bluuebunny/crossref_metadata_2025 huggingface dataset:
A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow inStaphylococcus aureus
Authors: Shahreen Nabia , Ahn Jongsam , Alsiyabi Adil , Chowdhury Niaz Bahar , Shinde Dhananjay , Chaudhari Sujata S , Bayles Kenneth W , Thomas Vinai C , Saha Rajib
Published: October 2024

During aerobic growth,S. aureusrelies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow inS. aureushave not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle, specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient forS. aureusto generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck providesS. aureusthe flexibility to redirect carbon towards maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offersS. aureusdistinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal-pathogen lifestyle.
Unraveling the developmental heterogeneity within the human retina to reconstruct the continuity of retinal ganglion cell maturation and stage-specific intrinsic and extrinsic factors
Authors: Kriukov Emil , Soucy Jonathan R. , Labrecque Everett , Baranov Petr
Published: October 2024

Tissue development is a complex spatiotemporal process with multiple interdependent components. Anatomical, histological, sequencing, and evolutional strategies can be used to profile and explain tissue development from different perspectives. The introduction of scRNAseq methods and the computational tools allows to deconvolute developmental heterogeneity and draw a decomposed uniform map. In this manuscript, we decomposed the development of a human retina with a focus on the retinal ganglion cells (RGC). To increase the temporal resolution of retinal cell classes maturation state we assumed the working hypothesis that that maturation of retinal ganglion cells is a continuous, non-discrete process. We have assembled the scRNAseq atlas of human fetal retina from fetal week 8 to week 27 and applied the computational methods to unravel maturation heterogeneity into a uniform maturation track. We align RGC transcriptomes in pseudotime to map RGC developmental fate trajectories against the broader timeline of retinal development. Through this analysis, we identified the continuous maturation track of RGC and described the cell-intrinsic (DEGs, maturation gene profiles, regulons, transcriptional motifs) and -extrinsic profiles (neurotrophic receptors across maturation, cell-cell interactions) of different RGC maturation states. We described the genes involved in the retina and RGC maturation, including de novo RGC maturation drivers. We demonstrate the application of the human fetal retina atlas as a reference tool, allowing automated annotation and universal embedding of scRNAseq data. Altogether, our findings deepen the current knowledge of the retina and RGC maturation by bringing in the maturation dimension for the cell class vs. state analysis. We show how the pseudotime application contributes to developmental-oriented analyses, allowing to order the cells by their maturation state. This approach not only improves the downstream computational analysis but also provides a true maturation track transcriptomics profile.
Detection of mesial temporal lobe epilepsy with OP-MEG
Authors: Mellor Stephanie , O’Neill George C. , Bush Daniel , Ramaswamy Arjun , Doig David , Tierney Tim M. , Spedden Meaghan E. , Walker Matthew C. , Barnes Gareth R. , Vivekananda Umesh
Published: October 2024

Background and Objectives

Magnetoencephalography (MEG) using optically pumped magnetometers (OP-MEG) is a relatively novel neuroimaging modality that holds great clinical promise for presurgical planning in epilepsy. However, there is limited data demonstrating that interictal discharges from deep neural sources can be visually identified and localised using OP-MEG. In this study, we sought to demonstrate the potential of OP-MEG for recording interictal epileptiform activity from patients with mesial temporal lobe epilepsy, the most common focal epilepsy, with a diverse range of aetiologies.

Methods

We recorded whole-head OP-MEG for a minimum of 30 minutes from 8 patients with temporal lobe epilepsies. Patients were seated with their head unconstrained. For comparison, we collected information from previous clinical assessment, including findings from MRI and EEG telemetry.

Results

We observed interictal epileptiform activity in 4 of the patients, in 3 of which the localisation of the activity was concordant with previous clinical MRI and EEG. In 2 of those patients, we also observed ictal events. Of those 2 patients, one had a clear abnormality in MRI, with which the localisation of this ictal activity was concordant. The other patient’s MRI was negative, but the ictal localisation is consistent with the seizure semiology.

Discussion

We demonstrate that interictal and ictal epileptiform activity from mesial temporal lobe epilepsies can be observed with OP-MEG and localised to the region of the anatomical lesion, identified in MRI. This affirms the utility of OP-MEG for epilepsy surgery planning.
Integrating Functional Protein Drug Target Data into a Precision Oncology Molecular Tumor Board
Authors: Hunt Allison L. , Randall Jamie , Mansukhani Mahesh M. , Nyberg Kara , Nutcharoen Aratara , Davis Justin , Corgiat Brian , Mueller Claudius , Melvin Savannah , Sharma Meenakshi , Johnston Laura , Swain Whitney , Abulez Tamara , Bateman Nicholas W. , Maxwell G. Larry , Deeken John , Benyounes Amin , Petricoin Emanuel F. , Cannon Timothy L. , Conrads Thomas P.
Published: October 2024

