bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-cost predictive models of dementia risk using machine learning and exposome predictors
Authors: Camacho Marina , Atehortúa Angélica , Wilkinson Tim , Gkontra Polyxeni , Lekadir Karim
Published: May 2023

Diagnosing dementia, a syndrome that currently affects more than 55 million people worldwide, remains a particularly challenging and costly task. It may involve undertaking several medical tests such as brain scans, cognitive tests and genetic tests to determine the presence and degree of cognitive decline. These procedures are associated with long procedures, subjective evaluations and high costs. As a result, patients are often diagnosed at a late stage, when symptoms become highly pronounced. Therefore, there is an urgent need for developing new strategies for early, accurate and cost-effective dementia screening and risk prediction. To overcome current limitations, we explored readily available exposome predictors for identifying individuals at risk of dementia and compared traditional statistical modeling and advanced machine learning.

From approximately 500,000 participants from the UK Biobank, 1523 participants diagnosed with dementia after their baseline assessment visit were included in our study. An equal number of healthy participants were randomly selected as the control group by matching statistical age mean and sex distribution. This resulted in a total of 3046 participants being selected for our study; 2740 participants from 19 of the 22 UK Biobank assessment centers were used for internal validation, and 306 participants from the remaining three centers were selected for external validation. We include data from the participants’ baseline visit and selected 128 low-cost exposome factors related to life course exposures that may be easily acquired through simple questionnaires. Subsequently, data imputation was performed to account for missing patient data. Two different predictive models were assessed for discriminating between participants that remained healthy and participants diagnosed with dementia after the baseline visit, i.e. (1) a classical logistic regression linear classifier and (2) a machine learning ensemble classifier based on XGBoost. We interpreted the results by estimating feature importance within the predictive models.

Our results demonstrate that machine learning models based on exposome data can reliably identify individuals that will be diagnosed with dementia. The XGBoost based model outperforms logistic regression model, achieving a mean AUC of 0.88 in the external validation tests. We identified novel exposome factors that might be combined as potential markers for dementia, such as facial aging, the frequency of use of sun/ultraviolet light protection, and the length of mobile phone use. Finally, we propose a novel neurocognitive assessment test that could be used as an online tool to screen individuals at risk of dementia for enrolment in preventive interventions and future clinical trials.
The plasma metabolome of long COVID-19 patients two years after infection
Authors: López-Hernández Yamilé , Aquino Joel Monárrez , García López David Alejandro , Zheng Jiamin , Borrego Juan Carlos , Torres-Calzada Claudia , Elizalde-Díaz José Pedro , Mandal Rupasri , Berjanskii Mark , Martínez-Martínez Eduardo , López Jesús Adrián , Wishart David S.
Published: May 2023

Background

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. The World Health Organization (WHO) recognized long COVID as a distinct clinical entity in 2021. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. This has put a tremendous strain on still-overstretched healthcare systems around the world.

Methods

In this study, our goal was to assess the plasma metabolome in a total of 108 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC-MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin concentrations were measured in long COVID patients by immunoenzymatic assay.

Results

The comparison of paired COVID-19/post-COVID-19 samples revealed 53 metabolites that were statistically different (FDR < 0.05). Compared to controls, 29 metabolites remained dysregulated even after two years. Notably, glucose, kynurenine, and certain acylcarnitines continued to exhibit altered concentrations similar to the COVID-19 phase, while sphingomyelins and long saturated and monounsaturated LysoPCs, phenylalanine, butyric acid, and propionic acid levels normalized. Post-COVID-19 patients displayed a heterogeneous metabolic profile, with some showing no symptoms while others exhibiting a variable number of symptoms. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, sarcosine, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients.

Conclusions

Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.
SARS-CoV-2 specific cellular and humoral immunity after bivalent BA.4/5 COVID-19 vaccination in previously infected and non-infected individuals
Authors: Urschel Rebecca , Bronder Saskia , Klemis Verena , Marx Stefanie , Hielscher Franziska , Abu-Omar Amina , Guckelmus Candida , Schneitler Sophie , Baum Christina , Becker Sören L. , Gärtner Barbara C. , Sester Urban , Widera Marek , Schmidt Tina , Sester Martina
Published: May 2023

Knowledge is limited as to how prior SARS-CoV-2 infection influences cellular and humoral immunity after booster-vaccination with bivalent BA.4/5-adapted mRNA-vaccines, and whether vaccine-induced immunity correlates with subsequent infection. In this observational study, individuals with prior infection (n=64) showed higher vaccine-induced anti-spike IgG antibodies and neutralizing titers, but the relative increase was significantly higher in non-infected individuals (n=63). In general, both groups showed higher neutralizing activity towards the parental strain than towards Omicron subvariants BA.1, BA.2 and BA.5. In contrast, CD4 or CD8 T-cell levels towards spike from the parental strain and the Omicron subvariants, and cytokine expression profiles were similar irrespective of prior infection. Breakthrough infections occurred more frequently among previously non-infected individuals, who had significantly lower vaccine-induced spike-specific neutralizing activity and CD4 T-cell levels. Thus, the magnitude of vaccine-induced neutralizing activity and specific CD4 T-cells after bivalent vaccination may serve as a correlate for protection in previously non-infected individuals.
Changing Trends in Mechanical Circulatory Support Utilization and Outcomes in Patients Undergoing Percutaneous Coronary Interventions for Acute Coronary Syndrome Complicated with Cardiogenic Shock: Insights from a Nationwide Registry in Japan
Authors: Nishimoto Yuji , Inohara Taku , Kohsaka Shun , Sakakura Kenichi , Kawai Tsutomu , Kikuchi Atsushi , Watanabe Tetsuya , Yamada Takahisa , Fukunami Masatake , Yamaji Kyohei , Ishii Hideki , Amano Tetsuya , Kozuma Ken ,   J-PCI Registry Investigators
Published: May 2023

