisby James A , Burgess Neil , Bush Daniel 
Published: December 2024

AbstractThe rodent hippocampal local field potential is dominated by 6-12 Hz theta oscillations during active behaviour that are strongly implicated in spatial coding and memory function across species. Invasive electrophysiology in both rodents and humans has shown increases in hippocampal theta power immediately before the onset of translational movement that persists throughout subsequent motion, and the magnitude of this increase correlates with the distance subsequently travelled. Using non-invasive magnetoencephalography (MEG) and an abstract navigation task, we observed increased theta power during both spatial planning and subsequent navigation. Importantly, theta power in the right hippocampus covaried with subsequent path distance during planning, only when participants were aware of the distance to their goal. During subsequent navigation, hippocampal theta power decreased dynamically as participants approached the goal, only when they were aware of how far they still needed to travel. In addition, theta phase during navigation modulated 70-140 Hz fast gamma amplitude in the entorhinal cortex while traversing novel paths; and 30-70 Hz slow gamma amplitude in the right hippocampus while traversing previously experienced paths. In both cases, theta-gamma phase-amplitude coupling increased with proximity to the goal during navigation, consistent with the hypothesis that sequences of upcoming locations were represented by gamma bursts occurring at successive theta phases. In sum, these findings are consistent with the proposed role of hippocampal theta oscillation in flexible planning and goal-directed spatial navigation across mammalian species.
A hybrid machine learning model for predicting gene expression from epigenetics across fungal species
Authors: Weinstock Laura , Schambach Jenna , Fisher Anna , Kunstadt Cameron , Lee Ethan , Koning Elizabeth , Morrell William , Mays Wittney , Davis Warren , Krishnakumar Raga 
Published: December 2024

AbstractUnderstanding and controlling gene expression in organisms is essential for optimizing biological processes, whether in service of bioeconomic processes, human health, or environmental regulation. Epigenetic modifications play a significant role in regulating gene expression by altering chromatin structure, DNA accessibility and protein binding. While a significant amount is known about the combinatorial effects of epigenetics on gene expression, our understanding of the degree to which the orchestration of these mechanisms is conserved in gene expression regulation across species, particularly for non-model organisms, remains limited. In this study, we aim to predict gene expression levels based on epigenetic modifications in chromatin across different fungal species, to enable transferring information about well characterized species to poorly understood species. We developed a custom hybrid deep learning model, EAGLE (Evolutionary distance-Adaptable Gene expression Learned from Epigenomics), which combines convolutional layers and multi-head attention mechanisms to capture both local and global dependencies in epigenetic data. We demonstrate the cross-species performance of EAGLE across fungi, a kingdom containing both pathogens and biomanufacturing chassis and where understanding epigenetic regulation in under-characterized species would be transformative for bioeconomic, environmental, and biomedical applications. EAGLE outperformed shallow learning models and a modified transformer benchmarking model, achieving up to 80% accuracy and 89% AUROC for intra-species validation and 77% accuracy and 83% AUROC in cross-species prediction tasks. SHAP analysis revealed that EAGLE identifies important epigenetic features that drive gene expression, providing insights for experimental design and potential future epigenome engineering work. Our findings demonstrate the potential of EAGLE to generalize across fungal species, offering a versatile tool for optimizing fungal gene expression in multiple sectors. In addition, our architecture can be adapted for cross-species tasks across the tree of life where detailed molecular and genetic information can be scarce.
Histopathological Evaluation of Pulmonary Arterial Remodeling in COVID-19
Authors: Gychka Sergiy G. , Nikolaienko Sofiia I. , Shults Nataliia V. , Vasylyk Volodymyr M. , Pasichnyk Bohdan O. , Kagan Iryna V. , Dibrova Yulia V. , Tuffaha Muin , Suzuki Yuichiro J. 
Published: December 2024

