bluuebunny/crossref_metadata_2025 huggingface dataset:
Living Longer Better
Authors: Woods, BA(Biol), MBA Tina , Manson Brown Stephanie , Page Ben
Published: November 2021

Aging is a universal feature of life and a complex process at all levels from the biological to the societal. What constitutes older age is subjective and flexible, and how one defines older age is influenced by everchanging individual, generational, and cultural expectations. As the global population ages at an unprecedented rate, we are increasingly confronted with a myriad of challenges associated with aging, including increased healthcare needs and the far-reaching negative consequences of individual and structural agism. However, the shift in world demographics toward an older population is not a growing burden, but an opportunity to reshape our view of older life and proactively embrace healthy aging. Indeed, a healthy person is not defined by the absence of illness, but by the potential for meaningful work, positive relationships, and longevity. Simple preventive measures, such as improved diet and increased exercise, can enhance overall health and quality of life, and growing evidence highlights the potential of positive psychology for improving psychological well-being and overall quality of life. Now more than ever, technological innovation including artificial intelligence can be leveraged to improve our understanding of the causes and consequences of aging, as well as the most effective interventions to enhance resilience and extend healthy longevity. Good health is our greatest asset. It is the responsibility of all—individuals, society, business, science, healthcare systems, and government—to ensure that everyone is well equipped to maintain good health. Together, we can all live better, longer.
A New Model to Simulate Human Facial Appearance, Accurately, and Realistically, across Age and Ethnicity
Authors: Matts Paul J. , Canfield Doug , D’Alessandro Brian
Published: November 2021

Background:

The human population is aging globally, and there is significant, growing interest in modeling and simulating facial appearance.

Methods:

The authors describe a new means to model and simulate aging in facial images, using an approach based entirely on 3D whole-face data collected from 1250 female subjects, across 5 ethnicities, ages 10–80.

Results:

Three models were built, each describing changes with age within each ethnic group, namely shape, color, and topography. These three models were used to build a simulation able to age or de-age a 2D image of a female subject’s face, with a degree of accuracy and realism not achievable with previous approaches. Simulated images were validated by a cloud-based age estimator.

Conclusions:

The authors have developed a new facial age simulation model, where the use of three submodels (shape, color and topography), built from acquired 3D data, provides both scientifically robust and realistic output. As the data were acquired across five of the world’s major ethnicities, this new model allows valuable insight into changes in the facial appearance of our aging global population.
The Rise of Induced Pluripotent Stem Cell Approach to Hair Restoration
Authors: Pinto Antonella , Terskikh Alexey V.
Published: November 2021

The advent of pluripotent stem cells following the discovery of Shinya Yamanaka (2012 Nobel prize in Medicine) brought about a regenerative medicine approach to virtually every human condition including hair loss. It is now possible to reprogram somatic cells (eg, blood or skin cells) from a person experiencing hair loss to generate autologous induced pluripotent stem cells (iPSCs), which could be amplified and cryopreserved. Subsequently, these iPSCs could be differentiated into various cell types such as dermal papilla cells, epithelial cells, melanocytes, and other cell types constituting functional hair follicle. Transplantation of human iPSC-derived folliculogenic cells into the nude mice has successfully generated xenografts with hair outgrowth. Because iPSCs provide a virtually unlimited source of folliculogenic cells for de novo formation of hair follicles, this approach has major advantages over current surgical hair restoration procedures, which merely redistribute existing hair follicles from one part of the sculp to another. Combined with robotics and automation of the transplantation process, this novel regenerative medicine approach is well poised to make hair restoration a routine procedure affordable for everybody who can benefit from it.
An Exploratory Study Into a New Head Ultrasound Marker for Predicting Neurodevelopmental Outcomes in Preterm Infants
Authors: Yuan Jing , Cao Xiang , Deng Yingping
Published: November 2021

Preterm infants are at risk of neurological impairments and long-term developmental delay. Head ultrasound (HUS) is a promising tool for early detection of preterm brain injury and prediction of neurodevelopmental outcomes. We performed a retrospective analysis of data of 42 preterm infants with neurodevelopmental follow-up at 12 to 24 months corrected age. Corpus callosum length (CC length) and corpus callosum-fastigium length (CCF length) were measured on the HUS scans. Motor function and communication skills were assessed using evaluation scales. Corpus callosum length and CCF length were correlated with neurodevelopmental outcomes using Spearman correlation analysis. Neither CC length nor CCF length correlated with motor developmental outcomes. On early HUS, the CCF length was negatively correlated with symbolic composite percentile ranks (Spearman ρ = −0.49, P = 0.033) and total percentile ranks (Spearman ρ = −0.545, P = 0.016). On follow-up HUS scans, the CCF length was also found to be negatively correlated with social composite raw scores and percentile ranks (Spearman ρ = −0.615, P = 0.005; and Spearman ρ = −0.64, P = 0.003, respectively), symbolic composite raw scores and percentile ranks (Spearman ρ = −0.609, P = 0.006; and Spearman ρ = −0.657, P = 0.002, respectively) and total raw scores and percentile ranks (Spearman ρ = −0.472, P = 0.041; and Spearman ρ = −0.504, P = 0.028, respectively). Corpus callosum-fastigium length measurement on serial HUS is useful in predicting cognitive and behavioral outcomes at corrected age 12 to 24 months.
Using systems thinking methodologies to address health care complexities and evidence implementation
Authors: Khalil Hanan , Lakhani Ali
Published: November 2021