Background

Temporal trends in the management of acute coronary syndrome (ACS) complicated with cardiogenic shock (CS) after the revision of the guideline recommendations for intra-aortic balloon pump (IABP) use and the approval of the Impella require further investigation as their impact remains uncertain.

Methods

Using the Japanese Percutaneous Coronary Intervention (J-PCI) registry database from 2019 to 2021 (734,379 patients from 1,190 hospitals), we extracted 24,516 patients undergoing PCI for ACS complicated with CS. Of those, 12,171 patients (49.6%) used mechanical circulatory support (MCS) during the procedure. The patients were stratified into three groups: (i) IABP alone, (ii) Impella, and (iii) venoarterial extracorporeal membrane oxygenation (VA-ECMO); the VA-ECMO group was further stratified into (iiia) VA-ECMO alone, (iiib) VA-ECMO in combination with the IABP, and (iiic) VA-ECMO in combination with the Impella (ECPella). The quarterly prevalence and outcomes were reported.

Results

During the study period, there were notable changes in the prevalence of different MCS modalities and their associated outcomes. The use of an IABP alone and VA-ECMO decreased significantly from 63.5% and 34.4% in the first quarter of 2019 to 58.3% and 33.0% in the fourth quarter of 2021, respectively (P for trend = 0.01 and 0.02, respectively). Among the subset of patients who required VA-ECMO (n= 4,245), the use of VA-ECMO in combination with the IABP decreased significantly from 78.7% to 67.3%, whereas the use of ECPella increased significantly from 4.2% to 17.0% (P for trend <0.001 for both). There was no significant change in the use of VA-ECMO alone. In-hospital mortality decreased significantly over time in both the overall population of patients requiring MCS and those requiring VA-ECMO (P for trend = 0.004 and <0.001, respectively).

Conclusions

In conclusion, our study revealed significant changes in the use of different MCS modalities and associated outcomes in ACS complicated with CS, highlighting the evolving patterns of MCS utilization during the study period.
The Dark Side of Mentalizing: Learning Signals in the Default Network During Social Exchanges Support Cooperation and Exploitation
Authors: Allen Timothy A. , Hallquist Michael N. , Dombrovski Alexandre Y.
Published: May 2023

The evolution of human social cognitive capacities such as mentalizing was associated with the expansion of frontoparietal cortical networks, particularly the default network. Mentalizing supports prosocial behaviors, but recent evidence indicates it may also serve a darker side of human social behavior. Using a computational reinforcement learning model of decision-making on a social exchange task, we examined how individuals optimized their approach to social interactions based on a counterpart’s behavior and prior reputation. We found that learning signals encoded in the default network scaled with reciprocal cooperation and were stronger in individuals who were more exploitative and manipulative, but weaker in those who were more callous and less empathic. These learning signals, which help to update predictions about others’ behavior, accounted for associations between exploitativeness, callousness, and social reciprocity. Separately, we found that callousness, but not exploitativeness, was associated with a behavioral insensitivity to prior reputation effects. While the entire default network was involved in reciprocal cooperation, sensitivity to reputation was selectively related to the activity of the medial temporal subsystem. Overall, our findings suggest that the emergence of social cognitive capacities associated with the expansion of the default network likely enabled humans to not only cooperate effectively with others, but to exploit and manipulate others as well.

Significance

To navigate complex social lives, humans must learn from their interactions with others and adjust their own behavior accordingly. Here, we show that humans learn to predict the behavior of social counterparts by integrating reputational information with both observed and counterfactual feedback acquired during social experience. We find that superior learning during social interactions is related to empathy and compassion and associated with activity of the brain’s default network. Paradoxically however, learning signals in the default network are also associated with manipulativeness and exploitativeness, suggesting that the ability to anticipate others’ behavior can serve both the light and dark sides of human social behavior.
Multiplexed fluorescence and scatter detection with single cell resolution using on-chip fiber optics for droplet microfluidic applications
Authors: Gupta Preksha , Mohan Ambili , Mishra Apurv , Nair Atindra , Chowdhury Neeladri , Balekai Dhanush , Rai Kavyashree , Mehta Pooja , Prabhakar Anil , Saiyed Taslimarif
Published: May 2023