Collaborative review of molecular profiling data by multidisciplinary molecular tumor boards (MTB) is increasingly important for improving patient management and outcomes, though currently relies nearly exclusively on nucleic acid next-generation sequencing (NGS) and limited panels of immunohistochemistry-based protein abundance data. We examined the feasibility of incorporating real-time laser microdissection (LMD) enrichment of tumor epithelium and commercial CLIA-based reverse phase protein array (RPPA) protein drug target expression/activation profiling into our cancer center’s MTB to complement standard clinical NGS-based profiling. The LMD-RPPA workflow was performed within a therapeutically permissive timeframe with a median dwell time of nine days, during which specimens were processed outside of standard clinical workflows. The RPPA-generated data supported additional and/or alternative therapeutic considerations for 54% of profiled patients following review by the MTB. These findings suggest that integrating proteomic/phosphoproteomic and NGS-based genomic data creates opportunities to further personalize clinical decision-making for precision oncology.
Validation of Machine-Learning Angiography-Derived Physiological Pattern of Coronary Artery Disease
Authors: Zhu Yueyun , Fezzi Simone , Bargary Norma , Ding Daixin , Scarsini Roberto , Lunardi Mattia , Mammone Concetta , Wagener Max , Mcinerney Angela , Toth Gabor , Pesarini Gabriele , Connolly David , Ribichini Flavio , Tu Shengxian , Wijns William , Simpkin Andrew J
Published: October 2024

Background

The classification of physiological patterns of coronary artery disease (CAD) is crucial for clinical decision-making, significantly affecting the planning and success of percutaneous coronary interventions (PCI).

Objectives

This study aimed to develop a novel index to reliably interpret and classify physiological CAD patterns based on virtual pullbacks from single-view Murray’s law-based quantitative flow ratio (μFR) analysis.

Methods

The pullback pressure gradient index (PPGi) was used to classify CAD patterns, with a cut-off value of PPGi=0.78 distinguishing focal from diffuse and non-focal disease. A machine learning method using penalized logistic regression models was proposed to assess CAD patterns. Scores derived from multivariate functional principal component analysis (MFPCA) of μFR and quantitative coronary analysis improved model performance. Expert panel interpretations served as the reference.

Results

A total of 179 vessels (134 patients) underwent classification. The PPGi cut-off of 0.78 achieved 70% accuracy (95% CI: 0.70 to 0.71) for focal vs. diffuse and 77% accuracy (95% CI: 0.76 to 0.77) for focal vs. non-focal classification. The penalized logistic regression model, including PPGi as a feature, provided superior accuracy: 95% (95% CI: 0.94 to 0.95) for focal vs. diffuse and 84% (95% CI: 0.83 to 0.84) for focal vs. non-focal classification. Positive predictive value (PPV) and negative predictive value (NPV) were 95% and 92% (focal vs. diffuse) and 84% each (focal vs. non-focal). Overall, the penalized logistic regression model successfully identified more focal lesions and ensured fewer diffuse or non-focal lesions were misclassified.

Conclusions

The machine learning method with penalized logistic regression outperformed the PPGi cut-off values, providing robust and generalizable classification across different study populations.
GLP-1 Receptor Agonists and Risk of Paralytic Ileus: A drug-target Mendelian Randomization Study
Authors: Ding Pingjian , Gao Zhenxiang , Gorenflo Maria P. , Xu Rong
Published: October 2024

Background

Paralytic ileus (PI), a condition characterized by reduced bowel motor activity without physical obstruction, can be affected by complications from type 2 diabetes (T2D) and anti-diabetic medications. It is unclear of the causal associations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with the risk of PI in the context of T2D management.

Methods

To investigate the causal relationship of GLP-1RAs with PI, we conducted a 2-sample mendelian randomization (MR) study based on summary statistics from genome-wide association studies (GWAS). Genetic variants in the GLP1R were identified as genetical proxies of GLP-1RAs by the glycemic control therapy, based on genetic associations with glycated hemoglobin (GWAS n=344,182) and T2D (ncases/controls=228,499/1,178,783). The effects of GLP-1RAs were estimated for PI risk (ncases/controls=517/182,423) using GWAS data from the FinnGen project.

Results

Based on MR analysis, GLP-1RAs are causally associated with a decreased risk of PI (OR per 1 mmol/mol decrease in glycated hemoglobin: 0.21; 95% confidence interval [CI]=0.06-0.69). The magnitude of these benefit exceeded those expected from improved glycemic control more generally.

Conclusions

Our study’s findings show that GLP-1RAs are causally associated with a lower risk for PI, which provides information to guide clinicians in the selection of appropriate therapies for individuals with T2D while mitigating the risk of developing PI. Investigating the underlying mechanisms that contribute to the lower PI risk associated with GLP-1RAs is essential for a deeper understanding of these associations.
Task-oriented vs. Goal-oriented: A New Paradigm for “Rooming” Patients
Authors: Tsige Temesgen , Bacchus Matthew , Flora Anthony , Ahn Gabriella , LoGalbo Sandhya , Sahadeo Vinayak , Sahadeo Prajna , Richman Mark
Published: October 2024

INTRODUCTION

In the fast-paced setting of the Emergency Department (ED), efficiency is important to delivering timely, effective care. A key aspect of this involves preparing patients by providing hospital gowns and connecting them to cardiac/vital signs monitors. These seemingly basic steps are crucial for ensuring patient safety and streamlining the provider’s evaluation process. However, in the ED, patients are often not fully prepared before a provider enters the room, leading to delays and inefficiencies. This study examines the rates at which patients are properly gowned and monitored upon rooming, to identify areas where ED workflows can be optimized to improve care delivery and better utilize staff and resources.

