bluuebunny/crossref_metadata_2025 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

Fatty 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.

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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

Objectives

To 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.

Methods

Using 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+).

Results

Participants 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.

Interpretation

Using 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

Spermatogenesis 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

G 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

Spatial 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

The 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

Understanding 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

A 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

Lysine 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

Synopsis

Background

The 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.

Methods

This 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.

Results

Most 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.

Conclusion

Common 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

Introduction

The 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.

Objective

To evaluate the T cell immune response induced by the Sin, SpV and SpV/Mod, against Wuhan, Gamma and Omicron viral variants.

Methods

Serum 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.

Results

The 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.

Conclusion

This 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.

Highlights

Strong 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-2

Sinopharm 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
APOE genotype and the effect of statins: a systematic review and meta-analysis
Authors: Asiimwe Innocent G. , Gebru Tsegay , Jorgensen Andrea L. , Pirmohamed Munir
Published: December 2024

Introduction

TheAPOEgenotype may affect statin therapy response. We conducted a systematic review and meta-analysis to update and quantify this association across various outcomes.

Methods

We searched seven databases (MEDLINE, Scopus, Web of Science, The Cochrane Library, APA PsycINFO, CINAHL Plus, andClinicalTrials.gov) on 9thMay 2024. Screening and data extraction were performed by two reviewers and a machine learning tool (ASReview).

Results

From 4,352 de-duplicated records, 68 studies were included in the systematic review and 52 in the meta-analysis. Biomarkers analysed included Low-Density Lipoprotein Cholesterol (LDLC), Total Cholesterol (TC), Triglycerides (TG), and High-Density Lipoprotein Cholesterol (HDLC). Compared toε3carriers,ε2carriers showed greater reductions in LDLC (mean difference: −2.98%, 95% CI: −5.88% to −0.08%) and similar reductions in TC (−2.73%, −5.62% to 0.16%), and TG (−4.95%, −11.93% to 2.04%) with no significant difference in HDLC (−0.09%, −3.10% to 2.91%). After adjusting for publication bias,ε4carriers showed less pronounced statin effects, with smaller reductions in LDLC (mean difference: 10.04%, 6.04% to 14.04%), TC (8.99%, 5.08% to 12.90%), and TG (8.24%, 2.15% to 14.33%), along with a smaller increase in HDLC (−10.08%, −15.30% to −4.85%) compared toε3carriers. Study quality was uncertain, and heterogeneity (partly explained by sex and Familial Hypercholesterolemia) was high, especially for the percentage changes. A stronger genotype effect was seen in males.

Conclusion

Our meta-analysis shows thatAPOEgenotype can significantly influence statin response, emphasizing the need to incorporate known genetic factors into personalized treatment regimes.
APOEGenotype and Statin Response: Evidence from Electronic Health Records in the UK Biobank and All of Us Research Program
Authors: Asiimwe Innocent G. , Jorgensen Andrea L. , Pirmohamed Munir ,   Mechanism and Therapeutic Research Collaborative
Published: December 2024

Introduction

APOE genotype may affect statin response. We investigated the relationship betweenAPOEgenotype and key outcomes in statin users using UK Biobank (UKB) and All of Us (AoU) data.

Methods

We analysed electronic health records from up to 45,515 UKB participants and 35,562 AoU participants. Using multivariable linear regression and Cox proportional hazards models, we assessed associations betweenAPOEgenotype and outcomes, including lipid biomarkers, all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE).

Results

After Bonferroni correction, significant changes in HDLC and triglyceride levels were observed in both cohorts (P< 0.01) following statin initiation. For all-cause mortality, significant associations were found in the UKB cohort, withε3ε4(HR: 1.08, 95% CI: 1.01–1.15) andε4ε4(HR: 1.54, 1.33–1.78) carriers showing higher risk compared to the referenceε3ε3genotype. In the AoU cohort, onlyε4ε4carriers showed an increased risk (HR: 1.64, 1.08–2.49). Cardiovascular-related mortality was assessed in only the UKB cohort, withε4ε4carriers having an increased risk (HR: 1.30, 1.01–1.68). In the AoU cohort, lipid level changes were significantly associated with reduced all-cause mortality risk: HDLC (median increase of 0.03 mmol/L, HR: 0.26 [0.16–0.41] per mmol/L), LDLC (median reduction of 0.82 mmol/L, HR: 0.82 [0.69–0.97] per mmol/L), and triglycerides (median reduction of 0.10 mmol/L, HR: 0.79 [0.72–0.87] per mmol/L). No significant associations with MACE were observed in either cohort.

