bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell, spatial, and fate-mapping analyses uncover niche dependent diversity of cochlear myeloid cells
Authors: Chiot Aude , Felgner Max J. , Brownell Dillon , Rott Katherine H. , Bogachuk Alina , Rosmus Dennis-Dominik , Masuda Takahiro , Ching Audrey , Atkinson Patrick J. , Prinz Marco , Sachs Karen , Cheng Alan G. , Wieghofer Peter , Ajami Bahareh
Published: November 2024

Recent advances in fate mapping and single-cell technologies have revealed how the dynamics and function of tissue-resident macrophages are shaped by their environment. However, macrophages in sensory organs such as the cochlea where the central nervous system and peripheral nervous system meet remain understudied. Combining single-cell transcriptomics, fate mapping, and parabiosis experiments, we show that five types of myeloid cells including three tissue-resident macrophage subpopulations, coexist in the mouse cochlea. The three macrophage subsets showed different potential functions in relationship with their specific topography across cochlear compartments. Further analysis revealed that they were partially derived from yolk sac progenitors during development, while in adulthood, most cochlear macrophages were long-term resident. Finally, we showed that cochlear macrophage morphology and density changed during aging. Our findings show that cochlea is a microenvironment with a unique heterogeneity of macrophages in terms of gene expression, spatial distribution, ontogeny, and function.
Loss of DOT1L function disrupts neuronal transcription, animal behavior, and leads to a novel neurodevelopmental disorder
Authors: Maroni Marissa J. , Barton Melissa , Lynch Katherine , Deshwar Ashish R. , Campbell Philip , Millard Josephine , Lee Rachel , Cohen Annastelle , Paranjapye Alekh , Faundes Víctor , Repetto Gabriela M. , McKenna Caoimhe , Shillington Amelle L. , Phornphutkul Chanika , Mancini Grazia MS. , Schot Rachel , Barakat Tahsin Stefan , Richmond Christopher M. , Lauzon Julie , Elsayed Ibrahim Ahmed Ibrahim , Benito Daniel Natera-de , Ortez Carlos , Estevez-Arias Berta , Lecoquierre François , Cassinari Kévin , Guerrot Anne-Marie , Levy Jonathan , Latypova Xenia , Verloes Alain , Innes A. Micheil , Yang Xiao-Ru , Banka Siddharth , Vill Katharina , Jacob Maureen , Kruer Michael , Skidmore Peter , Galaz-Montoya Carolina I. , Bakhtiari Somayeh , Mester Jessica L. , Granato Michael , Armache Karim-Jean , Costain Gregory , Korb Erica
Published: November 2024

Individuals with monoallelic pathogenic variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, the impact of monoallelic loss ofDOT1Lremains unclear. Here, we present a largely female cohort of 11 individuals withDOT1Lvariants with developmental delays and dysmorphic facial features. We found thatDOT1Lvariants include missense variants clustered in the catalytic domain, frameshift, and stop-gain variants. We demonstrate that specific variants cause loss of methyltransferase activity and therefore sought to define the effects of decreased DOT1L function. Using RNA-sequencing of cultured neurons and single nucleus RNA-sequencing of mouse cortical tissue, we found that partialDot1ldepletion causes sex-specific transcriptional responses and disrupts transcription of synaptic genes. Further,Dot1lloss alters neuron branching and expression of synaptic proteins. Lastly using zebrafish and mouse models, we found behavioral disruptions that include sex-specific deficits in mice. Overall, we define how DOT1L loss leads to neurological dysfunction by demonstrating that partialDot1lloss impacts transcription, neuron morphology, and behavior across multiple models and systems.
Association between polygenic risk and survival in breast cancer patients
Authors: Kurant Danielle E. , Groha Stefan , Ding Yi , German Chris , Wang Wei , Granka Julie M. , Holmes Michael V. ,   23andMe Research Team, Shringarpure Suyash S. , Gusev Alexander Sasha
Published: November 2024

Polygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. However, little is known about the association with subsequent outcomes for individuals who develop cancer. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer. We conducted a PRS survival analysis using 23,770 European cancer patients from the Dana-Farber Cancer Institute Profile cohort. We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89, p = 1.50×10-4, <5% FDR), implying that individuals at high genetic risk had better outcomes. High PRS individuals were also significantly less likely to harbor somatic TP53 mutations, consistent with having less aggressive tumors. This association persisted when including tumor grade and became more protective when restricting to ER-negative tumors (HR = 0.78, p = 1.69×10-4). Potential confounders such as hormone receptor status, age, grade, stage, and ER-targeted therapy did not fully explain this association, nor was there statistical evidence of index event bias at individual variants. We did not observe significant associations between cancer risk and survival for other cancers, suggesting that this mechanism may be largely unique to breast cancer. However, we did observe associations between shorter survival and type 2 diabetes, bipolar, and pancreatitis PRS (1% FDR). These findings suggest that higher germline risk may predispose individuals to less aggressive breast cancer tumors and provide novel insights into breast cancer development and prognosis.
Interplay between Sex and Disease Burden in Huntington’s Disease: Clinical and Neuroimaging Perspectives
Authors: Yao Jingwen , Feng B.S. Grayson , Shao M.S. Guowen , Mendizabal Adys , Telesca Donatello , Fang Kaiying , Ibragimova Lola , Shoaib Juwairia , Morrison Melanie A. , Lupo Janine M.
Published: November 2024

Background

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored.