Droplet microfluidics has emerged as a critical component of several high-throughput single cell analysis techniques in biomedical research and diagnostics. However, while there has been significant progress in the individual assays being developed, multi-parametric optical sensing of droplets and their encapsulated contents remains challenging. The current common approach of microscopy based high-speed imaging of droplets is technically complex and requires expensive instrumentation limiting their large-scale adoption. Here we have adapted the principles of the widely established technique of flow cytometry to a novel optofluidic setup – the OptiDrop platform, with on-chip detection of scatter and multiple fluorescence signals from microfluidic droplets and their contents using optical fibers. The highly customizable on-chip optical fiber-based signal detection system enables simplified, miniaturized, low-cost, multi-parametric sensing of optical signals with high sensitivity and single cell resolution within each droplet. Our work on differential expression analysis of the Major Histocompatibility Complex (MHC) protein in response to IFNγ stimulation further demonstrates the OptiDrop platforms capabilities in sensitively detecting cell surface biomarkers using fluorescently labeled antibodies. The OptiDrop platform thus combines the versatility of flow cytometry with the power of droplet microfluidics to provide wide-ranging optical sensing solutions for research and diagnostics.
Generation of a humanTropomyosin 1knockout iPSC line
Authors: Wilken Madison B , Maguire Jean Ann , Dungan Lea V , Gagne Alyssa , Osorio-Quintero Catherine , Waxman Elisa A , Chou Stella T , Gadue Paul , French Deborah L , Thom Christopher S
Published: May 2023

The CHOPWT17_TPM1KOc28 iPSC line was generated to interrogate the functions ofTropomyosin 1(TPM1) in primary human cell development. This line was reprogrammed from a previously published wild type control iPSC line.
Endothelial cells signaling and patterning under hypoxia: a mechanistic integrative computational model including the Notch-Dll4 pathway
Authors: Oliveira Rebeca Hannah M , Annex Brian H. , Popel Aleksander S.
Published: May 2023

Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between normoxia and hypoxia can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis. We calibrate and fit the model parameters based on well-established modeling techniques. Our results indicate that the main pathways involved in the patterning of tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia affects how a reaction affects patterning. Interestingly, the interaction of receptors with Neuropilin1 is also relevant for cell patterning. Our simulations under different oxygen concentrations indicate time- and oxygen-availability-dependent responses for the two cells. Following simulations with various stimuli, our model suggests that factors such as period under hypoxia and oxygen availability must be considered for pattern control. This project provides insights into the signaling and patterning of endothelial cells under hypoxia, contributing to studies in the field.
Engineered cytokine/antibody fusion proteins improve delivery of IL-2 to pro-inflammatory cells and promote antitumor activity
Authors: Leonard Elissa K. , Tomala Jakub , Gould Joseph R. , Leff Michael I. , Lin Jian-Xin , Li Peng , Porter Mitchell J. , Johansen Eric R. , Thompson Ladaisha , Cao Shanelle D. , Henclova Tereza , Huliciak Maros , Vaněk Ondřej , Kovar Marek , Leonard Warren J. , Spangler Jamie B.
Published: May 2023

Progress in cytokine engineering is driving therapeutic translation by overcoming the inherent limitations of these proteins as drugs. The interleukin-2 (IL-2) cytokine harbors great promise as an immune stimulant for cancer treatment. However, the cytokine’s concurrent activation of both pro-inflammatory immune effector cells and anti-inflammatory regulatory T cells, its toxicity at high doses, and its short serum half-life have limited clinical application. One promising approach to improve the selectivity, safety, and longevity of IL-2 is complexation with anti-IL-2 antibodies that bias the cytokine towards the activation of immune effector cells (i.e., effector T cells and natural killer cells). Although this strategy shows therapeutic potential in preclinical cancer models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multi-protein drug and concerns about complex stability. Here, we introduce a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine’s activities towards immune effector cells. We establish the optimal IC construction and further engineer the cytokine/antibody affinity to improve immune biasing function. We demonstrate that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared to natural IL-2 without inducing toxicities associated with IL-2 administration. Collectively, this work presents a roadmap for the design and translation of immunomodulatory cytokine/antibody fusion proteins.

One Sentence Summary

We developed an IL-2/antibody fusion protein that expands immune effector cells and shows superior tumor suppression and toxicity profile versus IL-2.
Delivery of human adipose-derived stromal cells withinin situforming chitosan/PEG-PTMC hydrogels induces adverse outcomes in a femoral artery ligation model in athymicnu/numice
Authors: Serack Fiona E. , Ronald John A. , Amsden Brian G. , Hess David A. , Flynn Lauren E.
Published: May 2023

