bluuebunny/crossref_metadata_2025 huggingface dataset:
Financial Impact of a Culturally Sensitive Hispanic Kidney Transplant Program on Increasing Living Donation
Authors: Wang Andrew , Caicedo Juan Carlos , Mathur Amit K. , Ruiz Richard M. , Gordon Elisa J.
Published: November 2022

Background.

In the United States, Hispanic/Latinx patients receive disproportionately fewer living donor kidney transplants (LDKTs) than non-Hispanic White patients. Northwestern Medicine’s culturally targeted Hispanic Kidney Transplant Program (HKTP) was found to increase LDKTs in Hispanic patients at 1 of 2 transplant programs with greater implementation fidelity.

Methods.

We conducted a budget impact analysis to evaluate HKTP’s impact on program financial profiles from changes in volume of LDKTs and deceased donor kidney transplants (DDKTs) in 2017 to 2019. We estimated HKTP programmatic costs, and kidney transplant (KT) program costs and revenues. We forecasted transplant volumes, HKTP programmatic costs, and KT program costs and revenues for 2022–2024.

Results.

At both programs, HKTP programmatic costs had <1% impact on total KT program costs, and HKTP programmatic costs comprised <1% of total KT program revenues in 2017–2019. In particular, the total volume of Hispanic KTs and HKTP LDKTs increased at both sites. Annual KT program revenues of HKTP LDKTs and DDKTs increased by 226.9% at site A and by 1042.9% at site B when comparing 2019–2017. Forecasted HKTP LDKT volume showed an increase of 36.4% (site A) and 33.3% (site B) with a subsequent increase in KT program revenues of 42.3% (site A) and 44.3% (site B) among HKTP LDKTs and DDKTs.

Conclusions.

HKTP programmatic costs and KT evaluation costs are potentially recoverable by reimbursement of organ acquisition costs and offset by increases in total KT program revenues of LDKTs; transplant programs may find implementation of the HKTP financially manageable.
Effects of Bushen Zhuangjin Decoction drug serum on SOX9 expression and Chondrocyte phenotype in vitro
Authors: Du Shaowen , Wang Shengdong , Liu Xiang , Ye Kaishan
Published: November 2022

Introduction Bushen Zhuangjin Decoction (BZD), a well-known formulation in Traditional Chinese Medicine, has been widely used for the treatment of osteoarthritis (OA). Due to the poor intrinsic repair capacity of chondrocytes, promoting the proliferation of chondrocytes is an efficient treatment to delay the progression of cartilage degradation.

Hypothesis/Gap Statement Therefore, to explore the regulatory mechanism of Bushen Zhuangjin Decoction in chondrocytes will contribute to the repair of chondrocyte injury in OA, and may serve as a potential therapy for OA diseases.

Aim To investigate the expression and distribution of SOX9 mediated by serum containing Bushen Zhuangjin Decoction (BZD) and its therapeutic effect on chondrocyte injury in rats.

Methodology. The subcultured second-generation rat chondrocytes were randomly divided into four groups, and they were intervened with medium containing different serums, including: blank serum group, low-concentration BZD group, medium-concentration BZD group, and high-concentration BZD group. The viability, proliferation and apoptosis of chondrocytes were detected by MTT assay and flow cytometry. The gene and protein levels of SOX9, aggrecan and type II collagen genes were analysed by qRT-PCR and Western blot analysis. Immunofluorescence staining was used to analyse the expression and distribution of SOX9. Inflammatory factors in different culture mediums of chondrocytes were detected by ELISA.

Results Compared with the control group, the activity of chondrocytes in the BZD drug-containing serum group was significantly enhanced, and the degree of apoptosis was significantly decreased. The gene and protein levels of SOX9, proteoglycan aggrecan and collagen II in chondrocytes increased significantly. The inflammatory factors in the culture medium also decreased significantly. And in the above experiments, the medium concentration group BZD drug-containing serum had the best effect.

Conclusion Our research results show that BZD medicated serum can up-regulate the expression of SOX9, reduce the release of inflammatory factors, and promote changes in the phenotype of chondrocytes, which protects chondrocytes from damage.
Phase angle is related to physical function and quality of life in preoperative patients with lumbar spinal stenosis
Authors: Otsubo Ryota , Hashida Ryuki , Murotani Kenta , Iwanaga Sohei , Hirota Keisuke , Koya Syunji , Tsukada Yuya , Ogata Yuta , Yokosuka Kimiaki , Yoshida Tatsuhiro , Nakae Ichiro , Fudo Takuma , Morito Shinji , Shimazaki Takahiro , Shimogawa Shingo , Yamaryo Reika , Ito Mai , Yamada Kei , Sato Kimiaki , Matsuse Hiroo , Shiba Naoto , Hiraoka Koji
Published: November 2022

Purpose

Lumbar spinal stenosis (LSS) causes various symptoms, which can interfere with daily life and Quality of Life (QOL). Evaluating both patients’ physical function and QOL and helping them to improve is the focus of rehabilitation. Phase angle (PhA) assessment has been widely used to measure body composition, and it has been reported to reflect physical function and QOL. The purpose of this study was to investigate the relationship between PhA and physical function, physical activity, and QOL in patients with LSS.