Objectives

To investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD.

Methods

We retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington’s Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates.

Results

Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate:βmale/female=–3.462/–2.935, p<0.05; putamen:βmale/female=–4.775/–3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score:βmale/female=3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test :βmale/female=–34.89/–38.91, p<0.0001), and greater functional decline (Total Functional Capacity:βmale/female=–6.449/–6.817, p<0.05; Independence Scale:βmale/female=–32.44/– 34.99, p<0.001).

Conclusions

The sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.
Outcome of Wage and Self-employment intervention for Persons with Severe Mental Illness availing Rural Community-based Rehabilitation Project: Experience from South India
Authors: Sivakumar Thanapal , Reddy K Shanivaram , Jagannathan Aarti , Kumar Channaveerachari Naveen , Thirthalli Jagadisha , Bhat Shyam K
Published: November 2024

Background

The World Health Organization advocates Community-Based Rehabilitation (CBR) for resource-constrained settings. There is a need for evidence-based models of employment for persons with severe mental illness (referred to as ‘patients’) from such settings.

Aims

To facilitate and study the employment outcome of patients aged 18-50 years, availing a rural CBR project in South India.

Methods

Of 98 consented patients, only three men chose wage employment, and eighty-nine chose self-employment. Patients seeking wage employment were offered training and job placement in the nearest metropolitan city. Ten patients were offered loans for self-employment as revolving funds without collateral through the family federation of persons with mental illness. The patients and families were followed up for ten months after recruitment into intervention. The AIMS-SEEP tool assessed the impact on families that availed of loans.

Results

All three men who chose wage employment in the city discontinued it. Two of ten families did not use it for the intended purpose, and one loan was written off. Seven families chose sheep rearing, and one bought a tailoring machine. Self-employment was a secondary source of income for families and was used for food, clothes, school expenses, health-related costs, household items, and debt repayment. The attendance at monthly meetings of the family federation has more than tripled since loans were issued. Families reported no adverse effects due to the intervention. Only three out of eight families had repaid the loan completely at the end of ten months. Reasons cited for delay in loan repayment were hospital expenses for a sick family member and children’s school expenses.

Conclusion

In impoverished rural areas, patients and their families prefer self-employment locally over shifting to the city for wage employment. Suggestions for implementing livelihood interventions in other resource-constrained settings are discussed. Families must own the initiative to ensure its sustainability.
Phylodynamic analysis reveals disparate transmission dynamics ofMycobacterium tuberculosis-complex lineages in Botswana
Authors: Wang Qiao , Barilar Ivan , Minin Volodymyr M. , Modongo Chawangwa , Moonan Patrick K. , Finlay Alyssa , Boyd Rosanna , Oeltmann John E. , Molefi Tuduetso L. , Zetola Nicola M. , Brewer Timothy F. , Niemann Stefan , Shin Sanghyuk S.
Published: November 2024

Tuberculosis epidemics have traditionally been conceptualized as arising from a single uniform pathogen. However,Mycobacterium tuberculosis-complex (Mtbc), the pathogen causing tuberculosis in humans, encompasses multiple lineages exhibiting genetic and phenotypic diversity that may be responsible for heterogeneity in TB transmission. We analysed a population-based dataset of 1,354 Mtbc whole-genome sequences collected over four years in Botswana, a country with high HIV and tuberculosis burden. We identified Lineage 4 (L4) as the most prevalent (87.4%), followed by L1 (6.4%), L2 (5.3%), and L3 (0.9%). Within L4, multiple sublineages were identified, with L4.3.4 being the predominant sublineage. Phylodynamic analysis revealed L4.3.4 expanded steadily from late 1800s to early 2000s. Conversely, L1, L4.4, and L4.3.2 showed population trajectories closely aligned with the HIV epidemic. Meanwhile, L2 saw rapid expansion throughout most of the 20thcentury but declined sharply in early 1990s. Additionally, pairwise genome comparison of Mtbc highlighted differences in clustering proportions due to recent transmission at the sublineage level. These findings emphasize the diverse transmission dynamics of strains of different Mtbc lineages and highlight the potential for phylodynamic analysis of routine sequences to refine our understanding of lineage-specific behaviors.
Plasma p-tau212 as a biomarker of sporadic and Down Syndrome Alzheimer’s disease
Authors: Kac Przemysław R. , Alcolea Daniel , Montoliu-Gaya Laia , Fernández Susana , Lantero Rodriguez Juan , Maure Lucía , González-Ortiz Fernando , Benejam Bessy , Turton Michael , Barroeta Isabel , Harrison Peter , Videla Laura , Ashton Nicholas J. , Lleó Alberto , Zetterberg Henrik , Carmona-Iragui María , Karikari Thomas K. , Fortea Juan , Blennow Kaj
Published: November 2024

Background

All individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD.

