bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal Fiber Intake and Perinatal Depression & Anxiety
Authors: Ebrahimi Neda , Tuner Tiffany , Gallant Faith , Chandrakumar Abinaa , Kohli Roshni , Lester Rebecca , Forte Victoria , Cooley Kieran
Published: March 2024

Background

Dietary fiber can significantly alter gut microbiota composition. The role of gut microbiome in the Gut-Brain Axis and modulation of neuropsychiatric disease is increasingly recognized. The role of antenatal diet, particularly fiber intake, in mitigating maternal mental health disorders remains unexplored. The objective of this review is to investigate the association between maternal fiber intake and perinatal depression and anxiety (PDA).

Methods

A literature review of PubMed and Google Scholar was conducted using appropriate keyword/MeSH terms for pregnancy, diet, fiber, and mental health. Observational and clinical trials published between 2015-2021 were included and data pertaining to dietary patterns (DP), food intake, mental health, and demographic data were extracted. The top three fiber-containing food groups (FG) per study were identified using a sum rank scoring system of fiber per 100 grams and fiber per serving size. The consumption of these top three fiber FGs was then ranked for each dietary pattern/group. Mental health outcomes for each study were simplified into three categories of improved, no change, and worsened. The relationship between top three fiber FGs consumed within each DP and mental health outcomes was analyzed using Spearman’s correlation.

Results

Thirteen of 52 studies met inclusion criteria. Ten (76.9%) studies assessed DPs (7 examined depression only, 2 examined depression and anxiety, and 1 examined anxiety only). Seven (53.9%) studies reported at least one significant positive relationship between mental health outcomes and DPs while 3 reported at least one negative outcome. Three (23.1%) studies compared intake of different food groups between depressed and non-depressed groups. In studies of DPs, the average consumption ranking of the top 3 fiber FGs, bore a significant inverse association with mental health outcomes [r=-0.419(95%CI: – 0.672—0.078)] p=0.015. In studies comparing intake of different FGs between depressed and non-depressed groups, consumption of top-ranking fiber foods was higher in the non-depressed groups, but significantly higher in 4 of the 10 high fiber FGs.

Conclusion

This study reframes findings from previously published studies of maternal diet and mental health outcomes to focus on fiber intake specifically, using a fiber ranking system. A significant correlation between lower intake of fiber and poorer mental health outcomes warrants further investigation in future studies.
The Burden of Cancer and Pre-cancerous Conditions Among Transgender Individuals in a Large Healthcare Network
Authors: Yang Shuang , Li Yongqiu , Wheldon Christopher W. , Prosperi Mattia , George Thomas J. , Shenkman Elizabeth A. , Wang Fei , Bian Jiang , Guo Yi
Published: March 2024

The current study aimed to examine the prevalence of and risk factors for cancer and pre-cancerous conditions, comparing transgender and cisgender individuals, using 2012-2023 electronic health record data from a large healthcare system. We identified 2,745 transgender individuals using a previously validated computable phenotype and 54,900 matched cisgender individuals. We calculated the prevalence of cancer and pre-cancer related to human papillomavirus (HPV), human immunodeficiency virus (HIV), tobacco, alcohol, lung, breast, colorectum, and built multivariable logistic models to examine the association between gender identity and the presence of cancer or pre-cancer. Results indicated similar odds of developing cancer across gender identities, but transgender individuals exhibited significantly higher risks for pre-cancerous conditions, including alcohol-related, breast, and colorectal pre-cancers compared to cisgender women, and HPV-related, tobacco-related, alcohol-related, and colorectal pre-cancers compared to cisgender men. These findings underscore the need for tailored interventions and policies addressing cancer health disparities affecting the transgender population.
Accounting for bias due to outcome data missing not at random: comparison and illustration of two approaches to probabilistic bias analysis: a simulation study
Authors: Kawabata Emily , Major-Smith Daniel , Clayton Gemma L , Shapland Chin Yang , Morris Tim P , Carter Alice R , Fernández-Sanlés Alba , Borges Maria Carolina , Tilling Kate , Griffith Gareth J , Millard Louise AC , Smith George Davey , Lawlor Deborah A , Hughes Rachael A
Published: March 2024

Background

Bias from data missing not at random (MNAR) is a persistent concern in health-related research. A bias analysis quantitatively assesses how conclusions change under different assumptions about missingness using bias parameters which govern the magnitude and direction of the bias. Probabilistic bias analysis specifies a prior distribution for these parameters, explicitly incorporating available information and uncertainty about their true values. A Bayesian approach combines the prior distribution with the data’s likelihood function whilst a Monte Carlo approach samples the bias parameters directly from the prior distribution. No study has compared a Monte Carlo approach to a fully Bayesian approach in the context of a bias analysis to MNAR missingness.

Methods

We propose an accessible Monte Carlo probabilistic bias analysis which uses a well-known imputation method. We designed a simulation study based on a motivating example from the UK Biobank study, where a large proportion of the outcome was missing and missingness was suspected to be MNAR. We compared the performance of our Monte Carlo probabilistic bias analysis to a principled Bayesian probabilistic bias analysis, complete case analysis (CCA) and missing at random implementations of inverse probability weighting (IPW) and multiple imputation (MI).

