bluuebunny/crossref_metadata_2025 huggingface dataset:
Approaches to defining health facility catchment areas in sub-Saharan Africa
Authors: Macharia Peter M , Odhiambo Julius N , Mumo Eda , Maina Alex , Giorgi Emanuele , Okiro Emelda A
Published: August 2022

The geographical area around a health facility characterizing the population that utilizes some or all of its services – a health facility catchment area (HFCA)-, forms the fundamental basis of estimating reliable population denominator for disease mapping and routine healthcare planning. Consequently, the approaches used to delineate the catchment area have a direct impact on the health of a population. To date, there is no systematic literature review documenting different approaches that have been used to define HFCAs while elucidating the implications on derived population denominators. To fill this gap, we systematically reviewed literature and documented approaches that have been used to define HFCA in sub–Saharan Africa (SSA). Simple to complex approaches have been used to define catchment areas in SSA with varying degrees of complexity and limitations in the last four decades. These approaches are mainly driven by lack of geocoded data on the residential address of care seekers and their care-seeking behaviour. To generate closer-to-reality HFCA, for robust disease mapping and healthcare planning, additional data and innovative approaches balancing between model complexity and routine programmatic use are required.
Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview
Authors: Choudhary Ashwani , Nayak Ritu , Peles David , Mizrahi Liron , Stern Shani
Published: August 2022

Schizophrenia (SCZ) is a highly heritable, polygenic neuropsychiatric disease, which disables the patients as well as decreases their life expectancy and quality of life. Common and Rare variants studies on SCZ subjects have provided more than 100 genomic loci that hold importance in the context of SCZ pathophysiology. Transcriptomic studies from clinical samples have informed about the differentially expressed genes (DEGs) and non-coding RNAs in SCZ patients. Despite these advancements, no causative genes for SCZ were found and hence SCZ is difficult to recapitulate in animal models. In the last decade, induced Pluripotent Stem Cells (iPSCs)-based models have helped in understanding the neural phenotypes of SCZ by studying patient iPSC-derived 2D neuronal cultures and 3D brain organoids. Here, we have aimed to provide a simplistic overview of the current progress and advancements after synthesizing the enormous literature on SCZ genetics and SCZ iPSC-based models. Although further understanding of SCZ genetics and mechanisms using these technological advancements is required, the recent approaches have allowed to delineate important cellular mechanisms and biological pathways affected in SCZ.
Pharmacokinetics of nirmatrelvir and ritonavir in COVID-19 patients with end stage renal disease on intermittent haemodialysis
Authors: Lingscheid Tilman , Kinzig Martina , Krüger Anne , Müller Nils , Bölke Georg , Tober-Lau Pinkus , Münn Friederike , Kriedemann Helene , Witzenrath Martin , Sander Leif E. , Sörgel Fritz , Kurth Florian
Published: August 2022

Background

Nirmatrelvir/ritonavir is an effective therapy against SARS-CoV-2. Patients with end-stage renal disease (ESRD) are at high risk for severe COVID-19 and show impaired vaccine responses underlining the importance of antiviral therapy. However, use of nirmatrelvir/ritonavir is not recommended in these patients due to lack of clinical and pharmacokinetic data.

Objective

To investigate pharmacokinetics and hepatic tolerance of nirmatrelvir/ritonavir in patients with ESRD and haemodialysis (HD).

Patients and methods

Four patients diagnosed with SARS-CoV-2 infection received nirmatrelvir/ritonavir 150/100mg twice daily as recommended for renal impairment; HD ran in two- to three-day intervals. Plasma and serum samples were drawn before and after each HD during the 5-day treatment and for ensuing 3-5 days.

Results

Median peak levels of nirmatrelvir obtained two hours after medication pre-HD in three patients were 7745ng/mL on day 3 and 6653ng/mL on day 5; median post-HD levels (C6h) declined to 5765ng/mL (74%) and 5521ng/mL (83%), on days 3 and 5 of treatment, respectively. Three days after end of treatment, median levels were 365ng/mL pre-HD and 30ng/mL post-HD. Measurements of the fourth patient, six hours after drug intake pre-HD showed nirmatrelvir-levels of 3704ng/mL on treatment day 3 which fell to 2308ng/mL post-HD, at one hour before intake of the next dose (Cmin).

Conclusion

Use of nirmatrelvir/ritonavir in patients with ESRD results in high nirmatrelvir blood concentrations, which are still within the range known from patients without renal failure. No accumulation of nirmatrelvir took place and levels declined to zero within few days after end of treatment.
Translation of Immunomodulatory Therapy to Treat Chronic Heart Failure: Preclinical Studies to First in Human
Authors: Humes H. David , Aaronson Keith D. , Buffington Deborah , Sabbah Hani N. , Westover Angela J. , Yessayan Lenar T. , Szamosfalvi Balazs , Pagani Francis D.
Published: August 2022

