bluuebunny/crossref_metadata_2025 huggingface dataset:
Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors
Authors: Adam Elie , Kowalski Marek , Akeju Oluwaseun , Miller Earl K. , Brown Emery N. , McCarthy Michelle M. , Kopell Nancy
Published: April 2024

Ketamine is an NMDA-receptor antagonist that produces sedation, analgesia and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1-4 Hz) at high doses. Ketamine’s primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and non-human primate local field potential recordings. We have discovered how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported, and provides important insights into ketamine’s mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.
qMAP enabled microanatomical mapping of human skin aging
Authors: Han Kyu Sang , Sander Inbal B. , Kumer Jacqueline , Resnick Eric , Booth Clare , Cheng Guoqing , Im Yebin , Starich Bartholomew , Kiemen Ashley L. , Phillip Jude M. , Reddy Sashank , Joshu Corrine E. , Sunshine Joel C. , Walston Jeremy D. , Wirtz Denis , Wu Pei-Hsun
Published: April 2024

Aging is a major driver of diseases in humans. Identifying features associated with aging is essential for designing robust intervention strategies and discovering novel biomarkers of aging. Extensive studies at both the molecular and organ/whole-body physiological scales have helped determined features associated with aging. However, the lack of meso-scale studies, particularly at the tissue level, limits the ability to translate findings made at molecular scale to impaired tissue functions associated with aging. In this work, we established a tissue image analysis workflow - quantitative micro-anatomical phenotyping (qMAP) - that leverages deep learning and machine vision to fully label tissue and cellular compartments in tissue sections. The fully mapped tissue images address the challenges of finding an interpretable feature set to quantitatively profile age-related microanatomic changes. We optimized qMAP for skin tissues and applied it to a cohort of 99 donors aged 14 to 92. We extracted 914 microanatomic features and found that a broad spectrum of these features, represented by 10 cores processes, are strongly associated with aging. Our analysis shows that microanatomical features of the skin can predict aging with a mean absolute error (MAE) of 7.7 years, comparable to state-of-the-art epigenetic clocks. Our study demonstrates that tissue-level architectural changes are strongly associated with aging and represent a novel category of aging biomarkers that complement molecular markers. Our results highlight the complex and underexplored multi-scale relationship between molecular and tissue microanatomic scales.
Generation of hiPSC-derived brain microvascular endothelial cells using a combination of directed differentiation and transcriptional reprogramming strategies
Authors: Cui Aomeng , Patel Ronak , Bosco Patrick , Akcan Ugur , Richters Emily , Delgado Paula Barrilero , Agalliu Dritan , Sproul Andrew A.
Published: April 2024

The blood-brain barrier (BBB), formed by specialized brain microvascular endothelial cells (BMECs), regulates brain function in health and disease.In vitromodeling of the human BBB is limited by the lack of robust hiPSC protocols to generate BMECs. Here, we report generation, transcriptomic and functional characterization of reprogrammed BMECs (rBMECs) by combining hiPSC differentiation into BBB-primed endothelial cells and reprogramming with two BBB transcription factors FOXF2 and ZIC3. rBMECs express a subset of the BBB gene repertoire including tight junctions and transporters, exhibit stronger paracellular barrier properties, lower caveolar-mediated transcytosis, and similar p-Glycoprotein activity compared to primary HBMECs. They can acquire an inflammatory phenotype when treated with oligomeric Aβ42. rBMECs integrate with hiPSC-derived pericytes and astrocytes to form a 3D neurovascular system using the MIMETAS microfluidics platform. This novel 3D system resembles thein vivoBBB at structural and functional levels to enable investigation of pathogenic mechanisms of neurological diseases.
(Pro)renin receptor inhibited ABCA1/G1 expression associated with low HDL-c and promoted atherosclerosis
Authors: Dong Yubing , Zhang Wei , Liu Wanyu , Bai Cuiping , Zhang Ying , Jiang Yinong , Song Wei
Published: April 2024

Background

(Pro)renin receptors [(P)RR] binding both renin and its inactive proenzyme for prorenin induce increasing the efficiency of angiotensin I conversion and the production of angiotensin II (Ang II). Recently, (P)RR was reported to played a pathological role in diabetic renal disease independent of Ang II. Ang II is involved in lipid metabolism and atherosclerosis, but the (P)RR participation in atherosclerosis remains unclear. Thus, the objective of this study was to examine the relative importance of Ang II-independent actions of (P)RR and its mechanism in the development of atherosclerosis.

Methods

Clinical demographic characteristics and laboratory profile data of 1189 essential hypertensive were collected. Patients were divided into four groups based on the quartiles of plasma renin activity (PRA). The plasma lipoprotein levels of four groups were compared. Furthermore, we examined serum and liver lipoprotein levels, as well as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) expression in ApoE-/-mice treated with prorenin. ABCA1 and ABCG1 expression and their function in mediating cholesterol efflux were evaluated in THP-1 cells by prorenin treatment. Agonists of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and liver X receptor α (LXRα) were used to investigate the mechanism involved in vitro.