MATERIALS AND METHODS

The study was conducted in the adult Emergency Department at Long Island Jewish Medical Center. Data were collected from 100 randomly selected patients between June and October 2024. Patients were excluded if they wore loose-fitting clothing that allowed easy access to the area being evaluated, or if their chief complaint involved a visibly accessible body part (e.g., face), eliminating the need for disrobing or monitoring. The need for a hospital gown or connection to a cardiac/vital signs monitor was determined based on standard triage criteria, such as cardiopulmonary symptoms or the need to examine areas not easily accessible through clothing. We measured the percentage of patients who were appropriately gowned or monitored prior to the provider entering the room.

RESULTS

Of the 100 patients, 89 required a hospital gown, but only 61 (69%) received one. Regarding cardiac monitoring, 46 patients required a monitor, but only 20 (43%) were connected to one. In 50% of cases, patients had the correct body part exposed for examination before the provider’s arrival.

CONCLUSION

This study highlights significant inefficiencies in patient preparation in the ED, specifically related to gowning and cardiac monitoring. While 89% of patients required a gown, only 69% had one before the provider’s arrival. Similarly, only 43% of the patients who required monitoring were appropriately connected to a monitor. Additionally, only half of the patients had the correct body parts exposed for examination. These gaps in preparation force providers to complete these tasks themselves, contributing to delays, increasing provider workload, and potentially leading to burnout. To address this, we recommend shifting from task-oriented to goal-oriented patient rooming, revising protocols, and implementing checklists. These changes could help optimize resource use, reduce delays, and improve overall efficiency.
Interrogating the complex relationship between Alzheimer’s disease and blood pressure: two instrumental variable approaches to focus on pre-clinical stages of Alzheimer’s disease in UK Biobank
Authors: Palmer Jennifer C , Hart Emma , Anderson Emma , Love Seth , Lawlor Deborah A
Published: October 2024

Background and Aims

Evidence suggests there may be a bidirectional relationship between high blood pressure (BP) and Alzheimer’s disease (AD). It is hypothesised that this is due to cerebral changes during pre-clinical AD that cause elevation of systemic BP. We aimed to test this by exploring the effect of risk of pre-clinical AD on blood pressure.

Methods

We used data from the UK Biobank, including adults without prevalent or incident (within first 5-years of follow-up) clinical AD (N = 501,420, mean age 56.6, SD 8 years). We used two instrumental variables, an age-weighted parental dementia instrument score and a participant genetic instrument score, that are vulnerable to differing biases, to instrument risk of pre-clinical AD (the exposure). We tested the association of both instrument scores with systolic BP (SBP), diastolic BP (DBP) and hypertension. Sensitivity analyses were undertaken to explore different biases.

Results

Both the higher parental dementia instrument and participant genetic instrument score were associated with higher mean SBP (difference in mean SBP mmHg per 1SD higher score: 0.12, 95% CI: 0.06 to 0.17, and 0.07, 95% CI: 0.00 to 0.13, respectively) but not DBP. Sensitivity analyses were largely consistent with these findings.

Conclusions

Our findings provide preliminary evidence that pre-clinical AD increases SBP. Further research is required to determine whether this increase in SBP is due to increased cerebrovascular resistance in pre-clinical AD. Obtaining a better understanding of the changing relationship with BP at different stages of AD may enable effective optimisation and targeting of therapies.
Estimated prevalence of multiple chronic conditions throughout adulthood using data from theAll of UsResearch Program
Authors: Li Xintong , Dreisbach Caitlin , Gustafson Carolina M. , Murali Komal Patel , Koleck Theresa A.
Published: October 2024

Estimation of multiple chronic condition (MCC) prevalence throughout adulthood provides a critical reflection of MCC burden. We analyzed electronic health record codes for 58 conditions to estimate MCC prevalence forAll of Us(AoU) Research Program adult participants (N=242,828). Approximately 76% ofAoUparticipants were diagnosed with MCCs, with over 40% having 6 or more conditions and prevalence increasing with age; the most frequently occurring MCC combinations varied by age category (i.e., mental health conditions in early adulthood and physical health conditions in middle adulthood through advanced old age). We report notable prevalence of MCC throughout adulthood and variability in MCC condition combinations by age category inAoUparticipants. These findings highlight the need for targeted, innovative care modalities and population health initiatives to address MCC burden throughout adulthood.
Multi-Cancer PRS Constellation Model for Cancer Risk Prediction
Authors: Moragas Núria , Díez-Villanueva Anna , Moratalla-Navarro Ferran , Fernández-Navarro Pablo , Pérez-Gómez Beatriz , Suárez-Varela María Morales , Molina-Barceló Ana , Castaño-Vinyals Gemma , Rius-Sansalvador Blanca , Riobó-Mayo Lois , Olmedo-Requena Rocío , Jiménez-Moleón José-Juan , Marcos-Gragera Rafael , Guevara Marcela , Fernandez-Tardon Guillermo , Amiano Exezarreta Pilar , Huerta José M. , Fernández-Villa Tania , Molina de la Torre Antonio José , Martín-Sánchez Vicente , Gómez-Acebo Inés , Dierssen Trinidad , Alguacil Juan , Guinó Elisabet , Kogevinas Manolis , Pollán Marina , Obón-Santacana Mireia , Moreno Victor
Published: October 2024

Cancer development is influenced by genetic factors and modifiable exposures. GWAS has identified genetic variants and developed of prediction models through Polygenic Risk Scores (PRS), but PRS alone has limitations for estimating cancer risk.