Methods

PhA, handgrip strength, walking speed, timed up and go test (TUG), Life Space Assessment (LSA), Prognostic Nutritional Index (PNI), Japanese Orthopaedic Association back pain evaluation questionnaire (JOABPEQ), and EQ-5D were assessed. Multiple regression analysis was conducted to investigate the relationship of PhA to physical function, physical activity, and QOL using.

Results

Statistical analysis was performed on 104 patients with LSS. The results of multiple regression analysis of PhA adjusted for age, gender, and BMI (Model 1) and PhA adjusted for age, gender, BMI, and PNI (Model 2) compared with physical function and physical activity showed significant correlations respectively (P<0.05) in handgrip strength, walking speed, TUG, and LSA. In QOL assessment, both models showed a significant correlation (P<0.05) with lumbar function in JOABPEQ and a significant trend (P<0.1) in EQ-5D.

Conclusion

PhA in LSS patients in this study was associated with physical function and QOL, and may be a useful new tool for clinical evaluation in preoperative LSS patients.
A comprehensive knowledgebase of known and predicted human genetic variants associated with COVID-19 susceptibility and severity
Authors: Kars Meltem Ece , Stein David , Sevim Bayrak Çiğdem , Stenson Peter D , Cooper David N , Itan Yuval
Published: November 2022

Host genetic susceptibility is a key risk factor for severe illness associated with COVID-19. Despite numerous studies of COVID-19 host genetics, our knowledge of COVID-19-associated variants is still limited, and there is no resource comprising all the published variants and categorizing them based on their confidence level. Also, there are currently no computational tools available to predict novel COVID-19 severity variants. Therefore, we collated 820 host genetic variants reported to affect COVID-19 susceptibility by means of a systematic literature search and confidence evaluation, and obtained 196 high-confidence variants. We then developed the first machine learning classifier of severe COVID-19 variants to perform a genome-wide prediction of COVID-19 severity for 82,468,698 missense variants in the human genome. We further evaluated the classifier’s predictions using feature importance analyses to investigate the biological properties of COVID-19 susceptibility variants, which identified conservation scores as the most impactful predictive features. The results of enrichment analyses revealed that genes carrying high-confidence COVID-19 susceptibility variants shared pathways, networks, diseases and biological functions, with the immune system and infectious disease being the most significant categories. Additionally, we investigated the pleiotropic effects of COVID-19-associated variants using phenome-wide association studies (PheWAS) in ∼40,000 BioMe BioBank genotyped individuals, revealing pre-existing conditions that could serve to increase the risk of severe COVID-19 such as chronic liver disease and thromboembolism. Lastly, we generated a web-based interface for exploring, downloading and submitting genetic variants associated with COVID-19 susceptibility for use in both research and clinical settings (https://itanlab.shinyapps.io/COVID19webpage/). Taken together, our work provides the most comprehensive COVID-19 host genetics knowledgebase to date for the known and predicted genetic determinants of severe COVID-19, a resource that should further contribute to our understanding of the biology underlying COVID-19 susceptibility and facilitate the identification of individuals at high risk for severe COVID-19.
The mode effect of web-based surveying on the 2018 HRS measure of cognitive functioning
Authors: Domingue Benjamin W. , McCammon Ryan , West Brady T. , Langa Ken , Weir David , Faul Jessica
Published: November 2022

Measuring cognition in an aging population is a public health priority. A move towards survey measurement via the web (as opposed to phone or in-person) is cost effective but challenging as it may induce bias in cognitive measures. We examine this possibility using an experiment embedded in the 2018 wave of data collection for the US Health and Retirement Study (HRS). We find evidence of an increase in scores for HRS respondents who are randomly assigned to the web-based mode of data collection in 2018. Web-based respondents score higher in 2018 than do phone-based respondents, and they show much larger gains relative to 2016 performance and subsequently larger declines in 2020. The bias in favor of web-based responding is observed across all item types, but most pronounced for the serial 7 and items on financial literacy. These results imply a larger threshold for web-based respondents in applications requiring an indicator of cognitive impairment. Implications for both use of HRS data and future survey work on cognition are discussed.
Continuous automated analysis workflow for MRS studies
Authors: Zöllner Helge J. , Davies-Jenkins Christopher W. , Lee Erik G. , Hendrickson Timothy J. , Clarke William T. , Edden Richard A. E. , Wisnowski Jessica L. , Gudmundson Aaron T. , Oeltzschner Georg
Published: November 2022

Background

Magnetic resonance spectroscopy (MRS) can non-invasively measure levels of endogenous metabolites in living tissue and is of great interest to neuroscience and clinical research. To this day, MRS data analysis workflows differ substantially between groups, frequently requiring many manual steps to be performed on individual datasets, e.g., data renaming/sorting, manual execution of analysis scripts, and manual assessment of success/failure. Manual analysis practices are a substantial barrier to wider uptake of MRS. They also increase the likelihood of human error and prevent deployment of MRS at large scale. Here, we demonstrate an end-to-end workflow for fully automated data uptake, processing, and quality review.