Results

Plasma TC, TG, LDL-c, and apoB were significantly increased, and HDL-c and apoA were dramatically decreased with a trend of higher plasma renin activity (PRA) ( allP< 0.05) in hypertensive patients. Prorenin accelerated atherosclerosis by inhibiting mRNA and protein expression of ABCA1/ABCG1 in the liver of ApoE-/-mice. Prorenin binding to (P)RR inhibited the functions of ABCA1- and ABCG1-mediated cholesterol efflux. Furthermore, Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPARγ/LXRα pathway.

Conclusions

(P)RR activated by prorenin inhibited the expression of ABCA1/ABCG1 through the PPARγ/LXRα pathway and the functions of ABCA1- and ABCG1-mediated cholesterol efflux, resulting in dyslipidemia and eventually atherosclerosis.

Highlights

With RPA increases in hypertension, plasma TC, TG, LDL-c, and apoB were higher, while HDL-c and apoA were lower.

Prorenin binding to (P)RR accelerated atherosclerosis by inhibiting ABCA1/G1 expression and function.

Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPARγ/LXRα pathway.
Human iPSC-derived cell grafts promote functional recovery by molecular interaction with stroke-injured brain
Authors: Weber Rebecca Z. , Achón Buil Beatriz , Rentsch Nora H. , Perron Patrick , Bosworth Allison , Zhang Mingzi , Kisler Kassandra , Bodenmann Chantal , Zürcher Kathrin J. , Uhr Daniela , Meier Debora , Peter Siri L. , Generali Melanie , Nitsch Roger M. , Zlokovic Berislav V. , Tackenberg Christian , Rust Ruslan
Published: April 2024

Stroke is a leading cause of disability and death due to the brain’s limited ability to regenerate damaged neural circuits. To date, stroke patients have only few therapeutic options and are often left with considerable disabilities. Induced pluripotent stem cell (iPSC)-based therapies are emerging as a promising therapeutic approach for stroke recovery. In this study, we demonstrate that local transplantation of good manufacturing practice (GMP)-compatible iPSC-derived neural progenitor cells (NPCs) improve long-term recovery-associated brain tissue responses and reduce neurological deficits after cerebral ischemia in mice. Usingin vivobioluminescence imaging andpost-mortemhistology, we showed long-term graft survival over the course of five weeks and preferential graft differentiation into mature neurons without signs of pluripotent residuals. Transplantation of NPCs led to a set of recovery-associated tissue responses including increased vascular sprouting and repair, improved blood-brain barrier integrity, reduced microglial activation, and increased neurogenesis compared to littermate control animals receiving sham transplantation. Employing deep learning-assisted behavior analysis, we found that NPC-treated mice displayed improved gait performance and complete fine-motor recovery in the horizontal ladder rung walk, five weeks post-injury. To dissect the molecular graft composition and identify graft-host interactions, single nucleus profiling of the cell transplants and host stroke tissue was performed. We identified graft differentiation preferentially towards GABAergic cells with remaining cells acquiring glutamatergic neuron, astrocyte, and NPC-like phenotypes. Interaction between graft and host transcriptome indicated that GABAergic cell grafts were primarily involved in graft-host communication through the regeneration-associated NRXN, NRG, NCAM and SLIT signalling pathways. In conclusion, our study reveals that transplanted iPSC-derived NPCs primarily differentiate into GABAergic neurons contributing to long-term recovery, and further delineates the regenerative interactions between the graft and the stroke-injured host tissue.
Future shapes present: autonomous goal-directed and sensory-focused mode switching in a Bayesian allostatic network model
Authors: Idei Hayato , Tani Jun , Ogata Tetsuya , Yamashita Yuichi
Published: April 2024

Trade-offs between moving to achieve goals and perceiving the surrounding environment highlight the complexity of continually adapting behaviors. The need to switch between goal-directed and sensory-focused modes, along with the goal emergence phenomenon, challenges conventional optimization frameworks, necessitating heuristic solutions. In this study, we propose a Bayesian recurrent neural network framework for homeostatic behavior adaptation via hierarchical multimodal integration. In it, the meta-goal of “minimizing predicted future sensory entropy” underpins the dynamic self-organization of future sensorimotor goals and their precision regarding the increasing sensory uncertainty due to unusual physiological conditions. We demonstrated that after learning a hierarchical predictive model of a dynamic environment through random exploration, our Bayesian agent autonomously switched self-organized behavior between goal-directed feeding and sensory-focused resting. It increased feeding before anticipated food shortages, explaining predictive energy regulation (allostasis) in animals. Our modeling framework opens new avenues for studying brain information processing and anchoring continual behavioral adaptations.
PsiPartition: Improved Site Partitioning for Genomic Data by Parameterized Sorting Indices and Bayesian Optimization
Authors: Xu Shijie , Onoda Akira
Published: April 2024

