bluuebunny/crossref_metadata_2025 huggingface dataset:
A small regulatory RNA controls antibiotic tolerance inStaphylococcus aureusby modulating efflux pump expression
Authors: Ha Kam Pou , Bouloc Philippe
Published: August 2024

Staphylococcus aureusis an opportunistic pathogen that poses a considerable burden to healthcare settings worldwide, aided by its ability to thrive in different environmental growth conditions and survive exposure to antibiotics. Small regulatory RNAs (sRNAs) are crucial in enhancing bacterial fitness by modulating gene expression in response to changing environmental conditions. We investigated the role of sRNAs inS. aureusantibiotic resistance and tolerance. By assessing the fitness of a library of sRNA mutants, we identified that RsaA sRNA is required for bacterial growth when exposed to low concentrations of fluoroquinolone, a class of antibiotics targeting DNA replication. We also found that in the absence of RsaA,S. aureusis less susceptible to β-lactam antibiotics, which act on the cell wall. RsaA has been reported to prevent the expression of MgrA, a master regulatory protein controlling the expression of efflux pumps. Here, we show that RsaA affects the sensitivity ofS. aureusto fluoroquinolone and β-lactam antibiotics through MgrA. RsaA has two forms, a short one that is commonly referred to in RsaA studies, and a long form about twice the length, of which not much is known. Interestingly, our phenotype was restored only when complemented with the long form of the gene. This work demonstrates the role of regulatory RNAs in the adaptation ofS. aureusto antibiotic resistance and highlights their value as potential therapeutic targets for manipulating individual sRNA responses to promote the efficacy of existing antibiotics.
Human Vascularized Macrophage-Islet Organoids to Model Immune-Mediated Pancreatic β cell Pyroptosis upon Viral Infection
Authors: Yang Liuliu , Han Yuling , Zhang Tuo , Dong Xue , Ge Jian , Roy Aadita , Zhu Jiajun , Lu Tiankun , Vandana J. Jeya , de Silva Neranjan , Robertson Catherine C. , Xiang Jenny Z , Pan Chendong , Sun Yanjie , Que Jianwen , Evans Todd , Liu Chengyang , Wang Wei , Naji Ali , Parker Stephen C.J. , Schwartz Robert E. , Chen Shuibing
Published: August 2024

There is a paucity of human models to study immune-mediated host damage. Here, we utilized the GeoMx spatial multi-omics platform to analyze immune cell changes in COVID-19 pancreatic autopsy samples, revealing an accumulation of proinflammatory macrophages. Single cell RNA-seq analysis of human islets exposed to SARS-CoV-2 or Coxsackievirus B4 (CVB4) viruses identified activation of proinflammatory macrophages and β cell pyroptosis. To distinguish viral versus proinflammatory macrophage-mediated β cell pyroptosis, we developed human pluripotent stem cell (hPSC)-derived vascularized macrophage-islet (VMI) organoids. VMI organoids exhibited enhanced marker expression and function in both β cells and endothelial cells compared to separately cultured cells. Notably, proinflammatory macrophages within VMI organoids induced β cell pyroptosis. Mechanistic investigations highlighted TNFSF12-TNFRSF12A involvement in proinflammatory macrophage-mediated β cell pyroptosis. This study established hPSC- derived VMI organoids as a valuable tool for studying immune cell-mediated host damage and uncovered mechanism of β cell damage during viral exposure.
Impact of clinical severity on plasma p-tau performance in predementia Alzheimer’s disease
Authors: Gonzalez-Ortiz Fernando , Kirsebom Bjørn-Eivind , Yakoub Yara , Gundersen Julia K. , Pålhaugen Lene , Waterloo Knut , Selnes Per , Jarholm Jonas Alexander , Gísladóttir Berglind , Rongve Arvid , Skogseth Ragnhild Eide , Bråthen Geir , Aarsland Dag , Turton Michael , Harrison Peter , Zetterberg Henrik , Villeneuve Sylvia ,   PREVENT AD research group, Fladby Tormod , Blennow Kaj
Published: August 2024

Background and objectives

Detecting Alzheimer’s disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Here we investigate the relationship between clinical severity and levels of phosphorylated tau, focusing on plasma biomarkers, in preclinical and prodromal AD.

Methods

In this study (n=621), we examined two independent cohorts consisting of preclinical and prodromal AD. Cohort-1 included 431 participants classified as either cognitively normal (CN) or mild cognitive impaired (MCI) with normal or abnormal cerebrospinal fluid (CSF) Aβ42/40 ratio (A) and p-tau181 (T) [CN A-/T-, n=169; A+/T-, CN=26; MCI=24; A+/T+, CN=40; MCI=105; CN=34; MCI=33]. A total of n=418 of the participants had longitudinal assessments of verbal memory up to 9.67 years from baseline. Cohort-2 included 190 participants in whom amyloid status was determined using Aβ positron emission tomography (PET) [Aβ- CN= 118; Aβ+ CN= 49; Aβ+ MCI= 21].

