bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostaglandin E-major urinary metabolites as a new biomarker for acute mesenteric ischemia
Authors: Suzuki Keisuke , Morishita Koji , Adachi Tomohiro , Suekane Akira , Nakatsutsumi Keita , Teeratakulpisarn Panu , Kojima Mitsuaki , Coimbra Raul , Otomo Yasuhiro
Published: February 2024

BACKGROUND

Acute mesenteric ischemia (AMI) is an emergent vascular disease caused by cessation of the blood supply to the small intestine. Despite advances in the diagnosis, intervention, and surgical procedures, AMI remains a life-threatening condition. Prostaglandin E2 major urinary metabolite (PGE-MUM), the urinary metabolite of prostaglandin E2, is known to be stable in urine and has been suggested to be a valuable biomarker for intestinal mucosal inflammation, such as ulcerative colitis. We therefore investigated whether or not PGE-MUM levels reflect the degree of ischemia in an intestinal ischemia-reperfusion model.

METHODS

Male rats were used to establish a superior mesenteric artery occlusion (SMAO) group, in which the superior mesenteric artery was clamped, and a sham group. The clamping times in the SMAO group were either 30 minutes or 60 minutes, and reperfusion times were either 3 hours or 6 hours, after which PGE-MUM values were measured.

RESULTS

The histological injury score of the SMAO (30-minute ischemia and 6-hour reperfusion group, 1.8 ± 0.4; 60-minute ischemia and 6-hour reperfusion group, 4.7 ± 0.5) and were significantly greater than that of the sham group (0.4 ± 0.7, p < 0.05). The PGE-MUM levels in the SMAO group (30-minutes ischemia and 6-hour reperfusion group, 483 ± 256; 60-minutes ischemia and 6-hour reperfusion group, 889 ± 402 ng/mL) were significantly higher than in the sham group (30-minute and 6-hour observation group, 51 ± 20; 60-minute and 6-hour observation group, 73 ± 32 ng/mL; p < 0.05). Furthermore, the PGE-MUM value was corrected by the concentration of urinary creatinine (Cr). The PGE-MUM/urinary Cr levels in the SMAO group were also significantly higher than in the sham group (p < 0.05).

CONCLUSION

We found that intestinal ischemia-reperfusion increased urinary PGE-MUM levels depending on the ischemic time. This suggests the potential utility of PGE-MUM as a noninvasive marker of intestinal ischemia.
Assessment of Dementia in Minority Ethnic Groups in Scotland
Authors: Tsai Somying , Ma Shuning , Nielsen Thomas Rune , Calia Clara
Published: February 2024

Objective:

Minority ethnic groups (MEGs) in Europe receive suboptimal dementia evaluation, yet related research in Scotland is lacking. This research examined the evaluation of dementia in MEGs in Scotland and compared it with previous research to highlight the changes in the clinical evaluation of dementia over the decade.

Design and Setting:

A self-administered survey was created online and emailed to 14 Heads of the boards under the Scottish National Health Service and dementia-associated settings and organizations.

Results:

Most surveyed centers (85.6%) received MEG referrals. Although 92.9% of the centers used professional translators when needed, 85.7% thought assessing dementia in MEGs was difficult, mostly due to the suitability of test instruments and rating scales and patients’ linguistic abilities. Very few found their skills to be good in evaluating MEGs. There was no mention of specialized dementia services for MEGs.

Conclusions:

The lack of culturally appropriate instruments and specialized dementia services reveals that the services are not ready to meet the demand for evaluating patients from diverse cultural and language backgrounds. Inadequate clinical evaluation may lead to misdiagnoses. Therefore, although significant work has been carried out in the past few years, improvements must be continued to enhance the current practices and apply suitable evaluation methods for MEGs.
Climate change and its effects on body size and shape: the role of endocrine mechanisms
Authors: Names Gabrielle R. , Grindstaff Jennifer L. , Westneat David F. , Heidinger Britt J.
Published: February 2024

In many organisms, rapidly changing environmental conditions are inducing dramatic shifts in diverse phenotypic traits with consequences for fitness and population viability. However, the mechanisms that underlie these responses remain poorly understood. Endocrine signalling systems often influence suites of traits and are sensitive to changes in environmental conditions; they are thus ideal candidates for uncovering both plastic and evolved consequences of climate change. Here, we use body size and shape, a set of integrated traits predicted to shift in response to rising temperatures with effects on fitness, and insulin-like growth factor-1 as a case study to explore these ideas. We review what is known about changes in body size and shape in response to rising temperatures and then illustrate why endocrine signalling systems are likely to be critical in mediating these effects. Lastly, we discuss research approaches that will advance understanding of the processes that underlie rapid responses to climate change and the role endocrine systems will have. Knowledge of the mechanisms involved in phenotypic responses to climate change will be essential for predicting both the ecological and the long-term evolutionary consequences of a warming climate.