New Method

The proposed continuous automated MRS analysis workflow integrates several recent innovations in MRS data and file storage conventions. They are efficiently deployed by a directory monitoring service that automatically triggers the following steps upon arrival of a new raw MRS dataset in a project folder: (1) conversion from proprietary manufacturer file formats into the universal format NIfTI-MRS; (2) consistent file system organization according to the data accumulation logic standard BIDS-MRS; (3) executing a command-line executable of our open-source end-to-end analysis software Osprey; (4) e-mail delivery of a quality control summary report for all analysis steps.

Results

The automated architecture successfully completed for a demonstration dataset. The only manual step required was to copy a raw data folder into a monitored directory.

Comparison with Existing Method(s)

The workflow presented here is the first implementation of a continuous automated MRS analysis ecosystem based on NIfTI-MRS and BIDS-MRS standards. Traditional MRS workflows are non-standardized, often require manual input, and frequently noy compatible with established neuroimaging workflows. This workflow should therefore facilitate integration of MRS into large-scale and multi-center studies.

Conclusions

Continuous automated analysis of MRS data can reduce the burden of manual data analysis and quality control, particularly for non-expert users and multi-center or large-scale studies.
Weighing psychosocial factors in relatives for the risk of depressive and anxious psychopathology: A sibling-pair comparison study
Authors: van Sprang Eleonore D. , Maciejewski Dominique F. , Milaneschi Yuri , Kullberg Marie-Louise J. , Elzinga Bernet M. , van Hemert Albert M. , Hartman Catharina A. , Penninx Brenda W. J. H.
Published: November 2022

Purpose

Siblings of probands with depressive and anxiety disorders are at increased risk for psychopathology, but little is known about how risk factors operate within families to increase psychopathology for siblings. We examined the additional impact of psychosocial risk factors in probands – on top of or in combination with those in siblings – on depressive/anxious psychopathology in siblings.

Methods

The sample included 636 participants (Mage= 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and their sibling(s) (N=380 proband-sibling pairs). Sixteen psychosocial risk factors were tested. In siblings, depressive and anxiety disorders were determined with standardized psychiatric interviews; symptom severity was measured using self-report questionnaires. Analyses were performed with mixed-effects models accounting for familial structure.

Results

In siblings, various psychosocial risk factors (female gender, low income, childhood trauma, poor parental bonding, being single, smoking, hazardous alcohol use) were associated with higher symptomatology and likelihood of disorder. The presence of the same risk factor in probands was independently associated (low income, being single) with higher symptomatology in siblings or moderated (low education, childhood trauma, hazardous alcohol use) – by reducing its strength – the association between the risk factor and symptomatology in siblings. There was no additional impact of risk factors in probands on likelihood of disorder in siblings.

Conclusion

Our findings demonstrate the importance of weighing psychosocial risk factors within a family context, as it may provide relevant information on the risk of affective psychopathology for individuals.
A personal, reference quality, fully annotated genome from a Saudi individual
Authors: Kulmanov Maxat , Tawfiq Rund , Al Ali Hatoon , Abdelhakim Marwa , Alarawi Mohammed , Aldakhil Hind , Alhattab Dana , Alsolme Ebtehal A. , Althagafi Azza , Angelov Angel , Bougouffa Salim , Driguez Patrick , Liu Yang , Park Changsook , Putra Alexander , Reyes-Ramos Ana M. , Hauser Charlotte A. E. , Cheung Ming Sin , Abedalthagafi Malak S , Hoehndorf Robert
Published: November 2022

We have used multiple sequencing approaches to sequence the genome of a volunteer from Saudi Arabia. We use the resulting data to generate ade novoassembly of the genome, and use different computational approaches to refine the assembly. As a consequence, we provide a contiguous assembly of the complete genome of an individual from Saudi Arabia for all chromosomes except chromosome Y, and label this assemblyKSA001. We transferred genome annotations from reference genomes and predicted genome features using methods from Artificial Intelligence to fully annotateKSA001, and we make all primary sequencing data, the assembly, and the genome annotations freely available in public databases using the FAIR data principles.
Dose-response relationships of LSD-induced subjective experiences in humans
Authors: Hirschfeld Tim , Prugger Johanna , Majić Tomislav , Schmidt Timo T.
Published: November 2022