The delivery of human adipose-derived stromal cells (hASCs) to ischemic tissues represents a promising strategy to promote vascular regeneration for patients with critical limb ischemia (CLI). Building on previous work, this study focused on thein vivocharacterization of a hydrogel cell delivery platform for hASCs composed of peptide-functionalized methacrylated glycol chitosan (MGC-RGD) and a terminally acrylated triblock copolymer of poly(ethylene glycol) and poly(trimethylene carbonate) (PEG(PTMC-A)2) in athymicnu/numice with femoral artery ligation-induced critical limb ischemia (FAL-CLI). This immunodeficient mouse strain was selected to enable human cell transplantation in a model with conserved monocyte/macrophage function, recognizing that macrophages are key regulators of the biomaterial implant response, as well as vascular repair and regeneration. The hASCs were engineered to co-express tdTomato and firefly luciferase to enable longitudinal cell tracking using bioluminescence imaging (BLI). Interestingly, the hASCs were better retained following delivery in saline compared to hydrogel delivery. However, laser Doppler perfusion imaging (LDPI) analysis indicated that the restoration of hindlimb perfusion was similar between the two cell treatment groups. Critically, delivery of the hASCs within the hydrogels was associated with adverse outcomes only observed within this treatment group, including severe swelling, discoloration, and necrosis, which necessitated early euthanasia of some mice. CD45 staining supported that the combination of the cells and the hydrogels induced an inflammatory host response. These findings contrast with previous positive results when the platform was tested for hASC delivery in more severely immunocompromised NOD/SCID mice with FAL-CLI, as well as allogeneic rat ASC delivery in a healthy immunocompetent rat model. Overall, this study emphasizes the potential importance of testing cell delivery platforms in pre-clinical disease models that have retained host immune cell function, especially for immunomodulatory cell populations such as ASCs.
Direct quantification of chemogenetic H2O2production in live human cells
Authors: den Toom Wytze T. F. , van Soest Daan M. K. , Polderman Paulien E. , van Triest Miranda H. , Bruurs Lucas J. M. , De Henau Sasha , Burgering Boudewijn M. T. , Dansen Tobias B.
Published: May 2023

Reactive Oxygen Species (ROS) in the form of H2O2can act both as physiological signaling molecules as well as damaging agents, depending on its concentration and localization. The downstream biological effects of H2O2were often studied making use of exogenously added H2O2, generally as a bolus and at supraphysiological levels. But this does not mimic the continuous, low levels of intracellular H2O2production by for instance mitochondrial respiration. The enzyme D-Amino Acid Oxidase (DAAO) catalyzes H2O2formation using D-amino acids, which are absent from culture media, as a substrate. Ectopic expression of DAAO has recently been used in several studies to produce inducible and titratable intracellular H2O2. However, a method to directly quantify the amount of H2O2produced by DAAO has been lacking, making it difficult to assess whether observed phenotypes are the result of physiological or artificially high levels of H2O2. Here we describe a simple assay to directly quantify DAAO activity by measuring the oxygen consumed during H2O2production. The oxygen consumption rate of DAAO can directly be compared to the basal mitochondrial respiration in the same assay, allowing to estimate whether the ensuing level of H2O2production is within the range of physiological mitochondrial ROS production. We show that the assay can also be used to select clones that express differently localized DAAO with the same absolute level of H2O2production to be able to discriminate the effects of H2O2production at different subcellular locations from differences in total oxidative burden. This method therefore greatly improves the interpretation and applicability of DAAO-based models, thereby moving the redox biology field forward.
Inhibition of dopamine neurons prevents incentive value encoding of a reward cue: With revelations from deep phenotyping
Authors: Iglesias Amanda G. , Chiu Alvin S. , Wong Jason , Campus Paolo , Li Fei , Liu Zitong (Nemo) , Patel Shiv A. , Deisseroth Karl , Akil Huda , Burgess Christian R. , Flagel Shelly B.
Published: May 2023

The survival of an organism is dependent on their ability to respond to cues in the environment. Such cues can attain control over behavior as a function of the value ascribed to them. Some individuals have an inherent tendency to attribute reward-paired cues with incentive motivational value, or incentive salience. For these individuals, termed sign-trackers, a discrete cue that precedes reward delivery becomes attractive and desirable in its own right. Prior work suggests that the behavior of sign-trackers is dopamine-dependent, and cue-elicited dopamine in the nucleus accumbens is believed to encode the incentive value of reward cues. Here we exploited the temporal resolution of optogenetics to determine whether selective inhibition of ventral tegmental area (VTA) dopamine neurons during cue presentation attenuates the propensity to sign-track. Using male tyrosine hydroxylase (TH)-Cre Long Evans rats it was found that, under baseline conditions, ∼84% of TH-Cre rats tend to sign-track. Laser-induced inhibition of VTA dopamine neurons during cue presentation prevented the development of sign-tracking behavior, without affecting goal-tracking behavior. When laser inhibition was terminated, these same rats developed a sign-tracking response. Video analysis using DeepLabCut revealed that, relative to rats that received laser inhibition, rats in the control group spent more time near the location of the reward cue even when it was not present and were more likely to orient towards and approach the cue during its presentation. These findings demonstrate that cue-elicited dopamine release is critical for the attribution of incentive salience to reward cues.

Significance Statement

Activity of dopamine neurons in the ventral tegmental area (VTA) during cue presentation is necessary for the development of a sign-tracking, but not a goal-tracking, conditioned response in a Pavlovian task. We capitalized on the temporal precision of optogenetics to pair cue presentation with inhibition of VTA dopamine neurons. A detailed behavioral analysis with DeepLabCut revealed that cue-directed behaviors do not emerge without VTA dopamine. Importantly, however, when optogenetic inhibition is lifted, cue-directed behaviors increase, and a sign-tracking response develops. These findings confirm the necessity of VTA dopamine during cue presentation to encode the incentive value of reward cues.
Factors associated with non-use of ART among men living with HIV in South Africa: findings from a population-based household survey
Authors: Naqvi Nuha , Swart Xan , Chikovore Jeremiah , Ayalew Kassahun , Moyo Sizulu , Morof Diane , Makapela David , Bedford Jason
Published: May 2023

Introduction

Although South Africa adopted the World Health Organization’s Test and Treat strategy for HIV epidemic control in 2016, antiretroviral therapy (ART) treatment initiation and retention remain below target. In 2017, an estimated 56.3% of men living with HIV were on ART. We aimed to investigate factors associated with non-use of ART among men in South Africa.