Background:

Despite health care advances, artificial intelligence and government interventions aiming to improve the health and wellbeing of citizens, huge disparities and failures in care provision exist. This is demonstrated by the rising number of medical errors, increase in readmission rates and mortality rates, and the failure of many health systems to successfully cope with events, such as pandemics and natural disasters. This shortfall is in part because of the complexity of the health care system, the interconnectedness of various parts of service, funding models, the complexity of patients’ conditions, patient and carer needs, and the clinical processes needed for patients via multiple providers.

Objective:

The objective of this paper is to describe the use of system thinking methodologies to address complex problems such as those in the public health and health services domains.

Method:

A description of the system thinking methodology and its associated methods including causal loop diagrams, social network analysis and soft system methodology are described with examples in the health care setting.

Results:

There are various models of knowledge translation that have been employed including the Joanna Briggs Institute model of implementation of evidence into practice, the triple C, and the Promoting Action on Research Implementation in Health Services. However, many of these models are neither scalable nor sustainable, and are most effective for localized projects implemented by trained clinicians and champions in relevant settings.

System thinking is essentially a modelling process, which aims to create opportunities for change via an appreciation of perspective, and recognition that complex problems are a result of interconnected factors. The article argues that systems thinking applications need to move beyond that of addressing complex health issues pertaining to a population, and rather consider complex problems surrounding the delivery of high-quality health care.

Conclusion:

It is important that methods to implement systems thinking methodologies in health care settings are developed and tested.
Invasive Geotrichum klebahnii fungal infection: A case report
Authors: Tshisevhe Vhudzani , Mitton Barend , Skosana Lebogang
Published: November 2021

Geotrichosis is a world-wide mycosis caused byGeotrichumspecies. We report a rare case of an invasive cutaneous infection byGeotrichum klebahniiin a female patient with undiagnosed diabetes mellitus. The patient presented with right facial swelling not responding to antibiotics and could not recall trauma to the site of the lesion. Histological examination showed fungal hyphae invading salivary glands and bony tissues, andG. klebahniiwas isolated from the culture of biopsy material. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) confirmed the fungal species. Broth microdilution showed low minimum inhibitory concentrations (MICs) for itraconazole, posaconazole, voriconazole and amphotericin B. Treatment with sequential administration of intravenous amphotericin B with voriconazole followed by itraconazole led to the resolution of the lesion.
Phylogenomics and population genomics of SARS-CoV-2 in Mexico during the pre-vaccination stage reveals variants of interest B.1.1.28.4 and B.1.1.222 or B.1.1.519 and the nucleocapsid mutation S194L associated with symptoms
Authors: Barona-Gómez Francisco , Delaye Luis , Díaz-Valenzuela Erik , Plisson Fabien , Cruz-Pérez Arely , Díaz-Sánchez Mauricio , García-Sepúlveda Christian A. , Sanchez-Flores Alejandro , Pérez-Abreu Rafael , Valencia-Valdespino Francisco J. , Vega-Magaña Natali , Muñoz-Valle José Francisco , García-González Octavio Patricio , Bernal-Silva Sofía , Comas-García Andreu , Cibrián-Jaramillo Angélica
Published: November 2021

Understanding the evolution of the SARS-CoV-2 virus in various regions of the world during the Covid-19 pandemic is essential to help mitigate the effects of this devastating disease. We describe the phylogenomic and population genetic patterns of the virus in Mexico during the pre-vaccination stage, including asymptomatic carriers. A real-time quantitative PCR screening and phylogenomic reconstructions directed at sequence/structure analysis of the spike glycoprotein revealed mutation of concern E484K in genomes from central Mexico, in addition to the nationwide prevalence of the imported variant 20C/S:452R (B.1.427/9). Overall, the detected variants in Mexico show spike protein mutations in the N-terminal domain (i.e. R190M), in the receptor-binding motif (i.e. T478K, E484K), within the S1–S2 subdomains (i.e. P681R/H, T732A), and at the basis of the protein, V1176F, raising concerns about the lack of phenotypic and clinical data available for the variants of interest we postulate: 20B/478K.V1 (B.1.1.222 or B.1.1.519) and 20B/P.4 (B.1.1.28.4). Moreover, the population patterns of single nucleotide variants from symptomatic and asymptomatic carriers obtained with a self-sampling scheme confirmed the presence of several fixed variants, and differences in allelic frequencies among localities. We identified the mutation N:S194L of the nucleocapsid protein associated with symptomatic patients. Phylogenetically, this mutation is frequent in Mexican sub-clades. Our results highlight the dual and complementary role of spike and nucleocapsid proteins in adaptive evolution of SARS-CoV-2 to their hosts and provide a baseline for specific follow-up of mutations of concern during the vaccination stage.
Off-label drug database
Authors: Grosjean J. , Letord C. , Zana I. , Advenier-Iakovlev E. , Duclos C. , Krebs MO. , Charlet J. , Darmoni SJ.
Published: November 2021