The objective of this study was to evaluate the use of an extracorporeal immunomodulatory device on the immune dysregulated state of chronic heart failure (CHF). Inflammation has been associated with progression and complications of CHF but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the inflammatory activity of circulating leukocytes of the innate immunologic system. SCD treatment in a canine model of systolic CHF diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and myocardial contractility by stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe systolic CHF ineligible for cardiac transplantation or left ventricular assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index, stabilization of renal function with progressive volume removal permitted successful LVAD implantation. This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in systolic CHF and supports the important role of inflammation in the progression of CHF.
Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa
Authors: Sun Kaiyuan , Tempia Stefano , Kleynhans Jackie , Gottberg Anne von , McMorrow Meredith L , Wolter Nicole , Bhiman Jinal N. , Moyes Jocelyn , Carrim Maimuna , Martinson Neil A , Kahn Kathleen , Lebina Limakatso , du Toit Jacques D. , Mkhencele Thulisa , Viboud Cécile , Cohen Cheryl ,   the PHIRST group
Published: August 2022

South Africa was among the first countries to detect the SARS-CoV-2 Omicron variant. Propelled by increased transmissibility and immune escape properties, Omicron displaced other globally circulating variants within 3 months of its emergence. Due to limited testing, Omicron’s attenuated clinical severity, and an increased risk of reinfection, the size of the Omicron BA.1 and BA.2 subvariants (BA.1/2) wave remains poorly understood in South Africa and in many other countries. Using South African data from urban and rural cohorts closely monitored since the beginning of the pandemic, we analyzed sequential serum samples collected before, during, and after the Omicron BA.1/2 wave to infer infection rates and monitor changes in the immune histories of participants over time. Omicron BA.1/2 infection attack rates reached 65% (95% CI, 60% – 69%) in the rural cohort and 58% (95% CI, 61% – 74%) in the urban cohort, with repeat infections and vaccine breakthroughs accounting for >60% of all infections at both sites. Combined with previously collected data on pre-Omicron variant infections within the same cohorts, we identified 14 distinct categories of SARS-CoV-2 antigen exposure histories in the aftermath of the Omicron BA.1/2 wave, indicating a particularly fragmented immunologic landscape. Few individuals (<6%) remained naïve to SARS-CoV-2 and no exposure history category represented over 25% of the population at either cohort site. Further, cohort participants were more than twice as likely to get infected during the Omicron BA.1/2 wave, compared to the Delta wave. Prior infection with the ancestral strain (with D614G mutation), Beta, and Delta variants provided 13% (95% CI, -21% – 37%), 34% (95% CI, 17% – 48%), and 51% (95% CI, 39% – 60%) protection against Omicron BA.1/2 infection, respectively. Hybrid immunity (prior infection and vaccination) and repeated prior infections (without vaccination) reduced the risks of Omicron BA.1/2 infection by 60% (95% CI, 42% – 72%) and 85% (95% CI, 76% – 92%) respectively. Reinfections and vaccine breakthroughs had 41% (95% CI, 26% – 53%) lower risk of onward transmission than primary infections. Our study sheds light on a rapidly shifting landscape of population immunity, along with the changing characteristics of SARS-CoV-2, and how these factors interact to shape the success of emerging variants. Our findings are especially relevant to populations similar to South Africa with low SARS-CoV-2 vaccine coverage and a dominant contribution of immunity from prior infection. Looking forward, the study provides context for anticipating the long-term circulation of SARS-CoV-2 in populations no longer naïve to the virus.
Seasonal polyphenism underlies the origin of a sterile caste in aphids
Authors: Uematsu Keigo , Kutsukake Mayako , Shigenobu Shuji , Yang Man-Miao , Shibao Harunobu , Fukatsu Takema
Published: August 2022

The origin of a sterile caste among eusocial animals has been a fundamental but still unresolved problem in understanding the evolution of biological complexity. At the origin of a sterile caste, recruitment of pre-existing plasticity may lead to produce physiologically, morphologically and behaviorally distinct caste phenotypes. Here, we provide convincing evidence that preexisting seasonal polyphenism has been recruited to generate a sterile soldier caste in host-alternating social aphids. We demonstrate that sterile soldier nymphs of Colophina aphids resemble those of monomorphic defensive nymphs produced in a different host-plant generation. Notably, the two morphs in the basal species show the closest similarity in morphology and gene expression among all morph pairs. Moreover, their evolutionary phenotypic changes along the phylogeny of four Colophina species are significantly correlated positively. These results suggest that they may share the common regulatory mechanisms of development, which underpin the heterochronic expression of monomorphic defenders on the different host plant leading to the evolution of a novel soldier phenotype. We further demonstrate that the monomorphic defenders can increase their inclusive fitness by killing predator’s eggs on a seasonally different host plant. Taken together, our findings suggest that preexisting plasticity that can gain indirect fitness benefits facilitates the early evolution of a sterile caste.
Deciphering the Evolutionary History of Complex Rearrangements in Head and Neck Cancer Patients Using Multi-Omic Approach
Authors: Chae Jeesoo , Lee Jin Seok , Park Jongkeun , Lee Dong-Sung , Park Weon Seo , Clock Benjamin , Dixon Jesse R. , Jung Yuh-Seog , Hong Dongwan
Published: August 2022