Conclusion

This study re-affirms thatAPOEgenotype significantly impacts statin response, highlighting the need to integrate genetics into personalized treatment regimens.
CSF pharmacokinetics-pharmacodynamics of linezolid in critically brain injured patients, with or without central nervous system healthcare-associated infection. The PK-Pop-LCR Study: A Multicenter Pharmacokinetics and Pharmacodynamics Population Study
Authors: Dahyot-Fizelier Claire , Chauzy Alexia , Chalard Kévin , Bernard Fanny , Courson Hugues de , Leblanc Pierre-Etienne , Francony Gilles , Chabanne Russel , Lakhal Karim , Cinotti Raphaël , Gregoire Charles , Pottecher Julien , Bouhemad Belaid , Merlaud Assil , Adier Christophe , Lecron Jean-Claude , Remy Ombeline , Couet William , Gregoire Nicolas , Marchand Sandrine ,   the PK-Pop-LCR Study Group
Published: December 2024

Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated. PK-Pop-LCR is a prospective population pharmacokinetic-pharmacodynamic multicenter study which included brain injured patients with an external ventricular drainage receiving linezolid at different dosing regimens. The cerebrospinal fluid (CSF) penetration of linezolid was investigated and a population pharmacokinetic model developed using plasma and CSF data. Monte Carlo simulations were conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) in CSF against methicillin-resistantStaphylococcus aureus(MRSA) and methicillin-resistantStaphylococcus epidermidis(MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF.

Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. The mean AUCCSF/fAUCplasmaratio was close to 80% with no difference between patients with and without CNS infection, despite higher CSF cytokines levels in CNS-infected patients. The recommended dose of 1200 mg/24h allowed to reach PTAs ≥ 90% only for MICs ≤ 0.5 mg/L, and CFR of 3.2% and 40% for MRSA and MRSE, respectively. 2 700 mg/24h would allow to achieve PTA > 90% for MIC up to 1 mg/L and CFR of 90% for MRSE but none of dosing regimens tested was appropriate for MRSA infections.

We confirmed the extensive CSF distribution of linezolid. Higher doses than those recommended should be considered to treat CNS infection in critically brain injured patients. However, pharmacodynamic target for CNS infections should be further investigated to confirm these findings.

Fundings

French Ministry of Health.
Greater lesion damage is bidirectionally related with accelerated brain aging after stroke
Authors: Khan Mahir H. , Marin-Pardo Octavio , Chakraborty Stuti , Borich Michael R. , Castillo Mayerly , Cole James H. , Cramer Steven C. , Donnelly Miranda R. , Fokas Emily E. , Fullmer Niko H. , Gumarang Jeanette R. , Hayes Leticia , Kim Hosung , Kumar Amisha , Marks Emily A. , Rosario Emily R. , Schambra Heidi M. , Schweighofer Nicolas , Song Grace C. , Taga Myriam , Tavener Bethany P. , Winstein Carolee J. , Liew Sook-Lei
Published: December 2024

Regional neuron loss following stroke can result in remote brain changes due to diaschisis and secondary brain atrophy. Whole brain changes post-stroke can be captured by the predicted brain age difference (brain-PAD), a neuroimaging-derived biomarker of global brain health previously associated with poorer chronic stroke outcomes. We hypothesized that greater lesion damage would be longitudinally associated with worsening brain-PAD during subacute stroke, and conversely, that poorer baseline brain-PAD would be associated with enlarged lesion damage.

We prospectively collected MRIs from 47 stroke patients across three sites within 3 weeks (baseline) and at 3 months (follow-up) post-stroke. Predicted brain age was estimated via a pretrained ridge regression model using 77 morphological features. Brain-PAD was calculated as predicted age minus chronological age. Robust linear mixed effects regression models were used to examine relationships between infarct volume and brain-PAD, adjusting for age, sex, time, and intracranial volume at baseline.