Methods

Using Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey post-hoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes.

Results

We have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0.867; p<0.001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0.91 and AUC = 0.86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive.

Conclusions

We have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD.
The emergence of a novel synthetic nicotine analog 6-methyl nicotine (6-MN) in proclaimed tobacco- and nicotine-free pouches available in Europe
Authors: Vanhee Celine , Dill Maarten , Canfyn Michael , Tuenter Emmy , Barhdadi Sophia
Published: November 2024

A new nicotine delivery system in the form of tobacco-free nicotine pouches, was introduced in Europe in 2019. These nicotine bags did not fall under the Tobacco Products Directive (TPD) II which brought forward regulatory requirements for both cigarettes, related products, and e-liquids. As these pouches did not fall under the scope of the TPD, it was up to the member states to decide which action to be taken if any. Some EU Member States banned these nicotine pouches, while others put restrictions on the amount of nicotine, warning messages, and presentation and packaging of the product, and some Member States did not take any action. Likely as a result of the ban or restrictions soon after also tobacco and nicotine-free pouches became available in the European Union (EU). Early 2024, “NoNIC” pouches, claiming to be tobacco- and nicotine-free, became available on the European market. These pouches are promoted online and clearly target a younger population with a youth-appealing package design and enticing flavors. Upon analysis of different samples utilizing gas chromatography coupled to MS (GC-MS), liquid chromatography coupled to high-resolution tandem mass spectrometry (HRAM LC-MS2) and nuclear magnetic resonance spectroscopy (NMR), it was demonstrated that these nicotine-free pouches contained the synthetic nicotine homolog 6-methyl nicotine (6-MN) and this up to 20 mg 6-MN per pouch for the highest strengths. Nonetheless, a part of a likely unaware/misled young adult subpopulation has easy access to these products, containing a novel molecule for which limited to no clinical effects are known.
Self-Stigma And Vicarious Stigma Experienced By Parents Of Children With Neurodevelopmental Disorders Living In Rivers State, Nigeria
Authors: Chukwunonso Onunze , Chukwuebuka Ohakpougwu , Isioma Steven , Sandra Obilor , Theresa Emezuo
Published: November 2024

Background

parents of children living with Neurodevelopmental Disorders (NDDs) continue to be shamed despite the herculean task of caring for these children. Under the weight of this “double burden” parents experience double stigma: internalized and public with consequent mental health challenges.

Aim

This study was conducted to explore the prevalence of self and vicarious stigma among parents of children with NDDs in Rivers State, Nigeria, as well as the correlations of these stigma with depression among these parents.

Methods

This was a cross-sectional study of 62 parents in Port Harcourt, Nigeria employing quantitative data collection methods. Data was collected via semi-structured interviewer administered questionnaires and analysed using SPSS version. Data was summarized using proportions, mean, standard deviations. Chi square and Spearman’s correlation test were done and the level of significance was pre-determined at 5% (p<0.005).

Results

Autism Spectrum Disorder (ASD) was the commonest primary diagnosis of children in the study centres at 62.9 %. The mean age of parents was 36.4+/-7.6 years. About half of parents experienced self-stigma (50.0 %), whereas 61.3 % of parents experienced sadness due to vicarious stigma and 54.8 % experienced anger due to vicarious stigma. Overall, 56.5 % of parents suffered from depression.

Conclusion

Vicarious stigma which is public stigma on parents of children with NDDs overshadowed self-stigma. This makes urgent the need for more public education on ways society can destigmatize NDDs and provide more support for parents. Across board, stigma in any form is present can cause depression in parents, hence there is need for long term psychosocial support for these parents.
Variation of malaria dynamics and its relationship to climate in western Kenya during 2008-2019: a wavelet approach
Authors: Martin-Makowka Alexis , Nyawanda Bryan O. , Beloconi Anton , Bigogo Godfrey , Khagayi Sammy , Munga Stephen , Munywoki Patrick K. , Danquah Ina , Utzinger Jürg , Vounatsou Penelope
Published: November 2024

Malaria is a vector-borne disease, subject to climate change. The true impact of climate change on malaria dynamics is, however, still debated. Between 2008-2019, we studied patterns of malaria dynamics in a lowland area of western Kenya. We used wavelet analysis to assess the seasonality of monthly malaria incidence and related climatic factors, including air temperature, land surface temperature, rainfall and Niño 3.4 sea surface temperature. We performed a maximal overlap discrete wavelet transform to decompose incidence and climatic factors and fitted bivariate linear regressions to analyse their relationships across time scales. We observed a strong semestrial seasonality of malaria with the emergence of an annual cycle with variation strongly associated with rainfall dynamics. Rainfall emerged as a significant short-term predictor, while temperature contributed more at higher time scales. We found a recent increase in the time lag between climatic factors and their related effects on malaria incidence. This augmentation is related to bed net coverage and El Niño events. Our study underlines the importance of considering long-term time scales when assessing malaria dynamics. The presented wavelet approach could be applicable to other infectious diseases.
Influence of BMI-associated genetic variants and metabolic risk factors on weight loss with semaglutide: a longitudinal clinico-genomic cohort study
Authors: Levy Matthew E. , Telis Natalie , Schiabor Barrett Kelly M. , Bolze Alexandre , Stoller Douglas , Chapman Christopher N. , Chahal C. Anwar A. , Judge Daniel P. , Olson Douglas A. , Grzymski Joseph J. , Washington Nicole L. , Lee William , Cirulli Elizabeth T.
Published: November 2024