Results

Estimates of CCA, IPW and MI were substantially biased, with 95% confidence interval coverages of 7–64%. Including auxiliary variables (i.e., variables not included in the substantive analysis which are predictive of missingness and the missing data) in MI’s imputation model amplified the bias due to assuming missing at random. With reasonably accurate and precise information about the bias parameter, the Monte Carlo probabilistic bias analysis performed as well as the fully Bayesian approach. However, when very limited information was provided about the bias parameter, only the Bayesian approach was able to eliminate most of the bias due to MNAR whilst the Monte Carlo approach performed no better than the CCA, IPW and MI.

Conclusion

Our proposed Monte Carlo probabilistic bias analysis approach is easy to implement in standard software and is a viable alternative to a Bayesian approach. We caution careful consideration of choice of auxiliary variables when applying imputation where data may be MNAR.
Glycosylation state of vWF in circulating extracellular vesicles serves as a novel biomarker for predicting depression
Authors: Yamada Norihiro , Tominaga Kana , Tominaga Naoomi , Kobayashi Ayumi , Niino Chihiro , Miyagi Yuta , Yamagata Hirotaka , Nakagawa Shin
Published: March 2024

The clinical diagnosis of major depressive disorder (MDD), a heterogeneous disorder, still depends on subjective information in terms of various symptoms regarding mood. Detecting extracellular vesicles (EVs) in blood may result in finding a diagnostic biomarker that reflects the depressive stage of patients with MDD. Here, we report the results on the glycosylation pattern of enriched plasma EVs from patients with MDD and age-matched healthy subjects. In this cohort, the levels ofTriticum vulgaris(wheat germ) agglutinin (WGA),N-acetyl glucosamine (GlcNAc) andN-acetylneuraminic acid (Neu5Ac, sialic acid) - binding lectin, were significantly decreased in patients with MDD in depressive state compared to healthy subjects (area under the curve (AUC): 0.87 (95% confidence interval (CI) 0.76 - 0.97)) and in remission state (AUC: 0.88 (95% CI 0.72 - 1.00)). Furthermore, proteome analysis revealed that the von Willebrand factor (vWF) was a significant factor recognized by WGA. WGA-binding vWF antigen differentiated patients with MDD versus healthy subjects (AUC: 0.92 (95% CI 0.82 - 1.00)) and the same patients with MDD in depressive versus remission state (AUC: 0.98 (95% CI 0.93 - 1.00)). In this study, the change patterns in the glycoproteins contained in plasma EVs support the usability of testing to identify patients who are at increased risk of depression during antidepressant treatment.
Evaluation of smartphone-based cough data in amyotrophic lateral sclerosis as a potential predictor of functional disability
Authors: Santos-Rocha Pedro , Bento Nuno , Folgado Duarte , Carreiro André Valério , Santos Miguel Oliveira , de Carvalho Mamede , Miranda Bruno
Published: March 2024

Objectives

Cough dysfunction is a feature of patients with amyotrophic lateral sclerosis (ALS). The cough sounds carry information about the respiratory system and bulbar involvement. Our goal was to explore the association between cough sound characteristics and the respiratory and bulbar functions in ALS.

Methods

This was a single-center, cross-sectional, and case-control study. On-demand coughs from ALS patients and healthy controls were collected with a smartphone. A total of 31 sound features were extracted for each cough recording using time-frequency signal processing analysis. Logistic regression was applied to test the differences between patients and controls, and in patients with bulbar and respiratory impairment. Support vector machines (SVM) were employed to estimate the accuracy of classifying between patients and controls and between patients with bulbar and respiratory impairment. Multiple linear regressions were applied to examine correlations between cough sound features and clinical variables.

Results

Sixty ALS patients (28 with bulbar dysfunction, and 25 with respiratory dysfunction) and forty age- and gender-matched controls were recruited. Our results revealed clear differences between patients and controls, particularly within the frequency-related group of features (AUC 0.85, CI 0.79- 0.91). Similar results were observed when comparing patients with and without bulbar dysfunction; and with and without respiratory dysfunction. Sound features related to intensity displayed the strongest correlation with disease severity.

Discussion

We found a good relationship between specific cough sound features and clinical variables related to ALS functional disability. The findings relate well with some expected impact from ALS on both respiratory and bulbar contributions to the physiology of cough. Finally, our approach could be relevant for clinical practice, and it also facilitates home-based data collection.
Health outcome priorities of people with multiple long-term conditions before and during the COVID-19 pandemic: Survey data from the UK
Authors: Sathanapally Harini , Chudasama Yogini V , Zaccardi Francesco , Rizzi Alessandro , Seidu Samuel , Khunti Kamlesh
Published: March 2024

Background

The outcome prioritisation tool (OPT) is a simple tool to ascertain the health outcome priorities of people with MLTC. Use of this tool in people aged under 65 years with MLTC has not previously been investigated. This study investigated the feasibility of using the OPT in people with MLTC aged 45 years or above, in a multi-ethnic primary-care setting, to describe the health outcome priorities of people with MLTC by age, clusters of long-term conditions and demographic factors, and to investigate any differences in prioritisation in light of the COVID-19 pandemic.

Methods

This was a multi-centre cross-sectional study using a questionnaire for online self-completion by people aged 45 years or above with MLTC in 19 primary care settings across the East Midlands, UK. Participants were asked to complete the OPT twice, first from their current perspective and second from their recollection of their priorities prior to COVID-19.