This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.
Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways
Authors: Tomkiewicz Céline , Coumoul Xavier , Nioche Pierre , Barouki Robert , Blanc Etienne B.
Published: February 2024

Organisms adapt to their environment through different pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP) which can also generate reactive toxic intermediates. In this review, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects. There is a large discrepancy between the limited number of proteins involved in these pathways (few dozens) and the diversity and complexity of the chemical exposome (tens of thousands of chemicals). Several XMP proteins have a low specificity which allows them to bind and/or metabolize a large number of chemicals. This leads to undesired consequences, such as cross-inhibition, inefficient metabolism, release of toxic intermediates, etc. Furthermore, several XMP proteins have endogenous functions that may be disrupted upon exposure to exogenous chemicals. The gut microbiome produces a very large number of metabolites that enter the body and are part of the chemical exposome. It can metabolize xenobiotics and either eliminate them or lead to toxic derivatives. The complex interactions between chemicals of different origins will be illustrated by the diverse roles of the aryl hydrocarbon receptor which binds and transduces the signals of a large number of xenobiotics, microbiome metabolites, dietary chemicals and endogenous compounds.

This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.
HPA flexibility and
FKBP5
: promising physiological targets for conservation
Authors: Zimmer Cédric , Jimeno Blanca , Martin Lynn B.
Published: February 2024

Hypothalamic–pituitary–adrenal axis (HPA) flexibility is an emerging concept recognizing that individuals that will cope best with stressors will probably be those using their hormones in the most adaptive way. The HPA flexibility concept considers glucocorticoids as molecules that convey information about the environment from the brain to the body so that the organismal phenotype comes to complement prevailing conditions. In this context, FKBP5 protein appears to set the extent to which circulating glucocorticoid concentrations can vary within and across stressors. Thus,
FKBP5
expression, and the HPA flexibility it causes, seem to represent an individual's ability to regulate its hormones to orchestrate organismal responses to stressors. As
FKBP5
expression can also be easily measured in blood, it could be a worthy target of conservation-oriented research attention. We first review the known and likely roles of HPA flexibility and FKBP5 in wildlife. We then describe putative genetic, environmental and epigenetic causes of variation in HPA flexibility and
FKBP5
expression among and within individuals. Finally, we hypothesize how HPA flexibility and
FKBP5
expression should affect organismal fitness and hence population viability in response to human-induced rapid environmental changes, particularly urbanization.

This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.
Fannyhessea vaginae causing bacteraemia and vertebral osteomyelitis: first report of invasive disease in a male
Authors: Jordan Victoria , Akram Ayesha , Pickles Robert , Arnold Alyssa , Naqvi Syeda
Published: February 2024

Introduction. Fannyhessea vaginae (formerly Atopobium vaginae) is an anaerobic organism commonly associated with female genital flora, with rare cases of invasive disease reported in females.
Case report. We discuss the case of an 81-year-old male who presented with an acute history of back pain and signs of urinary tract infection in the context of intermittent self-urinary catheterisation. Multiple blood cultures grew Fannyhessea vaginae with a later finding of lumbar vertebral osteomyelitis as the cause of back pain. Treatment was commenced with ampicillin, later switched to ceftriaxone, with improvement of acute signs of infection.
Conclusion. Gram positive anaerobic organisms including Fannyhessea vaginae are possibly under-recognised causes of urinary tract particularly in older males. These bacteria may prove challenging to grow in standard protocols for urine culture; anaerobic or extended incubation could be considered particularly in complicated cases of urinary tract infection without an identifiable pathogen.
Modeling Normal Mouse Uterine Contraction and Placental Perfusion with Non-invasive Longitudinal Dynamic Contrast Enhancement MRI
Authors: Cortes Devin Raine Everaldo , Stapleton Margaret C. , Schwab Kristina E. , West Dalton , Coulson Noah W. , O’Donnell Mary Gemmel , Powers Robert W. , Wu Yijen L.
Published: February 2024