Despite the large efforts in international cancer genome consortium studies, there are still a large proportion of tumors with complex genomic rearrangement often remained without a clinically relevant molecular characterization. Integration of multi-omic data helps elucidating evolutionary history of such cases and identifying predictive molecular markers. Here we present the findings of our proof-of-principle study that investigated the evolutionary history of complex rearrangements in primary head and neck tumor genomes integrating long-read whole-genome, Hi-C, and RNA sequencing. We report a HPV-positive case with development of complex genomic rearrangements tracing back to HPV-mediated genomic instability and a HPV-negative case with an enhancer hi-jacking in a region of chromothripsis predicted to co-occur with a neoloop and a super-enhancer. These structural alterations resulted in overexpression of the oncogenes CCND1 and ALK, respectively, validated with immunohistochemistry assay. Furthermore, we introduce a novel analytic approach utilizing long-read whole-genome data distinguishing somatic mutations before and after structural variants. Our findings highlight the need for multi-modal sequencing strategies to increase our understanding of cancer evolution and rare biomarkers in poorly understood cancers.
Development of a multi-sensor integrated midbrain organoid-on-a-chip platform for studying Parkinson’s disease
Authors: Spitz Sarah , Bolognin Silvia , Brandauer Konstanze , Füßl Julia , Schuller Patrick , Schobesberger Silvia , Jordan Christian , Schädl Barbara , Grillari Johannes , Wanzenboeck Heinz D. , Mayr Torsten , Harasek Michael , Schwamborn Jens C. , Ertl Peter
Published: August 2022

Due to its ability to recapitulate key pathological processes in vitro, midbrain organoid technology has significantly advanced the modeling of Parkinson’s disease over the last few years. However, some limitations such as insufficient tissue differentiation and maturation, deficient nutrient supply, and low analytical accessibility persist, altogether restricting the technology from reaching its full potential. To overcome these drawbacks, we have developed a multi-sensor integrated organ-on-a-chip platform capable of monitoring the electrophysiological, respiratory, and dopaminergic activity of human midbrain organoids. Our study showed that microfluidic cultivation resulted in a marked reduction in necrotic core formation, improved tissue differentiation as well as the recapitulation of key pathological hallmarks. Non-invasive monitoring employing an orthogonal sensing strategy revealed a clear time dependency in the onset of Parkinson’s disease-related phenotypes, reflecting the complex progression of the neurodegenerative disorder. Furthermore, drug-mediated rescue effects were observed after treatment with the repurposed compound 2-hydroxypropyl β-cyclodextrin, highlighting the platform’s potential in the context of drug screening applications as well as personalized medicine.
Investigating the human and non-obese diabetic mouse MHC class II immunopeptidome using protein language modelling
Authors: Hartout Philip , Počuča Bojana , Méndez-García Celia , Schleberger Christian
Published: August 2022

Identifying peptides associated with the major histocompability complex class II (MHCII) is a central task in the evaluation of the immunoregulatory function of therapeutics and drug prototypes. MHCII-peptide presentation prediction has multiple biopharmaceutical applications, including the safety assessment of biologics and engineered derivativesin silico, or the fast progression of antigen-specific immunomodulatory drug discovery programs in immune disease and cancer. This has resulted in the collection of large-scale data sets on adaptive immune receptor antigenic responses and MHC-associated peptide proteomics. In parallel, recent deep learning algorithmic advances in protein language modelling (PLM) have shown potential in leveraging large collections of sequence data and improve MHC presentation prediction. Here, we train a compact transformer model (AEGIS) on human and mouse MHCII immunopeptidome data, including a preclinical murine model, and evaluate its performance on the peptide presentation prediction task. We show that the transformer performs on par with existing deep learning algorithms and that combining datasets from multiple organisms increases model performance. We trained variants of the model with and without MHCII information. In both alternatives, the inclusion of peptides presented by the I-Ag7MHC class II molecule expressed by the non-obese diabetic (NOD) mice enabled for the first time the accuratein silicoprediction of presented peptides in a preclinical type 1 diabetes model organism, which has promising therapeutic applications.

0.1

Availability and implementation

The source code is available athttps://github.com/Novartis/AEGIS.
Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction
Authors: Dawson Matthew , Terstege Dylan J , Jamani Naila , Tsutsui Mio , Pavlov Dmitrii , Bugescu Raluca , Epp Jonathan R , Leinninger Gina M , Sargin Derya
Published: August 2022

