bluuebunny/crossref_metadata_2025 huggingface dataset:
Trafficking of Connexin36 (Cx36) in the early secretory pathway
Authors: Tetenborg Stephan , Ariakia Fatemeh , Martinez-Soler Elizabeth , Shihabeddin Eyad , Lazart Ignacio Cebrian , Miller Adam C. , O’Brien John
Published: March 2024

Gap junctions formed by the major neuronal connexin Cx36 function as electrical synapses in the nervous system and provide unique functions such as synchronizing activities or network oscillations. Although the physiological significance of electrical synapses for neuronal networks is well established, little is known about the pathways that regulate the transport of its main component: Cx36. Here we have used HEK293T cells as an expression system in combination with siRNA and BioID screens to study the transition of Cx36 from the ER to the cis Golgi. Our data indicate that the C-terminal tip of Cx36 is a key factor in this process, mediating binding interactions with two distinct components in the early secretory pathway: the COPII complex and the Golgi stacking protein Grasp55. The C-terminal amino acid valine serves as an ER export signal to recruit COPII cargo receptors Sec24A/B/C at ER exit sites, whereas the PDZ binding motif “SAYV” mediates an interaction with Grasp55. These two interactions have opposing effects in their respective compartments. While Sec24 subunits carry Cx36 out of the ER, Grasp55 stabilizes Cx36 in the Golgi as shown in over expression experiments. These early regulatory steps of Cx36 are expected to be essential for the formation, function, regulation and plasticity of electrical synapses in the developing and mature nervous system.
Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy
Authors: Lypova Nadiia , Dougherty Susan M. , Clem Brian F. , Feng Jing , Yin Xinmin , Zhang Xiang , Li Xiaohong , Chesney Jason A. , Imbert-Fernandez Yoannis
Published: March 2024

The efficacy of FDA-approved tyrosine kinase inhibitors (TKIs) targeting EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment. This study aimed to investigate the impact of the glycolytic regulator 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the metabolic adaptivity of lung cancer cells to EGFR TKI therapies. Using two EGFR-driven non-small cell lung cancer cell lines, PC9 and HCC827, we analyzed metabolic changes in cells exposed to EGFR inhibitors and evaluated the effect of PFKFB3 inhibition on metabolic adaptations during TKI treatment. Our results indicate that PFKFB3-mediated glycolysis sustains ATP production upon TKI treatment. Metabolomics studies revealed that PFKFB3 inhibition in TKI-treated cells limits glucose utilization in glycolysis, TCA cycle, and polyol pathway. Additionally, we show that pharmacological inhibition of PFKFB3 overcomes TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), which in turn, exacerbates oxidative stress. Our study also revealed that PFKFB3 contributes to DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. In TKI-treated cells, PFKFB3 inhibition reduced ATM expression and limited DNA damage repair, increasing sensitivity to DNA integrity insults.

In summary, our results suggest that inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR-TKI therapy before they enter the drug-resistant state.

STATEMENT OF IMPLICATION

Targeting PFKFB3 can improve the efficacy of EGFR-targeting TKIs by restricting non-genetic adaptations embraced by drug-tolerant cells.
Proton Free Induction Decay MRSI at 7T in the Human Brain Using an Egg-Shaped Modified Rosette K-Space Trajectory
Authors: Blömer Simon , Hingerl Lukas , Marjańska Małgorzata , Bogner Wolfgang , Motyka Stanislav , Hangel Gilbert , Klauser Antoine , Andronesi Ovidiu C , Strasser Bernhard
Published: March 2024

1.

1.1

Purpose

Proton (1H)-MRSI via spatial-spectral encoding poses high demands on gradient hardware at ultra-high fields and high-resolutions. Rosette trajectories help alleviate these problems, but at reduced SNR-efficiency due to their k-space densities not matching any desired k-space filter. We propose modified rosette trajectories, which more closely match a Hamming filter, and thereby improve SNR performance while still staying within gradient hardware limitations and without prolonging scan time.

1.2

Methods

Analytical and synthetic simulations were validated with phantom and in vivo measurements at 7 T. The rosette and modified rosette trajectories were measured in five healthy volunteers in six minutes in a 2D slice in the brain. A 3D sequence was measured in one volunteer within 19 minutes. The SNR, linewidth, CRLBs, lipid contamination and data quality of the proposed modified rosette trajectory were compared to the rosette trajectory.

1.3

Results

Using the modified rosette trajectories, an improved k-space weighting function was achieved resulting in an increase of up to 12% in SNR compared to rosette’s dependent on the two additional trajectory parameters. Similar results were achieved for the theoretical SNR calculation based on k-space densities, as well as when using the pseudo-replica method for simulated, in-vivo and phantom data. The CRLBs improved slightly, but non-significantly for the modified rosette trajectories, while the linewidths and lipid contamination remained similar.