The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual’s entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. Non-invasive imaging that can longitudinally probe murine placental healthin vivoare critical to understanding placental development throughout pregnancy. We developed advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. We developed a dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) pipeline combined with advanced image process methods to model uterine contraction and placental perfusion dynamics. Our novel imaging pipeline uses subcutaneous administration of gadolinium for steepest-slope based perfusion evaluation. This enables non-invasive longitudinal monitoring. Additionally, we advance the placental perfusion chamber paradigm with a novel physiologically-based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and continuing remodeling throughout gestation. Lastly, using optic flow to quantify placental motions arisen from uterine contractions in conjunction with time-frequency analysis, we demonstrated that the placenta exhibited asymmetric contractile motion.
Formation of a giant unilocular vacuole via macropinocytosis-like process confers anoikis resistance
Authors: Kim Jeongsik , Kim Dahyun , Kim Dong-Kyun , Lee Sang-Hee , Jang Wonyul , Lim Dae-Sik
Published: February 2024

Cell survival in metazoans depends on cell attachment to the extracellular matrix (ECM) or to neighboring cells. Loss of such attachment triggers a type of programmed cell death known as anoikis, the acquisition of resistance to which is a key step in cancer development. The mechanisms underlying anoikis resistance remain unclear, however. The intracellular F-actin cytoskeleton plays a key role in sensing the loss of cell-ECM attachment, but how its disruption affects cell fate during such stress is not well understood. Here, we reveal a cell survival strategy characterized by the formation of a giant unilocular vacuole (GUVac) in the cytoplasm of the cells whose actin cytoskeleton is disrupted during loss of matrix attachment. Time-lapse imaging and electron microscopy showed that large vacuoles with a diameter of >500 nm accumulated early after inhibition of actin polymerization in cells in suspension culture, and that these vacuoles subsequently coalesced to form a GUVac. GUVac formation was found to result from a variation of a macropinocytosis-like process, characterized by the presence of inwardly curved membrane invaginations. This phenomenon relies on both F-actin depolymerization and the recruitment of septin proteins for micron-sized plasma membrane invagination. The vacuole fusion step during GUVac formation requires PI(3)P produced by VPS34 and PI3K-C2α on the surface of vacuoles. Furthermore, its induction after loss of matrix attachment conferred anoikis resistance. Our results thus show that the formation of a previously unrecognized organelle promotes cell survival in the face of altered actin and matrix environments.
Germinal center BCR maturation in appendicitis reveals a role for antigen-specific adaptive immune responses during disease
Authors: Stewart Emma , Taghvaei Zainab , Leon Carmen , Shapiro Jason , Zhu Lisha , Alpert Lindsay , Turaga Kiran , Chowdhury Roshni Roy
Published: February 2024

Appendicitis is one of the most common abdominal emergencies globally, yet little is understood about the inflammatory mechanisms or potential drivers of disease. Neutrophil inflammation and increased cytokine expression such as IL-6 and IL-8 are hallmarks of appendicitis inflammation. However, early histological studies identified increased T and B cell infiltration during appendicitis, providing support for adaptive immune activation as well, although this has never been investigated in depth. We hypothesized that antigen-dependent activation of the adaptive immune response contributes to appendicitis pathology, in addition to the known innate-mediated processes. Via a series of transcriptomic approaches and lymphocyte repertoire analysis in human appendiceal tissue, we identified evidence of antigen-dependent B cell activation. Increased somatic hypermutation in the germinal center and plasma cell compartment was comprised of presumed high-affinity IgG and IgA B cells. We propose that the appendiceal microbiome acts as a source of antigen, as significant microbial dysbiosis was observed during appendicitis. This dysbiosis was characterized by outgrowth of pathobionts such asParvimonasand oral biofilm-formers such asFretibacteriumandFusobacterium, in line with previous reports. We also identified potential loss of epithelial barrier integrity via spatial transcriptomic analysis of the appendiceal epithelium, supporting the possibility of microbial invasion into the tissue during appendicitis. This study provides insight into the inflammatory mechanisms of a common disease and helps to define the immune and microbial compartment of an often-ignored organ, the appendix.
Hyper-diverse antigenic variation and resilience to transmission-reducing intervention in falciparum malaria
Authors: Zhan Qi , He Qixin , Tiedje Kathryn E. , Day Karen P. , Pascual Mercedes
Published: February 2024

Intervention against falciparum malaria in high transmission regions remains challenging, with relaxation of control efforts typically followed by rapid resurgence. Resilience to intervention co-occurs with incomplete immunity, whereby children eventually become protected from severe disease but not infection and a large transmission reservoir results from high asymptomatic prevalence across all ages. Incomplete immunity relates to the vast antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene family known asvar. Recent deep sampling ofvarsequences from individual isolates in northern Ghana showed that parasite population structure exhibited persistent features of high-transmission regions despite the considerable decrease in prevalence during transient intervention with indoor residual spraying (IRS). We ask whether despite such apparent limited impact, the transmission system had been brought close to a transition in both prevalence and resurgence ability. With a stochastic agent-based model, we investigate the existence of such a transition to pre-elimination with intervention intensity, and of molecular indicators informative of its approach. We show that resurgence ability decreases sharply and nonlinearly across a narrow region of intervention intensities in model simulations, and identify informative molecular indicators based onvargene sequences. Their application to the survey data indicates that the transmission system in northern Ghana was brought close to transition by IRS. These results suggest that sustaining and intensifying intervention would have pushed malaria dynamics to a slow-rebound regime with an increased probability of local parasite extinction.