Results

The questionnaire was completed by 2,454 people with MLTC. The majority of participants agreed or strongly agreed that the OPT was easy to complete, relevant to their healthcare and will be useful in communicating priorities to their doctor. Summary scores for the whole cohort of participants showed Keeping Alive and Maintaining Independence receiving the highest scores. Statistically significant differences in prioritisation by age, clusters of long-term conditions and employment status were observed, with respondents aged over 65 most likely to prioritise Maintaining independence, and respondents aged under 65 most likely to prioritise Keeping alive. There were no differences before or after COVID-19, or by ethnicity.

Conclusions

The OPT is feasible and acceptable for use to elicit the health outcome priorities of people with MLTC across both middle-aged and older age groups and in a UK setting. Individual factors could influence the priorities of people with MLTC and must be considered by clinicians during consultations.

HIGHLIGHTS

Survey data from 2,454 patients with MLTC showed that keeping alive and maintaining independence were the top first-choice priorities from the health outcome priorities tool (OPT).

The health outcomes priorities differed by socio-demographics and clusters of long-term conditions.

There were no differences in health outcomes priorities before and during COVID-19.

OPT is easy and acceptable to implement in a health care setting in a broad patient group.

Translation of the OPT into different languages is recommended to address any potential language barrier for people with MLTC completing the OPT
The repercussions of timing in the invasion of synthetic bacterial communities
Authors: Dooley Keven D. , Bergelson Joy
Published: March 2024

Microbial communities regularly experience ecological invasions that can lead to changes in composition and function. Factors thought to affect the outcome of invasions, like diversity and resource use, vary over the course of community assembly, potentially altering susceptibility to arriving invaders. We used synthetic bacterial communities to evaluate the success and impact of invasions occurring at different times during the community assembly process. Fifteen distinct communities were subjected to each of three bacterial invaders at the initial assembly of the community (“initial”), 24 hours into community assembly (“early”), when the community was still undergoing transient dynamics, and 7 days into community assembly (“late”), once the community had settled into its final composition. Communities were passaged daily and characterized through sequencing after reaching a stable composition. Invasions were most successful and had their largest effect on composition when they occurred before a community had settled into a stable composition. Surprisingly, we found instances where an invader was ultimately excluded yet had profound and long-lasting effects on invaded communities. We also found that common community members were more greatly impacted by invaders than rare community members. Higher invasion success and impact were associated with lower community resource use efficiency, which varied throughout assembly. Our results demonstrate that microbial communities experiencing transient community dynamics are more prone to invasion, a finding relevant to efforts to modify the composition of microbial communities.
Adult expression of the cell adhesion protein Fasciclin 3 is required for the maintenance of adult olfactory interneurons
Authors: Chithran Aarya Vaikakkara , Allan Douglas W. , O’Connor Timothy P.
Published: March 2024

The proper functioning of the nervous system is dependent on the establishment and maintenance of intricate networks of neurons that form functional neural circuits. Once neural circuits are assembled during development, a distinct set of molecular programs is likely required to maintain their connectivity throughout the lifetime of the organism. Here, we demonstrate that Fasciclin 3 (Fas3), an axon guidance cell adhesion protein, is necessary for the maintenance of the olfactory circuit in adultDrosophila. We utilized the TARGET system to spatiotemporally knockdownFas3in selected populations of adult neurons. Our findings show thatFas3knockdown results in the death of olfactory circuit neurons and reduced survival of adults. We also demonstrated thatFas3knockdown activates caspase-3 mediated cell death in olfactory local interneurons, which can be rescued by overexpressing p35, an anti-apoptotic protein. This work adds to the growing set of evidence indicating a critical role for axon guidance proteins in the maintenance of neuronal circuits in adults.

SUMMARY STATEMENT

Little is known about the maintenance of adult neural circuits. We show that the continuous expression of Fasciclin 3, a cell adhesion protein involved in axon guidance, is required for neuronal survival in the adult olfactory circuit.
Molecular basis for the assembly of the Vps5-Vps17 SNX-BAR proteins with Retromer
Authors: Chen Kai-En , Tillu Vikas A. , Gopaldass Navin , Chowdhury Sudeshna Roy , Leneva Natalya , Kovtun Oleksiy , Ruan Juanfang , Guo Qian , Ariotti Nicholas , Mayer Andreas , Collins Brett M.
Published: March 2024

Retromer mediates endosomal retrieval of transmembrane proteins in all eukaryotes and was first discovered in yeast in complex with the Vps5 and Vps17 sorting nexins (SNXs). Cryoelectron tomography (cryoET) studies of Retromer–Vps5 revealed a pseudo-helical coat on membrane tubules where dimers of the Vps26 subunit bind Vps5 membrane-proximal domains. However, the Vps29 subunit is also required for Vps5–Vps17 association despite being far from the membrane. Here, we show that Vps5 binds both Vps29 and Vps35 subunits through its unstructured N-terminal domain. A Pro-Leu (PL) motif in Vps5 binds Vps29 and is required for association with Retromer on membrane tubulesin vitro, and for the proper recycling of the Vps10 cargo inSaccharomyces cerevisiae. CryoET of Retromer tubules with Vps5–Vps17 heterodimers show a similar architecture to the coat with Vps5–Vps5 homodimers, however, the spatial relationship between Retromer units is highly restricted, likely due to more limited orientations for docking. These results provide new mechanistic insights into how Retromer and SNX-BAR association has evolved across species.
Transforming spontaneous premature neonatal EEG to unpaired spontaneous fetal MEG using a CycleGan learning approach
Authors: Gallard Alban , Brebion Benoit , Sippel Katrin , Zaylaa Amer , Preissl Hubert , Moghimi Sahar , Fregier Yael , Wallois Fabrice
Published: March 2024