1.4

Conclusion

By improving the rosette trajectory’s shape, modified rosette trajectories achieved higher SNR at the same scan time and data quality.
Time-varying reproduction number estimation: Fusing compartmental models with generalised additive models
Authors: Pang Xiaoxi , Han Yang , Tessier Elise , Abdul Aziz Nurin , Pellis Lorenzo , House Thomas , Hall Ian
Published: March 2024

The reproduction number, the mean number of secondary cases infected by each primary case, is a central metric in infectious disease epidemiology, and played a key role in the COVID-19 pandemic response. This is because it gives an indication of the effort required to control the disease. Beyond the well-knownbasicreproduction number, there are two natural versions, namely thecontrolandeffectivereproduction numbers. As behaviour, population immunity and viral characteristics can change with time, these reproduction numbers can vary over time and in different regions.

Real world data can be complex, for example with daily variation in numbers due to weekend surveillance biases as well as natural stochastic noise. As such, in this work we consider a Generalised Additive Model to smooth real data through the explicit incorporation of day-of-the-week effects, to provide a simple measure of the time-varying growth rate associated with the data.

Converting the resulting spline into an estimator for both the control and effective reproduction numbers requires assumptions on a model structure, which we here assume to be a compartmental model. The reproduction numbers calculated are based on both simulated and real world data, and are compared with estimates from an already existing tool.

The derived method for estimating the time-varying reproduction number is effective, efficient and comparable to other methods. It provides a useful alternative approach, which can be included as part of a toolbox of models, that is particularly apt at smoothing out day-of-the-week effects in surveillance.
Improved correction ofB0inhomogeneity-induced distortions in diffusion-weighted images of the prostate
Authors: Conlin Christopher C , Bagrodia Aditya , Barrett Tristan , Baxter Madison T , Do Deondre D , Hahn Michael E , Harisinghani Mukesh G , Javier-DesLoges Juan F , Kallis Karoline , Kane Christopher J , Kuperman Joshua M , Liss Michael A , Margolis Daniel JA , Murphy Paul M , Ohliger Michael , Ollison Courtney , Rakow-Penner Rebecca , Domingo Mariluz Rojo , Song Yuze , Wehrli Natasha , Woolen Sean , Seibert Tyler M , Dale Anders M
Published: March 2024

Background

Conventional distortion correction techniques include the Reversed Polarity Gradient (RPG) method and FSL-topup, which estimate tissue displacement from EPI images of opposite phase-encoding polarity, and scale image intensity by the Jacobian of the estimated displacement.

Purpose

To demonstrate that Jacobian intensity correction (JIC) can cause misleading improvement of EPI image distortion. We propose an alternative distortion correction approach (multi-bRPG; mRPG) that eliminates the JIC factor by normalizing opposite-polarity EPI images across multipleb-values.

Study type

Retrospective.

Population

163 prostate cancer patients without metallic implants.

Fieldstrength/Sequence

3T diffusion-weighted sequence with EPI readout, using multipleb-values.

Assessment

Maps of spatial shift (distortion) were estimated from opposite-polarity EPI volumes using RPG, topup, and mRPG. The estimated spatial shifts from each method were then applied to correct theb=0s/mm2images (both with and without JIC) and ADC maps (for which JIC is meaningless).

Distortion was quantified by the Pearson correlation between opposite-polarity volumes. The distribution of correlation coefficients across all patients was examined forb=0s/mm2images and ADC maps, before and after distortion correction by each method. The mean, median, and 10thpercentile were reported for each distribution.

Statistical tests

Wilcoxon signed-rank tests (α=0.05) were used to assess whether correlation increased significantly after distortion correction by each method, and whether mRPG yielded a larger increase versus RPG or topup.

Results

Median improvement in the correlation betweenb=0s/mm2volumes was significantly smaller without JIC (p<0.001): 0.04 vs 0.16 (RPG), 0.06 vs 0.18 (topup). mRPG yielded significantly larger improvements compared to RPG or topup (p<0.001).b=0s/mm2: 0.09 vs 0.04 (RPG) and 0.06 (topup). ADC: 0.09 vs 0.02 (RPG) and 0.03 (topup).

Data conclusion

Disparity in the distortion-correction performance of conventional methods with and without JIC suggests underestimation of tissue displacement. mRPG shows improved correction of distortion artifacts compared to conventional methods.
Trends of heart failure associated mortality in premenopausal women in the United states 1999-2020
Authors: Mannumbeth Renjithlal Sarath Lal , Magdi Mohamed Eid , Renjith Keerthi , Cordeiro Nikhil , Lever Hazel , Alexis Jeffrey , Thomas Sabu
Published: March 2024

Background

Heart Failure (HF)-related mortality has been showing an upward trend since 2012. In this study, we assessed nationwide trends in mortality related to HF among women and focused on women 15-55 years of age in the United States from 1999 to 2020.

Methods

Trends in mortality related to HF were assessed through a cross-sectional analysis of the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiological Research database. Age-adjusted mortality rates per 1,000,000 people and associated annual percent changes with 95% Confidence Intervals(CI) were determined. Joinpoint regression was used to assess the trends in the overall, demographic (sex, race and ethnicity, age), and regional groups.