One Sentence Summary

Population genomics of hyper-diversevargenes inform resurgence dynamics in falciparum malaria.
Self-supervised Learning for Chest CT - Training Strategies and Effect on Downstream Applications
Authors: Tariq Amara , Patel Bhavik N. , Banerjee Imon
Published: February 2024

Self-supervised pretraining can reduce the amount of labeled training data needed by pre-learning fundamental visual characteristics of the medical imaging data. In this study, we investigate several self-supervised training strategies for chest computed tomography exams and their effects of downstream applications. we bench-mark five well-known self-supervision strategies (masked image region prediction, next slice prediction, rotation prediction, flip prediction and denoising) on 15M chest CT slices collected from four sites of Mayo Clinic enterprise. These models were evaluated for two downstream tasks on public datasets; pulmonary embolism (PE) detection (classification) and lung nodule segmentation. Image embeddings generated by these models were also evaluated for prediction of patient age, race, and gender to study inherent biases in models’ understanding of chest CT exams. Use of pretraining weights, especially masked regions prediction based weights, improved performance and reduced computational effort needed for downstream tasks compared to task-specific state-of-the-art (SOTA) models. Performance improvement for PE detection was observed for training dataset sizes as large aswith maximum gain of 5% over SOTA. Segmentation model initialized with pretraining weights learned twice as fast as randomly initialized model. While gender and age predictors built using self-supervised training weights showed no performance improvement over randomly initialized predictors, the race predictor experienced a 10% performance boost when using self-supervised training weights. We released models and weights under open-source academic license. These models can then be finetuned with limited task-specific annotated data for a variety of downstream imaging tasks thus accelerating research in biomedical imaging informatics.
Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α
Authors: Wang Shuibang , Awad Keytam S. , Chen Li-Yuan , Siddique Mohammad A. H. , Ferreyra Gabriela A. , Wang Caroline L. , Joseph Thea , Yu Zu-Xi , Takeda Kazuyo , Demirkale Cumhur Y. , Zhao You-Yang , Elinoff Jason M. , Danner Robert L.
Published: February 2024

BACKGROUND

In hypoxic and pseudohypoxic rodent models of pulmonary arterial hypertension (PAH), hypoxia-inducible factor (HIF) inhibition reduces disease severity. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PAH in humans, indicating the involvement of other mechanisms.

METHODS

Pseudohypoxia was investigated in primary human lung endothelial cells by silencingPHD2,and inTie2-Cre/Phd2knockout mice, a rodent model of PAH. Lung vascular endothelial cells from PAH patients, and lung tissue from both SU5416/hypoxia PAH rats and PAH patients, were examined for validation.

RESULTS

PHD2silencing or inhibition, while activating HIF2α, induces apoptosis-resistance, hypo-proliferation, and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activates AKT and ERK, inhibits JNK, and reduces AIP1 (ASK1-interacting protein 1), all independent of HIF2α. Like PHD2,AIP1silencing affects these same kinase pathways and produces a similar dysfunctional endothelial cell phenotype, which can be partially reversed by AKT inhibition. These findings are corroborated in lung tissues of rodent PAH models and pulmonary vascular endothelial cells and tissues from PAH patients.

CONCLUSIONS

PHD2 deficiency in lung vascular endothelial cells induces an apoptosis-resistant, inflammatory, and hypo-proliferative phenotype. AKT activation and AIP1 loss, but not HIF signaling, drive these aberrant phenotypic changes. Our study suggests that HIF blockade alone may not suffice for PAH therapy; targeting PHD2, AKT, and AIP1 has the potential for developing more effective treatment.

GRAPHIC ABSTRACT

Highlights

PHD2silencing in human lung vascular endothelial cells suppresses apoptosis, inhibits proliferation, and activates STAT signaling, effects that persist despite HIF2α inhibition or knockdown.

PHD2silencing activates AKT and ERK, inhibits JNK, and decreases AIP1, all independently of HIF2α

Like PHD2,AIP1silencing led to similar alterations in kinase signaling and endothelial cell phenotypes, which are partially reversed by ATK inhibition.