This study assesses a novel PRS constellation approach that integrates Polygenic Risk Scores (PRS) from both lifestyle and genetic traits to enhance prediction models for colorectal, breast, and prostate cancers. The approach was developed using the UK Biobank dataset and validated in the independent GenRisk cohort.

The model, incorporating sex and age, achieved AUCs of 0.74 for CRC, 0.65 for BC, and 0.75 for PC in the UK Biobank. Including tumor-related PRSs improved PC prediction but had limited impact on CRC and BC. Age and sex inclusion boosted CRC and PC model accuracy. However, GenRisk validation showed reduced AUCs and limited utility of lifestyle PRSs, with CRC and BC models achieving 0.62 and PC 0.56.

Integrating lifestyle-related characteristics into PRS does not significantly enhance cancer-specific PRS prediction. However, PRSs for these traits show independent predictive power, highlighting the importance of considering lifestyle in cancer risk and the need for precision medicine to improve early detection.
Transcriptome analysis inC. elegansearly embryos upon depletion of the Topoisomerase 2/condensin II axis
Authors: Belew Mezmur D. , Michael W. Matthew
Published: October 2024

InC. elegans, the chromosome compaction factors topoisomerase 2 (TOP-2) and condensin II have been shown to globally repress transcription in multiple contexts. Our group has previously reported that TOP-2 and condensin II repress transcription in theC. elegansgermline during larval starvation, oocyte maturation, and in germline progenitor cells of the early embryo. Here, we assess the transcriptome of early embryos treated with RNAi against TOP-2 and the condensin II subunit CAPG-2. We found 144 upregulated and 172 downregulated genes. Further analysis showed that the upregulated genes are mostly somatic, with a host of neuronal cells present in our tissue enrichment analysis.
Social benefits of facial experssion in a cichlid fish: Testing the face concentration hypothesis
Authors: Satoh Shun , Fukuda Kazuya , Matsui Hiroshi , Kawasaka Kento , Matsuo Sayaka , Banda Takezo , Kanbe Kota , Konno Alu , Takei Shiro , Kohda Masanori , Kutsukake Nobuyuki
Published: October 2024

The face is a uniquely distinctive stimulus, encapsulating a wealth of information. Among the myriad of social cues conveyed by the face, emotional signals, known as facial expressions, are paramount not only for humans but also for numerous social animals. The evolution of facial expressions in these animals can also manifest in taxa other than mammals, as suggested by various studies highlighting the socio-ecological benefits of facial expressions. In this study, we elucidated the social function of facial coloration, determined by melanophores, in the neotropical social cichlidSymphysodon aequifasciatus. In this species, facial coloration exhibits instantaneous changes in response to varying social contexts. Through behavioral observations and experimental manipulation, we confirmed that facial coloration inS. aequifasciatusserves to attenuate unnecessary aggressive competition among conspecifics. Furthermore, we observed that the facial area subjected to coloration in this species is innervated by the adenosine triphosphate- and noradrenaline-ergic nervous system. These findings indicated that facial expression inS. aequifasciatusdepends on the sympathetic nervous system and has evolved independently of mammalian facial expressions. Our study highlights teleost fishes as valuable animal models for exploring the universality of facial expressions and their underlying cognitive mechanisms in vertebrates.
Physics-Informed Ellipsoidal Coordinate Encoding Implicit Neural Representation for high-resolution volumetric wide-field microscopy
Authors: Zhou You , Xu Chenyu , Jin Zhouyu , Chen Yanqin , Zheng Bei , Wang Meiyue , Xiong Bo , Cao Xun , Gu Ning
Published: October 2024

Wide-field fluorescence microscopy through axial scanning provides a simple way for volumetric imaging of cellular and intracellular activities, but the optical transfer function (OTF) of wide-field microscopy suffers from axial frequency deficiencies, leading to strong interference from out-of-focus fluorescence signals and reduced imaging quality. Richardson-Lucy (RL) deconvolution and its variants are commonly employed to reduce inter-plane signal interference of wide-field microscopy. However, these methods are still affected by the “missing cone” issue inherent in the OTF, compromising both the axial resolution and optical sectioning capability. Existing deep learning methods could realize high-fidelity 3D image stack restoration, but relying on high-quality paired datasets or specific assumptions about sample distributions. Here, we propose a novel method named physics-informed ellipsoidal coordinate encoding implicit neural representation (PIECE-INR), to tackle the challenges of background signal interference and resolution loss in axial scanning image stacks using the wide-field microscopy. In PIECE-INR, we integrate the wide-field fluorescence imaging model with the self-supervised INR network for high-fidelity reconstruction of 3D fluorescence data without the need of additional ground truth data for training. We further design a novel ellipsoidal coordinate encoding based on the system’s OTF constraints and incorporate implicit priors derived from the physical model as the loss function into the reconstruction process. Our approach enables block-wise reconstruction of large-scale images by using localized physical information. We demonstrate state-of-the-art performance of our PIECE-INR method in volumetric imaging of live HeLa cells, large-volumeC. eleganswhole-embryo, and mitochondrial dynamics.
Cell-to-cell mobility of the stem cell inducing WUSCHEL transcription factor is controlled by a balance of transport and retention
Authors: Fuchs Michael , Stiehl Thomas , Marciniak-Czochra Anna , Lohmann Jan U.
Published: October 2024