Results

Between 1999 and 2020, 1,035,383 women died of heart failure. The age-adjusted mortality rate remained stable from 1999-2005, saw a reduction till 2012 and then an increase till 2020. Higher mortality rates were observed for Black patients, and patients ≥55 years of age. Large metropolitan counties had lesser mortality burden compared to rural counterparts. In 15-55 age group,18,875 women died due to heart failure.The discrepancy in mortality rates was even more pronounced between races in 15-55 age group.

Conclusions

Following an initial period of stability, HF-related mortality in women worsened from 2012 to 2020 in the United States. Black women had higher AAMR compared with White women, with a significant geographic variation. In the premenopausal group, black women had 4 times worse AAMR compared to their white counterparts. Focus towards preventative medicine, early diagnosis, and bridging the disparities, including socioeconomic, to promote healthcare equality should be upheld.
Analysis of gliomas DNA methylation: Assessment of pre-analytical variables
Authors: Bomsztyk Karol , Mar Daniel , Denisenko Oleg , Powell Suzanne , Vishnoi Monika , Delegard Jennifer , Patel Anoop , Ellenbogen Richard G , Ramakrishna Rohan , Rostomily Robert
Published: March 2024

Precision oncology is driven by molecular biomarkers. For glioblastoma multiforme (GBM), the most common malignant adult primary brain tumor, O6-methylguanine-DNA methyltransferase (MGMT) gene DNA promoter methylation is an important prognostic and treatment clinical biomarker. Time consuming pre-analytical steps such as biospecimen storage before fixing, sampling, and processing are major sources of errors and batch effects, that are further confounded by intra-tumor heterogeneity ofMGMTpromoter methylation. To assess the effect of pre-analytical variables on GBM DNA methylation, tissue storage/sampling (CryoGrid), sample preparation multi-sonicator (PIXUL) and 5-methylcytosine (5mC) DNA immunoprecipitation (Matrix MeDIP-qPCR/seq) platforms were used.MGMTpromoter CpG methylation was examined in 173 surgical samples from 90 individuals, 50 of these were used for intra-tumor heterogeneity studies.MGMTpromoter methylation levels in paired frozen and formalin fixed paraffin embedded (FFPE) samples were very close, confirming suitability of FFPE forMGMTpromoter methylation analysis in clinical settings. Matrix MeDIP-qPCR yielded similar results to methylation specific PCR (MS-PCR). Warm ex-vivo ischemia (37°C up to 4hrs) and 3 cycles of repeated sample thawing and freezing did not alter 5mC levels atMGMTpromoter, exon and upstream enhancer regions, demonstrating the resistance of DNA methylation to the most common variations in sample processing conditions that might be encountered in research and clinical settings. 20-30% of specimens exhibited intratumor heterogeneity in theMGMTDNA promoter methylation. Collectively these data demonstrate that variations in sample fixation, ischemia duration and temperature, and DNA methylation assay technique do not have significant impact on assessment ofMGMTpromoter methylation status. However, intratumor methylation heterogeneity underscores the need for histologic verification and value of multiple biopsies at different GBM geographic tumor sites in assessment ofMGMTpromoter methylation. Matrix-MeDIP-seq analysis revealed thatMGMTpromoter methylation status clustered with other differentially methylated genomic loci (e.g. HOXA and lncRNAs), that are likewise resilient to variation in above post-resection pre-analytical conditions. TheseMGMT-associated global DNA methylation patterns offer new opportunities to validate more granular data-based epigenetic GBM clinical biomarkers where the CryoGrid-PIXUL-Matrix toolbox could prove to be useful.
Cyanamide-inducible expression of homing nuclease I-SceI for iterative genome engineering and parallel promoter characterisation in Saccharomyces cerevisiae
Authors: McDonnell Liam , Evans Samuel , Lu Zeyu , Suchoronczak Mitch , Leighton Jonah , Ordeniza Eugene , Ritchie Blake , Valado Nik , Walsh Niamh , Antoney James Peter , Wang Chengqiang , Scott Colin , Speight Robert , Vickers Claudia , Peng Bingyin
Published: March 2024

In synthetic biology, microbial chasses including yeast Saccharomyces cerevisiae are iteratively engineered with increasing complexity and scale. Wet-lab genetic engineering tools are developed and optimised to facilitate strain construction but are often incompatible with each other due to shared regulatory elements, such as the galactose-inducible (GAL) promoter in S. cerevisiae. Here, we prototyped the cyanamide-induced I-SceI-mediated double-strand DNA breaks (DSBs) for selectable marker recycling in yeast metabolic engineering. We further combined cyanamide-induced I-SceI-mediated DSB and maltose-induced MazF-mediated negative selection for plasmid-free in situ promoter replacement, which simplified the molecular cloning procedure for promoter characterisation in S. cerevisiae. We then characterised three tetracycline-inducible promoters of differential strength, a non-leaky β-estradiol-inducible promoter, cyanamide-inducible DDI2 promoter, bidirectional MAL32/MAL31 promoters, and five pairs of bidirectional GAL1/GAL10 promoters. Overall, alternative regulatory controls for genome engineering tools are important for the construction of complexed genotypes in microbial systems for synthetic biology and metabolic engineering applications.
The art of seeing the elephant in the room: 2D embeddings of single-cell data do make sense
Authors: Lause Jan , Kobak Dmitry , Berens Philipp
Published: March 2024