Phylogenetics has been widely used in molecular biology to infer the evolutionary relationships among species. With the rapid development of sequencing technology, genomic data with thousands of sites becomes increasingly common in phylogenetic analysis, while heterogeneity among sites arises as one of the major challenges. A single homogeneous model is not sufficient to describe the evolution of all sites and partitioned models are often employed to model the evolution of heterogeneous sites by partitioning them into distinct groups and utilizing distinct evolutionary models for each group. It is crucial to determine the best partitioning, which greatly affects the reconstruction correctness of phylogeny. However, the best partitioning is usually intractable to obtain in practice. Traditional partitioning methods rely on heuristic algorithms or greedy search to determine the best ones in their solution space, are usually time-consuming, and with no guarantee of optimality. In this study, we propose a novel partitioning approach, termed PsiPartition, based on the parameterized sorting indices of sites and Bayesian optimization. We apply our method to empirical data sets and it performs significantly better compared to existing methods, in terms of Bayesian information criterion (BIC) and the corrected Akaike information criterion (AICc). We test PsiPartition on the simulated data sets with different site heterogeneity, alignment lengths, and number of loci. It is demonstrated that PsiPartition evidently and stably outperforms other methods in terms of the Robinson-Foulds (RF) distance between the true simulated trees and the reconstructed trees, especially on the data with more site heterogeneity. More importantly, our proposed Bayesian optimization-based method, for the first time, provides a new general framework to efficiently determine the optimal number of partitions. The corresponding reproducible source code and data are available athttp://github.com/xu-shi-jie/PsiPartition.
Is ChatGPT detrimental to innovation? A field experiment among university students
Authors: Hassan Mazen , Amin Engi , Mansour Sarah , Kelani Zeyad
Published: April 2024

ChatGPT represents a momentous technological breakthrough whose implications – along with other AI innovations – are yet to fully materialize. This paper is among the first attempts to experimentally test the effect of AI applications (in the form of ChatGPT) on three dependent variables usually assumed to be AI-collaterals: innovation, readiness to exert effort, and risk behaviour. We took advantage of the delayed introduction of ChatGPT in Egypt and conducted a pre-registered field experiment with nearly 100 senior university students at a public university. Over one month during term time, participants were asked to submit three graded essay assignments. In the treatment group, students were asked to write the essays using ChatGPT whereas in the control group, such option was neither mentioned nor allowed (the experiment was fielded before ChatGPT was legally operable in Egypt). One week after all assignments were submitted, the two groups were invited to the lab to play an innovation game (deploying multiple strategies to increase the sales of a hypothetical lemonade stand), a risk game (bomb risk elicitation task), and do a real effort task. The ChatGPT group was significantly less innovative, significantly less risk averse, and exerted less effort (however not statistically significant). Our results point to possible negative effects of AI applications but need further testing and larger samples to be confirmed.
Adaptive trials in stroke: Current use & future directions
Authors: Hayward Kathryn S , Dalton Emily J , Campbell Bruce CV , Khatri Pooja , Dukelow Sean P , Johns Hannah , Walter Silke , Yogendrakumar Vignan , Pandian Jeyaraj , Sacco Simona , Bernhardt Julie , Parsons Mark , Saver Jeffrey L , Churilov Leonid
Published: April 2024

Inclusion of adaptive design features in a clinical trial provides pre-planned flexibility to dynamically modify a trial during its conduct, while preserving validity and integrity. Adaptive trials are needed to accelerate the conduct of more efficient, informative, and ethical clinical research in the field of neurology as compared to traditional fixed designs. Stroke is a natural candidate for adoption of these innovative approaches to trial design. This Research Methods in Neurology paper is informed by scoping review that identified 45 completed and ongoing adaptive clinical trials in stroke that were appraised: 14 trials had published results with or without a published protocol, 15 trials had a published protocol, and 16 trials were registered only. Treatments spanned acute (n=28), rehabilitation (n=8), prevention (n=8), and rehabilitation and prevention (n=1) domains. A subsample of these trials were selected to illustrate the utility of adaptive design features and discuss why each adaptive feature(s) were incorporated in the design to best achieve the aim, whether each individual feature was used and if it resulted in expected efficiencies, and any learnings during preparation, conduct or reporting. We then discuss the operational, ethical, and regulatory considerations that warrant careful consideration during adaptive trial planning and reflect on the workforce readiness to deliver adaptive trials in practice. We conclude that adaptive trials can be designed, funded, conducted, and published for a wide range of research questions and offer future directions to support adoption of adaptive trial designs in stroke and neurological research more broadly.
White matter lesion volumes on 3-T MRI in people with MS who had followed a diet- and lifestyle program for more than 10 years
Authors: Jaftha Mariaan , Robertson Frances , van Rensburg Susan J , Kidd Martin , van Toorn Ronald , Kemp Merlisa C. , Johannes Clint , Moremi Kelebogile E. , Whati Lindiwe , Kotze Maritha J , Engel-Hills Penelope
Published: April 2024

Background

Cerebral white matter lesions (WMLs) in people with multiple sclerosis (pwMS) are associated with the death of myelin-producing oligodendrocytes. MS treatment strategies aim to limit WML accumulation and disability progression. It is commonly accepted that nutrition is one of the possible environmental factors involved in the pathogenesis of MS, but its role as a complementary MS treatment is unclear and, to a large extent, ignored.