Thesein vitrofindings align with observations in lung vascular endothelial cells and tissues from rodent models of PAH as well as PAH patients.
Phosphoproteomic investigation of targets of protein phosphatases in EGFR signaling
Authors: Eguchi Akihiro , Olsen Jesper V.
Published: February 2024

Receptor tyrosine kinases (RTKs) initiate cellular signaling pathways, which are regulated through a delicate balance of phosphorylation anddephosphorylation events. While many studies of RTKs have focused on downstream-activated kinases catalyzing the site-specific phosphorylation, few studies have focused on the phosphatases carrying out thedephosphorylation. In this study, we analyzed six protein phosphatase networks using chemical inhibitors in context of epidermal growth factor receptor (EGFR) signaling by mass spectrometry-based phosphoproteomics. Specifically, we focused on protein phosphatase 2C (PP2C), involved in attenuating p38-dependent signaling pathways in various cellular responses, and confirmed its effect in regulating p38 activity in EGFR signaling. Furthermore, utilizing a p38 inhibitor, we classified phosphosites whose phosphorylation status depends on PP2C inhibition into p38-dependent and p38-independent sites. This study provides a large-scale dataset of phosphatase-regulation of EGF-responsive phosphorylation sites, which serves as a useful resource to deepen our understanding of EGFR signaling.
Structured Peer Review: Pilot results from 23 Elsevier Journals
Authors: Malički Mario , Mehmani Bahar
Published: February 2024

Background

Reviewers rarely comment on the same aspects of a manuscript, making it difficult to properly assess manuscripts’ quality and the quality of the peer review process. It was the goal of this pilot study to evaluate structured peer review implementation by: 1) exploring if and how reviewers answered structured peer review questions, 2) analysing reviewer agreement, 3) comparing that agreement to agreement before implementation of structured peer review, and 4) further enhancing the piloted set of structured peer review questions.

Methods

Structured peer review consisting of 9 questions was piloted in August 2022 in 220 Elsevier journals. We randomly selected 10% of these journals across all fields and IF quartiles and included manuscripts that in the first 2 months of the pilot received 2 reviewer reports, leaving us with 107 manuscripts belonging to 23 journals. Eight questions had open ended fields, while the ninth question (on language editing) had only a yes/no option. Reviews could also leaveComments-to-AuthorandComments-to-Editor. Answers were qualitatively analysed by two raters independently.

Results

Almost all reviewers (n=196, 92%) filled out the answers to all questions even though these questions were not mandatory in the system. The longest answer (Md 27 words, IQR 11 to 68) was for reporting methods with sufficient details for replicability or reproducibility. Reviewers had highest (partial) agreement (of 72%) for assessing the flow and structure of the manuscript, and lowest (of 53%) for assessing if interpretation of results are supported by data, and for assessing if statistical analyses were appropriate and reported in sufficient detail (also 52%). Two thirds of reviewers (n=145, 68%) filled out theComments-to-Authorsection, of which 105 (49%) resembled traditional peer review reports. Such reports contained a Md of 4 (IQR 3 to 5) topics covered by the structured questions. Absolute agreement regarding final recommendations (exact match of recommendation choice) was 41%, which was higher than what those journals had in the period of 2019 to 2021 (31% agreement, P=0.0275).

Conclusions

Our preliminary results indicate that reviewers adapted to the new format of review successfully, and answered more topics than they covered in their traditional reports. Individual question analysis indicated highest disagreement regarding interpretation of results and conducting and reporting of statistical analyses. While structured peer review did lead to improvement in reviewer final recommendation agreements, this was not a randomized trial, and further studies should be done to corroborate this. Further research is also needed to determine if structured peer review leads to greater knowledge transfer or better improvement of manuscripts.
Detection of novel influenza viruses through community and healthcare testing: Implications for surveillance efforts in the United States
Authors: Morris Sinead E. , Gilmer Matthew , Threlkel Ryan , Brammer Lynnette , Budd Alicia P. , Iuliano A. Danielle , Reed Carrie , Biggerstaff Matthew
Published: February 2024

Background

Novel influenza viruses pose a potential pandemic risk and rapid detection of infections in humans is critical to characterizing the virus and facilitating the implementation of public health response measures.

Methods

We use a probabilistic framework to estimate the likelihood that novel influenza virus cases would be detected through testing in different community and healthcare settings (urgent care, emergency department, hospital, and intensive care unit (ICU)) while at low frequencies in the United States. Parameters were informed by data on seasonal influenza virus activity and existing testing practices.