Lysergic acid diethylamide (LSD) is a potent classic serotonergic psychedelic, which facilitates a variety of altered states of consciousness. Here we present the first meta-analysis establishing dose-response relationship estimates of the altered experience induced by LSD. Data extracted from articles identified by a systematic literature review following PRISMA guidelines were obtained from the Altered States Database. The psychometric data comprised ratings of subjective effects from standardized and validated questionnaires: the Altered States of Consciousness Rating Scale (5D-ASC, 11-ASC) and the Mystical Experience Questionnaire (MEQ30). We performed meta-regression analyses using restricted cubic splines for data from studies with LSD doses of up to 200 μg base. Most scales revealed a sigmoid-like increase of effects with a plateauing at around 100 μg. The most strongly modulated factors referred to changes in perception and illusory imagination, followed by positively experienced ego-dissolution, while only small effects were found forAnxietyandDread of Ego Dissolution. The partly observed considerable variability of effects points to the importance of non-pharmacological effects on subjective experiences. The established dose-response relationships may be used as general references for future experimental and clinical research on LSD to relate observed with expected subjective effects and to elucidate phenomenological differences between psychedelics.
Symbiotic diazotrophic UCYN-A strains co-occurred with El Niño, relaxed upwelling, and varied eukaryotes over 10 years off Southern California Bight
Authors: Fletcher-Hoppe Colette , Yeh Yi-Chun , Raut Yubin , Weissman J.L. , Fuhrman Jed A.
Published: November 2022

Biological nitrogen fixation, the conversion of N2 gas into a more bioavailable form, is vital to sustaining marine primary production. Studies have shifted beyond traditionally studied tropical diazotrophs.CandidatusAtelocyanobacterium thalassa (or UCYN-A) has emerged as a research focal point due to its streamlined metabolism, intimate partnership with a haptophyte host, and broad distribution. Here, we explore the abiotic factors that govern UCYN-A’s presence at the San Pedro Ocean Time-series (SPOT), its partner fidelity, and statistical interactions with non-symbiotic eukaryotes. 16S and 18S rRNA sequences were amplified by “universal primers” from monthly samples and resolved into Amplicon Sequence Variants, allowing us to observe multiple UCYN-A symbioses. UCYN-A1 relative abundances increased following the 2015-2016 El Niño event. When this “open ocean ecotype” was present, coastal upwelling ceased, and Ekman transport brought tropical waters into the region. Network analyses reveal all strains of UCYN-A co-occur with dinoflagellates includingLepidodinium, a potential predator, and parasiticSyndiniales. UCYN-A2 appeared to pair with multiple hosts and was not tightly coupled to its predominate host, while UCYN-A1 maintained a strong host-symbiont relationship. These biological relationships are particularly important to study in the context of climate change, which will alter UCYN-A distribution patterns both locally and globally.
Laser ablation tomography (LATscan) as a new tool for anatomical studies of woody plants
Authors: Cunha Neto Israel L. , Hall Benjamin , Lanba Asheesh , Blosenski Joshua , Onyenedum Joyce G.
Published: November 2022

Traditionally, botanists study the anatomy of plants by carefully sectioning samples, histological staining to highlight tissues of interests, then imaging slides under light microscopy. This approach generates significant details; however, this traditional workflow is laborious and time consuming, and ultimately yields two-dimensional (2D) images. Laser Ablation Tomography (LATscan) is a high-throughput imaging system that yields hundreds of images per minute. This method has proven useful for studying the structure of delicate plant tissues, however its utility in understanding the structure of tougher woody tissues is underexplored.

We report LATscan-derived anatomical data from several woody stems (ca. 20 mm) of eight species and compare these results to those obtained through traditional anatomical techniques.

LATscan successfully allows the description of tissue composition by differentiating cell type, size, and shape, but also permits the recognition of distinct cell wall composition (e.g., lignin, suberin, cellulose) based on differential fluorescent signals on unstained samples.

LATscan generate high-resolution 2D images and 3D reconstructions of woody plant samples, therefore this new technology is useful for both qualitative and quantitative analyses. This high-throughput imaging technology has the potential to bolster phenotyping of vegetative and reproductive anatomy, wood anatomy, and other biological systems such as plant-pathogen and parasitic plant associations.
Dynamics of organelle DNA segregation inArabidopsisdevelopment and reproduction revealed with tissue-specific heteroplasmy profiling and stochastic modelling
Authors: Broz Amanda K , Sloan Daniel B , Johnston Iain G
Published: November 2022