AbstractA positive-sense single-stranded RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused the coronavirus disease 2019 (COVID-19) pandemic that devastated the world. While this is a respiratory virus, one feature of the SARS-CoV-2 infection was recognized to cause pathogenesis of other organs. Because the membrane fusion protein of SARS-CoV-2, the spike protein, binds to its major host cell receptor angiotensin-converting enzyme 2 (ACE2) that regulates a critical mediator of cardiovascular diseases, angiotensin II, COVID-19 is largely associated with vascular pathologies. In fact, we have previous reported that postmortem lung tissues collected from patients who died of COVID-19 exhibited thickened pulmonary vascular walls and reduced vascular lumen. The present study extended these findings by further characterizing the pulmonary vasculature of COVID-19 patients using larger sample sizes and providing mechanistic information through histological observations. The examination of 56 autopsy lung samples showed thickened vascular walls of small pulmonary arteries after 14 days of disease compared to H1N1 influenza patients who died before COVID- 19 pandemic started. Pulmonary vascular remodeling in COVID-19 patients was associated with hypertrophy of the smooth muscle layer, perivascular fibrosis, edema and lymphostasis, inflammatory infiltration, perivascular hemosiderosis and neoangiogenesis. We found a correlation between the duration of hospital stay and the thickness of the muscular layer of pulmonary arterial walls. These results further confirm that COVID-19 affects the pulmonary vasculature and warrants an evaluation of patients that survived COVID-19 for possible future development of pulmonary arterial hypertension.
A click chemistry-based biorthogonal approach for the detection and identification of protein lysine malonylation for osteoarthritis research
Authors: Binoy Anupama , Nanjan Pandurangan , Chellamuthu Kavya , Liu Huanhuan , Zhu Shouan 
Published: December 2024

AbstractLysine malonylation is a post-translational modification where a malonyl group, characterized by a negatively charged carboxylate, is covalently attached to the ε-amino side chain of lysine, influencing protein structure and function. Our laboratory identified Mak upregulation in cartilage under aging and obesity, contributing to osteoarthritis (OA). Current antibody-based detection methods face limitations in identifying Mak targets. Here, we introduce an alkyne-functionalized probe, MA-diyne, which metabolically incorporates into proteins, enabling copper(I) ion-catalyzed click reactions to conjugate labeled proteins with azide-based fluorescent dyes or affinity purification tags. In-gel fluorescence confirms MA-diyne incorporation into proteins across various cell types and species, including mouse chondrocytes, adipocytes, Hek293T cells, andC. elegans. Pull-down experiments identified known Mak proteins such as GAPDH and Aldolase. The extent of MA-diyne modification was higher in Sirtuin 5-deficient cells suggesting these modified proteins are Sirtuin 5 substrates. Pulse-chase experiments confirmed the dynamic nature of protein malonylation. Quantitative proteomics identified 1136 proteins corresponding to 8903 peptides with 429 proteins showing 1-fold increase in labeled group. Sirtuin 5 regulated 374 of these proteins. Pull down of newly identified proteins such as β-actin and Stat3 was also done. This study highlights MA-diyne as a powerful chemical tool to investigate the molecular targets and functions of lysine malonylation in OA conditions.
Effects of commonly used antibiotics on children’s developing gut microbiomes and resistomes in peri-urban Lima, Peru
Authors: Sehgal Neha , Pajuelo Monica J. , Gilman Robert H. , Pickering Amy J. , Earl Ashlee M. , Worby Colin J. , Nadimpalli Maya L. 
Published: December 2024