Larger baseline infarct volume was associated with accelerated brain aging at 3 months (β=0.87, p=0.023). Conversely, larger baseline brain-PAD predicted larger increase in infarct volume at 3 months (β=0.02, p=0.009). These findings reveal a bidirectional relationship between focal stroke damage and global brain health during the subacute period, underscoring the importance of assessing both.
Mechanistic Insights into Periplasmic Chaperones as Regulators of Protein Folding and Translocation in Gram-Negative Bacteria
Authors: Chaudhuri Deep , Bhatt Madhu , Haldar Shubhasis
Published: December 2024

In Gram-negative bacteria, periplasmic chaperones mediate the transport and folding of outer membrane proteins. While their substrate interaction mechanisms are well studied, their functional cycle during periplasmic translocation remains unclear. Using single-molecule force spectroscopy, we demonstrate that SecYEG-associated chaperones PpiD and DsbC act as foldases, delivering up to 45.5 zJ of mechanical work. This activity facilitates substrate extraction from the SecYEG translocation tunnel, reducing ATP consumption during SecA-mediated translocation. In contrast, chaperones such as Spy and Skp function as holdases, stabilizing unfolded substrates to prevent misfolding during translocation. Our findings reveal a unique mechanism by which chaperones adapt to mechanical constraints, optimizing protein folding and translocation in the periplasm.
Engineering the MarinePseudoalteromonas haloplanktisTAC125 via pMEGA Plasmid Targeted Curing Using PTasRNA Technology
Authors: Severino Angelica , Lauro Concetta , Calvanese Marzia , Riccardi Christopher , Colarusso Andrea , Fondi Marco , Parrilli Ermenegilda , Tutino Maria Luisa
Published: December 2024

Marine bacteria that have adapted to thrive in extreme environments, such asPseudoalteromonas haloplanktisTAC125 (PhTAC125), offer a unique biotechnological potential. The discovery of an endogenous megaplasmid (pMEGA) raised questions about its metabolic impact and functional role in this strain. This study aimed at streamlining the host genetic background by curingPhTAC125 from the pMEGA plasmid using a sequential genetic approach. We combined homologous recombination by exploiting a suicide vector with the PTasRNA gene silencing technology to interfere with pMEGA replication machinery. This approach led to the construction of the novelPhTAC125 KrPL2strain, cured from the pMEGA plasmid, which exhibited no significant differences in the growth behaviour, though showcasing enhanced resistance to oxidative stress and a reduced capability of biofilm formation. These findings represent a significant achievement for understanding of the role of pMEGA plasmid and for the biotechnological applications ofPhTAC125 in recombinant protein production. This opens up the possibility to exploit pMEGA valuable genetic elements and further advancing the genetic tools forPhTAC125.
Sustainable development goals, culture and advertising: tracing the roots to stride forward
Authors: Soni Pavleen , Vohra Jyoti , Ghuman Mandeep Kaur , Polsa Pia
Published: December 2024

Purpose

Growing concern about sustainability, which focuses on the triple bottom line, namely people, planet and profits, must integrate with local culture to ensure inclusive growth. Localized advertising themes adapted to suit a country’s culture borrow from that country’s culture. Global advertising themes, on the other side, influence and modify the existing culture of a nation. The present study looks at the potential of using traditional Indian sustainable themes to promote sustainability as a way of life, which can be used to craft advertising messages that contribute to the achievement of sustainable development goals (SDGs).

Design/methodology/approach

A content analysis of 395 advertisements displayed on Indian television during primetime has been done. Data have been analyzed using descriptive statistics.

Findings

The findings reveal that 4 SDGs (achieve gender equality, ensure affordable and clean energy, ensure good health and well-being and promote industry, innovation and infrastructure) out of a total of 17 SDGs find a place in 395 advertisements. They mostly appear for beauty and personal care products and automotive. Depictions of a frugal lifestyle, natural/green surroundings and women empowerment in advertisements “together” exemplify opportunities to use culture creatively in crafting advertising messages.

Research limitations/implications

As the multinational companies embrace the trends towards globalization in advertising, they can also extend the traditional cultural values and lifestyle from a country like India, which tremendously and conspicuously contribute to sustainability to appeal “differently” to buyers. It would offer an opportunity to synergize the growth outcomes in a thoughtful manner.

Originality/value

This is an original piece of research, as no such study has already been conducted in India (to the best of researchers' knowledge).
Toward BPM maturity assessment integrated with BPM implementation and use
Authors: Szelągowski Marek , Sliż Piotr
Published: December 2024

Purpose

The aim of this article is to develop an efficient method for the assessment of business process management (BPM) maturity, which identifies the present maturity level in the organization, as well as integrates itself with the methodology of implementing BPM and systemically eliminates the identified limitations of existing BPM maturity models (BPM MMs).

Design/methodology/approach

The methodological underpinning of this research involves a comprehensive review and critique of existing BPM MMs, dissecting their theoretical foundations and methodological constructs. Grounded in established research methodologies, the study integrates perspectives from Industry 4.0 and Industry 5.0.