A large body of electroencephalography (EEG) studies has characterized the spontaneous neural activity of premature neonates at different gestational ages. However, evaluation of normal and pathological fetal brain development is still a challenge due to the complexity of the extraction and analysis of fetal neural activity. Fetal magnetoencephalography (fMEG) is currently the only available technique to record fetal neural activity with a time resolution equivalent to that of EEG. However, the signatures and characteristics of fetal spontaneous neural activity are still largely unknown. Benefiting from progress in machine learning and artificial intelligence, we aimed to transfer premature EEG to fMEG, to characterize the manifestation of spontaneous activity using the knowledge obtained from premature EEG.

In this study, 30 high-resolution EEG recordings from premature newborns and 44 fMEG recordings, both from 34 to 37 weeks of gestation (wGA) were used to develop a transfer function to predict the spontaneous neural activity of the fetus. After preprocessing, bursts of spontaneous activity were detected using the non-linear energy operator over both EEG and fMEG signals. Next, we proposed a CycleGAN-based model to transform the premature EEG to fMEG and vice versa and evaluated its performance with both time and frequency measurements on both forward and inverse conversions.

In the time domain, the values were similar for the mean square error (< 5%) and correlation (0.91 ± 0.05 and 0.89 ± 0.08) for the EEG to fMEG and fMEG to EEG transformations between the original data and that generated by CycleGAN. However, considering the frequency content, the CycleGAN-based model modulated the frequency content of EEG to MEG transformed signals relative to the original signals by increasing the power, on average, in all frequency bands, except for the slow delta frequency band. Our developed model showed promising potential to generate a priori signatures of fMEG manifestations related to spontaneous neural activity. Collectively, this study represents the first steps toward identifying neurobiomarkers of fetal brain development.
A Set of Diagnostic Tests for Detection of ActiveBabesia duncaniInfection
Authors: Chand Meenal , Vydyam Pratap , Pal Anasuya C. , Thekkiniath Jose , Darif Dounia , Li Zeng , Choi Jae-Yeon , Magni Ruben , Luchini Alessandra , Tonnetti Laura , Horn Elizabeth J , Tufts Danielle M , Ben Mamoun Choukri
Published: March 2024

Human babesiosis is a rapidly emerging and potentially fatal tick-borne disease caused by intraerythrocytic apicomplexan parasites of theBabesiagenus. Among the various species ofBabesiathat infect humans,B. duncanihas been found to cause severe and life-threatening infections. Detection of activeB. duncaniinfection is critical for accurate diagnosis and effective management of the disease. While molecular assays for the detection ofB. duncaniinfection in blood are available, a reliable strategy to detect biomarkers of active infection has not yet been developed. Here, we report the development of the firstB. duncaniantigen capture assays that rely on the detection of twoB. duncani-exported immunodominant antigens, BdV234 and BdV38. The assays were validated using blood samples from cultured parasites in human erythrocytes andB. duncani-infected laboratory mice at different parasitemia levels and following therapy. The assays display high specificity with no cross-reactivity withB. microti,B. divergens,BabesiaMO1, orP. falciparum.The assay also demonstrates high sensitivity, detecting as low as 115 infected erythrocytes/µl of blood. Screening of 1,731 blood samples from diverse biorepositories, including previously identified Lyme and/orB. microtipositive human samples and new specimens from field mice, showed no evidence ofB. duncaniinfection in these samples. The assays could be useful in diverse diagnostic scenarios, including point-of-care testing for earlyB. duncaniinfection detection in patients, field tests for screening reservoir hosts, and high-throughput screening such as blood collected for transfusion.

Short summary

We developed two ELISA-based assays, BdACA38 and BdACA234, for detectingB. duncani, a potentially fatal tick-borne parasite causing human babesiosis. The assays target two immunodominant antigens, BdV234 and BdV38, demonstrating high specificity (no cross-reactivity with otherBabesiaspecies orPlasmodium falciparum) and sensitivity (detecting as low as 115 infected erythrocytes/µl). The assays were validated using in vitro-cultured parasites and infected mice. Screening diverse blood samples showed no evidence ofB. duncaniactive infection among 1,731 human and field mice blood samples collected from the north-eastern, midwestern, and western US. These assays offer potential in diverse diagnostic scenarios, including early patient detection, reservoir animal screening, and transfusion-transmitted babesiosis prevention.
Similar effect of lidocaine and saline on ciliary beating of nasal epithelial cells in vitro
Authors: Savas Sibel T , Tschanz Stefan A , Latzin Philipp , Casaulta Carmen , Müller Loretta
Published: March 2024

Rationale

Primary ciliary dyskinesia is a rare genetic disease affecting ciliary motility and causing respiratory symptoms. Diagnosis can be done by high-speed- videomicroscopy using nasal epithelial cells (NECs) obtained via brushings. This procedure can be painful, especially for children. The use of lidocaine is proposed to reduce this pain; however, it is not clear whether lidocaine changes ciliary beating frequency (CBF) or pattern (CBP) in the subsequent high-speed-videomicroscopy.