A recent paper inPLOS Computational Biology(Chari and Pachter, 2023) claimed thatt-SNE and UMAP embeddings of single-cell datasets fail to capture true biological structure. The authors argued that such embeddings are as arbitrary and as misleading as forcing the data into an elephant shape. Here we show that this conclusion was based on inadequate and limited metrics of embedding quality. More appropriate metrics quantifying neighborhood and class preservation reveal the elephant in the room: whilet-SNE and UMAP embeddings of single-cell data do not preserve high-dimensional distances, they can nevertheless provide biologically relevant information.
Conserved Lysine in transmembrane helix 5 is key for the inner gating of the LAT transporter BasC
Authors: Fort Joana , Nicolàs-Aragó Adrià , Maggi Luca , Molledo Maria Martinez , Kapiki Despoina , Zijlstra Niels , Bodoy Susanna , Pardon Els , Steyaert Jan , Llorca Oscar , Orozco Modesto , Cordes Thorben , Palacín Manuel
Published: March 2024

L-amino acid transporters (LATs) play a key role in a wide range of physiological processes. Defects in LATs can lead to neurological disorders and aminoacidurias, while the overexpression of these transporters is related to cancer. BasC is a bacterial LAT transporter with an APC fold. In this study, to monitor the cytoplasmic motion of BasC, we developed a smFRET assay that can characterize the conformational states of the intracellular gate in solution at room temperature. Based on combined biochemical and biophysical data and molecular dynamics simulations, we propose a model in which the conserved lysine residue in TM5 supports TM1a to explore both open and closed states within the cytoplasmic gate under apo conditions. This equilibrium can be altered by substrates, mutation of conserved lysine 154 in TM5, or transport-blocking nanobodies. Overall, these findings provide insights into the transport mechanism of BasC and highlight the significance of the lysine residue in TM5 in the cytoplasmic gating of LATs.
Clinical-Grade Validation of an Autofluorescence Virtual Staining System with Human Experts and a Deep Learning System for Prostate Cancer
Authors: Wong Pok Fai , McNeil Carson , Wang Yang , Paparian Jack , Santori Charles , Gutierrez Michael , Homyk Andrew , Nagpal Kunal , Jaroensri Tiam , Wulczyn Ellery , Steiner David F. , Chen Po-Hsuan Cameron , Restorick Luke , Roy Jonathan , Cimermancic Peter
Published: March 2024

The tissue diagnosis of adenocarcinoma and intraductal carcinoma of the prostate (IDC-P) includes Gleason grading of tumor morphology on the hematoxylin and eosin (H&E) stain, and immunohistochemistry (IHC) markers on the PIN-4 stain (CK5/6, P63, AMACR). In this work, we create an automated system for producing both virtual H&E and PIN-4 IHC stains from unstained prostate tissue using a high-throughput multispectral fluorescence microscope and artificial intelligence & machine learning. We demonstrate that the virtual stainer models can produce high-quality images suitable for diagnosis by genitourinary pathologists. Specifically, we validate our system through extensive human review and computational analysis, using a previously-validated Gleason scoring model, and an expert panel, on a large dataset of test slides. This study extends our previous work on virtual staining from autofluorescence, demonstrates the clinical utility of this technology for prostate cancer, and exemplifies a rigorous standard of qualitative and quantitative evaluation for digital pathology.
Highlighting Educational Gaps in Hairstyling Practices amongst Dermatologists and Trainees
Authors: Araoye Erinolaoluwa F. , Jamerson Taylor A. , Yin Lu , Lo Sicco Kristen , Aguh Crystal
Published: March 2024

Background

Hairstyling practices are associated with the development and/or exacerbation of various forms of alopecia. Exposure to various hairstyling practices ranges but is often insufficient in current dermatologic textbooks and training curricula. We therefore conducted a survey to establish dermatologists understanding of hairstyling practices, particularly those that have been implicated in alopecia.

Methods

A 34-item anonymous, electronic survey was distributed by email to 291 board-certified dermatologists and dermatology residents across the US between August 2020 and February 2021. Responses were rated on a 10-point scale to identify physician confidence in various styling practices

Results

Black providers were more confident in both the knowledge and counseling of all hair practices (chemical straightening, heat styling, braiding, weaving, and wigs) compared to non-Black providers (p <0.001), with the exception of counseling patients on hair dyes for which no significant difference was found (p=0.337). Female providers were only more likely to indicate confidence in knowledge regarding different heat styling methods and hair dyes, and counseling of heat styling methods compared to male providers (OR 15.72, p<0.001; OR 2.47, p=0.022; OR 3.78, p=0.001 respectively) across all hair practices surveyed. Overall, 63.8% of providers reported that the majority of their knowledge on hair practices was from personal experience as opposed to formal training.