Results

In cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying Aβ+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI Aβ+ (AUC: 0.89) versus CN Aβ+ (AUC: 0.79, p<.05) and for A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p<.05). P-tau181 and p-tau231 showed significantly weaker CSF-plasma correlations (rho= 0.47, and rho=0.32, p<.001, respectively) and levels were not as tightly associated with cognitive status in the Aβ+ group. While all the CSF p-tau markers were associated to future cognitive deterioration, p-tau217 was the only plasma biomarker associated with future memory decline (β=0.05, p<0.05). In cohort 1 and 2, plasma p-tau217 showed significantly higher concentrations in MCI Aβ+ as compared to CN Aβ+. Furthermore, plasma p-tau217 demonstrates similar biomarker elevations when compared to CN Aβ- controls in both cohorts.

Discussion

Our findings indicate that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in Aβ+ individuals and more closely reflects CSF biomarker abnormalities, potentially reducing discrepancies between clinical and biochemical findings. The associations of plasma p-tau217 with baseline and future cognitive decline make it a valuable complement to clinical evaluations in preclinical and prodromal AD, especially when CSF analysis or PET are not feasible.
Prevalence of early neonatal mortality and its predictors in sub-Saharan Africa: A Systematic review and Meta-Analysis
Authors: Zulu Teebeny , Jacobs Choolwe , Biemba Godfrey , Musonda Patrick
Published: August 2024

Background

Although early neonatal mortality (ENM) has been reported to have a greater contribution to the overall neonatal mortality compared to late neonatal mortality, no meta-analysis has studied this phenomenon in isolation. The prevalence of ENM and its predictors in sub-Saharan Africa (SSA) remains unknown. Therefore, this meta-analysis is aimed at pooling the prevalence of ENM and its predictors in SSA.

Methods

Google Scholar, PubMed, Scopus, CINAHL, and Google were searched for studies conducted in SSA that reported the prevalence and predictors of ENM. The data were extracted using a Microsoft Excel spreadsheet and imported into R version 4.4.1 for further analysis. Publication bias, heterogeneity, sensitivity analysis, and subgroup analysis were performed. Prevalence and odds ratios were pooled using the random effects model if significant heterogeneity existed; otherwise, the fixed effects model was used.

Results

A total of 26 studies were included in this systematic review and meta-analysis. The overall pooled prevalence of ENM in SSA was 11% (95% CI: 7-15;I2=100%). Birth asphyxia (OR=3.85; 95% CI: 1.12-13.21; P = 0.0388;I2= 86.6%), home delivery (OR=2.46; 95% CI: 1.79-3.38; p<0.001;I2= 0.0%), prematurity (OR=4.69; 95% CI: 3.57-6.16; p<0.001;I2= 36.8%), male gender (OR= 1.37; 95% CI: 1.28-1.46; P < 0.001;I2= 30.7%), delivery through caesarean section (OR=1.74; 95% CI: 1.49-2.02; P < 0.001;I2= 31.5%) and low birth weight (OR=3.00; 95% CI: 1.01-8.91; P = 0.0482;I2= 94.4%) were associated with a significant increase in pooled odds of ENM in SSA.

Conclusion

The prevalence of ENM in SSA in significantly high and it contributes greatly to the overall neonatal mortality. Therefore, tailor-made interventions that target the reduction of birth asphyxia, prematurity, home delivery, and low birth weight should be implemented in order to reduce the burden of ENM in SSA.
Personalized Fluid Management in Patients with Sepsis and AKI: A Policy Tree Approach
Authors: Oh Wonsuk , Takkavatakarn Kullaya , Kittrell Hannah , Shawwa Khaled , Gomez Hernando , Sawant Ashwin S. , Tandon Pranai , Kumar Gagan , Sterling Michael , Hofer Ira , Chan Lili , Oropello John , Kohli-Seth Roopa , Charney Alexander W , Kraft Monica , Kovatch Patricia , Kellum John A. , Nadkarni Girish N. , Sakhuja Ankit
Published: August 2024

Rationale

Intravenous fluids are mainstay of management of acute kidney injury (AKI) after sepsis but can cause fluid overload. Recent literature shows that restrictive fluid strategy may be beneficial in some patients with AKI, however, identifying these patients is challenging.

Objectives

We aimed to develop and validate a machine learning algorithm to identify patients who would benefit from a restrictive fluid strategy.

Methods

We included patients with sepsis who developed AKI within 48 hours of ICU admission and defined restrictive fluid strategy as receiving <500mL fluids within 24 hours after AKI. Our primary outcome was early AKI reversal at 24 hours of AKI onset, and secondary outcomes included sustained AKI reversal and major adverse kidney events by 30 days (MAKE30). We used a causal forest, a machine learning algorithm to estimate individual treatment effects and policy tree algorithm to identify patients who would benefit by restrictive fluid strategy. We developed the algorithm in MIMIC-IV and validated it in SICdb databases.

Measurements and Main Results

Among 2,044 patients in the external validation cohort, policy tree recommended restrictive fluids for 66.7%. Among these, patients who received restrictive fluids demonstrated significantly higher rate of early AKI reversal (47.1% vs 31.7%,p=0.004), sustained AKI reversal (28.7% vs 17.5%, p=0.013) and lower rates of MAKE30 (23.0% vs 37.1%, p=0.011). These results were consistent in adjusted analysis.