Background

Individual weight loss response to the GLP-1 receptor agonist semaglutide varies considerably, with many possible contributing factors. Leveraging multiple clinico-genomic cohorts, we analyzed differences in weight loss trajectories according to patient characteristics, including a polygenic score (PGS) and metabolic risk factors, in semaglutide initiators with BMI ≥27 kg/m2.

Methods

This longitudinal study utilized clinical-grade exome sequencing and electronic health record data from six U.S. cohorts within the Helix Research Network (n=134,806). A BMI PGS was calculated using 26,941 variants. Twelve-month weight loss trajectories were modeled using mixed effects models, and associations with demographics, PGS, comorbidities, medications, and laboratory results were evaluated.

Findings

Among 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses ≥1.7 mg, the mean body weight reduction was 7.3% at 6 months and 9.9% at 12 months. Over 12 months, low PGS was associated with an adjusted 1.5% and 1.8% additional weight loss compared to intermediate and high PGS, respectively (both p<0.01). Male sex, type 2 diabetes, hypertension, obstructive sleep apnea, and non-alcoholic fatty liver disease were each associated with 1.2%-1.9% less weight loss (all p<0.05). In type 2 diabetes, each 1%-increase in pretreatment hemoglobin A1c was associated with 0.6% less weight loss (p=0.0019).

Interpretation

Among adults with overweight or obesity, a lower genetic predisposition to obesity is linked to greater weight loss on semaglutide. Additionally, metabolic health significantly impacts the drug’s effectiveness. These findings underscore the importance of precision medicine in obesity management.

Funding

Renown Health Foundation. Nevada Governor’s Office of Economic Development. HealthPartners.
Comprehensive Risk Factors for Alzheimer's Disease and Cognitive Function Before Middle Age in the U.S.
Authors: Aiello Allison E. , Momkus Jennifer , Stebbins Rebecca C. , Zhang Yuan S. , Martin Chantel L. , Yang Y. Claire , Gaydosh Lauren , Hargrove Taylor , Zeki Al Hazzouri Adina , Harris Kathleen Mullan
Published: November 2024

Importance: Alzheimer's disease (AD) is a major health concern in the U.S., but most research has focused on older populations. Few studies investigate AD risk factors and cognitive function in young to early midlife adults. Objective: To examine whether key AD risk factors are associated with cognition before midlife. Design, Setting, Participants: Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) were analyzed. Participants were enrolled in 1994-95 (grades 7-12) and followed through 2018. We analyzed survey and biomarker data from Waves IV (median age 28) and V (median age 38). Exposures: Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score, APOE ϵ4 status, Amyloid Tau and Neurodegeneration markers (ATN), including total Tau and Neurofilament light (NfL), high sensitivity C-reactive protein (hsCRP), Interleukin (IL)-1β, IL-6, IL-8, IL-10, and Tumor necrosis factor alpha (TNF-α). Main Outcomes: Immediate word recall, delayed word recall, and digit span backwards. Results: We analyzed data separately in Wave IV (ranging from N=4,507 to N=11,449) and Wave V (ranging from N=529 to N=1,121). Approximately half were female. The CAIDE score was associated with all cognition measures in Wave IV. For example, among adults aged 24-34, each 1-point increase in CAIDE was associated with a 0.03 SD lower backward digit span score (95% CI: -0.04, -0.02). No significant associations were found between APOE ϵ4 and cognition. Total Tau was associated with immediate word recall in Wave V (β=-0.14, 95% CI: -0.24, -0.04). Wave IV hsCRP and IL-10 and Wave V IL-6, IL-1β, and IL-8 were also associated with lower cognitive scores. Conclusions: Key risk factors for AD, including cardiovascular, ATN, and immune markers, are linked to cognitive function as early as ages 24-44, highlighting the need for early prevention in the US.
A rubric for assessing conformance to the Ten Rules for credible practice of modeling and simulation in healthcare
Authors: Manchel Alexandra , Erdemir Ahmet , Mulugeta Lealem , Ku Joy P. , Rego Bruno V. , Horner Marc , Lytton William W , Myers Jerry G. , Vadigepalli Rajanikanth
Published: November 2024