Limitations

This survey is limited by its response rate and the inability to characterize non-responders due to anonymity.

Conclusion

Our study highlights educational gaps in dermatologic training on hair practices, especially those more common among Black patients. Interestingly, the majority of provider knowledge came from personal experience rather than dermatologic training emphasizing the need for formalized curricula to enhance understanding among all dermatology providers.
An adaptive weight ensemble approach to forecast influenza activity in the context of irregular seasonality
Authors: Tsang Tim K. , Du Qiurui , Cowling Benjamin J. , Viboud Cécile
Published: March 2024

Forecasting of influenza activity in tropical and subtropical regions such as Hong Kong is challenging due to irregular seasonality with high variability in the onset of influenza epidemics, and potential summer activity. To overcome this challenge, we develop a diverse set of statistical, machine learning and deep learning approaches to forecast influenza activity in Hong Kong 0-to 8- week ahead, leveraging a unique multi-year surveillance record spanning 34 winter and summer epidemics from 1998-2019. We develop a simple average ensemble (SAE), which is the average of individual forecasts from the top three individual models. We also consider an adaptive weight blending ensemble (AWBE) that allows for dynamic updates of each model contribution based on LASSO regression and uses decaying weights in historical data to capture rapid change in influenza activity. Overall, across all 9 weeks of horizon, all models outperform the baseline constant incidence model, reducing the root mean square error (RMSE) by 23%-29% and weighted interval score (WIS) by 25%-31%. The SAE ensemble only slightly better than individual models, reducing RMSE and WIS by 29%. The AWBE ensemble reduce RMSE by 45% and WIS by 46%, and outperform individual models for forecasts of epidemic trends (growing, flat, descending), and during both winter and summer seasons. Using the post-COVID surveillance data in 2023-2024 as another test period, the AWBE ensemble still reduces RMSE by 32% and WIS by 36%. Our framework contributes to the ensemble forecasting of infectious diseases with irregular seasonality.

Significance statement

In subtropical and tropical regions, irregular influenza seasonality makes accurate forecasting challenging. We test ensemble approaches using diverse statistical, machine learning, and deep learning models based on a unique multi-year surveillance record in Hong Kong. Performance of individual models varies by season and epidemic trend, but simple averaging ensemble cannot improve accuracy. Here we develop an adaptive weight ensemble approach, which updated individual model contributions dynamically. This approach halves the RMSE, outperforms all individual models in different settings and reducing RMSE by one-third even in post-COVID periods. Our method contributes to comparison and benchmarking of models in ensemble forecasts, enhancing the evidence base for synthesizing multiple models in disease forecasting in geographies with irregular influenza seasonality.
MRI assessment of adipose tissue fatty acid composition in the UK Biobank and its association with diet and disease
Authors: Thanaj Marjola , Basty Nicolas , Whitcher Brandon , Bell Jimmy D , Thomas E Louise
Published: March 2024

Objectives

This study aimed to assess the fatty acid (FA) composition of abdominal subcutaneous (ASAT) and visceral (VAT) adipose tissue in the UK Biobank imaging cohort (N = 33,823) using magnetic resonance imaging (MRI).

Methods

We measured the fractions of saturated (fSFA), monounsaturated (fMUFA), and polyunsaturated (fPUFA) in ASAT and VAT from multi-echo MRI scans. We selected a sub-cohort that followed a vegan and an omnivore diet (N=36) to validate the effect of diet on adipose tissue. In the wider imaging cohort, we examined the relationship between adipose tissue FA composition and various traits related to disease and body size.

Results

We measured adipose tissue FA composition for over 33,000 participants, revealing higher fSFA and fPUFA and lower fMUFA in VAT (p < 0.00016). fMUFA and fPUFA were higher in ASAT and lower in VAT for women (p<0.00016). Vegans exhibited lower fSFA in both ASAT and VAT (p < 0.00016). VAT fSFA and fMUFA showed significant associations with disease as well as anthropometric variables.

Discussion

This extensive analysis revealed the relationships between adipose tissue FA composition and a range of factors in a diverse population, highlighting the importance of studying body adipose tissue beyond its quantity.

Study importance

What is already known?

The fatty acid (FA) composition of adipose tissue is an independent risk factor for hypertension, type-2 diabetes (T2D) and cardiovascular disease.

There has yet to be a large-scale population study of adipose tissue FA composition, principally due to the invasive nature of available methods.

What does the study add?

We show that MRI-based methods can be readily applied across a large population (n=33,823) while confirming and expanding on the associations between dietary patterns and FA composition in both abdominal subcutaneous (ASAT) and visceral (VAT) adipose tissue.

Models involving saturated and monounsaturated FA composition in VAT demonstrate significant association with disease outcomes, anthropometric variables, dietary macronutrient intake and physical activity.

How might these results change the direction of research or the focus of clinical practice?

Our findings highlight the importance of evaluating adipose tissue composition and its relationship with dietary and disease traits.