Findings

The presented BPM maturity assessment (BPM MA) is targeted at showing the actions that lead to raising BPM maturity by drawing upon the potential of the organization in a way which is harmonious with methodologies of implementing and using BPM. It focuses on practical usability and, thanks to this, eliminates one of the most often discussed flaws of BPM MMs.

Research limitations/implications

The limitation of this study is, at this stage, the lack of empirical verification and the lack of postulated BPM MA tools, integrated with the BPM software available on the market. Though the proposed BPM MA offers a systematic approach, targeted at practical use, it will, however, in the further perspective, require tailoring to the specific nature of different sectors of the economy in order to reach its full potential by, e.g. adapting the evaluation surveys and adding dedicated recommendations.

Practical implications

Practitioners may reap the benefits of the presented BPM MA thanks to its harmonization with methodologies of implementing BPM and the possibility of its use as an element of the standard BPM lifecycle. Accounting for the requirements of Industry 4.0/5.0 in both assessment criteria and recommendations provides managers support in the rapidly changing business environment.

Originality/value

The originality of this study rests in the synthesis of theoretical and methodological rigor with a singular focus on the practical usability of the proposed BPM MA. Apart from conceptual progress, the contribution of this study rests in removing the theoretical-practical gap and accounting for the requirements of Industry 4.0 and the upcoming Industry 5.0.
Insights into CEO duality in corporate governance: a bibliometric and systematic analysis approach
Authors: Javed Maryam , Nasir Nadia , Bashir Adnan , Mehmood Kashif , Akhtar Hammad
Published: December 2024

Purpose

This study aims to analyze chief executive officer (CEO) duality in corporate governance by using Scopus data. It explores CEO duality research trends across diverse corporate governance contexts and disciplines, shaping the future research agenda, and proposing recommendations for further investigations in this area.

Design/methodology/approach

This analysis is conducted through VOSviewer software and Biblioshiny by extracting the bibliometric network from the output files of the Scopus bibliographic database.

Findings

Research on CEO duality centers on keywords such as corporate governance, agency theory, board of directors, board size and firm performance. Word tree maps uncover various research areas and gaps. Top authors are Elsyed K. & Rashid K, with the University of Utara Malaysia as the leading organization. Main disciplines are “Business Management and Accounting” followed by “Economics.” “Corporate Governance: An International Review” tops the journals with 1,120 citations. Quantitative methods using secondary data dominate (94%), mostly from nonfinancial industries (96%). Theoretical lenses include agency theory, stewardship theory, stakeholder theory, resource dependence theory and institutional theory. Firm performance is the most researched aspect (38% of studies) concerning CEO duality.

Practical implications

Bibliometric and systematic analysis offer researchers a general overview and in-depth insights into current CEO duality research trends, influential articles and keywords in corporate governance. This study’s findings benefit research institutions, professional bibliometric users and funding agencies alike.

Originality/value

By visualizing bibliometric networks and conducting systematic analysis of top-cited articles, this study not only advances the academic understanding of CEO duality in corporate governance but also provides actionable recommendations for researchers, practitioners and policymakers to enhance governance practices and contribute to the field’s evolving body of knowledge.
BIM adoption predictors for health and safety management among construction SMEs
Authors: Sila Nosabelo , Agumba Justus Ngala , Adebowale Oluseyi Julius
Published: December 2024

Purpose

Health and safety (H&S) management remains a significant global challenge in the construction industry. Small and medium enterprises (SMEs) particularly struggle to comply with H&S regulations, resulting in high accident records. To address this poor performance, experts suggest that SMEs adopt H&S management technologies, particularly building information modeling (BIM), due to their potential to improve H&S practices. This study aims to determine the key predictors of construction SMEs’ intentions to adopt BIM for H&S management. The study also explores the potential impact of selected demographic variables on construction SMEs’ adoption intentions.

Design/methodology/approach

Quantitative research was used using a questionnaire distributed to 357 randomly sampled SMEs. The questionnaire collected data regarding SMEs’ intention to adopt BIM for H&S management. Binary logistic regression analysis was used to analyze the research data.

Findings

The findings reveal specific “relative advantages”, which include “BIM for H&S management will be preferable to the manual use of the H&S file” and “BIM for H&S management will make it easier to comply with H&S regulations” as significant predictors of the intention to adopt BIM for H&S management. The study also underscores the significance of educational qualifications and professional affiliation as predictors of BIM adoption.