Background

Many drugs are still being prescribed in a “off-label mode” and especially in psychiatry. Off-label prescription situations may vary depending on several factors and such practice is not well identifiable in the literature. Methods: A new public academic drug database has been recently created and is able to contain off-label indications, especially in psychiatry in the context of the PSYHAMM French research project. For each situation, bibliographic references have been collected to make the scientific information available to all. Results: this new off-label drug database contains more than 18,154 lines. It is freely available at https://www.hetop.eu/hetop/medicaments. Several off-label usages have been formally described and the system is extensible to all drugs and all specialties. Conclusion: An off-label drug database can be a valuable tool for health professionals and students.
Reactivation of hedonic but not sensory representations in human emotional learning
Authors: Ehlers M. R. , Kryklywy J. H. , Beukers A. O. , Moore S. R. , Forys B. J. , Anderson A.K. , Todd R. M.
Published: November 2021

Learning which stimuli in our environment co-occur with painful or pleasurable events is critical for survival. Previous research has established the basic neural and behavioural mechanisms of aversive and appetitive conditioning; however, it is unclear what precisely is learned. Here we examined what aspects of the unconditioned stimulus (US) – sensory and hedonic – are transferred to the conditioned stimulus (CS). To decode the content of brain activation patterns elicited during appetitive (soft touch) and aversive (painful touch) conditioning of faces, a novel variation of representational similarity analysis (RSA) based on theoretically driven representational patterns of interest (POIs) was applied to fMRI data. Once face associations were learned through conditioning, globally the CS reactivated US representational patterns showing conditioning-dependent reactivation. More specifically, in higher order brain regions, the CS only reactivated hedonic but not sensory aspects of the US – suggesting that affective conditioning primarily carries forward the valence of the experience rather than its sensory origins.
Bitter taste perception in BaYaka hunter-gatherers
Authors: Keestra Sarai , Miabangana Edmond Sylvestre , Chaudhary Nikhil , Derkx Inez , Sikka Gaurav , Salali Gul Deniz
Published: November 2021

Aversion towards bitter tastes evolved across vertebrate species to enable the recognition of harmful plant toxins. Most studies to date have investigated the variation in bitter taste sensitivity between human populations. However, there is a lack of research investigating phenotypic plasticity and the variation in bitter taste perception within the same population. Here we examined bitter taste perception among the Mbendjele BaYaka hunter-gatherers from Congo, a group of forest hunter-gatherers who exhibit a variation in their levels of market integration. We conducted an experiment using phenylthiocarbamide (PTC) and thiourea infused paper strips and compared the prevalence of bitter tasting phenotypes between the BaYaka who grew up in town and forest camps. We found that 45.1% of BaYaka experience PTC as bitter, and 42.5% experience thiourea as bitter. There were no sex and age differences in bitter taste perception. Despite a shared genetic background, we found that BaYaka who grew up in town were more sensitive to bitter taste than those living in the forest, suggesting a developmental component in taste perception. We suggest that a decreased use of traditional plant medicine in town-born BaYaka may underlie this variation in bitter taste perception.
Survey on Open Science Practices in Functional Neuroimaging
Authors: Paret Christian , Unverhau Nike , Feingold Franklin , Poldrack Russell A. , Stirner Madita , Schmahl Christian , Sicorello Maurizio
Published: November 2021

Replicability and reproducibility of scientific findings is paramount for sustainable progress in neuroscience. Preregistration of the hypotheses and methods of an empirical study before analysis, the sharing of primary research data, and compliance with data standards such as the Brain Imaging Data Structure (BIDS), are considered effective practices to secure progress and to substantiate quality of research. We investigated the current level of adoption of open science practices in neuroimaging and the difficulties that prevent researchers from using them.

Email invitations to participate in the survey were sent to addresses received through a PubMed search of human functional magnetic resonance imaging studies between 2010 and 2020. 283 persons completed the questionnaire.