Results

In a baseline scenario reflecting the presence of 100 novel virus infections with similar severity to seasonal influenza viruses, the median probability of detecting at least one infection per month was highest in urgent care settings (72%) and when community testing was conducted at random among the general population (77%). However, urgent care testing was over 15 times more efficient (estimated as the number of cases detected per 100,000 tests) due to the larger number of tests required for community testing. In scenarios that assumed increased clinical severity of novel virus infection, median detection probabilities increased across all healthcare settings, particularly in hospitals and ICUs (up to 100%) where testing also became more efficient.

Conclusions

Our results suggest that novel influenza virus circulation is likely to be detected through existing healthcare surveillance, with the most efficient testing setting impacted by the disease severity profile. These analyses can help inform future testing strategies to maximize the likelihood of novel influenza detection.
TIAM1 signaling drives prostatic budding and branching phenotypes and is a potential therapeutic target for BPH
Authors: Khedmatgozar Hamed , Dutta Sayanika , Dominguez Michael , Latour Daniel , Johnson Melanie , Fokar Mohamed , Warraich Irfan , de Riese Werner , Haynes Allan , Matusik Robert J. , Brandi Luis , Nandana Srinivas , Tripathi Manisha
Published: February 2024

Benign prostatic hyperplasia (BPH) is the most prevalent urologic disease in men aged over 50 years. However, the molecular mechanisms that drive BPH pathophysiology remain elusive. In this study, we integrated bioinformatic and experimental analyses of human BPH to identify TIAM1-RAC1 signaling pathway as a promising candidate for a molecular-based approach for BPH therapy. First, elevated TIAM1 expression in a BPH transcriptomic signature that was generated from the analysis of RNA-seq data from three independent BPH patient cohorts was validated at the protein level in a fourth patient cohort. Additional bioinformatic analyses of the BPH transcriptomic signature pointed to TIAM1-RAC1 pathway as the potential lead therapeutic pathway; and NSC23766 - a small molecule inhibitor of TIAM1 signaling - as a developmental lead compound for BPH therapy. Next, a proof-of-concept pharmacological approach of TIAM1-RAC1 inhibition in human prostatic cells using NSC23766 resulted in attenuated organoid budding and branching - a developmental program associated with prostatic nodule formation and BPH pathogenesis. Finally, shRNA-based genetic knock-down of TIAM1 in human prostatic cells led to a reduction in budding and branching phenotypes thereby phenocopying the effects of NSC23766. Together, our observations implicate elevated TIAM1 as a driver of budding and branching in BPH, and our studies pave the way for TIAM1-RAC1 based targeted approach for the treatment of the disease.
Characterisation of behaviours relevant to apathy syndrome in the aged male rat
Authors: Jackson Megan G , Lightman Stafford L , Robinson Emma S J
Published: February 2024

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy.

Using the effort for reward and progressive ratio tasks we found that aged rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task.

While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.
Tunable Macroscopic Alignment of Self-Assembling Peptide Nanofibers
Authors: Farsheed Adam C. , Zevallos-Delgado Christian , Yu Le Tracy , Saeidifard Sajede , Swain Joseph W.R. , Makhoul Jonathan T. , Thomas Adam J. , Cole Carson C. , Huitron Eric Garcia , Grande-Allen K. Jane , Singh Manmohan , Larin Kirill V. , Hartgerink Jeffrey D.
Published: February 2024

Fibrous proteins that comprise the extracellular matrix (ECM) guide cellular growth and tissue organization. A lack of synthetic strategies able to generate aligned, ECM-mimetic biomaterials has hampered bottom-up tissue engineering of anisotropic tissues and led to a limited understanding of cell-matrix interactions. Here, we present a facile extrusion-based fabrication method to produce anisotropic, nanofibrous hydrogels using self-assembling peptides. The application of shear force coinciding with ion-triggered gelation is used to kinetically trap supramolecular nanofibers into aligned, hierarchical structures. We establish how modest changes in phosphate buffer concentration during peptide self-assembly can be used to tune their alignment and packing. In addition, increases in the nanostructural anisotropy of fabricated hydrogels are found to enhance their strength and stiffness under hydrated conditions. To demonstrate their utility as an ECM-mimetic biomaterial, aligned nanofibrous hydrogels are used to guide directional spreading of multiple cell types, but strikingly, increased matrix alignment is not always correlated with increased cellular alignment. Nanoscale observations reveal differences in cell-matrix interactions between variably aligned scaffolds and implicate the need for mechanical coupling for cells to understand nanofibrous alignment cues. In total, innovations in the supramolecular engineering of self-assembling peptides allow us to generate a gradient of anisotropic nanofibrous hydrogels, which are used to better understand directed cell growth.
Lipidomics of homeoviscous adaptation to low temperatures inStaphylococcus aureusutilizing exogenous straight-chain unsaturated fatty acids over biosynthesized endogenous branched-chain fatty acids
Authors: Barbarek Shannon C. , Shah Ritika , Paul Sharanya , Alvarado Gloria , Appala Keerthi , Henderson Emma C. , Strandquist Evan T. , Pokorny Antje , Singh Vineet K. , Gatto Craig , Dahl Jan-Ulrik , Hines Kelly M. , Wilkinson Brian J.
Published: February 2024