Organelle DNA (oDNA) in mitochondria and plastids is vital for plant (and eukaryotic) life. Selection against damaged oDNA is mediated in part by segregation – the sorting of different oDNA types into different cells in the germline. Plants segregate oDNA very rapidly, with oDNA recombination protein MutS Homolog 1 (MSH1), a key driver of this segregation, but in contrast to mammals, we have very limited knowledge of the dynamics of this segregation within plants and between generations. Here, we combine stochastic modelling with tissue-specific heteroplasmy measurements to reveal the trajectories of oDNA segregation inArabidopsis thalianadevelopment and reproduction. We obtain and use new experimental observations of oDNA through development to confirm and refine the predictions of the theory inferred from existing measurements. Ongoing segregation proceeds gradually but continually during plant development, with a more rapid increase between inflorescence formation and the establishment of the next generation. When MSH1 is compromised, we show that the majority of observed segregation could be achieved through partitioning at cell divisions. When MSH1 is functional, mtDNA segregation is far more rapid than can be achieved through cell divisions; we show that increased oDNA gene conversion is a plausible mechanism quantitatively explaining this acceleration. We also discuss the support for different models of the plant germline provided by these observations.
Effective design and inference for cell sorting and sequencing based massively parallel reporter assays
Authors: Gilliot Pierre-Aurélien , Gorochowski Thomas E.
Published: November 2022

The ability to measure the phenotype of millions of different genetic designs using Massively Parallel Reporter Assays (MPRAs) has revolutionised our understanding of genotype-to-phenotype relationships and opened avenues for data-centric approaches to biological design. However, our knowledge of how best to design these costly experiments and the effect that our choices have on the quality of the data produced is lacking. Here, we tackle this issue by developing FORE-CAST, a Python package that supports the accurate simulation of cell-sorting and sequencing based MPRAs and robust maximum like-lihood based inference of genetic design function from MPRA data. We use FORECAST’s capabilities to reveal rules for MPRA experimental design that help ensure accurate genotype-to-phenotype links and show how the simulation of MPRA experiments can help us better understand the limits of prediction accuracy when this data is used for training deep learning based classifiers. As the scale and scope of MPRAs grows, tools like FORECAST will help ensure we make informed decisions during their development and the most of the data produced.
Proteomic mapping reveals dysregulated angiogenesis in the cerebral arteries of rats with early-onset hypertension
Authors: Bastrup Joakim A. , Jepps Thomas A.
Published: November 2022

Hypertension is associated with presence of vascular abnormalities, such as remodeling and rarefaction. These processes play an important role in cerebrovascular disease development, however, the mechanistic changes leading to these diseases are not well characterized. Using data-independent acquisition-based mass spectrometry analysis, we determined the protein changes in cerebral arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR), a model that resembles essential hypertension. Our analysis identified 125 proteins with expression levels that were significantly up- or downregulated in 12-week old SHRs compared to normotensive Wistar Kyoto rats. Using an angiogenesis enrichment analysis, we identified a critical imbalance in angiogenic proteins, promoting an anti-angiogenic profile in cerebral arteries at the early-onset of hypertension. In a comparison to previously published data, we demonstrate that this angiogenic imbalance is not present in mesenteric and renal arteries from age-matched SHRs. Finally, we identified two proteins (Fbln5 and Cdh13), whose expression levels were critically altered in cerebral arteries compared to the other arterial beds. The observation of an angiogenic imbalance in cerebral arteries from the SHR reveals critical protein changes in the cerebrovasculature at the early-onset of hypertension and provides novel insight into the early pathology of cerebrovascular disease.
SOX9-positive pituitary stem cells differ according to their position in the gland and maintenance of their progeny depends on context
Authors: Rizzoti Karine , Chakravarty Probir , Sheridan Daniel , Lovell-Badge Robin
Published: November 2022

Stem cell (SC) differentiation and maintenance of resultant progeny underlie cell-turnover in many organs, but it is difficult to pinpoint the contribution of either process. In the pituitary, a central regulator of endocrine axes, adult SCs undergo activation following target organ ablation, providing a well-characterized paradigm to study an adaptative response in a multi-organ system. Here we used single cell technologies to characterize SC heterogeneity and mobilization together with lineage tracing. We show that SC differentiation occurs more frequently than thought previously. In adaptative conditions, differentiation increases and is more diverse than demonstrated by the lineage tracing experiments. Detailed examination of SC progeny suggests that maintenance of selected nascent cells underlies SC output, highlighting a trophic role for the microenvironment. Analyses of cell trajectories further predict pathways and potential new regulators. Our model provides a valuable system to study the influence of evolving states on the mechanisms of SC mobilization.