SynopsisBackgroundThe effects of antibiotic use on children’s gut microbiomes and resistomes are not well characterized in middle-income countries, where pediatric antibiotic consumption is exceptionally common. We characterized the effects of antibiotics commonly used by Peruvian children (i.e., amoxicillin, azithromycin, cefalexin, sulfa-trimethoprim) on gut diversity, genera, and antibiotic resistance gene (ARG) abundance from 3-16 months.MethodsThis study included 54 children from a prospective cohort of enteric infections in peri-urban Lima, 2016-2019. Stool collected at 3, 6, 7, 9, 12, and 16 months underwent DNA extraction and short-read metagenomic sequencing. We profiled the taxonomy of stool metagenomes and assessed ARG abundance by aligning reads to the ResFinder database. We used daily surveillance data (40,662 observations) to tabulate the number of antibiotic courses consumed in the 30 days prior to stool sampling. Using linear mixed models, the association of recent antibiotic use with species richness, diversity, gut genera, and ARG abundance over time was examined.ResultsMost children were vaginally delivered (73%), received breastmilk almost daily over the study period, and belonged to socioeconomically diverse households. Amoxicillin, azithromycin, cefalexin, and sulfa-trimethoprim did not impact gut diversity or genera abundance. Azithromycin use significantly impacted ARGs from the macrolide, aminoglycoside, and folate pathway antagonist classes. Amoxicillin use significantly increased total ARGs. Antibiotics’ effects on ARGs appeared to be independent of gut microbiome changes.ConclusionCommon antibiotics like amoxicillin and azithromycin may be key drivers of the gut resistome but not the microbiome during early childhood in this setting with frequent breastfeeding.
Evaluation of T Cell Immune Memory Response after Sinopharm (BBIBP-CorV), Gam-COVID-Vac (Sputnik V), and Heterologous Sputnik-V/mRNA-1273 (Moderna) COVID-19 Vaccination Schemes against Different SARS-CoV-2 Variants
Authors: Pereson Matías J. , Badano María Noel , Sabbione Florencia , Keitelman Irene , Aloisi Natalia , Fink Susana , Amaya Lucas , Garcia Gabriel H. , Martínez Alfredo P. , Di Lello Federico A. , Baré Patricia 
Published: December 2024

AbstractIntroductionThe adaptive immune response plays a crucial role in resolution of viral infections; however, there is limited data on the T cell response to SARS-CoV-2 vaccines like Sinopharm (Sin), Sputnik-V (SpV), and especially for the heterologous combination Sputnik-V/mRNA-1273 (Spv/Mod) scheme. Furthermore, emerging variants may compromise the adaptive immune response established in the population.ObjectiveTo evaluate the T cell immune response induced by the Sin, SpV and SpV/Mod, against Wuhan, Gamma and Omicron viral variants.MethodsSerum levels of IgG antibodies were assessed by CMIA (Abbott Diagnostics, Abbott Park, Illinois). T cell responses against Wuhan, Gamma, and Omicron were evaluated through an activation-induced marker assay. Sixty individuals, evenly distributed across the Sin, SpV, and SpV/Mod groups, were included.ResultsThe median age of participants was 48 years (IQR: 34-56), with 58.3% (n=35) being female. Seventeen (28.3%) individuals had a prior confirmed COVID-19 infection. Spv/Mod scheme elicited significantly higher humoral responses (p<0.001). However, the three vaccination platforms showed consistent T cell responses across the different Wuhan, Gamma and Omicron stimuli tested. Particularly, all three schemes induced stronger CD8 responses against the Wuhan variant. In addition, more responders to Wuhan were observed in the Sin and Spv groups, while the Spv/Mod group showed a higher proportion of responders to Omicron.ConclusionThis study provides new data on effective humoral and cellular immune responses against Wuhan, Gamma, and Omicron variants. Moreover, memory CD4 and CD8 T cell responses remain protective, and the heterologous scheme may elicit stronger T cell responses against emerging variants.HighlightsStrong adaptive T cell responses were observed across all vaccination schemes and viral variants.Higher frequency of activated CD8 lymphocytes was detected compared to CD4 in response to SARS-CoV-2Sinopharm and Sputnik-V showed a response biased toward the Wuhan variant.Sputnik-V/Moderna recipients showed higher T cell responses to Omicron.The Sputnik-V/Moderna vaccination scheme induced significantly enhanced humoral immune responses.Graphical Abstract