Non-cell autonomous induction of stem cell fate is a shared feature across multicellular organisms, however the underlying mechanisms diverge substantially between the kingdoms of live. In plants, cell to cell mobility of transcription factors has emerged as a key paradigm. For the shoot apical meristem of the reference plantArabidopsis thalianait has been described that the translocation of the WUSCHEL homeodomain transcription factor from niche cells to stem cells is essential for their maintenance. Here we systematically investigate the function of diverse WUS alleles and leverage multispectral live cell imaging coupled to computational analysis and mechanistic mathematical modelling to show that WUSCHEL protein mobility is the result of balance between active transport and retention in niche cells and likely independent of the stem cell signal CLAVATA3. Importantly, we show that diffusion across cell layers of the meristem is not symmetrical, suggesting that there is unexpected complexity in cellular connections.
Primary cilia shape postnatal astrocyte development through Sonic Hedgehog signaling
Authors: Bear Rachel , Sloan Steven A. , Caspary Tamara
Published: October 2024

Primary cilia function as specialized signaling centers that regulate many cellular processes including neuron and glia development. Astrocytes possess cilia, but the function of cilia in astrocyte development remains largely unexplored. Critically, dysfunction of either astrocytes or cilia contributes to molecular changes observed in neurodevelopmental disorders. Here, we show that a sub-population of developing astrocytes in the prefrontal cortex are ciliated. This population corresponds to proliferating astrocytes and largely expresses the ciliary protein ARL13B. Genetic ablation of astrocyte ciliain vivoat two distinct stages of astrocyte development results in changes to Sonic Hedgehog (Shh) transcriptional targets. We show that Shh activity is decreased in immature and mature astrocytes upon loss of cilia. Furthermore, loss of cilia in immature astrocytes results in decreased astrocyte proliferation and loss of cilia in mature astrocytes causes enlarged astrocyte morphology. Together, these results indicate that astrocytes require cilia for Shh signaling throughout development and uncover functions for astrocyte cilia in regulating astrocyte proliferation and maturation. This expands our fundamental knowledge of astrocyte development and cilia function to advance our understanding of neurodevelopmental disorders.
Role of CCK1 receptor in metabolic benefits of intestinal enteropeptidase inhibition in mice
Authors: Albarazanji Kamal , Hinke Simon A. , Cavanaugh Cassandre , Liu Jianying , Beck Stephen , Shukla Neetu , Meng Rong , Ho George , Camacho Raul C. , Leonard James , Nawrocki Andrea R.
Published: October 2024

Enteropeptidase (EP; enterokinase) is a serine protease that regulates intestinal protein digestion by converting trypsinogen into active trypsin, and thus initiates activation of the pancreatic zymogen cascade. Chronic inhibition of EP and trypsin (EP/T) with camostat (Foipan, FOY-305) or its active metabolite (FOY-251) causes weight loss in obese mice by reducing intestinal protein absorption and suppression of food intake, however, the mechanisms leading to appetite suppression are not well understood. We tested the hypothesis that cholecystokinin (CCK) signaling mediates the anorectic effects of EP/T inhibition using a CCK1R inhibitor (loxiglumide) or CCK1R knockout (KO) mice. Acute treatment with loxiglumide was able to partially reverse FOY-251-induced gallbladder contraction and delayed gastric emptying in mice. Chronic co-administration of loxiglumide reversed FOY-251 mediated effects on food intake and metabolism in diet-induced obese (DIO) mice. Chronic dosing of FOY-251 caused similar reductions in food intake but greater weight loss in CCK1R KO mice compared to wildtype (WT) mice, primarily due to fat mass loss. Pair fed (PF) groups revealed food intake-dependent and -independent mechanisms of weight loss by FOY-251. Notably, FOY-251 treatment induced sustained weight loss, whereas body weight loss rebounded in PF animals. In CCKR1 KO mice, FOY-251 caused greater weight loss, and increased protein calorie loss relative to that in WT mice, while having no effect on glycemic control or FGF21. Hence, CCK1R-dependent and - independent mechanisms modulate the metabolic effects of EP/T inhibition and may play a role in maintaining weight loss by this mechanism.
Two conserved arginine residues facilitate C-S bond cleavage and persulfide transfer in Suf family cysteine desulfurases
Authors: Gogar Rajleen K. , Conte Juliana V. , Dunkle Jack A. , Frantom Patrick A.
Published: October 2024