The power of computational modeling and simulation (M&S) is realized when the results are credible, and the workflow generates evidence that supports credibility for the context of use. The Committee on Credible Practice of Modeling & Simulation in Healthcare was established to help address the need for processes and procedures to support the credible use of M&S in healthcare and biomedical research. Our community efforts have led to the Ten Rules (TR) for Credible Practice of M&S in life sciences and healthcare. This framework is an outcome of a multidisciplinary investigation from a wide range of stakeholders beginning in 2012. Here, we present a pragmatic rubric for assessing the conformance of an M&S activity to the TR. This rubric considers the ability of the M&S to facilitate outreach of the results to a wide range of stakeholders from context-specific M&S practitioners to policymakers. It uses an ordinal scale ranging from Insufficient (zero) to Comprehensive (four) that is applicable to each rule, providing a uniform approach for comparing assessments across different reviewers and different models. We used the rubric to evaluate the conformance of two computational modeling activities: 1. six viral disease (COVID-19) propagation models, and 2. a model of hepatic glycogenolysis with neural innervation and calcium signaling. These examples were used to evaluate the applicability of the rubric and illustrate rubric usage in real-world M&S scenarios including those that bridge scientific M&S with policymaking. The COVID-19 M&S studies were of particular interest because they needed to be quickly operationalized by government and private decision-makers early in the COVID-19 pandemic and were accessible as open-source tools. Our findings demonstrate that the TR rubric represents a systematic tool for assessing the conformance of an M&S activity to codified good practices and enhances the value of the TR for supporting real-world decision-making.
Estimating the Smallest Worthwhile Difference (SWD) of Psychotherapy for Depression: Protocol for a Cross-Sectional Survey
Authors: Sahker Ethan , Luo Yan , Omae Kenji , Tajika Aran , Ferreira Manuela L. , Chevance Astrid , Leucht Stefan , Markham Sarah , Ede Roger , Cipriani Andrea , Salanti Georgia , Furukawa Toshi A.
Published: November 2024

Background

Psychotherapy is proven efficacious for the treatment of depression. However, the patient-perceived importance of its effect is not fully appreciated in the evidence base. The smallest worthwhile difference (SWD) represents the smallest beneficial effect of an intervention that patients deem worthwhile given the harms, expenses, and inconveniences associated with the intervention, and facilitates the interpretation of patient perceived importance of an intervention.

Methods

The proposed study will estimate the SWD of the American Psychological Association recommended psychotherapies for depression treatment with English-speaking American and British respondents aged 18 and older. Respondents will be recruited using research participant crowdsourcing sites. The SWD will be estimated using the Benefit-Harm Trade-off Method, presenting survey respondents with variable, hypothetical magnitudes of psychotherapy outcomes to find the smallest acceptable effect over a no treatment alternative. The overall average SWD, and subgroup distributions by participant depression treatment experiences and depression symptomology will be described. Participant characteristics will be included in a regression model to explore associated variability in the SWD.

Expected Results

We expect to find an estimate of the SWD for psychotherapy in the treatment of depression. Further, we expect that the SWD will vary between clinical subgroups based on depression symptomology and treatment experiences. We expect there to be variation between those who demonstrate depression symptoms consistent with a depressive disorder, based on PHQ-9 scores or self-reported diagnosis history. We think that the findings from this project will inform the treatment decision process about psychotherapy during the clinical consultation for people with depression.
Comprehensive Cerebral Aneurysm Rupture Prediction: From Clustering to Deep Learning
Authors: Zakeri Mostafa , Atef Amirhossein , Aziznia Mohammad , Jafari Azadeh
Published: November 2024

Cerebral aneurysm is a silent yet prevalent condition that affects a substantial portion of the global population. Aneurysms can develop due to various factors and present differently, necessitating diverse treatment approaches. Choosing the appropriate treatment upon diagnosis is paramount, as the severity of the disease dictates the course of action. The vulnerability of an aneurysm, particularly in the circle of Willis, is a critical concern; rupture can lead to irreversible consequences, including death. The primary objective of this study is to predict the rupture status of cerebral aneurysms using a comprehensive dataset that includes clinical, morphological, and hemodynamic data extracted from blood flow simulations of patients with actual vessels. Our goal is to provide valuable insights that can aid in treatment decision-making and potentially save the lives of future patients. Diagnosing and predicting the rupture status of aneurysms based solely on brain scans poses a significant challenge, often with limited accuracy, even for experienced physicians. However, harnessing statistical and machine learning (ML) techniques can enhance rupture prediction and treatment strategy selection. We employed a diverse set of supervised and unsupervised algorithms, training them on a database comprising over 700 cerebral aneurysms, which included 55 different parameters: 3 clinical, 35 morphological, and 17 hemodynamic features. Two of our models—stochastic gradient descent (SGD) and multi-layer perceptron (MLP) — predicted cerebral aneurysm rupture, achieving a maximum area under the curve (AUC) of 0.86, a precision rate of 0.86, and a recall rate of 0.90. Given the sensitivity of the data and the critical nature of the condition, recall is a more vital parameter than accuracy and precision; our study achieved an acceptable recall score. Key features for rupture prediction included ellipticity index, low shear area ratio, and irregularity. Additionally, a one-dimensional CNN model predicted rupture status along a continuous spectrum, achieving 0.78 accuracy on the testing dataset, providing nuanced insights into rupture propensity.
Meta-Analytical Approaches to Ordinal Outcome Data in Clinical Interventional Studies: A Scoping Review with Reproducible Research
Authors: Mulhem Ali
Published: November 2024

Background

Conducting meta-analyses on ordinal outcome data is more complex than on binary or continuous data. This study aims to summarise the current biomedical literature on meta-analytical methods for ordinal outcomes and attempts to reproduce the results of previous studies.