Teaser: Pituitary stem cells are diverse and differentiate more than thought but only selected progeny persist according to need.
Steady state visual evoked potentials reveal a signature of the pitch-size crossmodal association in visual cortex
Authors: Sciortino Placido , Kayser Christoph
Published: November 2022

Crossmodal correspondences describe our tendency to associate sensory features from different modalities with each other, such as the pitch of a sound with the size of a visual object. While such crossmodal correspondences (or associations) are described in many behavioural studies their neurophysiological correlates remain unclear. Under the current working model of multisensory perception both a low- and a high-level account seem plausible. That is, the neurophysiological processes shaping these associations could commence in low-level sensory regions, or may predominantly emerge in high-level association regions of semantic and object identification networks. We exploited steady-state visual evoked potentials (SSVEP) to directly probe this question, focusing on the associations between pitch and the visual features of size, hue or chromatic saturation. We found that SSVEPs over occipital regions are sensitive to the congruency between pitch and size, and a source analysis pointed to an origin around primary visual cortices. We speculate that this signature of the pitch-size association in low-level visual cortices reflects the successful pairing of congruent visual and acoustic object properties and may contribute to establishing causal relations between multisensory objects.
Screening of metabolism-disrupting chemicals on pancreatic α-cells using in vitro methods
Authors: Dos Santos Reinaldo Sousa , Babiloni-Chust Ignacio , Marroqui Laura , Nadal Angel
Published: November 2022

Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 μM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.
EXPLORING THE EFFECTS OF METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC α-CELL BIOLOGY: A SCREENING TESTING APPROACH
Authors: Al-Abdulla Ruba , Ferrero Hilda , Boronat-Belda Talía , Soriano Sergi , Quesada Iván , Alonso-Magdalena Paloma
Published: November 2022

Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic β-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis, altering pancreatic β-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic EDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. Our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology.
Landscape-scale exposure to multiazole-resistantAspergillus fumigatusbioaerosols
Authors: Shelton Jennifer M. G. , Rhodes Johanna , Uzzell Christopher B. , Hemmings Samuel , Brackin Amelie P. , Sewell Thomas R. , Alghamdi Asmaa , Dyer Paul S. , Fraser Mark , Borman Andrew M. , Johnson Elizabeth M. , Piel Frédéric B. , Singer Andrew C. , Fisher Matthew C.
Published: November 2022

We demonstrate country-wide exposures to aerosolized spores of a human fungal pathogen,Aspergillus fumigatus, that has acquired resistance to first line azole clinical antifungal drugs. Assisted by a network of citizen scientists across the United Kingdom, we show that 1 in 20 viable aerosolized spores of this mold are resistant to the agricultural fungicide tebuconazole and 1 in 140 spores are resistant to the four most used azoles for treating clinical aspergillosis infections. Season and proximity to industrial composters were associated with growth ofA. fumigatusfrom air samples, but not with the presence of azole resistance, and hotspots were not stable between sampling periods suggesting a high degree of atmospheric mixing. Genomic analysis shows no distinction between those resistant genotypes found in the environment and in patients, indicating that ~40% (58/150 sequenced genomes) of azole-resistantA. fumigatusinfections are acquired from environmental exposures. Due to the ubiquity of this measured exposure, it is crucial that we determine source(s) of azole-resistantA. fumigatus, who is at greatest risk of exposure and how to mitigate these exposures, in order to minimize treatment failure in patients with aspergillosis.

One sentence summary

UK-wide citizen science surveillance finds a ubiquitous exposure to aerosolized spores of a human fungal pathogen that have evolved in the environment cross-resistance to essential clinical antifungal drugs
Allosteric activation of cell wall synthesis during bacterial growth
Authors: Shlosman Irina , Fivenson Elayne M. , Gilman Morgan S.A. , Sisley Tyler A. , Walker Suzanne , Bernhardt Thomas G. , Kruse Andrew C. , Loparo Joseph J.
Published: November 2022

The peptidoglycan (PG) cell wall protects bacteria against osmotic lysis and determines cell shape, making this structure a key antibiotic target. Peptidoglycan is a polymer of glycan chains connected by peptide crosslinks, and its synthesis requires precise spatiotemporal coordination between glycan polymerization and crosslinking. However, the molecular mechanism by which these reactions are initiated and coupled is unclear. Here we use single-molecule FRET and cryo-EM to show that an essential PG synthase (RodA-PBP2) responsible for bacterial elongation undergoes dynamic exchange between closed and open states. Structural opening couples the activation of polymerization and crosslinking and is essentialin vivo.Given the high conservation of this family of synthases, the opening motion that we uncovered likely represents a conserved regulatory mechanism that controls activation of PG synthesis during other cellular processes, including cell division.
Bias in group-level EEG microstate analysis
Authors: Murphy M , Wang J , Jiang C , Wang L , Kozhemiako N , Wang Y ,   the GRINS consortium, Pan JQ , Purcell SM
Published: November 2022