Conclusion

Policy tree based on causal machine learning can identify septic patients with AKI who benefit from a restrictive fluid strategy. This approach needs to be validated in prospective trials.
Comparative Effectiveness of the Bivalent (Original/Omicron BA.4/BA.5) mRNA COVID-19 Vaccines mRNA-1273.222 and BNT162b2 Bivalent in Adults With Underlying Medical Conditions in the United States
Authors: Kopel Hagit , Nguyen Van Hung , Bogdanov Alina , Winer Isabelle , Boileau Catherine , Ducruet Thierry , Zeng Ni , Winer-Jones Jessamine , Esposito Daina B. , Bausch-Jurken Mary , Beck Ekkehard , Bonafede Mac , Mansi James A.
Published: August 2024

This retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (Original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19.

In a linked EHR-claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either bivalent vaccine between August 31, 2022, and February 28, 2023, were identified. Inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until May 31, 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions.

757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%-15.2%) against COVID-19-related hospitalization and 3.2% (1.7%-4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were: diabetes 15.1% (8.7%–21.0%), cardiovascular disease 14.7% (9.0%–20.1%), chronic lung disease 11.9% (5.1%–18.2%), immunocompromised 15.0% (7.2%–22.2%), chronic kidney disease 8.4% (0.5%–15.7%).

Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations.
Connecting intermediate phenotypes to disease using multi-omics in heart failure
Authors: Moore Anni , Venkatesh Rasika , Levin Michael G. , Damrauer Scott M. , Reza Nosheen , Cappola Thomas P. , Ritchie Marylyn D.
Published: August 2024

Heart failure (HF) is one of the most common, complex, heterogeneous diseases in the world, with over 1-3% of the global population living with the condition. Progression of HF can be tracked via MRI measures of structural and functional changes to the heart, namely left ventricle (LV), including ejection fraction, mass, end-diastolic volume, and LV end-systolic volume. Moreover, while genome-wide association studies (GWAS) have been a useful tool to identify candidate variants involved in HF risk, they lack crucial tissue-specific and mechanistic information which can be gained from incorporating additional data modalities. This study addresses this gap by incorporating transcriptome-wide and proteome-wide association studies (TWAS and PWAS) to gain insights into genetically-regulated changes in gene expression and protein abundance in precursors to HF measured using MRI-derived cardiac measures as well as full-stage all-cause HF. We identified several gene and protein overlaps between LV ejection fraction and end-systolic volume measures. Many of the overlaps identified in MRI-derived measurements through TWAS and PWAS appear to be shared with all-cause HF. We implicate many putative pathways relevant in HF associated with these genes and proteins via gene-set enrichment and protein-protein interaction network approaches. The results of this study (1) highlight the benefit of using multi-omics to better understand genetics and (2) provide novel insights as to how changes in heart structure and function may relate to HF.
Prevalence of blindness and vision impairment among people 50 years and older in Nepal: a national Rapid Assessment of Avoidable Blindness survey
Authors: Mishra Sailesh Kumar , Shah Ranjan , Gogate Parikshit , Sapkota Yuddha Dhoj , Gurung Reeta , Shrestha Mohan Krishna , Mactaggart Islay , McCormick Ian , Shahi Brish Bahadur , Khandekar Rajiv , Burton Matthew
Published: August 2024

Purpose

To determine the prevalence and causes of blindness and vision impairment among people 50 years and older in Nepal.

Methods

We conducted seven provincial-level Rapid Assessment of Avoidable Blindness (RAAB) cross-sectional, population-based surveys between 2018-2021. Provincial prevalence estimates were weighted to give nationally representative estimates. Sampling, enumeration, and examination of the population 50 years and older were done at the province level following standard RAAB protocol.

Results

Across seven surveys, we enrolled 33,228 individuals, of whom 32,565 were examined (response rate 98%). Females (n=17,935) made up 55% of the sample. The age-sex-province weighted national prevalence of blindness (better eye presenting visual acuity <3/60) was 1.1% (95% confidence interval [CI] 1.0-1.2%), and any vision impairment <6/12 was 20.7% (95% CI 19.9-21.5%). The prevalence of blindness and any vision impairment were both higher in women than men (1.3% [95% CI 1.1-1.5%] vs 0.9% [95% CI 0.7-1.0%]). Age-sex weighted blindness prevalence was highest in Lumbini Province (1.8% [95% CI 1.3-2.2%]) and lowest in Bagmati Province (0.7% [95% CI 0.4-0.9%]) and Sudurpaschim Province (0.7% [95% CI 0.4-0.9%]). Cataract (65.2%) was the leading cause of blindness in our sample, followed by corneal opacity (6.4%), glaucoma (5.8%) and age-related macular degeneration (5.3%). Other posterior segment diseases accounted for 8.4% of cases.