Methods

Utilizing data from the fifth South African National HIV Prevalence, Incidence, Behavior and Communication (SABSSM V) cross-sectional survey conducted in 2017, a subset of data from HIV-positive men was stratified based on presence/absence of antiretroviral drugs (ARVs) detected in dried blood spot samples. Data were weighted to be representative of the national population and analyzed using multivariable logistic regression to assess predictors of non-use of ART; p<0.05 was considered significant.

Results

A total of 6,920 men aged ≥15 years old were enrolled in the study, of whom 953 (13.8%) tested HIV-positive. Among those HIV-positive, 810 (85%) had a known ARV test result: 470 (58%) had ARVs detected, and 340 (42%) did not have ARVs detected. Non-use of ART in men was associated with high-risk alcohol use (adjusted odds ratio (AOR)=3.68, 95% confidence interval (CI): 1.03-13.23), being a widower compared to being unmarried (AOR=6.99, 95%CI: 1.46-33.42), and having drug-resistant HIV (AOR=28.12, 95%CI: 13.89-56.94). Per year increase in age (AOR=0.67, 95%CI: 0.47-0.96), residence in rural tribal localities compared to urban localities (AOR=0.38, 95%CI: 0.18-0.78), or having a co-morbidity such as tuberculosis or diabetes (AOR=0.06, 95%CI: 0.03-0.14) were positively associated with ART use.

Conclusions

Non-use of ART was strongly associated with HIV drug resistance. Young men who are living with HIV, those with high-risk alcohol use, and widowers, should be a priority for HIV programming and linkage to care. Identifying interventions that are effective at linking these men to ART will help reduce the burden of HIV in South Africa.
Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer
Authors: Chen Dorothy M. , Dong Ruocheng , Kachuri Linda , Hoffmann Thomas , Jiang Yu , Berndt Sonja I. , Shelley John P. , Schaffer Kerry R. , Machiela Mitchell J. , Freedman Neal D. , Huang Wen-Yi , Li Shengchao A. , Lilja Hans , Van Den Eeden Stephen K. , Chanock Stephen , Haiman Christopher A. , Conti David V. , Klein Robert J. , Mosley Jonathan D. , Witte John S. , Graff Rebecca E.
Published: May 2023

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility to screen for prostate cancer (PCa). We thus conducted a transcriptome-wide association study (TWAS) of PSA levels using genome-wide summary statistics from 95,768 PCa-free men, the MetaXcan framework, and gene prediction models trained in Genotype-Tissue Expression (GTEx) project data. Tissue-specific analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10e-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61e-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses that combined associations across 45 tissues identified 155 genes that were statistically significantly (p < 0.05/22,249 = 2.25e-6) associated with PSA levels. Based on conditional analyses that assessed whether TWAS associations were attributable to a lead GWAS variant, we found 20 novel genes (11 single-tissue, 9 cross-tissue) that were associated with PSA levels in the TWAS. Of these novel genes, five showed evidence of colocalization (colocalization probability > 0.5):EXOSC9, CCNA2, HIST1H2BN, RP11-182L21.6, andRP11-327J17.2. Six of the 20 novel genes are not known to impact PCa risk. These findings yield new hypotheses for genetic factors underlying PSA levels that should be further explored toward improving our understanding of PSA biology.
Examining Generalizability of Nutrient-Based Food Patterns and Their Cross-Sectional Associations with Cardiometabolic Health for Hispanic/Latino Adults in the US: Results from the National Health and Nutrition Examination Survey (NHANES) and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Varela Jeanette J , Mattei Josiemer , Sotres-Alvarez Daniela , Mossavar-Rahmani Yasmin , McClain Amanda C , Maldonado Luis E , Daviglus Martha L , Stephenson Briana J.K.
Published: May 2023

Background

Ethnicity, cultural background, and geographic location differ significantly amongst the US Hispanic/Latino population. These characteristic differences can greatly define measured diet and its relationship with cardiometabolic disease, thus influencing generalizability of results.

Objective

We aimed to examine dietary patterns of Hispanic/Latino adults and their association with cardiometabolic risk factors (high cholesterol, hypertension, obesity, diabetes) across two representative studies with differing sampling strategies.

Methods

Data were collected from Mexican or Other Hispanic adult participants from 2007-2012 National Health and Nutrition Examination Survey (NHANES, n=3,209) and 2007-2011 Hispanic Community Health Survey/Study of Latinos (HCHS/SOL, n=13,059). Nutrient-based food patterns (NBFPs) were derived using factor analysis on nutrient intake data estimated from 24-hour dietary recalls and interpreted using common foods prominent in these nutrients. Cross-sectional association between NBFPs (quintiles) and cardiometabolic risk factors, defined by clinical measures and self-report, were estimated using survey-weighted logistic regression.