Intraspecies social interactions are integral for survival and maintenance of society among all mammalian species. Yet, our understanding of the neural systems and mechanisms involved in the establishment of social connectedness are limited. Since their initial discovery as regulators of sleep/wakefulness and appetite in the brain, the hypocretin/orexin neurons have also been shown to play an essential role in modulating energy homeostasis, motivated and emotional behavior. These neurons are located exclusively in the hypothalamus which, regulates complex and goal-directed behaviors. The hypothalamus also plays an important role in the modulation of social behavior by encoding internal states. However, our understanding of the role of hypocretin neurons in social behavior is currently limited. To address this knowledge gap, we performed a combination of fiber photometry and machine learning based behavioral analysis in female and male mice expressing GCaMP6s in hypocretin neurons. We then applied optogenetic and pharmacological inhibition of hypocretin neuron signaling to determine the necessity of the hcrt neuron population for social behavior. Our results indicate that hypocretin neurons exhibit a robust increase in activity in response to social interaction in both female and male mice. We show here for the first time a social discrimination signal that is encoded differentially by hcrt neurons based on the nature of the social encounter. The intensity of the hcrt neuron activity predicts the subsequent duration of social interaction. The optogenetic inhibition of hypocretin neuron activity during social behavior leads to a reduction in the amount of time mice are engaged in social interaction in males but not in females. Blocking hcrt1 (orexin 1) receptors similarly reduces social interaction in males only. Reduced hcrt1 receptor signaling results in increased activity in the insular cortex and reduced activity in the VTA after social interaction in male mice. Together, these data implicate the lateral hypothalamus hypocretin neurons as a sexually dimorphic key regulator within the larger network of neural systems involved in social behavior. Our findings carry significant implications for the treatment of neuropsychiatric diseases characterized by social dysfunction, particularly considering the varying prevalence observed across different sexes.
Estimating Waiting Distances Between Genealogy Changes under a Multi-Species Extension of the Sequentially Markov Coalescent
Authors: McKenzie Patrick F. , Eaton Deren A. R.
Published: August 2022

Genomes are composed of a mosaic of segments inherited from different ancestors, each separated by past recombination events. Consequently, genealogical relationships among multiple genomes vary spatially across different genomic regions. Expectations for the amount of genealogical variation among unlinked (uncorrelated) genomic regions is well described for either a single population (coalescent) or multiple structured populations (multispecies coalescent). However, the expected similarity among genealogies at linked regions of a genome is less well characterized. Recently, an analytical solution was derived for the expected distribution of waiting distances between changes in genealogical trees spatially across a genome for a single population with constant effective population size. Here we describe a generalization of this result, in terms of the expected distribution of waiting distances between changes in genealogical trees and topologies, for multiple structured populations with branch-specific effective population sizes (i.e., under the multispecies coalescent). Our solutions establish an expectation for genetic linkage in multispecies datasets and provide a new likelihood framework for linking demographic models with local ancestry inference across genomes.
Herbarium records provide reliable phenology estimates in the understudied tropics
Authors: Park Daniel S. , Lyra Goia M. , Ellison Aaron M. , Maruyama Rogério Katsuhito Barbosa , Torquato Débora dos Reis , Asprino Renata C. , Cook Benjamin I. , Davis Charles C.
Published: August 2022

Plant phenology has been shifting dramatically in response to climate change, a shift that may have significant and widespread ecological consequences. Of particular concern are tropical biomes, which represent the most biodiverse and imperiled regions of the world. However, compared to temperate floras, we know little about phenological responses of tropical plants because long-term observational datasets from the tropics are sparse.

Herbarium specimens have greatly increased our phenological knowledge in temperate regions, but similar data have been underutilized in the tropics and their suitability for this purpose has not been broadly validated. Here, we compare phenological estimates derived from field observational data (i.e., plot surveys) and herbarium specimens at various spatial and taxonomic scales to determine whether specimens can provide accurate estimations of reproductive timing and its spatial variation.

Here we demonstrate that phenological estimates from field observations and herbarium specimens coincide well. Fewer than 5% of the species exhibited significant differences between flowering periods inferred from field observations versus specimens regardless of spatial aggregation. In contrast to studies based on field records, herbarium specimens sampled much larger geographic and climatic ranges, as has been documented previously for temperate plants, and effectively captured phenological responses across varied environments.

Herbarium specimens are verified to be a vital resource for closing the gap in our phenological knowledge of tropical systems. Tropical plant reproductive phenology inferred from herbarium records are widely congruent with field observations, suggesting that they can (and should) be used to investigate phenological variation and their associated environmental cues more broadly across tropical biomes.
Prediction of SUMOylation targets in Drosophila melanogaster
Authors: Ramtirtha Yogendra , Madhusudhan M. S.
Published: August 2022

SUMOylation is a post translational modification that involves covalent attachment of SUMO C-terminus to side chain amino group of lysine residues in target proteins. Disruption of the modification has been linked to neurodegenerative diseases and cancer. Recent improvements in mass spectrometry-coupled proteomics experiments have enabled high-throughput identification of SUMOylated lysines in mammalian cells. One such study was Hendriks et al, 2018, wherein the authors identified SUMOylated lysines in human and mouse cells. Information from this study was used as an input to a sequence homology based method to annotate putative SUMOylatable lysines from the proteome of fruit flyDrosophila melanogaster. 5283 human and 468 mouse SUMOylated proteins led to the identification of 8539 and 1700 fly homologs and putative SUMOylation sites therein respectively. Clustering analysis was carried out on these annotated sites to obtain three typs of information. First type of information revealed amino acid preferences in the local sequence vicinity of the annotated sites. This exercise confirmed that ψ – K – x – (E/D) where ψ = I/V/L, is the most frequently occurring sequence motif involving SUMOylated lysines.