Conclusion

The prevalence of blindness was higher among women than men and varied by province. The Lumbini and Madesh Provinces in the Terai (plains) region had higher prevalence of blindness than elsewhere. Cataract was the leading cause of blindness, severe vision impairment and moderate vision impairment while refractive error was the leading cause of mild vision impairment.
Drug-controlled CAR-T cells through the regulation of cell-cell interactions
Authors: Scheller Leo , Attianese Greta Maria Paola Giordano , Castellanos-Rueda Rocio , Di Roberto Raphael B , Barden Markus , Riboulet Melanie , Shui Sailan , Cribioli Elisabetta , Marchand Anthony , Georgeon Sandrine , Abken Hinrich , Reddy Sai , Correia Bruno , Irving Melita
Published: August 2024

CAR T-cell therapy is constrained by on-target, off-tumor toxicities as well as cellular exhaustion due to chronic antigen exposure. CARs comprising small-molecule controlled switches can enhance both safety and therapeutic efficacy but are limited by the scarcity of non-immunogenic protein elements responsive to non-immunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here, we combine rational design and library-based optimization of a protein-protein interaction (PPI) of human origin to develop venetoclax-controlled Drug-Regulated Off-switch PPI (DROP)-CARs. DROP-CARs enable dose-dependent release of the tumor-targeting scFv and consequent T-cell dissociation from the target tumor cell. Additionally, we present proof-of-concept for a dual DROP-CAR controlled by different small molecules, as well as for logic-gated synthetic receptors enabling logic-gated STAT3 signaling. We demonstrate in vitro and in vivo function of DROP-CAR T cells and conclude that the approach holds important promise for clinical application.
Inside Out: the physiology ofBrucellaVegetative and Intracellular Growth
Authors: Wade Nazarena , Comerci Diego J. , Soler-Bistué Alfonso , Marchesini María Inés
Published: August 2024

Growth rate is a key prokaryotic trait that allows estimating fitness and understanding cell metabolism. While in some clades it has been well studied in model organisms, there is little data on slow-growing bacteria. In particular, there is a lack of quantitative studies on the species of theBrucellagenus. This is an important microorganism since it is the causative agent of brucellosis, one of the most widespread bacterial zoonoses affecting several species of animals, including humans.Brucellaspecies exhibit approximately 97% genomic similarity. Despite this,Brucellaspecies show different host preferences, zoonotic risks, and pathogenicity. After more than one hundred years of research, numerous aspects ofBrucellabiology, such asin vivoandin vitrogrowth remain poorly characterized. In this work, we analyzed vegetative and intracellular growth of the classicalBrucellaspecies (B. abortus2308,B. melitensis16M.B. suis1330,B. ovis, andB. canis). Strikingly, each species displayed particular growth parameters in culture. Doubling time (DT) spanned from 2.7 hs-1inB. suisto 18h-1forB. ovis. In the context of intracellular infection of J774A.1 phagocytic cells, DT was higher, but it widely varied across species, closely correlating to the growth observedin vitro. Overall, despite high similarity of the genomes, we found species-specific growth parameters in the intracellular cell cycle.
Complex impact of stimulus envelope on motor synchronization to sound
Authors: Sun Yue , Michalareas Georgios , Ghitza Oded , Poeppel David
Published: August 2024

The human brain tracks temporal regularities in acoustic signals faithfully. Recent neuroimaging studies have shown complex modulations of synchronized neural activities to the shape of stimulus envelopes. How to connect neural responses to different envelope shapes with listeners’ perceptual ability to synchronize to acoustic rhythms requires further characterization. Here we examine participants’ motor and sensory synchronization to noise stimuli with periodic amplitude modulations (AM). We used three envelope shapes that varied in the sharpness of amplitude onset. In a synchronous motor finger-tapping task, we show that participants more consistently align their taps to the same phase of stimulus envelope when listening to stimuli with sharp onsets than to those with gradual onsets. This effect is replicated in a sensory synchronization task, suggesting a sensory basis for the facilitated phase alignment to sharp-onset stimuli. Surprisingly, despite less consistent tap alignments to the envelope of gradual-onset stimuli, participants are equally effective in extracting the rate of amplitude modulation from both sharp and gradual-onset stimuli, and they tapped consistently at that rate alongside the acoustic input. This result demonstrates that robust tracking of the rate of acoustic periodicity is achievable without the presence of sharp acoustic edges or consistent phase alignment to stimulus envelope. Our findings are consistent with assuming distinct processes for phase and rate tracking during sensorimotor synchronization. These processes may be underpinned by different neural mechanisms whose relative strengths are modulated by specific temporal dynamics of stimulus envelope characteristics.
RIPK4 driven by TP53 mutations promotes resistance to redox stress of CRC by phosphorylating MTHFD1
Authors: Yu Long , Zhou Sha , Xu Yan-Bo , Zhang Zhong-Jin , Cheng Xiao-Man , Zhou Chi , Li Wei-Hao , He Jia-Hua , Ou Qing-Jian , Qin Jia-Yi , Fang Yu-Jing , Peng Jian-Hong , Lin Jun-Zhong , Lin Bo , Hou Zhen-Lin , Pan Zhi-Zhong
Published: August 2024