Objective

A pilot case control study over a 10 year period to ascertain whether a dietary- and lifestyle modification Program in pwMS reduces or prevents WML formation.

Methods

MRI was performed at baseline and after an interval period of at least 10 years or longer in 22 pwMS. WML volumes were determined using Sequence Adaptive Multimodal SEGmentation (SAMSEG) software, part of FreeSurfer 7.2. Other variables include age at MRI, disease duration, disability status and medication.

Results

PwMS (n=13) who had followed the Program for more than 10 years, had significantly smaller lesion volumes (mm3) compared to pwMS who did not adhere to the Program (n=9) (4950 ± 5303 vs 17934 ± 11139; p=0.002). WML volumes were significantly associated (p=0.02) with disability (EDSS) but not with age (p=0.350), disease duration (p=0.709), or Interferon-β treatment (p=0.70).

Conclusion

Dietary- and lifestyle changes may lower the risk of developing cerebral WMLs in pwMS and potentially slow down disease progression. Larger studies are required to confirm the effectiveness of such interventions in pwMS.
Optimizing delivery strategies for 3HP TB preventive treatment in Tanzania: A qualitative study on acceptability of family approach in HIV care and treatment centers
Authors: Pamba Doreen , Sanga Erica , Mlalama Killian , Maganga Lucas , Mangu Chacha , Lwilla Anange , Olomi Willyhelmina , Minja Lilian Tina , Sabi Issa , Kisonga Riziki , Matechi Emmanuel , Jelly Isaya , Neema Peter , Rwebembera Anath , Aboud Said , Ntinginya Nyanda Elias
Published: April 2024

Introduction

Tanzania rolled-out a 12-dose, weekly regimen of isoniazid plus rifapentine (3HP) TB preventive treatment in January, 2024. Although 3HP completion rate is generally ≥ 80%, variations exist depending on type of delivery strategy and programmatic setting. Prior to the roll-out, a mixed methods study was conducted to assess whether a family approach involving family member support, SMS reminders and three health education sessions, was acceptable and optimized 3HP uptake and completion. This paper describes acceptability of the family approach among people living with HIV (PLHIV), treatment supporters (TS) and community health workers (CHWs).

Methods

This was a qualitative descriptive study in 12 HIV care and treatment centers across six administrative regions. We purposively sampled 20 PLHIV, 12 CHWs for in-depth interviews and 23 TS for three focus group discussions held between September to December, 2023. The theoretical framework of acceptability guided thematic-content analysis using a framework approach.

Results

Participants understood that PLHIV have high risk for active TB and that 3HP provides shortened treatment for TB disease prevention. They reported gaining TB and 3HP knowledge from health education sessions. However, participation of TS in health education sessions was low and many reported expensive transportation costs to clinics. Receiving support from someone close and SMS were perceived as good adherence reminders. The majority reported mild self-limiting side effects but expressed positive attitudes because of the shortened treatment, TB counselling, satisfaction from helping others, alignment with lifestyle and work responsibilities and reduced work burden. Some PLHIV reported difficulties in identifying family members for support thus, chose other close friends or CHWs.

Conclusions

Delivery of 3HP with support from family members and SMS reminders is widely accepted by CHWs, PLHIVs and TS. Restricting support from only family members was unacceptable and attendance of all three health education sessions by TS may not be feasible.
Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases
Authors: Taeubert M. Jazmin , Kuipers Thomas B. , Zhou Jiayi , Li Chihua , Wang Shuang , Wang Tian , Tobi Elmar W. ,   BBMRI-NL Metabolomics consortium, Belsky Daniel W. , Lumey L. H. , Heijmans Bastiaan T.
Published: April 2024

Background

Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type-2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to provide a deeper insight into the metabolic changes associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and explore their link to disease.

Methods

NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases.

Results

Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3×10-3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type-2 diabetes (r = 0.77, p = 3×10-27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1×10-18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 :< r :< 0.9, p < 3.2×10-4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index.