Objective

The aim of this study was to analyse the effect of lidocaine on the CBF and the CBP of differentiated, air-liquid-interface cultured NECs.

Methods

NECs from healthy volunteers were obtained via brushings and cultured at the air-liquid-interface. After differentiation, lidocaine or isotonic saline (IS, control) were added apically for 1 or 5 min each and CBF (in top view of whole inserts and side views of scratched cells) and CBP (only side view) were assessed and recorded up to 150 min. CBF was computed and CBP was analysed semiquantitatively.

Results

Lidocaine as well as IS increased the CBF in the top view approach significantly compared to baseline. However, we found no significant differences between lidocaine and IS (control) treatment. Additionally, no effect of lidocaine on CBF, CBP, amplitude, inter- and intracellular coordination or transport was seen in the side view approach.
Differences in COVID-19 Vaccination and Experiences among Patients with Hypertension in Colombia and Jamaica during the COVID-19 Pandemic
Authors: Duncan Jacqueline P , Geng Siyi , Lindsay Carene , Ferguson Trevor , Mills Katherine , Lopez-Lopez Jose Patricio , He Hua , Lanza Paola , Williams Makeda , Tutse-Tonwe Veronica , Reyes Mabel , Campo Alfonso , Marshall Allison , Lopez-Jaramillo Patricio , Tulloch-Reid Marshall K
Published: March 2024

Background

COVID-19 vaccination and shielding targeted hypertensive patients in low and middle income countries. We describe the COVID-19 experiences of hypertensive patients in Colombia and Jamaica and discuss factors associated with vaccine acceptance.

Methods

A cross-sectional study was conducted between December 2021 and February 2022 in 4 randomly selected primary care clinics in Colombia and 10 primary care clinics in Jamaica. Participants in Colombia were randomly selected from an electronic medical record. In Jamaica consecutive participants were selected on clinic days for non-communicable diseases. Interviewer-administered questionnaires were conducted by telephone.

Results

576 participants were recruited (50% Jamaica; 68.5% female). Jamaica’s participants were younger (36% vs 23% <60 years) and had a lower proportion of persons with “more than high school” education (17.2% vs 30.3%, p=0.011). Colombia’s participants more commonly tested positive for COVID-19 (24.2% vs 6.3%, p<0.001), had a family member or close friend test positive for COVID-19 (54.5% vs, 21.6%; p<0.001), experienced loss of a family member or friend due to COVID-19 (21.5% vs 7.8%, p<0.001) and had vaccination against COVID-19 (90.6% vs 46.7%, p<0.001). Fear of COVID-19 (AOR 2.71, 95% CI 1.20-6.13) and residence in Colombia (AOR 5.88 (95% CI 2.38-14.56) were associated with COVID-19 vaccination. Disruption in health services affecting prescription of medication or access to doctors was low (<10%) for both countries.

Conclusion

Health services disruption was low but COVID-19 experiences such as fear of COVID-19 and vaccine acceptance differed significantly between Colombia and Jamaica. Addressing reasons for these differences are important for future pandemic responses.
Biomarker potential of vitreous microRNA in retinal disease: a meta-analysis
Authors: Joseph Diana , Grover Brian , Telias Michael
Published: March 2024

Background

Acquired retinal diseases such as proliferative diabetic retinopathy and age-related macular degeneration pose significant challenges in diagnosis and prognosis. The vitreous fluid, situated in the posterior chamber of the eye behind the lens, holds a close relationship with the inner retina. Within this milieu, retinal cells secrete a diverse array of biomolecules, potentially harboring vital biomarkers. Among these, short, non-coding micro-RNAs (miRNAs) emerge as promising candidates. Their dynamic regulation by various gene signaling mechanisms, enhanced resistance to degradation, and secretion via separate exocytotic pathways make them particularly significant. Alterations in vitreal miRNA profiles may reflect pathological states and offer insights into disease etiology and progression.

We conducted a comprehensive meta-analysis of 22 peer-reviewed studies to assess the potential of vitreous miRNAs as biomarkers for retinal diseases. Our analysis demonstrates the potential utility of miRNAs as biomarkers in specific retinal pathologies. We show that miR-142, miR-9, and miR-21 emerge as robust biomarker candidates, displaying consistent and significant alterations correlating with proliferative vitreoretinal diseases. We also address the methodological challenges encountered in characterizing vitreous miRNA content, including the absence of standardized purification, amplification, and analysis protocols, as well as the scarcity of true control samples. Moreover, we make the case for the adoption of specific housekeeping genes and data normalization techniques to standardize miRNA analysis in the vitreous and explore potential methodologies for obtaining vitreous samples from healthy individuals.

Conclusion

Vitreous miRNAs hold promise as potential biomarkers for various retinal diseases, with miR-142, miR-9, and miR-21 emerging as particularly promising candidates. Enhancing methodologies for vitreous sampling and miRNA analysis presents an opportunity to expand the repertoire and utility of miRNA biomarkers in retinal disease diagnosis and prognosis.