Second type of information revealed protein families that contain the annotated sites. Results from this exercise reveal that members of thousands of protein families contain annotated SUMOylation sites. Third type of information revealed preferred biological and cellular functions of proteins containing the annotated lysines. This exercise revealed that nucleus and transcription are preferred cellular localization and biological function respectively.
Neural processing of goal and non-goal-directed movements on the smartphone
Authors: Kock Ruchella , Ceolini Enea , Groenewegen Lysanne , Ghosh Arko
Published: August 2022

The discrete behavioral events captured on the smartphone touchscreen may help unravel real-world neural processing. We find that neural signals (EEG) surrounding a touchscreen event show peculiarly contralateral motor preparation, visual processing, and the consolidation of information. We leveraged these events in conjunction with kinematic recordings of the thumb and an artificial neural network to separate highly similar movements according to whether they resulted in a smartphone touch (goal-directed) or not (non-goal-directed). Despite their kinematic similarity underscored by the model, the signatures of neural control of movement and the post-movement processing were substantially dampened for the non-goal-directed movements, and these movements uniquely evoked error-related signals. We speculate that these unnecessary movements are common in the real world and although inconsequential the brain still provides limited motor preparation and tracks the action outcome. Real-world behavior is composed of neural processes that are difficult to capture in conventional laboratory-based tasks.
SpatialDM: Rapid identification of spatially co-expressed ligand-receptor reveals cell-cell communication patterns
Authors: Li Zhuoxuan , Wang Tianjie , Liu Pengtao , Huang Yuanhua
Published: August 2022

Cell-cell communication is a key aspect of dissecting the complex cellular microenvironment. Existing single-cell and spatial transcriptomics-based methods primarily focus on identifying cell-type pairs for a specific interaction, while less attention has been paid to the prioritisation of interaction features or the identification of interaction spots in the spatial context. Here, we introduce SpatialDM, a statistical model and toolbox leveraging a bivariant Moran’s statistic to detect spatially co-expressed ligand and receptor pairs, their local interacting spots (single-spot resolution), and communication patterns. By deriving an analytical null distribution, this method is scalable to millions of spots and shows accurate and robust performance in various simulations. On multiple datasets including melanoma, Ventricular–Subventricular Zone (SVZ), and intestine, SpatialDM reveals promising communication patterns and identifies differential interactions between conditions, hence enabling the discovery of context-specific cell cooperation and signalling.
Cumulative Social Disadvantage and Health-Related Quality of Life: National Health Interview Survey 2013-2017
Authors: Hagan Kobina , Javed Zulqarnain , Cainzos-Achirica Miguel , Hyder Adnan A. , Mossialos Elias , Yahya Tamer , Acquah Isaac , Valero-Elizondo Javier , Pan Alan , Nwana Nwabunie , Taha Mohamad , Nasir Khurram
Published: August 2022

Background

Evidence of the association between social determinants of health (SDoH) and health-related quality of life (HRQoL) is largely based on single SDoH measures, with limited evaluation of cumulative social disadvantage. We examined the association between cumulative social disadvantage and the Health and Activity Limitation Index (HALex).

Methods

We used data of respondents from the 2013-2017 National Health Interview Survey. A cumulative SDoH index was created by aggregating 46 SDoH from 6 domains, and respondents were grouped by quartiles (SDoH-Q1 to Q4). A higher SDoH index or quartile indicates greater disadvantage. Two outcomes were assessed: HALex score using two-part models, and a binary “poor HALex” (HALex score < 0.79 [20th percentile]) using logistic regression. Regression analyses adjusted for demographics and comorbidities and were performed in the overall sample, and by age, sex, and race/ethnicity categories.

Results

Among 156,182 adults (mean age 46 years; 51.7% women), higher SDoH quartile groups averaged lower HALex scores and had higher proportions with poor HALex. A unit increase in SDoH index was associated with 0.01 decrease in HALex score (β = −0.01; 95% CI [−0.01, −0.01]) and 14% higher odds of poor HALex (odds ratio, OR = 1.14; 95% CI [1.14, 1.15]). Relative to SDoH-Q1, SDoH-Q4 was associated with HALex score decrease of −0.13 (95% CI [−0.13, −0.13]) and OR 8.67 (95% CI [8.08, 9.30]) for poor HALex. Hispanic persons, despite a relatively higher burden of cumulative social disadvantage, had a weaker SDoH-HALex association than their counterparts.