It is well established thatStaphylococcus aureuscan incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media, and when growingin vivoin an infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain. We show that incorporation of C18:1Δ9 and its elongation product C20:1Δ9 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol (PG) and diglycosyldiacylglycerol (DGDG) lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin; however, this was not an obligatory requirement for cold adaptation. Enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth ofS. aureusat low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms.

IMPORTANCE

We show thatS. aureuscan use its known ability to incorporate exogenous fatty acids to enhance its growth at low temperatures. Individual species of phosphatidylglycerols and diglycosyldiacylglycerol bearing one or two degrees of unsaturation derived from incorporation of C18:1Δ9 at 12°C are described for the first time. In addition, enhanced production of the carotenoid staphyloxanthin occurs at low temperatures. The studies describe a biochemical reality underlying in membrane biophysics. This is an example of homeoviscous adaptation to low temperatures utilizing exogenous fatty acids over the regulation of the biosynthesis of endogenous fatty acids. The studies have likely relevance to food safety in that unsaturated fatty acids may enhance growth ofS. aureusin the food environment.
Online early supportive psychological intervention for bereaved families during COVID-19: Lessons Learned and Implementation Challenges
Authors: Hashemzadeh Mona , Jamaloo Samira , Shahmohamadi Elnaz , Rahmani Anahita , Damavandi Gilda Rajabi , Mousavi Mehri Seyed , Sotoudeh Hossein Gharaati , Artounian Valentin
Published: February 2024

As the COVID-19 pandemic has created complex conditions and the horrific loss of numerous lives, grieving the loss of loved ones in close families can be extremely difficult. To reduce the suffering of the loss and prevent the development of complicated grief, it is necessary to provide bereavement care as soon as possible. Therefore, we quickly developed a complete online program that included supportive psychotherapeutic interventions and psychiatric counseling. The structure of all services is the main emphasis of the study, which also emphasizes the quantitative components and the unique characteristics of the interventions. Based on the lesson learned, we discussed the difficulties experienced in putting into practice an internet-based preventive service.
Predicting Donor Selection and Multi-Organ Transplantation within Organ Procurement Organizations Using Machine Learning
Authors: Tanchip Chelsea , Noaeen Mohammad , Kazari Kamyar , Shakeri Zahra
Published: February 2024

Organ procurement organizations (OPOs) play a crucial role in the field of organ transplantation, serving as key intermediaries in the process of organ donation. However, despite their vital function, there exists a pressing issue of transparency within the organ allocation process. This opacity not only impedes the overall effectiveness of OPOs but also raises ethical and societal concerns regarding organ distribution. This study utilizes the recently published ORCHID dataset, containing 133,101 records of organ donor referrals, to understand organ procurement and donor selection strategies in OPOs using machine learning (ML). We developed seven ML classification models to predict donor selection and the likelihood of at least four organs being suitable for transplantation, in line with established definitions of multi-organ transplantation. The models demonstrated variable recall values for donor selection, ranging between 0.62 and 0.80, while achieving consistently high performance across other evaluation metrics, notably with AUC values exceeding 0.95. Particularly in the context of multi-organ transplant predictions, the models exhibited remarkable effectiveness, with recall values spanning from 0.88 to 0.98 and AUC metrics consistently above 0.97. Administrative milestones and particular organ transplants were identified as key determinants in the organ allocation process. This study’s findings suggest significant opportunities to improve organ allocation strategies by focusing on the optimization of administrative practices, highlighting their substantial impact on transplantation success rates.
Identifying Prediabetes in Canadian Populations Using Machine Learning
Authors: Lu Katherine , Sheth Paijani , Zhou Zhi Lin , Kazari Kamyar , Guergachi Aziz , Keshavjee Karim , Noaeen Mohammad , Shakeri Zahra
Published: February 2024