Results

Five NBFPs were identified in both studies: (1) meats, (2) grains/legumes, (3) fruits/vegetables, (4) dairy, and (5) fats/oils. Association to cardiometabolic risk factors differed by NBFP and study. In HCHS/SOL, persons in the highest quintile of meats NBFP had higher odds of diabetes (OR=1.43, 95%CI: 1.10, 1.86) and obesity (OR=1.36, 95%CI: 1.14, 1.63). Those in the lowest quintile of grains/legumes NBFP (OR=1.22, 95%CI: 1.02, 1.47) and the highest quintile of fats/oils (OR=1.26, 95%CI: 1.03, 1.53) also had higher odds of obesity. In NHANES, NBFPs associated with higher odds of diabetes included those in the lowest quintile of dairy (OR=1.66, 95%CI: 1.01, 2.72) and highest quintile of grains/legumes (OR=2.10, 95%CI: 1.26, 3.50). Persons in the fourth quintile of meats (OR=0.68, 95%CI: 0.47, 0.99) had lower odds of cholesterol.

Conclusion

Diet-disease relationships among Hispanic/Latino adults vary according to two representative studies. These differences have research and practical implications when generalizing inferences on heterogeneous underrepresented populations.
Structural and biochemical characterisation of the N-Carbamoyl-β-Alanine Amidohydrolase fromRhizobium radiobacterMDC 8606
Authors: Paloyan Ani , Sargsyan Armen , Karapetyan Mariam D. , Hambardzumyan Artur , Kocharov Sergey , Panosyan Henry , Dyukova Karine , Kinosyan Marina , Krüger Anna , Piergentili Cecilia , Stanley Will A. , Baslé Arnaud , Marles-Wright Jon , Antranikian Garabed
Published: May 2023

N-Carbamoyl-β-Alanine Amidohydrolase (CβAA) constitute one of the most important groups of industrially relevant enzymes used in production of optically pure amino acids and derivatives. In this study, a N-carbamoyl-β-alanine amidohydrolase encoding gene fromRhizobium radiobacterMDC 8606 was cloned and overexpressed inEscherichia coli. The purified recombinant enzyme (RrCβAA) showed a specific activity of 14 U/mg using N-carbamoyl-β-alanine as a substrate with an optimum activity of 55°C at pH 8.0. In this work, we report also the first prokaryotic N-carbamoyl-β-alanine amidohydrolases structure at a resolution of 2.0 Å. A discontinuous catalytic domain and a dimerization domain attached through a flexible hinge region at the domain interface has been revealed. We have found that the ligand is interacting with a conserved glutamic acid (Glu131), histidine (H385) and arginine (Arg291) residues. Studies let us to explain the preference on the enzyme for linear carbamoyl substrates as large carbamoyl substrates cannot fit in the active site of the enzyme. This work envisages the use of RrCβAA from theRhizobium radiobacterMDC 8606 for the industrial production of L-α-, L-β-, and L-γ – amino acids. The structural analysis provides new insights on enzyme–substrate interaction, which shed light on engineering of N-carbamoyl-β-alanine amidohydrolases for high catalytic activity and broad substrate specificity.
Human Smc5/6 recognises transcription-generated positive DNA supercoils
Authors: Diman Aurélie , Panis Gaël , Castrogiovanni Cédric , Prados Julien , Baechler Bastien , Strubin Michel
Published: May 2023

Beyond its essential roles in ensuring faithful chromosome segregation and genomic stability, the human Smc5/6 complex acts as an antiviral factor. It binds to and impedes the transcription of extrachromosomal DNA templates; an ability which is lost upon chromosomal DNA integration. How the complex distinguishes among different DNA templates is unknown. Here we show that, in human cells, Smc5/6 preferentially binds to circular rather than linear extrachromosomal DNA. We further show that this binding is unlikely due to differences in the chromatin composition. Instead, the transcriptional process, per se, and more specifically the accumulation of DNA secondary structures known to be substrates for topoisomerases, is responsible for Smc5/6 recruitment. Those findings, in conjunction with our genome-wide Smc5/6 binding analysis showing that Smc5/6 localizes at few but highly transcribe chromosome loci, reveal a previously unforeseen role of Smc5/6 in DNA topology management during transcription.
Anterior forebrain pathway in parrots is necessary for producing learned vocalizations with individual signatures
Authors: Zhao Zhilei , Teoh Han Kheng , Carpenter Julie , Nemon Frieda , Kardon Brian , Cohen Itai , Goldberg Jesse H.
Published: May 2023