Conclusions

Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.
Evaluating biomedical feature fusion on machine learning’s predictability and interpretability of COVID-19 severity types
Authors: West-Page Haleigh , McGoff Kevin , Latimer Harrison , Olufadewa Isaac , Chen Shi
Published: April 2024

Background

Accurately differentiating severe from non-severe COVID-19 clinical types is critical for the healthcare system to optimize workflow, as severe patients require intensive care. Current techniques lack the ability to accurately predict COVID-19 patients’ clinical type, especially as SARS-CoV-2 continues to mutate.

Objective

In this work, we explore both predictability and interpretability of multiple state-of-the-art machine learning (ML) techniques trained and tested under different biomedical data types and COVID-19 variants.

Methods

Comprehensive patient-level data were collected from 362 patients (214 severe, 148 non-severe) with the original SARS-CoV-2 variant in 2020 and 1000 patients (500 severe, 500 non-severe) with the Omicron variant in 2022-2023. The data included 26 biochemical features from blood testing and 26 clinical features from each patient’s clinical characteristics and medical history. Different types of ML techniques, including penalized logistic regression (LR), random forest (RF),k-nearest neighbors (kNN), and support vector machines (SVM) were applied to build predictive models based on each data modality separately and together for each variant set.

Results

All ML models performed similarly under different testing scenarios. The fused characteristic modality yielded the highest area under the curve (AUC) score achieving 0.914 on average. The second highest AUC was 0.876 achieved by the biochemical modality alone, followed by 0.825 achieved by clinical modality alone. All ML models were robust when cross-tested with original and Omicron variant patient data. Upon model interpretation, our models ranked elevated d-dimer (biochemical feature), elevated high sensitivity troponin I (biochemical feature), and age greater than 55 years (clinical feature) as the most predictive features of severe COVID-19.

Conclusions

We found ML to be a powerful tool for predicting severe COVID-19 based on comprehensive individual patient-level data. Further, ML models trained on the biochemical and clinical modalities together witness enhanced predictive power. The improved performance of these ML models when trained and cross-tested with Omicron variant data supports the robustness of ML as a tool for clinical decision support.
“It’s not about the money, money” - Well, actually it is. Divergent views on drivers of early phase clinical trial participation among ethnically diverse potential trial participants in the United Kingdom: A Mixed Methods Study
Authors: Hortelano Pilar Artiach , Morton Neil , Wicks Paul , Young Michael , Burdell Rebecca , Richards Duncan
Published: April 2024

Background

Novel therapeutics should always be tested in a sample representative of the population in need of treatment. Initial efforts of drug development take place in early phase trials (phase-I and -II), setting the direction for late-stage studies (phase-III and -IV). However, study samples in early phase trials typically fail to recruit Black, Asian and minority ethnic groups, which might produce results which don’t generalise to a broader population in later trials, and ultimately, clinical practice. Focusing on early phase clinical trials the present study (1) explored the barriers and incentives that determine participation of ethnic minorities in clinical research, and (2) proposes strategies that mitigate such barriers.

Methods

A systematic literature review explored barriers affecting participation rates from individuals from diverse ethnic backgrounds. An exploratory phase involved two online surveys (researchers and general population) and focus groups (general population) analysed using thematic analysis.

Results

The systematic review found little published evidence, with most studies undertaken in the USA and focused on specific clinical areas. The exploratory phase showed a discordance between researchers’ and general public’s perspectives on both drivers and barriers to early phase trial participation.

Discussion

These findings were synthesised into aClinical Trials Participatory Framework, which contextualises reasons for reduced trial participation, while providing mechanisms/strategies to increase uptake among minority ethnic participants. This may guide researchers when implementing strategies to aid under-representation in their samples. Further research should evaluate the framework by actively implementing, testing, and iterating upon the strategies.
Trust and transfer during the covid-19 pandemic: did digital cash transfer save lives?
Authors: Tampubolon Gindo
Published: April 2024

BACKGROUND

In the first semester of 2020 one in six people in the world (1.36 billion) received cash transfers to tide them over the spreading pandemic that originated in Wuhan. By December 2021 it had claimed up to 18.2 million excess deaths. Compared to no (digital) transfer, did digital cash transfer reduce excess deaths? Serendipitously, two years earlier the world reported levels of trust in science. Did such trust inoculate societies from the pandemic?

MATERIALS & METHODS

The growing excess deaths literature distinguishes causal factors (e.g. digital transfer) from risk factors (e.g. trust). During the pandemic period, no randomised trials of digital transfer with excess deaths as primary outcome were registered. This study used reports from 170 countries and applied endogenous treatment models to overcome the endogeneity of digital transfer.

RESULTS & DISCUSSION

I found that serendipity matters: countries with high trust in science suffered fewer excess deaths. But creativity matters more. Digital transfers –some creatively scrambled from scratch– reduced excess deaths by many more. Equally marked, North-South inequity in excess deaths persists, consistent with the concentration of vaccine distributions in the North early on. All three are statistically significant.