Although half of the participants were experienced with preregistration, the willingness to preregister studies in the future was modest. The majority of participants had experience with the sharing of primary neuroimaging data. Most of the participants were interested in implementing a standardized data structure such as BIDS in their labs. Based on demographic variables, we compared participants on seven subscales, which had been generated through factor analysis. It was found that experienced researchers at lower career level had higher fear of being transparent, researchers with residence in the EU had a higher need for data governance, and researchers at medical faculties as compared to other university faculties reported a higher need for data governance and a more unsupportive environment.

The results suggest growing adoption of open science practices but also highlight a number of important impediments.
Genome-wide analyses reveal a strong association between LEPR gene variants and body fat reserves in ewes
Authors: Macé Tiphaine , González-García Eliel , Foulquié Didier , Carrière Fabien , Pradel Julien , Durand Christian , Douls Sebastien , Parisot Sara , Hazard Dominique
Published: November 2021

Among the adaptive capacities of animals, the management of energetic body reserves (BR) through the BR mobilization and accretion processes (BR dynamics, BRD) has become an increasingly valuable attribute for livestock sustainability, allowing animals to cope with more variable environments. BRD has previously been reported to be heritable in ruminants. In the present study, we conducted genome-wide studies (GWAS) in sheep to determine genetic variants associated with BRD. BR levels and BR changes over time were obtained through body condition score measurements at eight physiological stages throughout each productive cycle in Romane ewes (n=1034) and were used as phenotypes for GWAS. After quality controls and imputation, 48,513 single nucleotide polymorphisms (SNP) were included in the GWAS. Among the QTLs identified, a major QTL associated with BR levels during pregnancy and lactation was identified on chromosome 1. In this region, several significant SNPs mapped to the leptin receptor gene (LEPR), among which one SNP mapped to the coding sequence. The point mutation induces the p.P1019S substitution in the cytoplasmic domain, close to tyrosine phosphorylation sites. The frequency of the SNP associated with increased BR levels was 32%, and the LEPR genotype explained up to 5% of the variance of the trait. These results provide strong evidence for involvement of LEPR in the regulation of BRD in sheep and highlight it as a major candidate for improving adaptive capacities.
Case Study of High-Throughput Drug Screening and Remote Data Collection for SARS-CoV-2 Main Protease by Using Serial Femtosecond X-ray Crystallography
Authors: Guven Omur , Gul Mehmet , Ayan Esra , Johnson J. Austin , Cakilkaya Baris , Usta Gozde , Ertem Fatma Betul , Tokay Nurettin , Yuksel Busra , Gocenler Oktay , Buyukdag Cengizhan , Botha Sabine , Ketawala Gihan , Su Zhen , Hayes Brandon , Poitevin Frederic , Batyuk Alexander , Yoon Chun Hong , Kupitz Christopher , Durdagi Serdar , Sierra Raymond G. , DeMirci Hasan
Published: November 2021

Since early 2020, COVID-19 has grown to affect the lives of billions globally. A worldwide investigation has been ongoing for characterizing the virus and also for finding an effective drug and developing vaccines. As time has been of the essence, a crucial part of this research has been drug repurposing; therefore, confirmation of in-silico drug screening studies has been carried out for this purpose. Here we demonstrated the possibility of screening a variety of drugs efficiently by leveraging a high data collection rate of 120 images/second with the new low-noise, high dynamic range ePix10k2M Pixel Array Detector installed at the Macromolecular Femtosecond Crystallography (MFX) instrument at the Linac Coherent Light Source (LCLS). The X-ray Free-Electron Laser (XFEL) is used for remote high-throughput data collection for drug repurposing of the main protease (Mpro) of SARS-CoV-2 at ambient temperature with mitigated X-ray radiation damage. We obtained multiple structures soaked with 9 drug candidate molecules in two crystal forms. Although our drug binding attempts failed, we successfully established a high-throughput Serial Femtosecond X-ray crystallographic (SFX) data collection protocol.
Myeloid cell-driven nonregenerative pulmonary scarring is conserved in multiple nonhuman primate species regardless of SARS-CoV-2 infection modality
Authors: Fears Alyssa C , Beddingfield Brandon J , Chirichella Nicole R , Slisarenko Nadia , Killeen Stephanie Z , Redmann Rachel K , Goff Kelly , Spencer Skye , Picou Breanna , Golden Nadia , Bush Duane J , Branco Luis M , Boisen Matthew L , Gao Hongmei , Montefiori David C , Blair Robert V , Doyle-Meyers Lara A , Russel-Lodrigue Kasi , Maness Nicholas J , Roy Chad J
Published: November 2021