Under conditions of oxidative stress or iron starvation, iron-sulfur cluster biogenesis inE. coliis initiated by the cysteine desulfurase, SufS, via the SUF pathway. SufS is a type II cysteine desulfurase that catalyzes the PLP-dependent breakage of an L-cysteine C-S bond to generate L-alanine and a covalent active site persulfide as products. The persulfide is transferred from SufS to SufE and then to the SufBC2D complex, which utilizes it in iron-sulfur cluster biogenesis. Several lines of evidence suggest two conserved arginine residues that line the solvent side of the SufS active site could be important for function. To investigate the mechanistic roles of R56 and R359, the residues were substituted using site-directed mutagenesis to obtain R56A/K and R359A/K SufS variants. Steady state kinetics indicated R56 and R359 have moderate defects in the desulfurase half reaction but major defects in the transpersulfurase step. Fluorescence polarization binding assays showed that the loss of activity was not due to a defect in forming the SufS/SufE complex. Structural characterization of R56A SufS shows loss of electron density for the α3-α4 loop at the R56/G57 positions, consistent with a requirement of R56 for proper loop conformation. The structure of R359A SufS exhibits a conformational change in the α3-α4 loop allowing R56 to enter the active site and mimics the residue’s position in the PLP-cysteine aldimine structure. Taken together, the kinetic, binding, and structural data support a mechanism where R359 plays a role in linking SufS catalysis with modulation of the α3-α4 loop to promote a close-approach interaction of SufS and SufE conducive to persulfide transfer.
Post-transcriptional regulation ofcyclin Aandcyclin BmRNAs is mediated by Bruno 1 and Cup, and further fine-tuned within P-bodies
Authors: Bayer Livia V. , Milano Samantha N. , Kaur Harpreet , Bratu Diana P.
Published: October 2024

Cell cycle progression is tightly controlled by the regulated synthesis and degradation of Cyclins, such as Cyclin A and Cyclin B, which activate CDK1 to trigger mitosis. Mutations affecting Cyclin regulation are often linked to tumorigenesis, making the study of cyclin mRNA regulation critical for identifying new cancer therapies. In this study, we demonstrate via super-resolution microscopy thatcyclin Aandcyclin BmRNAs associate with Bruno 1 and Cup in nurse cells. The depletion of either protein leads to abnormal Cyclin A and Cyclin B protein expression and a reduction in mRNA levels for both Cyclins. We further reveal that bothcyclin Aandcyclin BmRNAs accumulate in P-bodies marked by Me31B. Interestingly, Me31B is not involved in regulatingcyclin AmRNA, as no changes incyclin AmRNA levels or repression are observed upon Me31B depletion. However,cyclin BmRNA shows stage-specific derepression and reduced levels when Me31B is absent. Notably, the association betweencyclin Band Cup is strengthened in the absence of Me31B, indicating that this interaction occurs independently of P-bodies. These results highlight the nuanced, mRNA-specific roles of P-body condensates in post-transcriptional regulation, challenging the idea of a uniform, binary mechanism of mRNA repression in P-bodies.
Exploring clinical care pathways of individuals with comorbid mental health disorders after presenting to emergency due to acute musculoskeletal pain: A Narrative Review
Authors: Arora Priya , Elliott James Michael , Pourkazemi Fereshteh
Published: October 2024

Complex Musculoskeletal (MSK) pain conditions are the leading cause of Years Lived with Disability (YLD) globally [1]. Alarmingly, this has remained the same since 1990 [2] suggesting that research into prevention and rehabilitation of MSK pain over the past 25+ years has had limited effect on its overall global burden. The reasons some fail to report full recovery while others follow a less problematic recovery trajectory are becoming clearer with psychological predictors (anxiety, depression, stress) showing some prognostic value [3]. Effective interventions however have proven elusive. Treatment of chronic MSK pain in many clinical settings tends to focus on the physical modalities such as pharmacologic, surgical, and other physical therapies excluding holistic interventions targeting psychosocial causes [4]. An integrative approach towards assessing and effectively managing a patient’s pain should cover the physical, behavioural, and psychosocial drivers of the patient’s pain experience. Moreover, a better understanding of the myriad of biopsychosocial mechanisms driving the clinical course for each patient seems particularly germane to the acute care encounter, given the current challenges with pharmaceutical dependence and overutilisation of and reliance on diagnostic tests that rarely inform management; or worse, promote ineffective management.
Dynamic dysregulation of retrotransposons in neurodegenerative diseases at the single-cell level
Authors: Deng Wankun , Citu Citu , Liu Andi , Zhao Zhongming
Published: October 2024

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.
Stark many-body localization under periodic driving
Authors: Duffin Christian , Deger Aydin , Lazarides Achilleas
Published: October 2024

We study the stability of localization under periodic driving in Stark many-body systems. We find that localization is stable except near special resonant frequencies, where resonances cause delocalization. We provide approximate analytical arguments and numerical evidence in support of these results. This shows that disorder-free broken ergodicity is stable to driving, opening up the way to studying nonequilibrium driven physics in a different setting.