Research limitations/implications

The study’s sample population consisted of SMEs registered with the Construction Industry Development Board register of contractors in Gauteng province, South Africa. This regional focus limits the generalizability of the findings to the entire country. Further research is recommended to investigate the adoption of BIM for H&S management among SMEs in other South African provinces. Additionally, a comparative study exploring BIM adoption for H&S between large construction enterprises and SMEs within the South African context could provide valuable insights.

Practical implications

This study presents a novel approach, leveraging the diffusion of innovation (DOI) theory and demographic analysis, to determine the key predictors of SMEs’ intentions to adopt BIM for H&S management.

Social implications

Socially, the study promotes the adoption of BIM for H&S. Digital technology is advancing and upgrades social standard, it is crucial for the society to adopt BIM for H&S.

Originality/value

Existing BIM for H&S management research has neglected SMEs’ adoption intentions, focusing instead on broader adoption enablers. This study presents a novel approach, leveraging the DOI theory and demographic analysis, to determine the key predictors of SMEs’ intentions to adopt BIM for H&S management.
Aerodynamic characteristics of the race car in pitch and roll attitude
Authors: Ma Xiaojing , Li Jie , Zhao Jun , Chen Jiliang
Published: December 2024

Purpose

Aerodynamics plays a crucial role in enhancing the performance of race cars. Due to the low ride height, the aerodynamic components of race cars are affected by ground effects. The changes in pitch and roll attitudes during the car’s movement impact its ride height. This study aims to analyze the aerodynamic characteristics of race cars under specific pitch and roll attitudes to understand the underlying aerodynamic mechanisms. This paper focuses on the aerodynamic characteristics of racing cars under variations in body posture associated with different vehicle ride heights. It examines not only the force and pressure distribution resulting from changes in the overall vehicle posture but also the flow field behavior of both surface flow and off‑body flow. Analyzing individual components reveals the impact of the front wing on the overall aerodynamic performance and aerodynamic balance of the racing car under these posture variations.

Design/methodology/approach

The grid strategy for the computational fluid dynamics (CFD) method was established under baseline conditions and compared with the results from wind tunnel experiments. The CFD approach was further employed to investigate the aerodynamic characteristics of the racing car under varying body postures associated with different vehicle ride heights. Emphasis is placed on the overall aerodynamic performance of the vehicle and the various components’ influence on the changing trends of aerodynamic forces. By considering the surface pressure distribution of the car, the primary reasons behind the changes in aerodynamic forces for each component are investigated. In addition, the surface flow and detached flow (wake and vortex distributions) of the car were observed to gain insights into the overall flow field behavior under different attitudes.

Findings

The findings indicate that both pitch and roll attitudes result in a considerable loss of downforce on the front wing compared with other components, thereby affecting the overall downforce and aerodynamic balance of the vehicle.

Originality/value

This paper focuses on the aerodynamic characteristics of racing cars under variations in body posture associated with different vehicle ride heights. It examines not only the force and pressure distribution resulting from changes in the overall vehicle posture but also the flow field behavior of both surface flow and off-body flow. Analyzing individual components reveals the impact of the front wing on the overall aerodynamic performance and aerodynamic balance of the racing car under these posture variations.
Generative AI in banking: empirical insights on integration, challenges and opportunities in a regulated industry
Authors: Moharrak Moayad , Mogaji Emmanuel
Published: December 2024

Purpose

This study aims to fill critical research gaps by providing empirical evidence on the practical application of generative AI in the banking sector. It explores managerial preparedness, regulatory compliance and data privacy challenges in implementing this technology, offering insights into its operational effectiveness and potential in financial services.

Design/methodology/approach

The research employs a qualitative approach, conducting in-depth interviews with bank managers and industry experts. These interviews are analysed to identify key factors influencing the integration of generative AI in financial institutions.

Findings

The study identifies five critical factors – recognition, requirement, reliability, regulatory and responsiveness – that collectively impact the adoption and operational effectiveness of generative AI in banking. These factors highlight the challenges and opportunities of integrating this technology within the highly regulated financial industry.

Practical implications

The findings have significant theoretical and managerial implications. Theoretically, the research contributes to understanding AI integration in regulated industries, particularly financial services. Managerially, it provides a roadmap for financial institutions to adopt generative AI responsibly, balancing innovation with regulatory compliance and ethical considerations.

Originality/value

This study is among the first to provide empirical data on generative AI’s practical application in the banking sector, addressing the lack of real-world evidence and offering a comprehensive analysis of the factors influencing its successful implementation in a highly regulated environment.