The novel coronavirus SARS-CoV-2 has caused a worldwide pandemic resulting in widespread efforts in development of animal models that recapitulate human disease for evaluation of medical countermeasures, and to dissect COVID-19 immunopathogenesis. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM) of nonhuman primates. Species-specific cohorts of RM and AGM Rhesus macaques (Macaca mulatta, RMs) and African green monkeys (Chlorocebus aethiops, AGMs) were experimentally infected with homologous SARS-CoV-2 by either direct mucosal instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated equivalent infection initially by either exposure route although the magnitude and duration of viral loading was greater in AGMs than that of the RM. Clinical onset was nearly immediate (+1dpi) in mucosally-exposed cohorts whereas aerosol-infected animals began to show signs +7dpi. Myeloid cell responses indicative of the development of pulmonary scarring and extended lack of regenerative capacity in the pulmonary compartment was a conserved pathologic response in both species by either exposure modality. This pathological commonality may be useful in future anti-fibrosis therapeutic evaluations and expands our understanding of how SARS-CoV-2 infection leads to ARDS and functional lung damage.
A stochastic mathematical model of 4D tumour spheroids with real-time fluorescent cell cycle labelling
Authors: Klowss Jonah J. , Browning Alexander P. , Murphy Ryan J. , Carr Elliot J. , Plank Michael J. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J.
Published: November 2021

In vitro tumour spheroid experiments have been used to study avascular tumour growth and drug design for the last 50 years. Unlike simpler two-dimensional cell cultures, tumour spheroids exhibit heterogeneity within the growing population of cells that is thought to be related to spatial and temporal differences in nutrient availability. The recent development of real-time fluorescent cell cycle imaging allows us to identify the position and cell cycle status of individual cells within the growing population, giving rise to the notion of a four-dimensional (4D) tumour spheroid. In this work we develop the first stochastic individual-based model (IBM) of a 4D tumour spheroid and show that IBM simulation data qualitatively and quantitatively compare very well with experimental data from a suite of 4D tumour spheroid experiments performed with a primary human melanoma cell line. The IBM provides quantitative information about nutrient availability within the spheroid, which is important because it is very difficult to measure these data in standard tumour spheroid experiments. Software required to implement the IBM is available on GitHub, https://github.com/ProfMJSimpson/4DFUCCI.
Development of machine learning model for predicting hospitalization in the prehospital setting
Authors: Morisawa Kenichiro , Goto Tadahiro , Fujitani Shigeki
Published: November 2021

Background

Studies have developed models for predicting patient outcomes for successful risk stratification in the prehospital setting. However, these models generally require many predictors to achieve high prediction ability, resulting in a bar for implementing models in the real clinical setting.

Objective

We aimed to develop a simple and implementable machine learning model using automatically-collected data (age, sex, vital signs) to predict patient outcomes during transportation in comparison with National Early Warning Score (NEWS).

Methods

This is a retrospective cohort study using data from the ED of three tertiary care hospitals in Japan from April 2017 to March 2020. We included adult patients (aged ≥18 years) who were transported to the ED of participating hospitals. We excluded patients with trauma/injury, cardiac arrest, transferred from other hospitals, patients with missing vital signs data, or having data of obvious outliers. The predictors were patient age, sex, mental status evaluated with Japan Coma Scale, systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and oxygen saturation. The primary outcome was hospitalization. We developed a model using XGBoost.

Results

During the study period, 3528 visits transported by emergency medical services were eligible. The median NEWS was 4.0, and 2081 patients were hospitalized. The discrimination ability of the newly developed model was 0.70 (95%CI 0.67-0.73), which was better than those of NEWS 0.64 (95%CI 0.61-0.68). The newly developed model’s performance measures (e.g., sensitivity, specificity) were comparable with NEWS.

Conclusions

Our newly developed machine learning model using routinely available data has moderate prediction ability and was better than NEWS.
The HUSH complex controls brain architecture and protocadherin fidelity
Authors: Hagelkruys Astrid , Horrer Marion , Taubenschmid-Stowers Jasmin , Kavirayani Anoop , Novatchkova Maria , Orthofer Michael , Pai Tsung-Pin , Cikes Domagoj , Zhuk Sergei , Balmaña Meritxell , Esk Christopher , Koglgruber Rubina , Cronin Shane J.F. , Elling Ulrich , Knoblich Jürgen A. , Penninger Josef M.
Published: November 2021

Abstract

Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.
Using child-friendly movie stimuli to study the development of face, place, and object regions from age 3 to 12 years
Authors: Kamps Frederik S. , Richardson Hilary , Ratan Murty N. Apurva , Kanwisher Nancy , Saxe Rebecca
Published: November 2021