Published by the American Physical Society
2024
Reactor neutrino liquid xenon coherent elastic scattering experiment
Authors: Cai Chang , Chen Guocai , Chen Jiangyu , Fang Rundong , Gao Fei , Guo Xiaoran , Guo Jiheng , He Tingyi , Jia Chengjie , Jin Gaojun , Jing Yipin , Ju Gaojun , Lei Yang , Li Jiayi , Li Kaihang , Li Meng , Li Minhua , Li Shengchao , Li Siyin , Li Tao , Lin Qing , Liu Jiajun , Liu Minghao , Lv Sheng , Luo Guang , Ma Jian , Shen Chuanping , Song Mingzhuo , Tong Lijun , Wang Xiaoyu , Wang Wei , Wang Xiaoping , Wang Zihu , Wei Yuehuan , Weng Liming , Xiao Xiang , Xie Lingfeng , Xu Dacheng , Yang Jijun , Yang Litao , Yang Long , Ye Jingqiang , Yu Jiachen , Yue Qian , Yue Yuyong , Zhang Bingwei , Zhang Shuhao , Zhao Yifei , Zhu Chenhui ,   RELICS Collaboration
Published: October 2024

Coherent elastic neutrino-nucleus scattering (CEνNS) provides a unique probe for neutrino properties beyond the Standard Model physics. The reactor neutrino liquid xenon coherent scattering experiment (RELICS), a proposed reactor neutrino program using liquid xenon time projection chamber technology, aims to investigate the CEνNS process of antineutrinos off xenon atomic nuclei. In this work, the design of the experiment is studied and optimized based on Monte Carlo simulations. To achieve a sufficiently low-energy threshold for CEνNS detection, an ionization-only analysis channel is adopted for RELICS. A high emission rate of delayed electrons after a big ionization signal is the major background, leading to an analysis threshold of 120 photoelectrons in the CEνNS search. The second largest background, nuclear recoils induced by cosmic-ray neutrons, is suppressed via a passive water shield. The physics potential of RELICS is explored with a 30  kg·yr exposure at a baseline of 25 m from a reactor core with a 3 GW thermal power. In an energy range of 120–300 photoelectrons, corresponding to an average nuclear recoil from 0.63 to 1.36 keV considering the liquid xenon response and detector-related effect, we expect 4639.7 CEνNS and 1687.8 background events. The sensitivity of RELICS to the weak mixing angle is investigated at a low momentum transfer. Our study shows that RELICS can further improve the constraints on the nonstandard neutrino interaction compared to the current best results.

Published by the American Physical Society
2024
Driving the zero-carbon construction strategy: key barriers and enablers
Authors: Siva Jessica , Gajendran Thayaparan , Toinpre Owi , Vaughan Josephine
Published: October 2024

Purpose

In the fast-changing field of zero-carbon construction there is a gap in understanding how zero-carbon construction strategies are experienced in practice. This paper aims to identify the key barriers and enablers to driving a zero-carbon construction strategy by industry, policymakers and educators.

Design/methodology/approach

The research was conducted in two stages. The first stage used a literature review to determine thematic areas from which to develop discussion points for the second stage of the research, which gathered insights into key barriers and enablers to driving a zero-carbon construction strategy from analysing recorded discussion with industry, policymakers and educators. This study adopts a qualitative research methodological design underpinned by dialectical approach of enquiries involving 31 participants. The philosophical standpoint aligns with a constructivist participatory worldview based on multiple stakeholder perspectives. Data involving virtual and face-to-face engagement held simultaneously in Australia and India were transcribed, coded and synthesised to identify the barriers and enablers to driving zero-carbon construction strategy.

Findings

The paper identified key barriers and enablers driving zero-carbon construction strategy. Barriers included limited awareness of industry dynamics; fixed mental models of professional practice; complexities in identifying appropriate skillsets; difficulties associated with reviewing education and training models and integrating sustainable strategies at early stages of projects. Enablers included: fostering education reform and supporting frameworks and procurement strategies for developers and clients; implementing efficient building designs, construction and operationalisation of zero-carbon buildings and; utilising an industry-led integrated approach. A framework was developed to provide an illustrative view of the linkage between the research projects’ focus areas and emergent themes.

Originality/value

The paper provides zero-carbon action priorities for four significant stakeholder groups in the build environment, developers, building occupiers, educators and government. As the priorities are derived in the research from examination of current literature and analysis of stakeholder viewpoints, this paper presents a unique, realistic and timely identification of barriers and key enablers driving zero-carbon construction strategies. Methodology applied in terms of data collection involved a public discourse and a unique technology-driven collaborative approach where participants simultaneously contributed across countries and time zones in a synchronous manner across key topics related to driving the zero-carbon construction strategy.
Digital transformation and the future of work: closing the digital skills gap
Authors: Hoe Siu Loon
Published: October 2024

Purpose

The purpose of this article is to discuss the near future digital technology landscape and propose several specific in-demand digital skills for organizations and individuals in the next few years.

Design/methodology/approach

This article reviews some recent publications from representative inter-governmental, governmental, non-governmental, and commercial organizations on the rise of digital technologies and corresponding growth in digital jobs. Within this context, several specific in-demand skills are proposed by the author who has written a book on the topic of digital transformation.