A series of robustness analyses points to the results being reliable to change in outcome estimates, change in trust sources, and change in treatment of omitted countries. Mechanistic analyses show evidence that digital transfer created leg room for governments to expand stringent restrictions to control the spread of SARS-CoV-2, while in the South it weakened the correlation between informal economy and excess deaths. This study of the causal effect of digital cash transfer on a hard outcome (excess deaths) revealed ample global digital dividends across the largest number of countries. This new evidence also suggests that improving and monitoring trust in science can offer considerable benefits for humanity.
Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer
Authors: Zhang Yin , Lindström Sara , Kraft Peter , Liu Yuxi
Published: April 2024

Importance

Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown.

Objective

To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers.

Design, Setting, and Participants

We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank.

Exposures

Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet).

Main Outcomes and Measures

Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer.

Results

A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). An unfavorable lifestyle (highest vs. lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest.

Conclusions and Relevance

Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.
Identification of novel candidate genes associated with the symbiotic compatibility of soybean with rhizobia under natural conditions
Authors: Teraishi Masayoshi , Sakaguchi Kosuke , Tsuchimoto Takahiro , Yoshikawa Takanori
Published: April 2024

A robust symbiotic relationship between soybean and rhizobia can enhance the yield and quality of soybeans by reducing nitrogen fertilizer inputs, thereby contributing to sustainable agriculture. The genetic interplay between soybean cultivars and the rhizobial species colonizing their roots under natural conditions remains underexplored. This study builds on the observation that the prevalence of rhizobial species associated with the soybean cultivars ‘Peking’ and ‘Tamahomare’ varies significantly. Herein, we performed a quantitative trait loci (QTL) analysis of the proportion ofRhizobiumspecies present in the root nodules of these cultivars using recombinant inbred lines derived from a cross between ‘Peking’ and ‘Tamahomare.’ A major QTL was identified on chromosome 18, accounting for 42% of the phenotypic variation, and was subsequently localized to a 240 kb region. The RNA-seq analysis indicated that a single gene featuring nucleotide binding site–leucine-rich repeat domains exhibited markedly different expression levels in parent cultivars within the QTL region. As this locus is distinct from the chromosomal regions containing known nodule-related genes, such asRjorrj, it likely represents a novel gene involved in symbiosis between rhizobia and soybeans. Further research of the function and role of this new gene has potential to improve soybean yield and contribute to sustainable agriculture under low nitrogen fertilizer conditions.
Sepal shape variability is robust to cell size heterogeneity in Arabidopsis
Authors: Trinh Duy-Chi , Lionnet Claire , Trehin Christophe , Hamant Olivier
Published: April 2024

How organisms produce organs with robust shapes and sizes is still an open question. In recent years, the Arabidopsis sepal has been used as a model system to study this question because of its highly reproducible shape and size. One interesting aspect of the sepal is that its epidermis contains cells with very different sizes. Previous reports had qualitatively shown that sepals with more or less giant cells exhibit comparable final size and shape. Here we investigate this question using quantitative approaches. We find that a mixed population of cell size modestly contribute to the normal width of the sepal, but is not essential for its shape robustness. Furthermore, in a mutant with increased cell and organ growth variability, the change in final sepal shape caused by giant cells is exaggerated, but the shape robustness is not affected. This formally demonstrates that sepal shape variability is robust to cell size heterogeneity.

Main conclusion

A mixed population of cells with varied sizes plays a limited role in ensuring the symmetrical shape of the sepal, and is not essential for sepal shape robustness in Arabidopsis.
Impairment of proteasome-associated deubiquitinating enzyme Uchl5/UBH-4 affects autophagy
Authors: Jha Sweta , Pispa Johanna , Holmberg Carina I.
Published: April 2024

The autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS) are the two major intracellular proteolytic systems that mediate protein turnover in eukaryotes. Although a crosstalk exists between these two systems, it is still unclear how UPS and ALP interactin vivo. Here, we have investigated how impaired function of the proteasome-associated deubiquitinating enzyme (DUB) Uchl5/UBH-4, a regulator of proteasome activity, affects autophagy in human cells and in various tissues in a multicellular organism. We have used the established GFP-LC3-RFP-LC3ΔG autophagy reporter HeLa cell line and show that downregulation ofUchl5by siRNA reduces autophagy, which is similar to a previously reported role of the proteasome-associated DUB Usp14 on autophagy. ExposingCaenorhabditis eleganscarrying the autophagy reporter mCherry::GFP::LGG-1 toubh-4orusp-14RNAi, or to their pharmacological inhibitors, results in diverse effects regarding the numbers of autophagosomes and autolysosomes in the intestine, hypodermal seam cells and the pharynx. Our results reveal that the proteasome-associated DUBs Uchl5/UBH-4 and Usp14 affect autophagy in a differential tissue manner. A deeper insight into the interplay between UPS and ALP in various tissuesin vivohas the potential to promote development of therapeutic approaches for disorders associated with proteostasis dysfunction.