These insights will contribute to formulating more informed lifestyle recommendations to alleviate or even reverse metabolic conditions associated with obesity.
Depression, Brain Structure and Socioeconomic Status: A UK Biobank Study
Authors: Johns Sasha , Lea-Carnall Caroline , Shryane Nick , Maharani Asri
Published: March 2024

Background

Depression results from interactions between biological, social, and psychological factors. Literature shows that depression is associated with abnormal brain structure, and that socioeconomic status (SES) is associated with depression and brain structure. However, limited research considers the interaction between each of these factors.

Methods

Multivariate regression analysis was conducted using UK Biobank data on 39,995 participants to examine the relationship between depression and brain volume in 23 cortical regions for the whole sample and then separated by sex. It then examined whether SES affected this relationship.

Results

Eight out of 23 brain areas had significant negative associations with depression in the whole population. However, these relationships were diminished in seven areas when SES was included in the analysis. For females, three regions had significant negative associations with depression when SES was not included, but only one when it was. For males, lower volume in six regions was significantly associated with higher depression without SES, but this relationship was abolished in four regions when SES was included. The precentral gyrus was robustly associated with depression across all analyses.

Limitations

Participants with conditions that could affect the brain were not excluded. UK Biobank is not representative of the general population which may limit generalisability. SES was made up of education and income which were not considered separately.

Conclusions

SES affects the relationship between depression and cortical brain volume. Health practitioners and researchers should consider this when working with imaging data in these populations.
A structural mean modelling Mendelian randomization approach to investigate the lifecourse effect of adiposity: applied and methodological considerations
Authors: Power Grace M. , Palmer Tom , Warrington Nicole , Heron Jon , Richardson Tom G. , Didelez Vanesa , Tilling Kate , Davey Smith George , Sanderson Eleanor
Published: March 2024

The application of a lifecourse approach to genetic epidemiology is key to better understanding causal effects of adversities on health outcomes over time. For some time-varying phenotypes, it has been shown that genetic effects may have differential importance in the development of an exposure at different periods in the lifecourse. Mendelian randomization (MR) is a technique that uses genetic variation to address causal questions about how modifiable exposures influence health. MR studies often employ conventional instrumental variable (IV) methods designed to estimate lifelong effects. Recently, several extensions of MR have been used to investigate time-varying effects, including structural mean models (SMMs). SMMs exploit IVs through g-estimation and circumvent some of the parametric assumptions of other MR methods.

In this study, we apply g-estimation of SMMs to MR. We aim to estimate the period effects of adiposity measured at two different life stages on cardiovascular disease (CVD), type 2 diabetes (T2D) and breast cancer in later life. We found persistent period effects of higher adulthood adiposity on increased risk of CVD and T2D. Higher childhood adiposity had a protective period effect on breast cancer. We compare this method to an inverse variance weighted multivariable MR approach: a technique also using multiple IVs to assess time-varying effects, however, relying on a different set of assumptions and subsequent interpretations. We discuss the strengths and limitations of each approach and emphasise the importance of underlying methodological assumptions in the application of MR to lifecourse research questions.
An Interpretable Population Graph Network to Identify Rapid Progression of Alzheimer’s Disease Using UK Biobank
Authors: Meng Weimin , Inampudi Rohit , Zhang Xiang , Xu Jie , Huang Yu , Xie Mingyi , Bian Jiang , Yin Rui
Published: March 2024

Alzheimer’s disease (AD) manifests with varying progression rates across individuals, necessitating the understanding of their intricate patterns of cognition decline that could contribute to effective strategies for risk monitoring. In this study, we propose an innovative interpretable population graph network framework for identifying rapid progressors of AD by utilizing patient information from electronic health-related records in the UK Biobank. To achieve this, we first created a patient similarity graph, in which each AD patient is represented as a node; and an edge is established by patient clinical characteristics distance. We used graph neural networks (GNNs) to predict rapid progressors of AD and created a GNN Explainer with SHAP analysis for interpretability. The proposed model demonstrates superior predictive performance over the existing benchmark approaches. We also revealed several clinical features significantly associated with the prediction, which can be used to aid in effective interventions for the progression of AD patients.
CONTRAST SENSITIVITY IS IMPAIRED IN SUSPECTED PRIMARY OPEN-ANGLE GLAUCOMA PATIENTS
Authors: Tripolone María Constanza , Issolio Luis Alberto , Perez Daniel , Barrionuevo Pablo Alejandro
Published: March 2024

Purpose

To assess contrast sensitivity (CS) for detecting visual changes in suspected POAG patients.

Methods

CS was measured foveally at photopic conditions and peripherally at mesopic conditions using sinusoidal gratings of 4 cycles/degree. In experiment 1, foveal and peripheral CS were assessed in suspected POAG patients and age-matched healthy control subjects. In experiment 2, foveal CS was assessed in early POAG patients age-matched with suspected POAG group. Analysis was done considering two age ranges (Under and Over 50 years of age). Correlations between CS and clinical parameters were evaluated.