Conclusion

Higher cumulative social disadvantage was independently associated with lower HRQoL in an incremental fashion. The more favorable HRQoL profile observed in the Hispanic could be related to a resilient concept of health derived from cultural values and acceptance, and this highlights the need for population “wellness” interventions to be responsive to such phenomenon.
Transcriptomic profiling of cerebrospinal fluid predicts shunt surgery responses in patients with Normal Pressure Hydrocephalus
Authors: Levin Zachary , Leary Owen P. , Mora Victor , Kant Shawn , Brown Sarah , Svokos Konstantina , Akbar Umer , Serre Thomas , Klinge Petra , Fleischmann Alexander , Ruocco Maria Grazia
Published: August 2022

Molecular biomarkers for neurodegenerative diseases are critical for advancing diagnosis and therapy. Normal Pressure Hydrocephalus (NPH) is a neurodegenerative disorder characterized by progressive gait impairment, urinary incontinence, and cognitive decline. In contrast to most other neurodegenerative disorders, NPH symptoms can be improved by the placement of a ventricular shunt that drains excess cerebrospinal fluid (CSF). A major challenge in NPH management is the identification of patients who benefit from shunt surgery. Here, we perform genome-wide RNA sequencing of extracellular vesicles in CSF of 42 NPH patients, and we identify genes and pathways whose expression levels correlate with gait, urinary or cognitive symptom improvement after shunt surgery. We describe a machine learning algorithm trained on these gene expression profiles that can predict shunt surgery response with high accuracy. The transcriptomic signatures we identified have important implications for improving NPH diagnosis and treatment and for understanding disease etiology.
Ngfr suppresses Lcn2/Slc22a17 signaling, induces neurogenesis and reduces amyloid pathology in the hippocampus of APP/PS1dE9 mouse
Authors: Siddiqui Tohid , Cosacak Mehmet Ilyas , Popova Stanislava , Bhattarai Prabesh , Lee Annie J. , Min Yuhao , Wang Xue , Allen Mariet , İş Özkan , Atasavum Zeynep Tansu , Vardarajan Badri N. , Santa-Maria Ismael , Tosto Giuseppe , Mayeux Richard , Ertekin-Taner Nilüfer , Kizil Caghan
Published: August 2022

Neurogenesis relates to the brain resilience and is reduced in Alzheimer’s disease (AD). Restoring healthy levels of neurogenesis could have beneficial effects for coping with neurodegeneration. However, molecular mechanisms that could enhance neurogenesis from astroglial progenitors in AD pathology are largely unknown. We used lentiviruses to expressNgfrin the hippocampus of the APP/PS1dE9 mouse model of AD, histologically analyzed the changes in proliferation of neural stem cells and neurogenesis; performed single-cell transcriptomics, spatial proteomics, and functional knockdown studies. We found that expression ofNgfr, a neurogenic determinant in pathology-induced neuroregeneration in zebrafish, stimulated proliferative and neurogenic outcome in the APP/PS1dE9 AD mouse model. Ngfr suppressed reactive astrocyte marker Lipocalin-2 (Lcn2) in astroglia. Blockage of Lcn2 receptor, Slc22a17, recapitulated the neurogenic effects of NGFR, and long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Furthermore, immunostaining on postmortem human hippocampi with AD or primary age-related Tauopathy and 3D human astroglial cultures showed that elevated LCN2 levels correlate with gliosis. By comparing transcriptional changes in mouse hippocampus, zebrafish brain, and human AD brains in terms of cell intrinsic differential gene expression analyses as well as weighted gene co-expression network analysis, we observed common potential downstream effectors of NGFR signaling,C4BandPFKP, that are relevant to AD. Our study links the regulatory role of an autocrine molecular mechanism in astroglia to the neurogenic ability and modulatory effects on amyloid and tau phosphorylation, opening new research avenues and suggesting that neurogenesis-oriented therapeutic approaches could be a potential clinical intervention for AD.
Noise-induced symmetry breaking in a network of excitable ecological systems
Authors: Narang Arzoo , Banerjee Tanmoy , Dutta Partha Sharathi
Published: August 2022

Noise-induced symmetry breaking has barely been unveiled on the ecological grounds, though its occurrence may elucidate mechanisms responsible for maintaining biodiversity and ecosystem stability. Here, for a network of excitable consumer-resource systems, we show that the interplay of network structure and noise intensity manifests a transition from homogeneous steady state to inhomogeneous steady states, resulting in noise-induced symmetry breaking. On further increasing the noise intensity, there exist asynchronous oscillations, leading to heterogeneity crucial for maintaining a system’s adaptive capacity. The observed collective dynamics can be understood analytically in the framework of linear stability analysis of the corresponding deterministic system.
Age-dependent changes in the dynamic functional organization of the brain at rest – a cross-cultural replication approach
Authors: Yang Xi , Zhou Xinqi , Xin Fei , Becker Benjamin , Linden David , Hernaus Dennis
Published: August 2022

Age-associated changes in brain function play an important role in the development of neurodegenerative diseases. Although previous work has examined age-related changes in static functional connectivity (FC), accumulating evidence suggests that advancing age is especially associated with alterations in the dynamic interactions and transitions between different brain states, which hitherto has received less attention. Moreover, conclusions of previous studies in this domain are limited by suboptimal replicability of resting state fMRI and culturally homogenous cohorts. Here, we investigate the robustness of age-associated changes in dynamic functional connectivity (dFC) by capitalizing on the availability of fMRI cohorts from two cultures (Western European and Chinese). In both cohorts we consistently identify two distinct connectivity states: a more frequent segregated within-network connectivity state (state I) and a less frequent integrated between-network connectivity state (state II). In both cohorts, older (55-80 years) compared to younger participants (20-35 years) exhibited lower occurrence of and spent less time in state I. Moreover, older participants tended to exhibit more transitions between networks and greater variance in global efficiency. Overall, our cross-cultural replication of age-associated changes in key dFC metrics implies that advancing age is robustly associated with a reorganization of dynamic brain activation that favors the use of less functionally-specific networks.