Modulation of UPS via pharmacological or genetic impairment of the proteasome-associated DUB Uchl5/UBH-4 affects autophagy in human cells and in a tissue-differential manner inC. elegans.
Super-resolution going viral: T4 virus particles as perfect nature-designed 3D-Bio-NanoRulers
Authors: Gallea José Ignacio , Nevskyi Oleksii , Kaźmierczak Zuzanna , Chen Tao , Miernikiewicz Paulina , Chizhik Anna , Dąbrowska Krystyna , Bates Mark , Enderlein Jörg
Published: April 2024

In the burgeoning field of super-resolution fluorescence microscopy, significant efforts are being dedicated to expanding its applications into the three-dimensional domain. Various methodologies have been developed that enable isotropic resolution at the nanometer scale, facilitating the visualization of three-dimensional subcellular structures with unprecedented clarity. Central to this progress is the need for reliable 3D structures that are biologically compatible for validating resolution capabilities. Choosing the optimal standard poses a considerable challenge, necessitating, among other attributes, precisely defined geometry and the capability for specific labeling at sub-diffraction-limit distances.

In this context, we introduce the use of the non-human-infecting virus, bacteriophage T4, as an effective and straightforward bio-ruler for three-dimensional super-resolution imaging. Employing DNA point accumulation for imaging in nanoscale topography (DNA-PAINT) along with the technique of astigmatic imaging, we uncover the icosahedral capsid of the bacteriophage T4, measuring 120 nm in length and 86 nm in width, and its hollow viral tail. This level of detail in light microscopy represents a significant advancement. We further outline a simple protocol for the production and preparation of samples. Moreover, we explore the extensive potential of bacteriophage T4 as a multi-faceted 3D bio-ruler, proposing its application as a novel benchmark for three-dimensional super-resolution imaging in biological studies.
Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy
Authors: Pandya Pinakin , Vendetti Frank P. , El-Ghoubaira Joseph , Pathak Sudipta , Deppas Joshua J. , Jones Reyna , Columbus Anthony V. , Zhang Yunqi , Ivanov Daniel , Huang Ziyu , MacDonald Kate M. , Harding Shane M. , Buj Raquel , Aird Katherine M. , Beumer Jan H. , Sobol Robert W. , Bakkenist Christopher J.
Published: April 2024

DNA damage and cytoplasmic DNA induce type-1 interferon (IFN-1) and potentiate responses to immune checkpoint inhibitors. Our prior work found that inhibitors of the DNA damage response kinase ATR (ATRi) induce IFN-1 and deoxyuridine (dU) incorporation by DNA polymerases, akin to antimetabolites. Whether and how dU incorporation is required for ATRi-induced IFN-1 signaling is not known. Here, we show that ATRi-dependent IFN-1 responses require uracil DNA glycosylase (UNG)-initiated base excision repair and STING. Quantitative analyses of nine distinct nucleosides reveals that ATRi induce dU incorporation more rapidly in UNG wild-type than knockout cells, and that induction of IFN-1 is associated with futile cycles of repair. While ATRi induce similar numbers of micronuclei in UNG wild-type and knockout cells, dU containing micronuclei and cytoplasmic DNA are increased in knockout cells. Surprisingly, DNA fragments containing dU block STING-dependent induction of IFN-1, MHC-1, and PD-L1. Furthermore, UNG knockout sensitizes cells to IFN-γin vitro, and potentiates responses to anti-PD-L1 in resistant tumorsin vivo. These data demonstrate an unexpected and specific role for dU-rich DNA in suppressing STING-dependent IFN-1 responses, and show that UNG-deficient tumors have a heightened response to immune checkpoint inhibitors.

STATEMENT OF SIGNIFICANCE

Antimetabolites disrupt nucleotide pools and increase dU incorporation by DNA polymerases. We show that unrepaired dU potentiates responses to checkpoint inhibitors in mouse models of cancer. Patients with low tumor UNG may respond to antimetabolites combined with checkpoint inhibitors, and patients with high tumor UNG may respond to UNG inhibitors combined with checkpoint inhibitors.
Re-appraising the role of T-cell derived interferon gamma in restriction ofMycobacterium tuberculosisin the murine lung
Authors: Maciag Karolina , Plumlee Courtney , Cohen Sara , Gern Benjamin , Urdahl Kevin
Published: April 2024