Findings

Rapid advancements in digital technologies continue to shape organizational practices and the future of work. To take advantage of emerging digital technologies and better compete in the marketplace, organizations and individuals need to upskill and reskill.

Practical implications

The main purpose of this article is to suggest a list of specific digital skills for executive management and human resources professionals to help prepare employees for digital jobs in the next few years. Corporate policy makers could introduce and promote these digital skills as part of the organizations’ training and development curriculum. In the area of talent management, organizations could also formulate hiring policies and assessment mechanisms to attract, develop, and retain employees with the requisite digital skills. For information technology and business professionals seeking to upskill and reskill, they could acquire these digital skills to enhance their current roles and prepare for the future digital workplace environment.

Originality/value

This article contributes to a better understanding of the digital technology landscape and digital skills. A list of specific in-demand skills is proposed to help organizations and individuals close the digital skills gap.
Identification and prioritization of the influential factors of blockchain technology adoption in the United States electricity supply chain
Authors: Gheibdoust Hamed , Jabbari Zideh Mehdi
Published: October 2024

Purpose

Nowadays, the electricity supply chain is significant for most societies, so it is necessary to use new technologies such as blockchain in the electricity industry. This study aims to identify and prioritize the factors influencing the adoption of blockchain technology in the electricity supply chain of the US.

Design/methodology/approach

In this study, after reviewing the research literature, the influential factors of blockchain adoption in the electricity industry are identified and the consensus of the experts is reached. Experts have a thorough understanding of blockchain technology and the US electricity industry. Data is collected using a Step-Wise Weight Assessment Ratio Analysis (SWARA) questionnaire from November 2022 to July 2023. Using the SWARA questionnaire, experts compared 16 influential subcriteria of blockchain adoption. Then, using the Fuzzy SWARA method, the following influential subcriteria of blockchain adaptation in the US electricity industry are evaluated and prioritized.

Findings

The results show that the most significant subcriterion among the 16 influential subcriteria for the adoption of blockchain technology in the electricity supply chain is reducing cost, whereas the collaborating with supply chain partners subcriterion is recognized as the least important subcriterion.

Originality/value

The present study helps managers improve their knowledge to apply blockchain technology and also have the best performance for applying blockchain technology in the electricity supply chain.
Hemodynamic characteristics of pulsatile blood flow through bifurcated stenosed carotid artery
Authors: Rajmane Swapnil Narayan , Tiwari Shaligram
Published: October 2024

Purpose

Carotid artery is often associated with plaque deposition because of its shape and associated flow features. The shape of stenosed bifurcation is characterised by bifurcation angle (ß), planarity angle (α) and severity of stenosis (b). In the present work, three-dimensional numerical computations have been performed to analyse the effect of these geometrical parameters of carotid bifurcation on the characteristics of flow.

Design/methodology/approach

Governing equations of this study were solved using ANSYS Fluent 20.1 and the blood flow was considered as laminar, pulsatile and non-Newtonian. Instantaneous flow behaviour has been illustrated using vorticity, velocity and helicity contours, whereas the time-averaged wall shear stress (

τw¯) and oscillatory shear index (OSI) quantify the time-averaged behaviour.

Findings

The recirculation zone and secondary flow are ascertained to be stronger for higher bifurcation angle as compared to the lower bifurcation angle. Strength of the secondary flow is found to reduce with increase in α from 0° to 10°, whereas it grows as α varies from 10° to 20°. For higher bifurcation angles,

τw¯ is lower than 2 Pa and OSI is greater than 0.2 on the outer walls. Similar observations were made for

τw¯ and OSI distribution on bottom wall in non-planar cases, which predicted atherogenic locations.

Originality/value

The values for ß were taken as 30°, 45°, 60° and 75°, whereas for α, range of 0°–20° was chosen. The stenosis was considered on the outer wall of internal carotid artery and its severity was considered within the range of 0%–60%.
The determinant factors of continuance use of customer service chatbot in Indonesia e-commerce: extended expectation confirmation theory
Authors: Sundjaja Arta Moro , Utomo Prio , Colline Fredella
Published: October 2024

Purpose

The implementation of customer service chatbots in various industries is increasingly accepted globally. Previous research has not extensively explored the relationship between chatbot disclosure, technology anxiety, chatbot quality, customer experience and customer satisfaction derived from using chatbot customer service in e-commerce. Therefore, this paper aims to examine the determinant factors of customer service chatbot continuance intention by extending the expectation confirmation theory (ECT). The researchers integrate chatbot quality, technology anxiety and disclosure into ECT to comprehensively understand the phenomena.

Design/methodology/approach

The quantitative study uses the partial least square structural equation model disjoint two-stage approach with a sample of 310 respondents collected using purposive sampling.

Findings

The study reveals that perceived usefulness, confirmation and satisfaction positively affect customer service chatbot continuance intentions. Moreover, chatbot disclosure can enhance chatbot quality. However, technology anxiety negatively affects chatbot quality.

Originality/value

This research contributed to adapting customer service chatbots in Indonesian e-commerce, focusing on chatbot quality, technological anxiety and transparency. Furthermore, it underscores the need for clarity, addresses transaction-specific concerns and artificial intelligence-driven customer assistance in the Indonesian market.