Results

Peripheral CS was decreased only for older POAG suspect patients from the control group (Over 50: p = 0.008. Under 50: p = 0.566). Foveal CS was reduced in POAG suspect participants for both age ranges (Over 50: p = 0.028. Under 50: p < 0.001) and in early POAG patients (Under 50: p = 0.001; Over 50: p < 0.001), both compared to the control group. Foveal CS was lower in early POAG compared to POAG suspect for older patients (Over 50: p = 0.019. Under 50: p = 0.824). Foveal CS was correlated with cup-disc ratio in early POAG patients (Early: p < 0.001. Suspect: p = 0.766) and with age in both patient groups (Early: p = 0.001. Suspect: p = 0.002).

Conclusion

CS is affected in patients with a high risk of developing POAG and recently diagnosed. Our results suggest that CS could serve as a screening tool, detecting early damage even before structural changes occur.
Solicited Cough Sound Analysis for Tuberculosis Triage Testing: The CODA TB DREAM Challenge Dataset
Authors: Huddart Sophie , Yadav Vijay , Sieberts Solveig K. , Omberg Larson , Raberahona Mihaja , Rakotoarivelo Rivo , Lyimo Issa N. , Lweno Omar , Christopher Devasahayam J , Viet Nhung Nguyen , Theron Grant , Worodria William , Yu Charles Y. , Bachman Christine M , Burkot Stephen , Dewan Puneet , Kulhare Sourabh , Small Peter M , Cattamanchi Adithya , Jaganath Devan , Grandjean Lapierre Simon
Published: March 2024

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.
Protocol: Trust Your Gut: An Analysis of Dermatologic Diagnostic Accuracy
Authors: Jolley Dana , Korman Abraham M.
Published: March 2024

Background

The current clinical misdiagnosis rate among all medical specialties is approximately 10-15%, but diagnostic error within the field of dermatology has not been studied thoroughly1,2. As a field that relies heavily on visual perception, many physicians consider clinical intuition to be advantageous in diagnosing skin diseases and consider it to be a rapid and unconscious phenomenon7. Therefore, too much contemplation may lead to more incorrect diagnoses4. However, while clinical intuition is a valuable clinical tool, it is widely considered to be developed throughout medical training and only successfully employed by experienced attending physicians, perhaps due to experiential knowledge and associated confidence1,2,5. One may expect that self-reported confidence in diagnosis would correlate with diagnostic accuracy, but this is not supported in the literature9. The focus of our study is to examine the development and reliability of clinical intuition as well as associated self-reported confidence levels in diagnoses at different levels of medical training among dermatologists.

Methods

Approximately 20 dermatologists who are PGY-2 or higher will be recruited for study participation via email. Participants will be sent a Qualtrics survey at two separate time points with a month waiting period in between. The survey will contain demographics questions, photos of 10 different dermatologic conditions for dermatologists to diagnose, and a self-reported confidence level for each diagnosis. The first survey will allow 5 seconds to evaluate a clinical photo prior to diagnosis, and this timeframe will be extended to 15 seconds in the second survey. The second survey will contain the same diagnoses, but with different pictures to avoid recall of specific photos. Following completion of all surveys, descriptive statistics will be completed with goal of publication.

Discussion

This study has the potential to provide invaluable information regarding the development of clinical intuition among dermatologic physicians while also examining their confidence levels and likelihood of changing correct diagnoses when given more time to ruminate. It is possible that physicians are more likely to second guess original diagnoses based off of certain demographic factors, as one systematic review found that women in medicine perceive their clinical performance as deficient more often than men10. Therefore, this study may give insight to the ways that complicated societal factors contribute to clinical decision making. Data from this study may be used to aid dermatologists in understanding their thought processes when diagnosing patients, and may be useful in developing education curriculum. The protocol will hopefully serve as a blueprint for creation of studies in a multitude of fields, ultimately leading to better understanding of clinical decision making and, thus, improved patient care.
Sulfated N-glycans Upregulation in Sera Predicts Early-Stage Breast Cancer in Patients
Authors: Feleke Dereje G. , Montalban Bryan M. , Gizaw Solomon T. , Hinou Hiroshi
Published: March 2024

Alterations in sulfated glycans are associated with several pathological conditions, including cancer. However, analysis of sulfated glycans poses challenges, making the investigation of sulfated glycan profiles a topic of significant interest in the search for novel biomarkers for early BC detection. We used a glycoblotting-based sulphoglycomics workflow to examine sulfated N-glycans present in the serum of Ethiopian patients with BC. Seven mono-sulfated glycans were significantly upregulated in the sera of BC patients compared to the control group. Each identified glycan showed significant abundance with AUC ≥ 0.8 and demonstrated high diagnostic accuracy in predicting early stage BC patients. Importantly, the sulfated glycans were analyzed without removing the sialic group, allowing for comprehensive evaluation of the sialylation status of the identified sulfated glycans. This study represents the first quantitative analysis of sulfated N-glycans in patients with BC and identifies novel biomarkers with discriminatory potential in the early stages of BC.