Microstate analysis is a promising technique for analyzing high-density electroencephalographic data, but there are multiple questions about methodological best practices. Between and within individuals, microstates can differ both in terms of characteristic topographies and temporal dynamics, which leads to analytic challenges as the measurement of microstate dynamics is dependent on assumptions about their topographies. Here we focus on the analysis of group differences, using simulations seeded on real data from healthy control subjects to compare approaches that derive separate sets of maps within subgroups versus a single set of maps applied uniformly to the entire dataset. In the absence of true group differences in either microstate maps or temporal metrics, we found that using separate subgroup maps resulted in substantially inflated type I error rates. On the other hand, when groups truly differed in their microstate maps, analyses based on a single set of maps confounded topographic effects with differences in other derived metrics. We propose an approach to alleviate both classes of bias, based on a paired analysis of all subgroup maps. We illustrate the qualitative and quantitative impact of these issues in real data by comparing waking versus non-rapid eye movement sleep microstates. Overall, our results suggest that even subtle chance differences in microstate topography can have profound effects on derived microstate metrics and that future studies using microstate analysis should take steps to mitigate this large source of error.
The genetic structure within a single tree is determined by the behavior of the stem cells in the meristem
Authors: Iwasa Yoh , Tomimoto Sou , Satake Akiko
Published: November 2022

Genomic sequencing revealed that somatic mutations cause a genetic differentiation of the cells in a single tree. In this study, we consider a mathematical model for stem cell proliferation in the shoot apical meristem (abbrev. SAM), which results in genetic diversification between the cells differing in the distance along the shoot and the angle around a shoot axis. The assumptions are as follows. Stem cells in the SAM normally undergo asymmetric cell division and produce successor stem cells and differentiated cells. The differentiated cells proliferate and contribute to shoot elongation.

Occasionally, a stem cell is replaced by a copy of an adjacent stem cell. We discuss the “coalescent length” between cells indicating their genetic difference with respect to neutral mutations. A mathematical analysis revealed the following. The genetic diversity of cells sampled at the same position along the shoot increases with the distance from the bottom of the shoot. Stem cells hold a larger variation if they are replaced only by the nearest neighbors than if they are replaced by any cells. The coalescent length between two cells increases not only with the difference in the position along the shoot but also in the angle around the shoot axis. The dynamics of stem cells at the SAM determine the genetic pattern of the entire shoot.
Kinesin-12 KLP-18 contributes to the kinetochore-microtubule poleward flux during the metaphase ofC. elegansone-cell embryo
Authors: Soler Nina , Da Silva Mathis , Tascon Christophe , Chesneau Laurent , Foliard Pauline , Bouvrais Hélène , Pastezeur Sylvain , Le Marrec Loïc , Pecreaux Jacques
Published: November 2022

The mitotic spindle, a key structure to partition chromosomes during cell division, connects its poles to the chromosomes through microtubules. Their plus-ends, oriented towards the chromosomes, exhibit dynamic instability crucial for kinetochores’ correct attachment. Involved in this process, the poleward flux implicates the displacement of microtubules towards the spindle poles, coordinated with polymerisation at the plus ends. The mechanisms behind this are diverse. It includes treadmilling powered by microtubule depolymerisation at the spindle poles, sliding of spindle microtubules by molecular motors like Kinesin-5, and pushing microtubules away from the chromosomes by chromokinesins. Interestingly, no such flux was reported in theCaenorhabditis eleganszygote, although all proteins contributing to flux in mammals have homologous in the nematode.

To explore this, we fluorescently labelled microtubules and conducted photobleaching. We found no global poleward flow; the bleached zone’s edges moved inward. The centrosome-side front motion was caused by dynamic instability, while the chromosome-side front exhibited faster recovery, suggesting an additional mechanism. This extra velocity was localised near chromosomes, indicating that only kinetochore microtubules may undergo flux. Consistently, this flux depended on proteins ensuring the chromosome attachment and growth of the kinetochore microtubules, notably NDC-80, CLS-2CLASP, and ZYG-9XMAP215. Furthermore, this flux decreased as metaphase progressed and attachments transitioned from side- to end-on; it was reduced by SKA-1 recruitment. Traditional treadmilling was unlikely as many kinetochore microtubules do not reach spindle poles in the zygote spindle. Conversely, the depletion of kinesin-12 KLP-18KIF15, which cross-links and focuses microtubules at meiosis, reduced the front rate. Ultimately, we propose that the sole kinetochore microtubules slide along spindle microtubules likely powered by KLP-18, contrasting with solid displacement in other systems, aligning with observations in human cells of decreasing flux with increasing chromosome distance.
High Coverage Mitogenomes and Y-Chromosomal Typing Reveal Ancient Lineages in the Modern-day Székely Population in Romania
Authors: Borbély Noémi , Székely Orsolya , Szeifert Bea , Gerber Dániel , Máthé István , Benkő Elek , Gusztáv Mende Balázs , Egyed Balázs , Pamjav Horolma , Szécsényi-Nagy Anna
Published: November 2022