Prediabetes is a critical health condition characterized by elevated blood glucose levels that fall below the threshold for Type 2 diabetes (T2D) diagnosis. Accurate identification of prediabetes is essential to forestall the progression to T2D among at-risk individuals. This study aims to pinpoint the most effective machine learning (ML) model for prediabetes prediction and to elucidate the key biological variables critical for distinguishing individuals with prediabetes. Utilizing data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN), our analysis included 6,414 participants identified as either nondiabetic or prediabetic. A rigorous selection process led to the identification of ten variables for the study, informed by literature review, data completeness, and the evaluation of collinearity. Our comparative analysis of seven ML models revealed that the Deep Neural Network (DNN), enhanced with early stop regularization, outshined others by achieving a recall rate of 60%. This model's performance underscores its potential in effectively identifying prediabetic individuals, showcasing the strategic integration of ML in healthcare. While the model reflects a significant advancement in prediabetes prediction, it also opens avenues for further research to refine prediction accuracy, possibly by integrating novel biological markers or exploring alternative modeling techniques. The results of our work represent a pivotal step forward in the early detection of prediabetes, contributing significantly to preventive healthcare measures and the broader fight against the global epidemic of Type 2 diabetes.
Pesticide chemical leads inhibiting protein-protein interactions
Authors: Ben Shushan Rotem Shelly , Cohen Elad , Ben Naim Noam , Amram Eytan , Gressel Jonathan , Peleg Dotan , Dotan Nesly , Bloch Itai , Gal Maayan
Published: February 2024

Pesticides, especially herbicides, have revolutionized agriculture by providing energy-efficient solutions for pest control that replaces labor-intensive cultivation methods. However, the widespread evolution of pesticide resistance poses a significant challenge to current agriculture. Most pesticides function by binding to specific pockets on target enzymes, enabling a single mutation to confer resistance. An alternative approach is the disruption of protein-protein interactions (PPI), thus for resistance to occur, it requires complementary mutations on both interacting partners. Despite extensive efforts, no herbicides with new modes of action have been commercialized for decades. Thus, we focused on the discovery and design of small molecule inhibitors that target the interface of the PPI complex of O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key plant enzymes involved in the biosynthesis of the essential amino acid cysteine. Using in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT. Subsequently, we conducted chemical optimizations to evaluate biophysical enzyme disruption, followed by cellular and in-planta activity in plants. These new compounds described herein can serve as promising starting points for further optimization as herbicides acting on a new mode of action.
Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction and leads to increased glucose uptake in tafazzin-deficient cells
Authors: Liang Zhuqing , Ralph-Epps Tyler , Schmidtke Michael W. , Lazcano Pablo , Denis Simone W. , Balážová Mária , Chakkour Mohamed , Hazime Sanaa , Ren Mindong , Schlame Michael , Houtkooper Riekelt H. , Greenberg Miriam L.
Published: February 2024

Barth syndrome (BTHS) is a rare disorder caused by mutations in theTAFAZZINgene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems.

In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.
Bundle Analytics based Data Harmonization for Multi-Site Diffusion MRI Tractometry
Authors: Chandio Bramsh Qamar , Villalon-Reina Julio E. , Nir Talia M. , Thomopoulos Sophia I. , Feng Yixue , Benavidez Sebastian , Jahanshad Neda , Harezlak Jaroslaw , Garyfallidis Eleftherios , Thompson Paul M.
Published: February 2024

The neural pathways of the living human brain can be tracked using diffusion MRI-based tractometry. Alongtract statistical analysis of microstructural metrics can reveal the effects of neurological and psychiatric diseases with 3D spatial precision. To maximize statistical power to detect disease effects and factors that influence them, data from multiple sites and scanners must often be combined, yet scanning protocols and hardware may vary widely. For simple scalar metrics, data harmonization methods - such as ComBat and its variants - allow modeling of disease effects on derived brain metrics, while adjusting for effects of scanning site or protocol. Here, we extend this method to pointwise segment analyses of 3D fiber bundles by integrating ComBat into the BUndle ANalytics (BUAN) tractometry pipeline. In a study of the effects of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) on 38 white matter tracts, we merge data from 7 different scanning protocols used in the Alzheimer’s Disease Neuroimaging Initiative, which vary in voxel size and angular resolution. By incorporating ComBat harmonization, we model site- and scanner-specific effects, ensuring the reliability and comparability of results by mitigating confounding variables. We also evaluate choices that arise in extending batch adjustment to tracts, such as the regions used to estimate the correction. We also compare the approach to the simpler approach of modeling the site as a random effect. To the best of our knowledge, this is one of the first applications to adapt harmonization to 3D tractometry.