Graphic abstract

From left to right, the diagram shows the location of the retina and the vitreous humor within the eye; the microanatomy of the retinal layers showcasing the secretion of exosomes and biomolecules into the vitreous from its anterior side (inner retinal layers); a magnified illustration of miRNA secretion process from gene expression in the cell nucleus to exosome -dependent and - independent secretion pathways; and the process of intravitreal biopsy for collection and analysis of miRNA expression using quantitative PCR methods.
A Novel Digital Twin Strategy to Examine the Implications of Randomized Clinical Trials for Real-World Populations
Authors: Thangaraj Phyllis M. , Shankar Sumukh Vasisht , Huang Sicong , Nadkarni Girish N. , Mortazavi Bobak J. , Oikonomou Evangelos K. , Khera Rohan
Published: March 2024

Randomized clinical trials (RCTs) are essential to guide medical practice; however, their generalizability to a given population is often uncertain. We developed a statistically informed Generative Adversarial Network (GAN) model, RCT-Twin-GAN, that leverages relationships between covariates and outcomes and generates a digital twin of an RCT (RCT-Twin) conditioned on covariate distributions from a second patient population. We used RCT-Twin-GAN to reproduce treatment effect outcomes of the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial, which tested the same intervention but found different treatment effects. To demonstrate treatment effect estimates of each RCT conditioned on the other RCT’s patient population, we evaluated the cardiovascular event-free survival of SPRINT digital twins conditioned on the ACCORD cohort and vice versa (ACCORD twins conditioned on SPRINT). The conditioned digital twins were balanced across intervention and control arms (mean absolute standardized mean difference (MASMD) of covariates between treatment arms 0.019 (SD 0.018), and the conditioned covariates of the SPRINT-Twin on ACCORD were more similar to ACCORD than SPRINT (MASMD 0.0082 SD 0.016 vs. 0.46 SD 0.20). Notably, across iterations, SPRINT conditioned ACCORD-Twin datasets reproduced the overall non-significant effect size seen in ACCORD (5-year cardiovascular outcome hazard ratio (95% confidence interval) of 0.88 (0.73-1.06) in ACCORD vs. median 0.87 (0.68-1.13) in the SPRINT conditioned ACCORD-Twin), while the ACCORD conditioned SPRINT-Twins reproduced the significant effect size seen in SPRINT (0.75 (0.64-0.89) vs. median 0.79 (0.72-0.86)) in the ACCORD conditioned SPRINT-Twin). Finally, we demonstrate the translation of this approach to real-world populations by conditioning the trials on an electronic health record population. Therefore, RCT-Twin-GAN simulates the direct translation of RCT-derived treatment effects across various patient populations.
Gag proteins encoded by endogenous retroviruses are required for zebrafish development
Authors: Chang Ni-Chen , Wells Jonathan N. , Wang Andrew Y. , Schofield Phillip , Huang Yi-Chia , Truong Vinh H. , Simoes-Costa Marcos , Feschotte Cédric
Published: March 2024

Transposable elements (TEs) make up the bulk of eukaryotic genomes and examples abound of TE-derived sequences repurposed for organismal function. The process by which TEs become coopted remains obscure because most cases involve ancient, transpositionally inactive elements. Reports of active TEs serving beneficial functions are scarce and often contentious due to difficulties in manipulating repetitive sequences. Here we show that recently active TEs in zebrafish encode products critical for embryonic development. Knockdown and rescue experiments demonstrate that the endogenous retrovirus family BHIKHARI-1 (Bik-1) encodes a Gag protein essential for mesoderm development. Mechanistically, Bik-1 Gag associates with the cell membrane and its ectopic expression in chicken embryos alters cell migration. Similarly, depletion of BHIKHARI-2 Gag, a relative of Bik-1, causes defects in neural crest development in zebrafish. We propose an “addiction” model to explain how active TEs can be integrated into conserved developmental processes.
Microtubule-based nucleation results in a large sensitivity to cell geometry of the plant cortical array
Authors: Saltini Marco , Deinum Eva E.
Published: March 2024

Many plant cell functions, including cell morphogenesis and anisotropic growth, rely on the self-organisation of cortical microtubules into aligned arrays with the correct orientation. An important ongoing debate is how cell geometry, wall mechanical stresses, and other internal and external cues are integrated to determine the orientation of the cortical array. Here, we demonstrate that microtubule-based nucleation can markedly shift the balance between these often competing forces. For this, we developed a novel, more realistic model for microtubule-based nucleation in the simulation platform CorticalSim, which avoids the longstanding inhomogeneity problem stemming from previous, less realistic models for microtubule-based nucleation. We show that microtubule-based nucleation increases the sensitivity of the array to cell geometry, extending the regime of spontaneous alignment compared to isotropic nucleation. In the case of cylindrical cell shapes, we show that this translates in a strong tendency to align in the transverse direction rather than along the vertical axis, and this is robust against small directional cues in the longitudinal direction. Our model provides a powerful tool for investigating how plant cells integrate multiple biases to orient their cortical arrays, offering new insights into the biophysical mechanisms underlying cell shape and growth.
State-dependent Online Reactivations for Different Learning Strategies in Foraging
Authors: Son Sangkyu , Wang Maya Zhe , Hayden Benjamin Y. , Yoo Seng Bum Michael
Published: March 2024