This study investigates advanced colorectal cancer (CRC), focusing on its tendency for distant metastasis and chemotherapy resistance. It highlights the importance of PANoptosis, a cell death pathway, and the role of the Receptor-interacting serine/threonine-protein kinase (RIPK) family in tumor progression. RIPK4’s tissue-specific functions in cancer cell behavior are emphasized, including its influence on invasion, migration, and oxidative stress resistance. The study reveals the critical balance of reactive oxygen species (ROS) in cancer cells, linked to antioxidant defenses and NADPH production for survival. A key finding is the connection between TP53 mutations in CRC and increased RIPK4 expression, which enhances MTHFD1 phosphorylation, boosts NADPH production, reduces ROS, and promotes resistance to PANoptosis, leading to metastasis. The research identifies the molecular basis of CRC metastasis, showing how RIPK4 regulates MTHFD1 to resist PANoptosis, offering new therapeutic targets for metastatic CRC and potential improvements in patient outcomes.
Temporal misexpression ofEn1during limb development causes distinct phenotypes
Authors: Ringel Alessa R. , Magg Andreas , Benetti Natalia , Schöpflin Robert , Kühnlein Mira , Stiege Asita Carola , Fischer Ute , Wittler Lars , Lorenz Stephan , Mundlos Stefan , Allou Lila
Published: August 2024

The precise spatiotemporal regulation of developmental genes is required for proper organogenesis.Engrailed-1(En1) is essential for dorsal-ventral patterning during mouse limb development from embryonic day E9.5 to E11.5. Previously, we identified the long non-coding RNA locusMaenli, which drives limb-specificEn1expression at E9.5. In this study, we investigated the regulatory mechanisms sustainingEn1expression at later developmental stages whenMaenlitranscriptional activity is drastically reduced. Usingin vivoCRISPR editing, we identified two intergenic enhancer elements, LSEE1 and LSEE2, that maintainEn1expression at E10.5 and E11.5. Mice lacking these enhancers exhibit only a subset of the limb malformations observed inEn1andMaenlimutants, indicating that the timing ofEn1misexpression causes distinct phenotypes. These findings underscore the role of temporally restricted activities ofcis-regulatory elements, including lncRNA loci and enhancers, in modulating gene expression and explaining subtle differences in complex disease phenotypes.
Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells
Authors: Taylor Olivia , DeGroff Nick , El-Hodiri Heithem , Gao Chengyu , Fischer Andy J.
Published: August 2024

The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.
Nutrient competition predicts gut microbiome restructuring under drug perturbations
Authors: Shi Handuo , Newton Daniel P. , Nguyen Taylor H. , Estrela Sylvie , Sanchez Juan , Tu Michael , Ho Po-Yi , Zeng Qinglin , DeFelice Brian , Sonnenburg Justin , Huang Kerwyn Casey
Published: August 2024

Human gut commensal bacteria are routinely exposed to various stresses, including therapeutic drugs, and collateral effects are difficult to predict. To systematically interrogate community-level effects of drug perturbations, we screened stool-derivedin vitrocommunities with 707 clinically relevant small molecules. Across ∼5,000 community–drug interaction conditions, compositional and metabolomic responses were predictably impacted by nutrient competition, with certain species exhibiting improved growth due to adverse impacts on competitors. Changes to community composition were generally reversed by reseeding with the original community, although occasionally species promotion was long-lasting, due to higher-order interactions, even when the competitor was reseeded. Despite strong selection pressures, emergence of resistance within communities was infrequent. Finally, while qualitative species responses to drug perturbations were conserved across community contexts, nutrient competition quantitatively affected their abundances, consistent with predictions of consumer-resource models. Our study reveals that quantitative understanding of the interaction landscape, particularly nutrient competition, can be used to anticipate and potentially mitigate side effects of drug treatment on the gut microbiota.
Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in aMecp2mouse model for Rett syndrome
Authors: Medeiros Destynie , Polepalli Likhitha , Li Wei , Pozzo-Miller Lucas
Published: August 2024

Social memory impairments inMecp2knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments inMecp2KO mice has yet to be elucidated. We confirmedsocial memory(but notsociability) deficits inMecp2KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneousin vivofiber photometry of Ca2+-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca2+signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs ofMecp2KO mice showed smaller Ca2+signals during interactions only with live mice. On the other hand, mPFC PV-INs ofMecp2KO mice showed larger Ca2+signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network ofMecp2KO mice during social interactions, potentially driving their deficit in social memory.
Transcriptomic profiling of healthy individual-derived LCLs revealed inter-individual variability towards-hypoxia-responsive pathways
Authors: Singh Dayanidhi , Mehta Komal , Rani Ritu , Agrawal Satyam Kumar , Prasher Bhavana
Published: August 2024

Hypoxia, or low oxygen levels, affects various developmental, physiological, and pathological processes. It’s been consistently reported that there is an inter-individual variability at genetic and molecular pathways related to oxygen sensing and response. Understanding the underlying variability towards hypoxia sensing and response in health and disease conditions is challenging. ThePrakritistratification method of Ayurveda offers solutions, which classifies healthy individuals into different groups based on multisystem phenotyping. Our lab has previously used this method and provided evidence for the variability in hypoxia responsiveness physiologically among healthy individuals at population levels.