Highlights

Aging is associated with a reorganization of dynamic functional brain connectivity.

Age-dependent dynamic functional connectivity changes are relatively stable across cultures.

Dynamic properties are promising neural indexes for brain aging in older healthy populations.
Honokiol and alfa-Mangostin inhibit Mayaro virus replication by stimulating the type I interferon pathway
Authors: Valdés-Torres Patricia , Campos Dalkiria , Bhakta Madhvi , Galán-Jurado Paola Elaine , Durant-Archibold Armando A. , González-Santamaría José
Published: August 2022

Mayaro virus (MAYV) is an emerging arbovirus with increasing circulation across the Americas. In the present study, we evaluated the potential antiviral activity of the following natural compounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA and α-Mangostin. Sanguinarine and Shikonin showed significant cytotoxicity, whereas Fisetin, Honokiol, Tanshinone IIA and α-Mangostin were well-tolerated in all the cell lines tested. Honokiol and α-Mangostin treatment protected Vero-E6 cells against MAYV-induced damage and resulted in a dose-dependent reduction in viral progeny yields for each of the MAYV strains and human cell lines assessed. Also, Honokiol and α-Mangostin disrupted MAYV infection at different stages of the virus life cycle. Moreover, these compounds decreased Una, Chikungunya and Zika viral titers and downmodulated the expression of E1 and nsP1 viral proteins from MAYV, Una and Chikungunya. Finally, in Honokiol- and α-Mangostin-treated cells, we observed an upregulation in the expression of type I interferon and specific interferon-stimulated genes, including IFNα, IFNβ, MxA, ISG15, OAS2, MDA-5, TNFα and IL-1β, which may promote an antiviral cellular state. Our results indicate that Honokiol and α-Mangostin present potential broad-spectrum activity against different arboviruses through a possible modulation of the interferon pathway.
Size-dependence of food intake and mortality interact with temperature and seasonality to drive diversity in fish life histories
Authors: Kindsvater Holly K. , Juan-Jordá Maria-José , Dulvy Nicholas K. , Horswill Cat , Matthiopoulos Jason , Mangel Marc
Published: August 2022

Understanding how growth and reproduction will adapt to changing environmental conditions is a fundamental question in evolutionary ecology, but predicting the responses of specific taxa is challenging. Analyses of the physiological effects of climate change upon life history evolution rarely consider alternative hypothesized mechanisms, such as size-dependent foraging and the risk of predation, simultaneously shaping optimal growth patterns. To test for interactions between these mechanisms, we embedded a state-dependent energetic model in an ecosystem size-spectrum to ask whether prey availability (foraging) and risk of predation experienced by individual fish can explain observed diversity in life histories of fishes. We found that asymptotic growth emerged from size-based foraging and reproductive and mortality patterns in the context of ecosystem food web interactions. While more productive ecosystems led to larger body sizes, the effects of temperature on metabolic costs had only small effects on size. To validate our model, we ran it for abiotic scenarios corresponding to the ecological lifestyles of three tuna species, considering environments that included seasonal variation in temperature. We successfully predicted realistic patterns of growth, reproduction, and mortality of all three tuna species. We found that individuals grew larger when environmental conditions varied seasonally and spawning was restricted to part of the year (corresponding to their migration from temperate to tropical waters). Growing larger was advantageous because foraging and spawning opportunities were seasonally constrained. This mechanism could explain the evolution of gigantism in temperate tunas. Our approach addresses variation in food availability and individual risk as well as metabolic processes and offers a promising approach to understand fish life-history responses to changing ocean conditions.
Testing the ion-current model for flagellar length sensing and IFT regulation
Authors: Ishikawa Hiroaki , Moore Jeremy , Diener Dennis R. , Delling Markus , Marshall Wallace F.
Published: August 2022