Parrots have enormous vocal imitation capacities and produce individually unique vocal signatures. Like songbirds, parrots have a nucleated neural song system with distinct anterior (AFP) and posterior forebrain pathways (PFP). To test if song systems of parrots and songbirds, which diverged over 50 million years ago, have a similar functional organization, we first established a neuroscience-compatible call-and-response behavioral paradigm to elicit learned contact calls in budgerigars (Melopsittacus undulatus). Using variational autoencoder-based machine learning methods, we show that contact calls within affiliated groups converge but that individuals maintain unique acoustic features, or vocal signatures, even after call convergence. Next, we transiently inactivated the outputs of AFP to test if learned vocalizations can be produced by the PFP alone. As in songbirds, AFP inactivation had an immediate effect on vocalizations, consistent with a premotor role. But in contrast to songbirds, where the isolated PFP is sufficient to produce stereotyped and acoustically normal vocalizations, isolation of the budgerigar PFP caused a degradation of call acoustic structure, stereotypy, and individual uniqueness. Thus the contribution of AFP and the capacity of isolated PFP to produce learned vocalizations have diverged substantially between songbirds and parrots, likely driven by their distinct behavioral ecology and neural connectivity.
Structural basis and functional roles for Toll-like receptor binding to Latrophilin adhesion-GPCR in embryo development
Authors: Carmona-Rosas Gabriel , Li Jingxian , Smith Jayson J. , Cheng Shouqiang , Baltrusaitis Elana , Nawrocka Wioletta I. , Zhao Minglei , Kratsios Paschalis , Araç Demet , Özkan Engin
Published: May 2023

Latrophilins/ADGRLs are conserved adhesion-type G protein-coupled receptors associated with early embryonic morphogenesis defects, lethality, and sterility across multiple model organisms. However, their mechanistic roles in embryogenesis and the identity of their binding ligands remain unknown. Here, we identified a cell-surface receptor, TOL-1, the sole Toll-like receptor inC. elegans, as a novel ligand for theC. elegansLatrophilin, LAT-1. The extracellular lectin domain of LAT-1 directly binds to the second leucine-rich repeat domain of TOL-1. The highresolution crystal structure and the cryo-EM density map of the LAT-1–TOL-1 ectodomain complex reveal a previously-unobserved mode of one-to-one interaction enabled by a large interface. CRISPR/Cas9-mediated mutation of key interface residues selectively disrupted the endogenous LAT-1–TOL-1 interaction inC. elegans,leading to partial sterility, lethality, and malformed embryos. Thus, TOL-1 binding to LAT-1 represents a receptor-ligand axis essential for animal morphogenesis.
Biosynthesis of gibberellin-related compounds modulates far-red light responses in the liverwortMarchantia polymorpha
Authors: Sun Rui , Okabe Maiko , Miyazaki Sho , Ishida Toshiaki , Mashiguchi Kiyoshi , Inoue Keisuke , Yoshitake Yoshihiro , Yamaoka Shohei , Nishihama Ryuichi , Kawaide Hiroshi , Nakajima Masatoshi , Yamaguchi Shinjiro , Kohchi Takayuki
Published: May 2023

The phytohormone gibberellins (GAs) are key regulators of growth, development and environmental responses in angiosperms. From an evolutionary perspective, all major steps of GA biosynthesis are conserved among vascular plants, while GA biosynthetic intermediates such asent-kaurenoic acid (KA) are also produced by bryophytes. Here we show that in the liverwortMarchantia polymorpha, KA and GA12are synthesized by evolutionarily conserved enzymes, which are required for developmental responses to far-red light (FR). Under FR-enriched conditions, mutants of various biosynthesis enzymes consistently altered thallus growth allometry, delayed the initiation of gametogenesis, and affected the morphology of gamete-bearing structures (gametangiophores). By chemical treatments and LC-MS/MS analyses, we confirmed these phenotypes were caused by deficiency of some GA-related compounds derived from KA, but not bioactive GAs from vascular plants. Transcriptome analysis showed that FR enrichment induced the up-regulation of genes related to stress responses and secondary metabolism inM. polymorpha, which was largely dependent on the biosynthesis of GA-related compounds. Due to the lack of the canonical GA receptors in bryophytes, we hypothesize that GA-related compounds are commonly synthesized in land plants but co-opted independently to regulate responses to light quality change in different lineages during the past 450 million years of evolution.
A Method for Monitoring the Effective Air Change Rate for Respiratory Aerosols Using Real-Time Tracers
Authors: Pathak Saurabh , Kottapalli Kalyan , Santarpia Joshua L. , Botham Aaron D. , Molyneux Sam D. , Balarashti Jamie
Published: May 2023

Ventilation is one of the most critical components in a layered approach toward reducing the spread of airborne infectious diseases in indoor spaces. However, building ventilation systems act together with natural ventilation, local filtration systems and other aerosol removal processes to remove infectious aerosols from an occupied space. Airflow-based determinations of ACH do not account for the full range of aerosol removal processes; however understanding the effective aerosol removal rate is critical to providing airborne infection control.

In this study, we investigated the relationship between the calculated air change rate of a space (i.e. volumetric airflow based) and the effective air change rate for aerosol particle removal within the breathing zone based on direct measurements of the rate of change in tracer particle concentrations at representative occupant locations in a room. Further, we examined positional effects under well mixed and non-well mixed conditions.

Our results demonstrate that tracer particles combined with real-time sensors can be used to make rapid, accurate measurements of the effective air change rate (eACH) for respiratory aerosols within the breathing zone of non-well mixed rooms. We used two experimental test beds for these analyses. First, numerical simulation (computational fluid dynamic simulation, CFD) was conducted to visualize airflow and particle removal paths within a realistic large room. Here, simulated sensors were placed in concentric zones around a nebulizer providing test-particle releases. This CFD model allowed a direct comparison of the differences between eACH and airflow ACH values under varying levels of mixing and airflow, in a fully controlled system.