Scanning young children while watching short, engaging, commercially-produced movies has emerged as a promising approach for increasing data retention and quality. Movie stimuli also evoke a richer variety of cognitive processes than traditional experiments – allowing the study of multiple aspects of brain development simultaneously. However, because these stimuli are uncontrolled, it is unclear how effectively distinct profiles of brain activity can be distinguished from the resulting data. Here we develop an approach for identifying multiple distinct subject-specific Regions of Interest (ssROIs) using fMRI data collected during movie-viewing. We focused on the test case of higher-level visual regions selective for faces, scenes, and objects. Adults (N=13) were scanned while viewing a 5.5 minute child-friendly movie, as well as a traditional experiment with isolated faces, scenes, and objects. We found that just 2.7 minutes of movie data could identify subject-specific face, scene, and object regions. While successful, the movie approach was still less effective than a traditional localizer. Having validated our approach in adults, we then used the same methods on movie data collected from 3–12-year-old children (N=122). Movie response timecourses in 3-year-old children’s face, scene, and object regions were already significantly and specifically predicted by timecourses from the corresponding regions in adults. We also found evidence of continued developmental change, particularly in the face-selective posterior superior temporal sulcus. Taken together, our results reveal both early maturity and functional change in face, scene, and object regions, and more broadly highlight the promise of short, child-friendly movies for developmental cognitive neuroscience.
Adolescent ethanol drinking promotes hyperalgesia, neuroinflammation and serotonergic deficits in mice that persist into adulthood
Authors: Khan Kanza M. , Bierlein-De La Rosa Gabrielle , Biggerstaff Natalie , Pushpavathi Selvakumar Govindhasamy , Mason Suzanne , Dailey Michael E. , Marcinkiewcz Catherine A.
Published: November 2021

Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use predispose to pain disorders or exacerbate existing pain conditions, but the neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of Cx3cr1-cre-GFP mice reproduced the effects of AIE on pain and social interaction. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain and negative affect after AIE.
Ectosome effect on endothelial monolayers in hyperglycemic and normoglycemic conditions
Authors: Drożdż Anna , Kołodziej Tomasz , Wróbel Sonia , Misztal Krzysztof , Targosz-Korecka Marta , Drab Marek , Jach Robert , Przybyło Małgorzata , Rajfur Zenon , Stępień Ewa Ł
Published: November 2021

Extracellular vesicles, namely those larger ones - Ectosomes (Ect), are thought to be important cell-to-cell communication medium. Ect are considered as a potential therapeutic for type-1 and type-2 diabetes mellitus. Ect can be internalized by endothelial cells and, owing to their cargo, they modulate targeted cell behavior. Under hyperglycemic conditions (HGC), endothelial cells changed their properties and became stiffer and less mobile which causes endothelial dysfunction and abnormalities in micro- and macrovascular systems. The aim of this study was to find whether Ect restore mobility and motility of macrovascular endothelial cells under HGC. Uptake of Ect, cell morphology, cytoskeleton organization and membrane stiffness (by atomic force microscopy) were analyzed after the exposure to isolated Ect. To find which cellular pathways were deregulated by HGC and whether Ect could potentially restore gene expression profile, transcriptome analysis was done. We observed that endothelial cells internalized more Ect under normoglycemic conditions (NGC) then HGC. Hyperglycemic cells (HG) were bigger and showed the stiffer surface with denser actin cytoskeleton in comparison to normoglycemic cells. Number of metabolic pathways was influenced under HGC, especially those related to intracellular transport, metabolism and cellular component organization and Ect did not restore HGC impaired cell signaling. Ectosomes cannot reverse this harmful effect of hyperglycemia in endothelial cells, which can have clinical implication in use Ect as therapeutic target in diabetes treatment.
A subcellular cookie cutter for spatial genomics in human tissue
Authors: Bury Alexander G. , Pyle Angela , Marcuccio Fabio , Turnbull Doug M. , Vincent Amy E. , Hudson Gavin , Actis Paolo
Published: November 2021

Intracellular heterogeneity contributes significantly to cellular physiology and, in a number of debilitating diseases, cellular pathophysiology. This is greatly influenced by distinct organelle populations and to understand the aetiology of disease it is important to have tools able to isolate and differentially analyse organelles from precise location within tissues. Here we report the development of a subcellular biopsy technology that facilitates the isolation of organelles, such as mitochondria, from human tissue. We compared the subcellular biopsy technology to laser capture microdissection (LCM) that is the state of art technique for the isolation of cells from their surrounding tissues. We demonstrate an operational limit of (>20μm) for LCM and then, for the first time in human tissue, show that subcellular biopsy can be used to isolate mitochondria beyond this limit.
Diversity of Lepidoptera in urban parks at Pasir Gudang, Johor, Malaysia
Authors: Syed Nisranshah Sharifah Fatin Naqliah , Zakaria Nurulhuda
Published: November 2021