Statement of significance

This study presents a quantitative analysis of sulfated N-glycans in BC, aiming to identify novel glyco-biomarkers that demonstrate high diagnostic accuracy for early stage BC. Analyzing sulfated glycans without removing sialic acids offers comprehensive insights. These findings advance the understanding of BC, potentially enhance early detection, and improve patient outcomes.
Development and Organization of the Retinal Orientation Selectivity Map
Authors: Vita Dominic J. , Orsi Fernanda S. , Stanko Nathan G. , Clark Natalie A. , Tiriac Alexandre
Published: March 2024

Orientation or axial selectivity, the property of neurons in the visual system to respond preferentially to certain angles of a visual stimuli, plays a pivotal role in our understanding of visual perception and information processing. This computation is performed as early as the retina, and although much work has established the cellular mechanisms of retinal orientation selectivity, how this computation is organized across the retina is unknown. Using a large dataset collected across the mouse retina, we demonstrate functional organization rules of retinal orientation selectivity. First, we identify three major functional classes of retinal cells that are orientation selective and match previous descriptions. Second, we show that one orientation is predominantly represented in the retina and that this predominant orientation changes as a function of retinal location. Third, we demonstrate that neural activity plays little role on the organization of retinal orientation selectivity. Lastly, we usein silicomodeling followed by validation experiments to demonstrate that the overrepresented orientation aligns along concentric axes. These results demonstrate that, similar to direction selectivity, orientation selectivity is organized in a functional map as early as the retina.

One Sentence Summary

Development and organization of retinal orientation selectivity
Loss of LasR function leads to decreased repression ofPseudomonas aeruginosaPhoB activity at physiological phosphate concentrations
Authors: Conaway Amy , Todorovic Igor , Mould Dallas L. , Hogan Deborah A.
Published: March 2024

While thePseudomonas aeruginosaLasR transcription factor plays a role in quorum sensing (QS) across phylogenetically-distinct lineages, isolates with loss-of-function mutations inlasR(LasR– strains) are commonly found in diverse settings including infections where they are associated with worse clinical outcomes. In LasR– strains, the transcription factor RhlR, which is controlled by LasR, can be alternately activated in low inorganic phosphate (Pi) concentrations via the two-component system PhoR-PhoB. Here, we demonstrate a new link between LasR and PhoB in which the absence of LasR increases PhoB activity at physiological Pi concentrations and raises the Pi concentration necessary for PhoB inhibition. PhoB activity was also less repressed by Pi in mutants lacking different QS regulators (RhlR and PqsR) and in mutants lacking genes required for the production of QS-regulated phenazines suggesting that decreased phenazine production was one reason for decreased PhoB repression by Pi in LasR– strains. In addition, the CbrA-CbrB two-component system, which is elevated in LasR– strains, was necessary for reduced PhoB repression by Pi and a Δcrcmutant, which lacks the CbrA-CbrB-controlled translational repressor, activated PhoB at higher Pi concentrations than the wild type. The ΔlasRmutant had a PhoB-dependent growth advantage in a medium with no added Pi and increased virulence-determinant gene expression in a medium with physiological Pi, in part through reactivation of QS. This work suggests PhoB activity may contribute to the virulence of LasR–P. aeruginosaand subsequent clinical outcomes.

Importance

Loss-of-function mutations in the gene encoding thePseudomonas aeruginosaquorum sensing (QS) regulator LasR occur frequently and are associated with worse clinical outcomes. We have found that LasR–P. aeruginosahave elevated PhoB activity at physiological concentrations of inorganic phosphate (Pi). PhoB activity promotes Pi acquisition as well as the expression of QS and virulence-associated genes. Previous work has shown that PhoB induce RhlR, another QS regulator, in a LasR-mutant in low Pi conditions. Here, we demonstrate a novel relationship wherein LasR represses PhoB activity, in part through the production of phenazines and Crc-mediated translational repression. This work suggests PhoB activity may contribute to the increased virulence of LasR–P. aeruginosa.
The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication
Authors: Baker Paul J. , Bohrer Andrea C. , Castro Ehydel , Amaral Eduardo P. , Snow-Smith Maryonne , Torres-Juárez Flor , Gould Sydnee T. , Queiroz Artur T. L. , Fukutani Eduardo R. , Jordan Cassandra M. , Khillan Jaspal S. , Cho Kyoungin , Barber Daniel L. , Andrade Bruno B. , Johnson Reed F. , Hilligan Kerry L. , Mayer-Barber Katrin D.
Published: March 2024

SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. We demonstrate here that immune events in the mouse lung closely preceding SARS-CoV-2 infection significantly impact viral control and we identify key innate immune pathways required to limit viral replication. A diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections withS. aureusor influenza, ongoing pulmonaryM. tuberculosisinfection, ovalbumin/alum-induced asthma or airway administration of defined TLR ligands and recombinant cytokines, all establish an antiviral state in the lung that restricts SARS-CoV-2 replication upon infection. In addition to antiviral type I interferons, the broadly inducible inflammatory cytokines TNFα and IL-1 precondition the lung for enhanced viral control. Collectively, our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation that precedes or accompanies SARS-CoV-2 exposure may be a significant factor contributing to the population-wide variability in COVID-19 disease outcomes.