We then recapitulated this system in physical space to validate the CFD results under real-world conditions that include all mechanisms of particle removal that contribute to true aerosol clearance rates, including deposition and leakage. Here, we measured eACH using the decay of DNA tracer aerosols nebulized and monitored in real-time. We find that a standard sampling time of 15 minutes from the end of nebulization is sufficient to produce an accurate eACH value under non-well mixed conditions. The availability of a rapid direct test for eACH will enable empirical optimization of a wide range of ventilation and filtration mechanisms to reach and maintain target aerosol clearance rates that deliver reliable airborne infection control in typical indoor environments.
Geometric approach for non pharmaceutical interventions in epidemiology
Authors: Evain Laurent , Loeb Jean-Jacques
Published: May 2023

Various non pharmaceutical interventions have been settled to minimise the burden of the COVID-19 outbreak. We build a framework to analyse the dynamics of non pharmaceutical interventions, to distinguish between mitigations measures leading to objective scientific improvements and mitigations based on both political and scientific considerations. We analyse two possible strategies within this framework. Namely, we consider mitigations driven by the limited resources of the health system and mitigations where a constant set of measures is applied at different moments. We describe the optimal interventions for these scenarios. Our approach involves sir differential systems, it is qualitative and geometrical rather than computational. Along with the analysis of these scenarios, we collect several results that may be useful on their own, in particular on the ground when the variables are not known in real time.
Rme-6 integrates EGFR trafficking and signalling to regulate ERK1/2 signalosome dynamics
Authors: Alshahrani Fahad , Zhu Zhou , Ferreira Filipe , McComb Alasdair , Maib Hannes , Pruzina Sara , Robinson Darren , Murray David , Smythe Elizabeth
Published: May 2023

Epidermal growth factor receptor (EGFR) signalling results in a variety of cell behaviours, including cell proliferation, migration and apoptosis, which depend on cell context. Here we have explored how the Rab5GEF, Rme-6, regulates EGFR signalling by modulating endocytic flux. We demonstrate that Rme-6, which acts early in the endocytic pathway, regulates EGFR trafficking through an endocytic compartment that is competent for ERK1/2 signalling. While overexpression of Rme-6 results in enhanced ERK1/2 nuclear localisation and c-Fos activation, loss of Rme-6 results in aberrant ERK1/2 signalling with increased cytoplasmic ERK1/2 phosphorylation (Thr202/Tyr204) but decreased ERK1/2 nuclear translocation and c-Fos activation, the latter leading to decreased cell proliferation. Phosphorylation of ERK1/2 by protein kinase 2 (CK2) is required for its nuclear translocation and our data support a model whereby Rme-6 provides a scaffold for a population of CK2 which is required for efficient nuclear translocation of ERK1/2. Rme-6 is itself a substrate for CK2 on Thr642 and Ser996 and phosphorylation on these sites can activate its Rab5GEF activity and endocytic trafficking of EGFR. Together our results indicate that Rme-6 co-ordinates EGFR trafficking and signalling to regulate the assembly and disassembly of an ERK1/2 signalosome.

Summary statement

Here we demonstrate how Rme-6, a Rab5GEF, co-ordinates trafficking and signalling of EGFR on the early endocytic pathway to ensure appropriate regulation of downstream ERK1/2 signalling.
Post-translational regulation of photosynthetic activity via the TOR kinase in plants
Authors: D’Alessandro Stefano , Velay Florent , Lebrun Régine , Mehrez Marwa , Romand Shanna , Saadouni Rim , Forzani Céline , Citerne Sylvie , Montané Marie-Hélène , Robaglia Christophe , Menand Benoît , Meyer Christian , Field Ben
Published: May 2023

Chloroplasts are the powerhouse of the plant cell, yet they are resource-intensive and will cause photooxidative damage if their activity overshoots the demands of growth. The adjustment of chloroplast activity to match growth is therefore vital for stress acclimation. Here we identify a novel post-translational mechanism linking the conserved eukaryotic TOR kinase that promotes growth and the guanosine tetraphosphate (ppGpp) signaling pathway of prokaryotic origin that regulates chloroplast activity, and photosynthesis in particular. We show that RelA SpoT Homologue 3 (RSH3), a nuclear-encoded chloroplastic enzyme responsible for ppGpp biosynthesis, interacts directly with the TOR complex via a plant-specific N-terminal region (NTR) which is hyper-phosphorylated in a TOR-dependent manner. Downregulation of TOR activity reduces NTR phosphorylation, enhances ppGpp synthesis by RSH3, and causes a ppGpp-dependent decrease in photosynthetic capacity. Altogether we demonstrate that the TOR-RSH3 signaling axis is a novel and direct post-translational mechanism that allows chloroplast activity to be matched with plant growth, setting a new precedent for the regulation of organellar function by TOR.

One sentence summary

The TOR kinase post-translationally controls guanosine tetraphosphate signaling to regulate plant photosynthetic activity.