Eukaryotic cilia and flagella are microtubule-based organelles whose relatively simple shape makes them ideal for investigating the fundamental question of organelle size regulation. Most of the flagellar materials are transported from the cell body via an active transport process called intraflagellar transport (IFT). The rate of IFT entry into flagella, known as IFT injection, has been shown to negatively correlate with flagellar length. However, it remains unknown how the cell measures the length of its flagella and controls IFT injection. One of the most-discussed theoretical models for length sensing to control IFT is the ion-current model, which posits that there is a uniform distribution of Ca2+channels along the flagellum and that the Ca2+current from the flagellum into the cell body increases linearly with flagellar length. In this model, the cell uses the Ca2+current to negatively regulate IFT injection. The recent discovery that IFT entry into flagella is regulated by the phosphorylation of kinesin through a calcium-dependent protein kinase has provided further impetus for the ion-current model. To test this model, we measured and manipulated the levels of Ca2+inside ofChlamydomonasflagella and quantified IFT injection. Although the concentration of Ca2+inside of flagella was weakly correlated with the length of flagella, we found that IFT injection was reduced in calcium-deficient flagella, rather than increased as the model predicted, and that variation in IFT injection was uncorrelated with the occurrence of flagellar Ca2+spikes. Thus, Ca2+does not appear to function as a negative regulator of IFT injection, hence it cannot form the basis of a stable length control system.
scPerturb: Harmonized Single-Cell Perturbation Data
Authors: Peidli Stefan , Green Tessa D. , Shen Ciyue , Gross Torsten , Min Joseph , Garda Samuele , Yuan Bo , Schumacher Linus J. , Taylor-King Jake P. , Marks Debora S. , Luna Augustin , Blüthgen Nils , Sander Chris
Published: August 2022

Recent biotechnological advances led to growing numbers of single-cell perturbation studies, which reveal molecular and phenotypic responses to large numbers of perturbations. However, analysis across diverse datasets is typically hampered by differences in format, naming conventions, and data filtering. In order to facilitate development and benchmarking of computational methods in systems biology, we collect a set of 44 publicly available single-cell perturbation-response datasets with molecular readouts, including transcriptomics, proteomics and epigenomics. We apply uniform pre-processing and quality control pipelines and harmonize feature annotations. The resulting information resource enables efficient development and testing of computational analysis methods, and facilitates direct comparison and integration across datasets. In addition, we introduce E-statistics for perturbation effect quantification and significance testing, and demonstrate E-distance as a general distance measure for single cell data. Using these datasets, we illustrate the application of E-statistics for quantifying perturbation similarity and efficacy. The data and a package for computing E-statistics is publicly available at scperturb.org. This work provides an information resource and guide for researchers working with single-cell perturbation data, highlights conceptual considerations for new experiments, and makes concrete recommendations for optimal cell counts and read depth.
Peptaibol Production and Characterization from Trichoderma asperellum and their Action as Biofungicide
Authors: Alfaro-Vargas Pamela , Bastos-Salas Alisson , Muñoz-Arrieta Rodrigo , Pereira-Reyes Reinaldo , Redondo-Solano Mauricio , Fernández Julián , Mora-Villalobos Aníbal , López-Gómez José Pablo
Published: August 2022

Peptaibols (Paib), are a class of biologically active peptides isolated from soil, fungi and molds, which have interesting properties as antimicrobial agents. Paib production was optimized in flasks by adding sucrose as a carbon source, Aib as an additive amino acid, and F. oxysporum cell debris as an elicitor. Paib were purified, sequenced and identified by HPLC coupled to mass spectrometry. Afterward, a Paib prototype was prepared with the extracts obtained from the optimized fermentations. The biological activity of these prototypes was evaluated using in vitro and in vivo methods. The prototype inhibited the growth of specific plant pathogens, and it showed inhibition rates similar to those from commercially available fungicides. Growth inhibition rates were 92.2, 74.2, 58.4 and 36.2% against Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria alternata and Fusarium oxysporum, respectively. Furthermore, the antifungal activity was tested in tomatoes inoculated with A. alternata, the incidence of the disease in tomatoes treated with the prototype was 0%, while the untreated fruit showed a 92.5% of infection. Scanning electron microscopy images showed structural differences between fungi treated with or without Paib. The most visual alterations were sunk and shriveled morphology in spores, while the hyphae appeared to be fractured, rough, and dehydrated.
A mutation rate model at the basepair resolution identifies the mutagenic effect of Polymerase III transcription
Authors: Seplyarskiy Vladimir , Lee Daniel J. , Koch Evan M. , Lichtman Joshua S. , Luan Harding H. , Sunyaev Shamil R.
Published: August 2022

De novomutations occur with substantially different rates depending on genomic location, sequence context and DNA strand1–4. The success of many human genetics techniques, especially when applied to large population sequencing datasets with numerous recurrent mutations5–7, depends strongly on assumptions about the local mutation rate. Such techniques include estimation of selection intensity8, inference of demographic history9, and mapping of rare disease genes10. Here, we present Roulette, a genome-wide mutation rate model at the basepair resolution that incorporates known determinants of local mutation rate (http://genetics.bwh.harvard.edu/downloads/Vova/Roulette/). Roulette is shown to be more accurate than existing models1,6. Roulette has sufficient resolution at high mutation rate sites to model allele frequencies under recurrent mutation. We use Roulette to refine estimates of population growth within Europe by incorporating the full range of human mutation rates. The analysis of significant deviations from the model predictions revealed a 10-fold increase in mutation rate in nearly all genes transcribed by Polymerase III, suggesting a new mutagenic mechanism. We also detected an elevated mutation rate within transcription factor binding sites restricted to sites actively utilized in testis and residing in promoters.