Our current study seeks to understand hypoxia sensing and response pathways at cellular levels. We used eight Lymphoblastoid cell lines (LCLs) developed from healthy individuals of extremePrakrititypes. Hypoxia challenge experiments were performed using 0.2% oxygen for 24 and 48 hrs. of chronic hypoxia and captured global transcriptomics profiles. Differentially expressed genes revealed activation of core hypoxia-induced transcriptomic signatures, such as HIF-1⍺ signaling and their metabolic reprogramming in pooled as well as in all Prakriti groups. However, there werePrakriti-specific differences, such as activation of TGF-β mediated ROS and PI3K/AKT/mTOR driven mTORC1complex in Kapha, downregulation of cholesterol homeostasis and regulation of Phosphoinositide biosynthesis in membrane potential observed in the Pitta group. In contrast, ER stress-induced activation of cell survival response via Unfolded protein response in the Vata group. ThePrakritistratification method will provide a novel method to understand inter-individual differences in hypoxia response pathways.

Significance

Hypoxia can significantly impact various aspects of our health and well-being. All nucleated cells sense and respond to hypoxia, depending upon their cellular and metabolic activities. Its wide utility and spatiotemporal regulation make it a crucial target to study. We have used thePrakritistratification method of Ayurveda to explore hypoxia sensing and response at cellular levels. Lymphoblastoid Cell Lines (LCLs) developed from the peripheral blood of stratified healthy individuals have been utilized to study the expression level variability at the baseline and hypoxia-induced conditions. The outcomes of our study will be crucial to understanding inter-individual variability in response to hypoxia overlayed baseline variations. Resulting in differential susceptibility towards hypoxic response in health and contributes to understanding variable outcomes in disease conditions. Molecular targets from our study will further be utilized for interventional drug targets in hypoxia-induced disease conditions.
Evidences of an inhibitory effect and other functions of human P53 inEscherichia coli
Authors: Ben Abid Sihem , Yacoubi Ines , Djemal Lamia , Dardouri Mosbeh , Gargouri Ali
Published: August 2024

The human tumor suppressor P53 has so far been shown to inhibit growth in the yeast model as well as in other eukaryotic contexts. Despite a considerable number of sudies involving p53 in bacteria, the question of effects on cell growth and viability has never been explored. In this work, we report similar negative effect on cell viability of the protein expressed inEscherichia colistrain BL21(DE3). This inhibition still needs to be characterized in lights of the distinction between yeast and other organisms with different P53-caused deaths and pathways. Primary tests leaned towards an active p53 in this bacterial context, both under normal and stresseful conditions. Special effects were noticed either with phage infection or antibiotic treatment, using a GST-p53 fusion form. These results open the way for further investigations involving P53 in prokaryote systems.
Pembrolizumab monotherapy for previously treated metastatic HER2-negative breast cancer with germlineAPOBEC3Bdeletion: results of the phase II AUROR study
Authors: Ho Gwo Fuang , Lee Soo Chin , Bustam Anita Zarina , Alip Adlinda , Abdul Satar Nur Fadhlina , Saad Marniza , Abdul Malik Rozita , Lim Siew Eng , Ow Samuel G. W. , Wong Andrea , Chong Wan-Qin , Ang Yvonne L. E. , Lee Audrey Weng Yan , Hasan Siti Norhidayu , Tuan Zaid Nabilah , Law Kian Boon , Toh Yok Yong , Tan Hooi Chiao , Selvam Bawani , Lim Joanna , Pan Jia-Wern , Teo Soo Hwang
Published: August 2024

Background

A common germline deletion polymorphism in theAPOBEC3Bgene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of theAPOBEC3Bdeletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients.

Patients and methods

Eligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion ofAPOBEC3B. Patients received 200 mg of pembrolizumab intravenously every 3 weeks for up to 2 years. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression-free survival, and overall survival.

Results

All enrolled patients (N = 44) were women, 36% had PD-L1-positive tumours, and 62% had received ≥2 previous lines of therapy for metastatic disease. ORR (95% CI) was 20.5% (9.8 – 35.5) in the total and 30.0% (6.7 – 65.3) in the PD-L1-positive populations. Disease control rate (95% CI) was 52.3% (36.7 – 67.5) and 40% (12.2 – 73.8), respectively. Median PFS was 3.1 months (95% CI, 2.1 – 4.3), and 6-month PFS rate was 29.5% (95% CI, 18.7 – 46.6). Median OS was 15.2 months (95% CI, 11.7 – 26.5), and 12-month OS rate was 60.2% (95% CI, 46.5 – 77.7). Treatment-related adverse events occurred in 30 (68.2%) patients, including 1 (2.3%) with grade 3 AE. There were no deaths due to AEs.

Conclusions

Pembrolizumab monotherapy demonstrated durable antitumour activity in a subset of previously treated metastatic HER2-breast cancer patients with germline APOBEC3B deletion.