Reactivation of neural responses associated with navigation is thought to facilitate learning. We wondered whether reactivation is subject to contextual control, meaning that different types of learning promote different reactivation patterns. We trained macaques to forage in a first-person virtual maze and identified two distinct learning states prioritizing reward and information using unsupervised ethogramming based on low-level features. In orbitofrontal (OFC) and retrosplenial (RSC) cortices, representations of the goal, the path towards it, and recently traveled paths were strongly reactivated - online - during reward-prioritizing choices. During learning, reactivation of optimal paths increased in RSC after reward-prioritizing choices, and reactivation of uninformative paths decreased in RSC and OFC after information-prioritizing choices. Reactivation in OFC selectively covaried with ongoing RSC activity when prioritizing information; vice versa during prioritizing reward. These results highlight that cognitive states can drive learning and reactivation patterns can be tailored to the needs of the moment.
A network of interacting ciliary tip proteins with opposing activities imparts slow and processive microtubule growth
Authors: Saunders Harriet A. J. , van den Berg Cyntha M. , Hoogebeen Robin , Schweizer Donna , Stecker Kelly E. , Roepman Ronald , Howes Stuart C. , Akhmanova Anna
Published: March 2024

Cilia are essential motile or sensory organelles found on many eukaryotic cells. Their formation and function rely on axonemal microtubules, which exhibit very slow dynamics, however the underlying biochemical mechanisms are largely unexplored. Here, we reconstitutedin vitrothe individual and collective activities of the ciliary tip module proteins, CEP104, CSPP1, TOGARAM1, ARMC9 and CCDC66, which interact with each other and with microtubules, and, when mutated, cause ciliopathies such as Joubert syndrome. CEP104, a protein containing a tubulin-binding TOG domain, is an inhibitor of microtubule growth and shortening that interacts with EBs on the microtubule surface and with a luminal microtubule-pausing factor CSPP1. Another TOG-domain protein, TOGARAM1, overcomes growth inhibition imposed by CEP104 and CSPP1. CCDC66 and ARMC9 do not affect microtubule dynamics directly but act as scaffolds for their partners. Cryo-electron tomography showed that together, ciliary tip module members form plus-end-specific cork-like structures which reduce protofilament flaring. The combined effect of these proteins is very slow processive microtubule elongation, which recapitulates axonemal dynamics in cells.
Core-N-glycans are atypically abundant at the neuronal surface and regulate glutamate receptor signaling
Authors: Zhang Chun-Lei , Moutoussamy Cédric , Tuffery Matthieu , Varangot Alexandre , Piskorowski Rebecca , Hanus Cyril
Published: March 2024

Neurotransmitter receptors, like most surface proteins, are extensively modified by covalent addition of N-glycans during their synthesis. Surprisingly, the most abundant N-glycans in the mammalian brain are core-glycans, sugars that typically earmark immature intracellular proteins in non-neuronal cells. The function of these glycans in neurons is yet largely unknown. To address this, we combined conditional gene knockout, mass spectrometry, quantitative imaging and electrophysiological recordings in cultured neurons and brain slices. We show that core-glycans are expressed at high levels at the neuronal surface, indicating expression on functional proteins. Focusing on excitatory synapses, we found that core-glycans reduce dendritic spine density and synaptic AMPA receptor expression but are overall sufficient to sustain functional synapses. Our results indicate that core-glycans slow the desensitization of AMPA receptor complexes and reduce NMDA receptor signaling at synapses. Core-glycans hence impair NMDA receptor-dependent synaptic plasticity, unraveling a previously unrecognized role for N-glycosylation in regulating synaptic composition and transmission efficacy.
Accelerated Bayesian inference of population size history from recombining sequence data
Authors: Terhorst Jonathan
Published: March 2024

I presentphlash, a new Bayesian method for inferring population history from whole genome sequence data.phlashispopulationhistorylearning byaveragingsampledhistories: it works by drawing random, low-dimensional projections of the coalescent intensity function from the posterior distribution of apsmc-like model, and averaging them together to form an accurate and adaptive size history estimator. On simulated data,phlashtends to be faster and have lower error than several competing methods includingsmc++,msmc2, and FitCoal. Moreover, it provides a full posterior distribution over population size history, leading to automatic uncertainty quantification of the point estimates, as well to new Bayesian testing procedures for detecting population structure and ancient bottlenecks. On the technical side, the key advance is a novel algorithm for computing the score function (gradient of the log-likelihood) of a coalescent hidden Markov model: when there areMhidden states, the algorithm requires. 𝒪(M2) time and. 𝒪(1) memory per decoded position, the same cost as evaluating the log-likelihood itself using the naïve forward algorithm. This algorithm is combined with a hand-tuned implementation that fully leverages the power of modern GPU hardware, and the entire method has been released as an easy-to-use Python software package.
Metabolic Disease and The Risk of Post-COVID Conditions: A Retrospective Cohort Study
Authors: Xie Wubin , Hsu Heather E. , Shafer Paul R. , Podolsky Meghan I. , Stokes Andrew C.
Published: March 2024

Objective

To examine the influence of having a baseline metabolic disorder (diabetes, hypertension, and/or obesity) on the risk of developing new clinical sequelae potentially related to SARS-CoV-2 in a large sample of commercially insured adults in the US.

Design, setting, and participants

Deidentified data were collected from the IBM/Watson MarketScan Commercial Claims and Encounters (CCAE) Databases and Medicare Supplemental and Coordination of Benefits (MDCR) Databases from 2019 to 2021. A total of 839,344 adults aged 18 and above with continuous enrollment in the health plan were included in the analyses. Participants were grouped into four categories based on their COVID-19 diagnosis and whether they had at least one of the three common metabolic disorders at baseline (diabetes, obesity, or hypertension).