Methods

A systematic search was conducted in three databases, MEDLINE, EMBASE, and PsycINFO, from inception to 05/05/2024. Forward and backward citation searches were also performed. The screening was conducted in two phases using Covidence software. Studies were included if they reported or compared methods for meta-analysis of ordinal outcomes in clinical interventional studies. Relevant studies were summarised and discussed. If sufficient data for methods comparison were available, either in the retrieved reports or after contacting the authors, an attempt at reproducible research was made.

Results

333 records were screened, yielding four methodological studies that met the inclusion criteria. These studies addressed meta-analytical methods for ordinal scales ranging from 5 to 20 ordered categories. The three primary approaches identified were (1) ordinal models (proportional odds and generalised odds), (2) binary models (dichotomisation of ordinal scales), and (3) continuous models (treating ordinal scales as continuous variables). None of the included studies provided a comprehensive comparison of all three approaches. Two studies compared different proportional odds models; one compared binary with proportional odds, but the full results were not published, and one compared continuous and generalised odds models using simulated data with one scenario. The latter study allowed for reproducibility, but our analysis produced different results, and attempts to clarify the discrepancy with the authors were unsuccessful.

Conclusions

A significant knowledge gap exists regarding the optimal meta-analytical method for ordinal outcomes in clinical interventional studies. Further methodological research is required to establish a robust evidence base for choosing the most appropriate approach.
UNCONVENTIONAL SECRETION OF THE AUTOPHAGY-RELATED PROTEIN VMP1 VIA EXTRACELLULAR VESICLES AS A POTENTIAL BIOMARKER FOR PANCREATIC CELL INJURY
Authors: Tadic Mariana S. , Renna Felipe J. , López Malena Herrera , Orquera Tamara , Mingorance Fabiana López , Ropolo Alejandro , Vaccaro Maria I.
Published: November 2024

Cellular stress activates various mechanisms, including autophagy and vesicular trafficking, to maintain homeostasis and cope with pathological conditions such as acute pancreatitis. One of these mechanisms involves the unconventional secretion of extracellular vesicles (EVs), lipid bilayer-delimited particles released by almost all cell types into the extracellular medium. Recently, an autophagy-related secretory pathway that releases EVs has been discovered. Our study focuses on Vacuole Membrane Protein 1 (VMP1), an autophagy-related protein implicated in pancreatitis, diabetes, pancreatic cancer, and cellular stress management. VMP1 expression triggers autophagy in mammalian cells through its ubiquitination and its direct binding to BECN1. Here, we demonstrate that VMP1 is secreted to the extracellular medium integrated into the membrane of EVs. Using cell lines expressing different VMP1-tag expression plasmids, we successfully isolated and purified VMP1-containing EVs (VMP1-EVs) from the extracellular medium through ultracentrifugation and immune isolation techniques. The secretion of VMP1-EVs was reduced by mTOR inhibition and in the absence of proteins essential for autophagosome formation, such as ATG5. The secretion of endogenous VMP1 by pancreatic acinar cells was highly induced in experimental models of cell stress, including blocked autophagic flux with Bafilomycin and exposure to supramaximal doses of caerulein. Moreover, immuno-isolation of VMP1-EVs from cell models revealed that VMP1 is a component of EV membranes. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis of immuno-isolated VMP1-EVs indicated a diameter of around 150 nm. Western blot assay demonstrated that the autophagy related protein LC3-II and p62 are co-secreted with VMP1 in cellular stress models. Furthermore, VMP1-EVs are taken up by different host cells, suggesting that VMP1-EVs may be able to mediate remote communication between cells. In conclusion, we have demonstrated for the first time that the pancreatitis-associated transmembrane protein VMP1 is unconventionally secreted as a component of extracellular vesicles via a secretory autophagy pathway.
Exploring phenotype-related single-cells through attention-enhanced representation learning
Authors: Wu Qinhua , Ding Junxiang , He Ruikun , Hui Lijian , Liu Junwei , Li Yixue
Published: November 2024