Clinical trial registration

ClinicalTrials.gov,NCT03989089.
Tuning the electronic structure of monolayer
MoS2
towards metal like via vanadium doping
Authors: Maity Dipak , Sharma Rahul , Sahoo Krishna Rani , Lal Ashique , Arenal Raul , Narayanan Tharangattu N.
Published: August 2024

Doping of two-dimensional layered semiconducting materials is becoming pivotal in tailoring their electronic properties, enabling the development of advanced electronic and optoelectronic devices, where the selection of dopant is important. Here, we demonstrate the potential of substitutional vanadium (V) doping in monolayer molybdenum disulfide (MoS2) lattice in different extents leading to tunable electronic and optoelectronic properties. We found that low-level V doping (∼1 at.%) induces p-type characteristics in otherwise n-type monolayer MoS2, whereas medium-level doping (∼5 at.%) leads to an ambipolar semiconductor. Degenerately doped MoS2 (∼9 at.%) facilitates a transition from semiconducting towards metallic (metal-like) with reduced electrical resistivity (∼4.5 Ωm of MoS2 to ∼2.2×10−5Ωm), low activation energy for transport (∼11 meV), and electric field independent drain current in field effect transistor–based transfer characteristics. A detailed temperature- and power-dependent photoluminescence study along with density functional theory–based calculations in support unravels the emergence of an excitonic transition at ∼850 nm with its intensity dependent on the amount of vanadium. This study shows the potential of V doping in MoS2 for generating multifunctional two-dimensional materials for next generation electronics, optoelectronics, and interconnects with systematic control over its electronic structure in a wide range.

Published by the American Physical Society
2024
Honeybee-like collective decision making in a kilobot swarm
Authors: March-Pons David , Múgica Julia , Ferrero Ezequiel E. , Miguel M. Carmen
Published: August 2024

Drawing inspiration from honeybee swarms' nest-site selection process, we assess the ability of a kilobot robot swarm to replicate this captivating example of collective decision making. Honeybees locate the optimal site for their new nest by aggregating information about potential locations and exchanging it through their waggle dance. The complexity and elegance of solving this problem rely on two key abilities of scout honeybees: self-discovery and imitation, symbolizing and , respectively. We employ a mathematical model to represent this nest-site selection problem and program our kilobots to follow its rules. Our experiments demonstrate that the kilobot swarm can collectively reach consensus decisions in a decentralized manner, akin to honeybees. However, the strength of this consensus depends not only on the interplay between independence and interdependence but also on critical factors such as swarm density and the motion of kilobots. These factors enable the formation of a percolated communication network, through which each robot can receive information beyond its immediate vicinity. By shedding light on this crucial layer of complexity—the crowding and mobility conditions during the decision making—we emphasize the significance of factors typically overlooked but essential to living systems and life itself.

Published by the American Physical Society
2024
The lived experiences of South African Black accountants within the framework of the chartered accountancy profession sector code
Authors: Musundwa Sedzani , Moses Olayinka
Published: August 2024

Purpose

This study investigates the progress of the Broad-Based Black Economic Empowerment (B-BBEE) Act 2003, and its associated Chartered Accountancy Profession Sector Code. In doing so, we explore why B-BBEE affirmative action has not yet achieved the Code's representational intentions, including systemic subtleties inhibiting this success.

Design/methodology/approach

Using semi-structured interviews, we explore the lived experiences of Black aspirant Chartered Accountants (CAs) undertaking articles in global audit firms. The experiences are thematically analysed, embracing a comprehensive theoretical approach that encompasses professional and social closure, as well as boundary work, to adequately understand why affirmative transformational endeavours persistently face uphill tasks. The utilisation of multifaceted theorisation is deemed essential for a more nuanced portrayal of the intricacies inherent in the CA profession in South Africa.

Findings

The narratives presented by Black aspiring CAs unveil a complex web of exclusionary practices entrenched in institutionalised historical, professional, and social contexts. The multifaceted nature of closures, symbolised by racial, cultural, and linguistic factors, significantly impacts the experiences of Black trainees. The findings furthermore show that deliberate intervention beyond compliance with the Government’s framework is necessary for meaningful transformation.

Practical implications

The paper brings to the fore the current lived experiences of underrepresented Black CAs in global auditing firms. In doing so, these firms are empowered with incremental knowledge of the prevailing challenges and can thus make tangible improvements towards authentic transformation. Additionally, the results help in tracking the advancements made through affirmative action, acting as a feedback loop for future developments in transformation policy.

Originality/value

Contributing to the critical accounting literature, our study extends scholarship on the barriers faced by CAs and the limitations in their capacity to challenge these obstacles within global audit firms. We offer practical policy-focused recommendations that, if implemented, can address the complex socio-political realities obstructing the success of affirmative action. By sharing first-hand accounts, our study aims to empower auditing firms and other related stakeholders with actionable insights, enabling them to improve genuine inclusivity and foster equitable representation in the accounting profession.
Utilizing FSA conservation loan programs to support farm conservation activities
Authors: Atkinson Sarah A. , Dodson Charles B. , Wengrin Melinda
Published: August 2024

Purpose

The Farm Service Agency (FSA) conservation loan program was introduced in the 2008 Farm Bill to provide additional credit to assist producers implementing approved Natural Resources Conservation Service (NRCS) conservation projects. This paper explores why this program has been widely underutilized despite an overall increase in United States Department of Agriculture (USDA) Conservation Program participation.