T cells producing interferon gamma (IFNγ) have long been considered a stalwart for immune protection againstMycobacterium tuberculosis(Mtb), but their relative importance to pulmonary immunity has been challenged by murine studies which achieved protection by adoptively transferredMtb-specific IFNγ-/-T cells. Using IFNγ-/-T cell chimeric mice and adoptive transfer of IFNγ-/-T cells into TCRβ-/-δ-/-mice, we demonstrate that control of lungMtbburden is in fact dependent on T cell-derived IFNγ, and furthermore, mice selectively deficient in T cell-derived IFNγ develop exacerbated disease compared to T cell-deficient controls despite equivalent lung bacterial burdens. Deficiency in T cell-derived IFNγ skews infected and bystander monocyte-derived macrophages (MDMs) to an alternative M2 phenotype, and promotes neutrophil and eosinophil influx. Our studies support an important role for T cell-derived IFNγ in pulmonary immunity against TB.
Dietary protein source alters gut microbiota composition and function
Authors: Blakeley-Ruiz J. Alfredo , Bartlett Alexandria , McMillan Arthur S , Awan Ayesha , Vanhoy Walsh Molly , Meyerhoffer Alissa K , Vintila Simina , Maier Jessie L , Richie Tanner , Theriot Casey M , Kleiner Manuel
Published: April 2024

The source of protein in a persons diet affects their total life expectancy. However, the mechanisms by which dietary protein sources differentially impact human health and life expectancy are poorly understood. Dietary choices have major impacts on the composition and function of the intestinal microbiota that ultimately modulate host health. This raises the possibility that health outcomes based on dietary protein sources might be driven by interactions between dietary protein and the gut microbiota. In this study, we determined the effects of seven different sources of dietary protein on the gut microbiota of mice using an integrated metagenomics-metaproteomics approach. The protein abundances measured by metaproteomics can provide microbial species abundances, and evidence for the molecular phenotype of microbiota members because measured proteins indicate the metabolic and physiological processes used by a microbial community. We showed that dietary protein source significantly altered the species composition and overall function of the gut microbiota. Different dietary protein sources led to changes in the abundance of microbial proteins involved in the degradation of amino acids and the degradation of glycosylations conjugated to dietary protein. In particular, brown rice and egg white protein increased the abundance of amino acid degrading enzymes. Egg white protein increased the abundance of bacteria and proteins usually associated with the degradation of the intestinal mucus barrier. These results show that dietary protein sources can change the gut microbiotas metabolism, which could have major implications in the context of gut microbiota mediated diseases.
High temperature treatment optimized for symbiont suppression in an obligatory gut bacterial symbiosis in the stinkbugPlautia stali
Authors: Cai Wen-Jin , Moriyama Minoru , Fukatsu Takema
Published: April 2024

In the era of global warming, much attention has been paid to the possibility that high temperature may influence diverse insects not only directly but also indirectly via effects on their symbiotic microorganisms. The stinkbugPlautia stalidevelops a midgut symbiotic organ that harbors a specific bacterial symbiont indispensable for its growth and survival. Being maintainable in laboratory and tractable experimentally,P. staliis recently highlighted as a model system to investigate the mechanisms underpinning insect-microbe symbiotic interactions. In this study, we reared newly-emerged adult insects ofP. staliunder different temperature conditions for 8 days and monitored how their symbiotic organs and symbiotic bacteria are affected. While all insects survived at temperatures from 25°C to 37°C, some insects died at 38°C, 39°C and 40°C, wherein mortality rates increased as temperature elevated. While the symbiotic organs of the normal insects exhibited vivid yellow color, the symbiotic organs of the insects reared at 35°C or higher frequently exhibited abnormal colors such as pale yellow, yellowish white, or white, the extent of which became more severe as temperature elevated. Symbiont quantification revealed that, while the symbiont titers were almost constant for 8 days at 25°C and 30°C, the symbiont titers on the 8thday drastically declined to 1/100 at 35℃ and 1/10000 at 37°C and 39°C. Based on these results, we propose that rearing at 37°C for a week is a recommended treatment regime by which the symbiont is effectively suppressed with minimal damage to the host insect.
Modulation of metastable ensemble dynamics explains optimal coding at moderate arousal in auditory cortex
Authors: Papadopoulos Lia , Jo Suhyun , Zumwalt Kevin , Wehr Michael , McCormick David A. , Mazzucato Luca
Published: April 2024

Performance during perceptual decision-making exhibits an inverted-U relationship with arousal, but the underlying network mechanisms remain unclear. Here, we recorded from auditory cortex (A1) of behaving mice during passive tone presentation, while tracking arousal via pupillometry. We found that tone discriminability in A1 ensembles was optimal at intermediate arousal, revealing a population-level neural correlate of the inverted-U relationship. We explained this arousal-dependent coding using a spiking network model with a clustered architecture. Specifically, we show that optimal stimulus discriminability is achieved near a transition between a multi-attractor phase with metastable cluster dynamics (low arousal) and a single-attractor phase (high arousal). Additional signatures of this transition include arousal-induced reductions of overall neural variability and the extent of stimulus-induced variability quenching, which we observed in the empirical data. Our results elucidate computational principles underlying interactions between pupil-linked arousal, sensory processing, and neural variability, and suggest a role for phase transitions in explaining nonlinear modulations of cortical computations.