The scope of atlas-level single-cell investigations reveals the pathogenesis and progression of various diseases. Accurate interpretation of phenotype-related single-cell data necessitates the pre-definition of single-cell subtypes and the identification of their abundance variations for downstream analysis. In this context, biases from batch correlation and the selection of clustering resolutions can significantly impact single-cell data analysis and result interpretation. To strengthen the associations across single cells in each sample and their clinical phenotype, and to enhance single-cell exploration by integrating cell and gene-level information. This study proposes a method to learn phenotype-related sample representations from single cells via the attention-based multiple instance learning (AMIL) mechanism. This approach incorporates gene expression profiles from each single cell for sample-level clinical phenotype prediction. By integrating deep learning interpretation methods and phenotype-specific single-cell attention weights across sample groups, this method highlights critical gene programs and cell subtypes that mostly contribute to the sample-level clinical phenotype, and facilitate mechanistic exploration. Using single-cell atlases from COVID-19 infected patients and age-related healthy human blood, we demonstrate that this method can accurately predict disease severity and age-related phenotypes. Additionally, variations in cellular attention reflect the underlying biological mechanisms associated with these phenotypes. This method proposes a supervised framework for single-cell data interpretation and can be further adapted for other atlas-level clinical phenotype analyses.
Bacterial cell-free DNA profiling reveals co-elevation of multiple bacteria in newborn foals with suspected sepsis
Authors: Chen Li-Ting , Wesdorp Emmy , Jager Myrthe , Siegers Esther W. , Theelen Mathijs J.P. , Besselink Nicolle , Vermeulen Carlo , Zomer Aldert L. , Broens Els M. , Wagenaar Jaap A. , de Ridder Jeroen
Published: November 2024

Background

Sepsis is the leading cause of death in newborn foals. This study investigates whether cell-free DNA (cfDNA) sequencing can enhance bacterial pathogen detection in foals with suspected sepsis and addresses existing knowledge gaps and diagnostic challenges.

Methods

We developed afoalcfDNA sequencing forbacteriaidentification (cfFBI) workflow, integrating wetlab and computational protocols to detect increased bacterial cfDNA abundance in blood. Specifically, cfFBI focusses on enriching bacterial cfDNA molecules and preventing false positive bacterial identifications. cfFBI was applied to blood samples of 25 hospitalized foals categorized according to the neonatal Systemic Inflammatory Response Syndrome (nSIRS) criteria and 7 healthy foals.

Results

cfDNA levels of potential sepsis-causing bacterial genera were elevated in all 11 nSIRS-positive foals compared to healthy foals (n=7), and in 8/11 (72.7%) when compared to both nSIRS-negative (n=4; nSIRS=0) and healthy foals, with multiple genera elevated in 5/11 (45.5%). The total cfDNA concentration, bacterial cfDNA fraction and bacterial diversity were not different between the foal groups. However, nSIRS-positive foals showed significantly different end-motifs in host chromosomal cfDNA, and a decrease in host mitochondrial cfDNA fraction.

Conclusions

This study is the first to demonstrate that cfDNA sequencing in blood samples from newborn foals enables detection of pathogenic bacteria and can help identify novel host-related sepsis biomarkers. The elevated presence of multiple sepsis-causing genera in nSIRS-positive foals and the difference in end-motif, suggests that multibacterial elevation may be more common than previously thought. These findings indicate that cfDNA sequencing holds promise as a future diagnostic tool for identifying sepsis in newborn foals.
WhaleLM: Finding Structure and Information in Sperm Whale Vocalizations and Behavior with Machine Learning
Authors: Sharma Pratyusha , Gero Shane , Rus Daniela , Torralba Antonio , Andreas Jacob
Published: November 2024

Language models (LMs), which are neural sequence predictors trained to model distributions over natural language texts, have come to play a central role in human language technologies like machine translation and information retrieval. They have also contributed to the scientific study of human language itself, enabling progress on long-standing questions about the learnability, optimality, and universality of key features of human languages. Many analogous questions exist in the study of communication between non-human animals—for which, in many cases, we have only a preliminary understanding of signals’ structure and use. Can neural sequence models help us understand these animal communication systems as well? We use these models to characterize the structure and information content of sperm whale vocalizations. Sperm whales (Physeter macrocephalus) engage in complex, coordinated behaviours like foraging and navigation in the darkness of the ocean while exchanging sequences of rhythmic clicks known as codas. However, little is known about whether there are any systematic patterns governing coda production, or how codas influence group decision-making and behaviour. To begin to answer these questions, we first train a neural sequence model (a ‘sperm whale language model’) to predict whales’ future vocalizations from their conversational history. By systematically manipulating the information available to this model, and measuring the change in predictive accuracy, we show that sperm whale vocalizations exhibit order dependence, long-range dependencies on up to the past eight codas in an exchange, and predictable turn-taking. Second, we train the sequence model to predict whales’ behaviour from their vocal exchanges, and find that both current behavioural context and future actions are predictable, with accuracies of 72% and 86% respectively, from coda sequences. Our study provides the first evidence that sperm whale vocalizations contain information that could be used to coordinate behaviour. More generally, it offers a framework for using modern machine learning tools for hypothesis generation and to assist in investigating the structure and function of unknown communication systems.
DJ-1 mediates regulation of metabolism and immune response in Parkinson’s disease astrocytes and Glioblastoma cells
Authors: Mencke Pauline , Ohnmacht Jochen , Jeannelle Félicia , Ries Adrien J , de la Maza Mónica Miranda , Ullrich Mathilde , Massart François , Mulica Patrycja , Badanjak Katja , Hanss Zoé , Rybicki Arkadiusz , Antony Paul , Delcambre Sylvie , Arena Giuseppe , Cruciani Gérald , Jarazo Javier , Gavotto Floriane , Jäger Christian , Ewen Anouk , Pacheco Maria Pires , Brenner Dirk , Schwamborn Jens , Sauter Thomas , Sinkkonen Lasse , Dittmar Gunnar , Taipa Ricardo , Bouvier David , Meiser Johannes , Grünewald Anne , Bonifati Vincenzo , Platten Michael , Krüger Rejko , Boussaad Ibrahim
Published: November 2024