Design/methodology/approach

The FSA administrative loan data are merged with NRCS program participation and payments data for 2010–2021. The share of project costs paid by producers and resulting savings achieved by farmers participating in both programs if their cost-share portion was paid by FSA loans are estimated, as well as the impact on farmer conservation spending under different estimates of increased participation.

Findings

A significant share of FSA farmers are likely to take advantage of NRCS programs, with the majority of participants paying under $25,000 in cost-share portions. These loans are less suited to guaranteed conservation loans and more appropriate for the discontinued direct conservation loan program. Few FSA borrowers participating in NRCS cost-share programs pay more than $50,000 in cost-share portions. These loans would receive the majority of benefits from interest reduction schemes under the current guaranteed loan program.

Practical implications

Our results and suggestions provide valuable information when discussing the Guaranteed Conservation Loan Program in the 2023 Farm Bill legislation.

Originality/value

No prior research has attempted to merge FSA guaranteed or direct loan data with conservation program participation and payment data, focused on producer cost-share levels or the FSA Guaranteed Conservation Loan Program in the last decade, making this study a valuable contribution to the literature.
Research on the influence of digital human avatar characteristics on brand fans effect
Authors: Xie Jifei , Wu Haoyu , Li Zhe , Ma Lulu , Liu Kexi
Published: August 2024

Purpose

This study aims to provide supplements to the research on digital human avatar (DHA) and suggestions for brands to use DHA appropriately to build brand fans effect.

Design/methodology/approach

On the basis of integrating Avatar theory and Stimulus-organism-response theory, this study obtains data from 733 Chinese respondents aged 18–25 and uses regression analysis and bootstrap analysis to verify the relationships among the variables: DHA characteristics (form realism, behavioral realism and brand alignment) as the independent variables, brand fans effect as the dependent variable, consumer positive emotion as the mediating variable and product type (experience vs search) as the moderating variable.

Findings

The results show that DHA characteristics positively influence brand fans effect and consumer positive emotion, consumer positive emotion positively influences brand fans effect and consumer positive emotion plays a mediating role. Meanwhile, for experience products, the impact of DHA’s form realism and behavioral realism on consumer positive emotion is higher than that of brand alignment; for search products, the impact of DHA’s brand alignment on consumer positive emotion is higher than that of form realism and behavioral realism.

Originality/value

This study enriches and expands the empirical research perspectives and conclusions in the DHA field, improves its research framework and provides suggestions for brands to appropriately use DHA to build brand fans effect.
Are clusters and industrial districts really driving sustainability innovation?
Authors: Hervas-Oliver Jose-Luis , Márquez García Juan Antonio Antonio , F. García-Chamizo , Rojas-Alvarado Ronald
Published: August 2024

Purpose

The purpose of this study is to explore and conducts a critical literature review to answer a fundamental question in the industrial district literature: are clusters and industrial (clusters/IDs) driving sustainability innovation? By intersecting different yet related strands of literature, the authors take stock of what the authors know about sustainability innovation in clusters/IDs.

Design/methodology/approach

This paper reviews the literature for conceptualizing sustainability innovation in clusters/districts.

Findings

Insights point out that the sustainability innovation process (development and diffusion) in clusters/IDs and their firms couples into mainstream cluster/IDs framework; clusters/IDs enable sustainability innovation through usual mechanisms, fostering collective change toward sustainability innovation, vis-à-vis other settings and strengthening firm sustainability innovation and performance. Sustainability innovation in clusters/IDs requires coupling different multi-scalar institutional systems effectively, and the cooperation of local organizations and policymakers for co-designing dedicated policies. Collective actions are important and firm heterogeneity needs to be considered in the clusters/IDs framework.

Originality/value

This study is original because it provides state-of-the-art on sustainability innovation in clusters/districts, enabling the topic to advance in this direction.
Big data analytics-artificial intelligence and supply chain ambidexterity impacts on corporate image and green communication
Authors: Chen Chin-Tsu , Chen Shih-Chih , Khan Asif , Lim Ming K. , Tseng Ming-Lang
Published: August 2024

Purpose

The theoretical background bases on the big data analytics-artificial intelligence (BDA-AI) technologies and supply chain ambidexterity (SCAX) in the firms to assess their sustainability endeavors such as green supply chain management (GSCM) to improve their green communication and corporate image.

Design/methodology/approach

Around 220 participants in the manufacturing firms are participants' industry expertise, diverse roles, and representation as key stakeholders.

Findings

The results show BDA-AI and SCAX affected on GSCM and found the significant relationships with green communication and corporate image. Green communication was discovered to impact corporate image significantly.

Originality/value

Prior studies are neglected to address the relationship among the AI, powered by rapid computational and BDA breakthroughs, redefines cognitive tasks, achieving feats previously deemed impossible-making implicit judgments, simulating emotions, and driving operations. This study selects manufacturing firms as respondents due to their forefront of BDA-AI and supply chain ambidexterity adoption to benefit the operational efficiency and competitiveness. The firms intricate supply chains, diverse stakeholders, and strategic emphasis on corporate image make it an ideal context to examine the nuanced impact of these technologies.