Urban parks are a valuable habitat for Lepidoptera, which are often neglected despite their potential role as pollinators and important food source for small animals. Lepidoptera in urban parks in Pasir Gudang are still under-studied. Yet, there is no publication on Lepidoptera in these urban parks. The objectives of this study were to determine and to compare the diversity of Lepidoptera in three urban parks (Laman Rekreasi Sungai Buluh, Tasik Dahlia and Taman Bandar) at Pasir Gudang, Johor. Visual Encounter Survey (VES) method was used to capture the Lepidoptera from February 2021 until April 2021. Four sampling sessions were conducted for each study site. A total of nine species from 117 individuals comprised of family Pieridae (43%), Nymphalidae (29%) and Lycaenidae (28%) were recorded from this study. The most abundant species were Zizula hylax and Elymnias hypermnestra, while Leptosia nina was the least abundant. The results from this study showed that the diversity of Lepidoptera have established in these three urban parks. Diversity of Lepidoptera in Tasik Dahlia was significantly lower compared to the other two study sites. The findings from this study could be useful as a baseline data for future research and conservation management of the order Lepidoptera around the urban parks and indirectly can support the sustainable development of the urban parks.
Validating a computational framework for ionic electrodiffusion with cortical spreading depression as a case study
Authors: Ellingsrud Ada Johanne , Enger Rune , Dukefoss Didrik Bakke , Halnes Geir , Pettersen Klas Henning , Rognes Marie E
Published: November 2021

Cortical spreading depression (CSD) is a wave of pronounced depolarization of brain tissue accompanied by substantial shifts in ionic concentrations and cellular swelling. Here, we validate a computational framework for modelling electrical potentials, ionic movement, and cellular swelling in brain tissue during CSD. We consider different model variations representing wild type or knock-out/knock-down mice and systematically compare the numerical results with reports from a selection of experimental studies. We find that the data for several CSD hallmarks obtained computationally, including wave propagation speed, direct current shift duration, peak in extracellular K+ concentration as well as a pronounced shrinkage of extracellular space, are well in line with what has previously been observed experimentally. Further, we assess how key model parameters including cellular diffusivity, structural ratios, membrane water and/or K+ permeabilities affect the set of CSD characteristics.

Significance Statement

Movement of ions and molecules in and between cellular compartments is fundamental for brain function. Cortical spreading depression (CSD) is associated with dramatic failure of brain ion homeostasis. Better understanding the sequence of events in CSD could thus provide new insight into physiological processes in the brain. Despite extensive experimental research over the last decades, even basic questions related to mechanisms underlying CSD remain unanswered. Computational modelling can play an important role going forward, since simulation studies can address hypotheses that are difficult to target experimentally. Here, we assess the physiological validity of a novel mathematical framework for detailed modelling of brain electrodiffusion and osmosis – and provide a platform for in silico studies of CSD and other cerebral electro-mechanical phenomena.
Consistent predictors of microbial community composition across scales in grasslands reveal low context-dependency
Authors: Radujković Dajana , Vicca Sara , van Rooyen Margaretha , Wilfahrt Peter , Brown Leslie , Jentsch Anke , Reinhart Kurt O. , Brown Charlotte , De Gruyter Johan , Jurasinski Gerald , Askarizadeh Diana , Bartha Sandor , Beck Ryan , Blenkinsopp Theodore , Cahill James , Campetella Giandiego , Canullo Roberto , Chelli Stefano , Enrico Lucas , Fraser Lauchlan , Hao Xiying , Henry Hugh A. L. , Hohn Maria , Jouri Mohammad Hassan , Koch Marian , Lawrence Lodge Rachael , Li Frank Yonghong , Lord Janice M. , Milligan Patrick , Minggagud Hugjiltu , Palmer Todd , Schröder Birgit , Szabó Gábor , Zhang Tongrui , Zimmermann Zita , Verbruggen Erik
Published: November 2021

Environmental circumstances shaping soil microbial communities have been studied extensively, but due to disparate study designs it has been difficult to resolve whether a globally consistent set of predictors exists, or context-dependency prevails. Here, we used a network of 18 grassland sites (11 sampled across regional plant productivity gradients) to examine i) if the same abiotic or biotic factors predict both large- and regional-scale patterns in bacterial and fungal community composition, and ii) if microbial community composition differs consistently with regional plant productivity (low vs high) across different sites. We found that there is high congruence between predictors of microbial community composition across spatial scales; bacteria were predominantly associated with soil properties and fungi with plant community composition. Moreover, there was a microbial community signal that clearly distinguished high and low productivity soils that was shared across worldwide distributed grasslands suggesting that microbial assemblages vary predictably depending on grassland productivity.
Distinctive nuclear zone for RAD51-mediated homologous recombinational DNA repair
Authors: Horikoshi Yasunori , Shima Hiroki , Sun Jiying , Kobayashi Wataru , Schmid Volker J. , Ochiai Hiroshi , Shi Lin , Fukuto Atsuhiko , Kinugasa Yasuha , Kurumizaka Hitoshi , Ikura Tsuyoshi , Markaki Yolanda , Tate Shin-ichi , Igarashi Kazuhiko , Cremer Thomas , Tashiro Satoshi
Published: November 2021