An inverse correlation for the expression of Parkinson’s disease (PD)- and cancer-associated genes has been previously reported. Genes that are upregulated in cancer are frequently downregulated in PD andvice versa. PARK7, encoding DJ-1, was initially identified as an oncogene, but loss of DJ-1 causes early-onset PD. However, it remains elusive how differential DJ-1 levels contribute to opposite cell fates in cancer and PD. Here, we demonstrate specific effects of differential DJ-1 protein levels on the energy metabolism and cell growth in patient-derived cellular models of PD and glioblastoma (GBM) cell lines. Impaired energy metabolism was associated with an increased immune response upon IL-1β stimulation and increased apoptosis and decreased cell growth in models of PD, whereas in GBM cells increased metabolic activity translated into a reduced immune response and increased cell growth. Furthermore, we found decreased glutathione (GSH) synthesis and therefore increased levels of reactive oxygen species (ROS) and oxidized glutathione (GSSG) in models of DJ-1 deficiency and decreased ROS levels in GBM cell lines. Thus, the mechanism by which DJ-1 modulates these phenotypes is the same in both diseases.

Graphical Abstract

DJ-1 levels modulate GSSG/GSH ratio and ROS levels, which results in divergent effects on cell growth and immune response in DJ-1-dependent glial pathologies in glioblastoma and PD. In models of PD, DJ-1 level dependent phenotypes can be rescued by antioxidant treatment that reduces the GSSG/GSH ratio and ROS levels.
The N-terminal extension region of BamE coordinates interaction between the β-barrel domain of BamA and BamD for efficient assembly
Authors: Maruno Yuki , Germany Edward Marshall , Nakajima Yukari , Ohyama Rei , Masumura Yukihiko , Shiota Takuya
Published: November 2024

In the Gram-negative bacteria, the assembly of β-barrel proteins into the outer membrane is mediated by the β-barrel Assembly Machinery (BAM) complex. BamA is a central component of the BAM complex. The molecular mechanisms of BamA when the substrate protein is assembled has been well elucidated and further the inhibitors targeting key mechanisms of BamA have been isolated. Although the BAM complex is a multi-subunit machine and its coordination is necessary for full function, the molecular mechanism remains unclear. Here we report on a fine-tuning system with a subunit called BamE, which is required for the cooperation of two essential subunits BamA and BamD. BamE is a lipoprotein with an N-terminal extension region between the lipid-modifying cysteine on the N-terminus and the periplasmic folding domain. Our interaction mapping revealed that the N-terminal extension region of BamE interacts with the β-barrel domain of BamA, which contains a catalytic site for assembly termed lateral gate. The mutational analysis demonstrated that the N-terminal extension region of BamE fine-tunes the assembly stage dependent BamA-BamD interaction, responsible for the crucial role for assembly and integrity of the outer membrane. We suggest that this fine-tuning system plays an important role in the substrate relay system from the receptor BamD to the insertase BamA. Furthermore, structure prediction-based analysis suspects that the C-terminal region of BamD acts as the replacement of BamE in BamE-less bacteria.
Developmental and transcriptomic responses of Hawaiian bobtail squid early stages to ocean warming and acidification
Authors: Otjacques E. , Paula J.R. , Ruby E.G. , Xavier J.C. , McFall-Ngai M.J. , Rosa R. , Schunter C.
Published: November 2024

1

Cephalopods play a central ecological role across all oceans and realms. However, under the current climate crisis, their physiology and behaviour are impacted, and we are beginning to comprehend the effects of environmental stressors at a molecular level. Here, we study the Hawaiian bobtail squid (Euprymna scolopes), known for its specific binary symbiosis with the bioluminescent bacteriumVibrio fischeriacquired post-hatching. We aim to understand the response (i.e., developmental and molecular) ofE. scolopesafter the embryogenetic exposure to different conditions: i) standard conditions (control), ii) increased CO2(ΔpH 0.4 units), iii) warming (+3ºC), or iv) a combination of the two treatments. We observed a decrease in hatching success across all treatments relative to the control. Using transcriptomics, we identified a potential trade-off in favour of metabolism and energy production, at the expense of development under increased CO2. In contrast, elevated temperature shortened the developmental time and, at a molecular level, showed signs of alternative splicing and the potential for RNA editing. The data also suggest that the initiation of the symbiosis may be negatively affected by these environmental drivers of change in the biosphere, although coping mechanisms by the animal may occur.