Here we present 115 whole mitogenomes and 92 Y-chromosomal STR and SNP profiles from a Hungarian ethnic group, the Székelys (in Romanian: Secuii, in German: Sekler) living in southeast Transylvania (Romania). The Székelys can be traced back to the 12th century in the region, and numerous scientific theories exist as to their origin. We carefully selected sample providers that had local ancestors inhabiting small villages in the area of Odorheiu Secuiesc/Székelyudvarhely in Romania. The results of our research and the reported data signify a qualitative leap compared to previous studies, since complete mitochondrial DNA sequences and Y-chromosomal data containing 23 STRs have not been available from the region until now. We evaluated the results with population genetic and phylogenetic methods, in the context of the modern and ancient populations that are either geographically or historically related to the Székelys. Our results demonstrate a predominantly local uniparental make-up of the population that also indicates limited admixture with neighbouring populations. Phylogenetic analyses confirmed the presumed eastern origin of certain maternal (A, C, D) and paternal (Q, R1a) lineages and, in some cases, they could also be linked to ancient DNA data from Migration Period (5th-9thcenturies AD) and Hungarian Conquest Period (10th century AD) populations.
Adaptive variation in avian eggshell structure and gas conductance across elevational gradients?
Authors: Ocampo David , Cadena Carlos Daniel , Londoño Gustavo A.
Published: November 2022

Many tropical species have restricted elevational distributions, which are potentially bounded by constraints imposed by physical conditions on physiological processes. Although some studies have examined variation in the physiology of adult birds with respect to elevation, little attention has been paid to the structure and function of eggshells, which mediate gas exchange between the embryo and the environment. At high elevations, dry air is expected to increase water loss from the egg; selection to avoid desiccation might therefore be expected to favor reduced gas conductance by means of increased eggshell thickness or reduced pore size. We used gas diffusion experiments and scanning electron microscopy to examine water vapor conductance rates and eggshell structures in 197 bird species distributed along an elevational gradient in the Andes. As predicted, water vapor conductance across the eggshell declined in a narrow range with elevation among all species and among species within families, but not among individuals within species. Variation among species in eggshell conductance was lower at high-elevation sites, potentially indicating greater constraints at such sites. Structural changes in eggshells with respect to elevation varied among taxonomic families of birds, suggesting potentially different adaptive responses to common selective pressures in terms of eggshell thickness and pore density, and size. We suggest that considering functional and structural traits of eggshells, which influence embryo development, may help one to better understand the elevational distributions of species and to forecast their responses to global climate change.
Live Imaging of Cutaneous Wound Healing in Zebrafish
Authors: Greenspan Leah J. , Ameyaw Keith , Castranova Daniel , Mertus Caleb A. , Weinstein Brant M.
Published: November 2022

Cutaneous wounds are common afflictions that follow a stereotypical healing process involving hemostasis, inflammation, proliferation, and remodeling phases. In the elderly or those suffering from vascular or metabolic diseases, poor healing following cutaneous injuries can lead to open chronic wounds susceptible to infection. The discovery of new therapeutic strategies to improve this defective wound healing requires a better understanding of the cellular behaviors and molecular mechanisms that drive the different phases of wound healing and how these are altered with age or disease. The zebrafish provides an ideal model for visualization and experimental manipulation of the cellular and molecular events during wound healing in the context of an intact, living animal. To facilitate studies of cutaneous wound healing in the zebrafish, we have developed an inexpensive, simple, and effective method for generating reproducible cutaneous injuries in adult zebrafish using a rotary tool. Using our injury system in combination with live imaging, we can monitor skin re-epithelialization, immune cell recruitment, and vessel regrowth and remodeling in the same animal over time. This injury system provides a valuable new experimental platform to study key cellular and molecular events during wound healingin vivowith unprecedented resolution.
Folding stabilities of ribosome-bound nascent polypeptides probed by mass spectrometry
Authors: Tan Ruiyue , Hoare Margaret , Welle Kevin A. , Swovick Kyle , Hryhorenko Jennifer R. , Ghaemmaghami Sina
Published: November 2022

The folding of most proteins occurs during the course of their translation while their tRNA-bound C-termini are embedded in the ribosome. How the close proximity of nascent proteins to the ribosome influences their folding thermodynamics remains poorly understood. Here, we have developed a mass spectrometry-based approach for determining the stabilities of nascent polypeptide chains using methionine oxidation as a folding probe. This approach enables quantitative measurements sub-global folding stabilities of ribosome nascent chains (RNCs) within complex protein mixtures and extracts. To validate the methodology, we analyzed the folding thermodynamics of three model proteins (DHFR, CheY and DinB) in soluble and ribosome-bound states. The data indicated that the ribosome can significantly alter the stability of nascent polypeptides. Ribosome-induced stability modulations were highly variable among different folding domains and were dependent on localized charge distributions within nascent polypeptides. The results implicated electrostatic interactions between the ribosome surface and nascent polypeptides as the cause of ribosome-induced stability modulations. The study establishes a robust proteomic methodology for analyzing localized stabilities within ribosome-bound nascent polypeptides and sheds light on how the ribosome influences the thermodynamics of protein folding.