Genome-based functions are inseparable from the dynamic higher-order architecture of the cell nucleus. In this context, the repair of DNA damage is coordinated by precise spatiotemporal controls that target and regulate the repair machinery required to maintain genome integrity. However, the mechanisms that pair damaged DNA with intact template for repair by homologous recombination (HR) without illegitimate recombination remain unclear. This report highlights the intimate relationship between nuclear architecture and HR in mammalian cells. RAD51, the key recombinase of HR, forms spherical foci in S/G2 phases spontaneously. Using super-resolution microscopy, we show that following induction of DNA double-strand breaks RAD51 foci at damaged sites elongate to bridge between intact and damaged sister chromatids; this assembly occurs within bundle-shaped distinctive nuclear zones, requires interactions of RAD51 with various factors, and precedes ATP-dependent events involved the recombination of intact and damaged DNA. We observed a time-dependent transfer of single-stranded DNA overhangs, generated during HR, into such zones. Our observations suggest that RAD51-mediated homologous pairing during HR takes place within the distinctive nuclear zones to execute appropriate recombination.
Public T-Cell Receptors (TCRs) Revisited by Analysis of the Magnitude of Identical and Highly-Similar TCRs in Virus-Specific T-Cell Repertoires of Healthy Individuals
Authors: Huisman Wesley , Hageman Lois , Leboux Didier A.T. , Khmelevskaya Alexandra , Efimov Grigory A. , Roex Marthe C.J. , Amsen Derk , Falkenburg J.H.F. , Jedema Inge
Published: November 2021

Since multiple different T-cell receptor (TCR) sequences can bind to the same peptide-MHC combination and the number of TCR-sequences that can theoretically be generated even exceeds the number of T cells in a human body, the likelihood that many public identical (PUB-I) TCR-sequences frequently contribute to immune responses has been estimated to be low. Here, we quantitatively analyzed the TCR-repertoires of 190 purified virus-specific memory T-cell populations, directed against 21 antigens of Cytomegalovirus, Epstein-Barr virus and Adenovirus isolated from 29 healthy individuals, and determined the magnitude, defined as prevalence within the population and frequencies within individuals, of PUB-I TCR and of TCR-sequences that are highly-similar (PUB-HS) to these PUB-I TCR-sequences. We found that almost one third of all TCR nucleotide-sequences represented PUB-I TCR amino-acid (AA) sequences and found an additional 12% of PUB-HS TCRs differing by maximally 3 AAs. We illustrate that these PUB-I and PUB-HS TCRs were structurally related and contained shared core-sequences in their TCR-sequences. We found a prevalence of PUB-I and PUB-HS TCRs of up to 50% among individuals and showed frequencies of virus-specific PUB-I and PUB-HS TCRs making up more than 10% of each virus-specific T-cell population. These findings were confirmed by using an independent TCR-database of virus-specific TCRs. We therefore conclude that the magnitude of the contribution of PUB-I and PUB-HS TCRs to these virus-specific T-cell responses is high. Because the T cells from these virus-specific memory TCR-repertoires were the result of successful control of the virus in these healthy individuals, these PUB-HS TCRs and PUB-I TCRs may be attractive candidates for immunotherapy in immunocompromised patients that lack virus-specific T cells to control viral reactivation.

Significance statement

Public T-cell responses, in which T cells expressing the same T-cell receptor (TCR) are found in different individuals, have been described. However, the magnitude of the contribution of these TCRs to immune responses, defined as prevalence within the population and frequencies within individuals, is not known. In this study we characterized and quantified public T-cell responses within virus-specific memory T cells of healthy individuals by determining identical and highly-similar TCRs recognizing the same antigen and sharing conserved CDR3 motifs. The magnitude of public T-cell responses was surprisingly high and we argue that these dominant TCRs with shared core-sequences could be utilized for diagnostic purposes and may provide attractive TCRs to be used for immunotherapy in immunocompromised patients.
Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence
Authors: Mohammadi Shabnam , Herrera-Álvarez Santiago , Yang Lu , Pilar Rodríguez-Ordoñez María del , Zhang Karen , Storz Jay F. , Dobler Susanne , Crawford Andrew J. , Andolfatto Peter
Published: November 2021

A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution’s effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases.

Significance Statement

Individual amino acid residues within a protein work in concert to produce a functionally coherent structure that must be maintained even as orthologous proteins in different species diverge over time. Given this dependence, we expect identical mutations to have more similar effects on protein function in more closely related species. We tested this hypothesis by performing protein-engineering experiments on ATP1A, an enzyme mediating target-site insensitivity to cardiotonic steroids (CTS) in diverse animals. These experiments reveal that the phenotypic effects of substitutions can sometimes be background-dependent, but also that the magnitude of these phenotypic effects does not correlate with overall levels of ATP1A sequence divergence. Our results suggest that epistatic constraints are determined by states at a small number of sites, potentially explaining the frequent convergent CTS resistance substitutions among Na,K-ATPases of highly divergent taxa.