Measures and methods

ICD-10-CM codes were used to determine new symptoms and conditions after the acute phase of SARS-CoV-2 infection, defined as ending 21 days after initial diagnosis date, or index period for those who did not have a COVID-19 diagnosis. Propensity score matching (PSM) was used to create comparable reference groups. Cox proportional hazard models were conducted to estimate hazard ratios and 95% confidence intervals.

Results

Among the 772,377 individuals included in the analyses, 36,742 (4.8%) without and 20,912 (2.7%) with a baseline metabolic disorder were diagnosed with COVID-19. On average, COVID-19 patients with baseline metabolic disorders had more 2.4 more baseline comorbidities compared to those without baseline metabolic disorders. Compared to adults with no baseline metabolic condition, the risks of developing new clinical sequelae were highest among COVID-19 patients with a baseline metabolic condition (HRs ranging from 1.51 to 3.33), followed by those who had a baseline metabolic condition but with no COVID-19 infection (HRs ranging from 1.33 to 2.35), and those who had COVID-19 but no baseline metabolic condition (HRs ranging from 1.34 to 2.85).

Conclusions

In a large national cohort of commercially insured adults, COVID-19 patients with a baseline metabolic condition had the highest risk of developing new clinical sequelae post-acute infection phase, followed by those who had baseline metabolic condition but no COVID-19 infection and those who had COVID-19 but no baseline metabolic disorder.
Anorexia nervosa is associated with higher brain mu-opioid receptor availability
Authors: Pak Kyoungjune , Tuisku Jouni , Karlsson Henry K. , Hirvonen Jussi , Rebelos Eleni , Pekkarinen Laura , Sun Lihua , Latva-Rasku Aino , Helin Semi , Rajander Johan , Karukivi Max , Nuutila Pirjo , Nummenmaa Lauri
Published: March 2024

Anorexia nervosa (AN) is a severe psychiatric disorder, characterized by restricted eating, fear to gain weight, and a distorted body image. Mu-opioid receptor (MOR) functions as a part of complex opioid system and supports both homeostatic and hedonic control of eating behavior. Thirteen patients with AN and thirteen healthy controls (HC) were included in this study. We measured 1) MOR availability with [11C]carfentanil positron emission tomography (PET), 2) brain glucose uptake (BGU) with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) PET during hyperinsulinemic-euglycemic clamp and 3) blood-oxygen-level-dependent signal with functional magnetic resonance imaging. All subjects underwent a screening visit consisting of physical examination, anthropometric measurements, fasting blood samples, an oral glucose tolerance test, psychiatric assessment, and an inquiry regarding medical history. Body fat mass (%) was measured and M value was calculated. MOR availability from caudate and putamen was higher in patients with AN and those from nucleus accumbens (NAcc) and thalamus showed the higher trend in patients with AN. There was no area where MOR availability was lower in patients with AN. BGU was not different between AN and HC. MOR availability and BGU were negatively correlated in caudate, NAcc and thalamus and showed the trend of negative association in putamen. In conclusion, AN is associated with higher MOR availability in the brain regions implicated in reward processing, while BGU remains unaltered. Therefore, the endogenous opioid system might be one of the key components underlying AN. This better understanding of AN could support the development of new treatments for AN.
Comparative Analysis of DNA Structural Parameters and the Corresponding Computational Tools to Differentiate Regulatory DNA Motifs and Promoters
Authors: Manivelan Vasumathi , Kavyashree Basavaraju , Sadanandan Bindu , Vaidya Sravanti , Acharya Kshitish K
Published: March 2024

Analyzing and distinguishing functionally distinct DNA regions is crucial for various applications, including predicting DNA motifs and promoters, and exploring the mechanisms of gene expression regulation in disease conditions. Our understanding of mammalian promoters, particularly those associated with differentially expressed genes (DEGs), particularly remains limited. However, existing methods for such analysis require refinement. Despite the value of DNA Structural Parameters (DSPs), users often struggle to objectively select parameters and tools, especially given the limited options available. This study addresses this challenge by thoroughly investigating DSP-tool combinations – particularly the local structural parameters that can be analyzed via web-interfaces, with a goal to discern human DNA motifs and promoters. What sets this study apart are the following aspects: a) examination of disease-associated promoters; b) attention to regulatory specific DNA motifs; c) compilation and comparison of all publicly available online tools and parameters for analyzing DNA structures, and test all available DSP-tool combinations. Through the execution of over half a million queries, the study identified DSP-tool combinations that consistently outperformed others in differentiating DNA sequences across various types of analyses. Notably, the ‘propeller twist’ emerged as a standout DSP, while DNAshape, complemented by DNAshapeR scripts, demonstrated exceptional performance among the tools across four distinct types of analyses: testing motifs, sequences post motif insertion, comparing promoters with control sequences, and analyzing promoters of genes either up- or down-regulated under disease conditions. Significant alterations were observed in the values of multiple DSPs for 100-nucleotide-long promoter and control sequences following the insertion of single motifs such as triplex target sites (TTS), quadruplex-forming structural motifs (QSFM), and transcription factor binding sites (TFBS). However, no single combination proved universally successful. For instance, when analyzing promoters associated with differential gene expression, different combinations proved effective across various human diseases. These findings provide valuable insights for making informed selections among available options for sequence-based queries.