bluuebunny/crossref_metadata_2025 huggingface dataset:
The E3/E4 ubiquitin ligase UFD-2 mediates negative feedback on Raf protein stability
Authors: Townley Robert , Deniaud Augustin , Stacy Kennedy S. , Rodriguez Torres Claudia S. , Cheraghi Fatemeh , de la Cova Claire C.
Published: April 2022

Signaling by the kinase cascade comprised of Raf, MEK, and ERK is critical for animal development; moreover, its inappropriate activation is commonly found in human malignancies. In a genetic screen for factors that control signaling by the Caenorhabditis elegans Raf ortholog LIN-45, we found that it is negatively regulated by the E3/E4 ubiquitin ligase UFD-2. Both UFD-2 and its partner, the ATP-dependent unfoldase CDC-48, were required for degradation of LIN-45 protein. Our structure-function studies showed that disruption of LIN-45 domains that mediate protein interactions and complex formation, including the Ras binding domain, cysteine-rich domain, or C-terminus, allow for UFD-2-independent degradation. We propose a model whereby UFD-2 mediates a novel step of Raf degradation, by acting with the CDC-48 unfoldase machinery to extract Raf from multiprotein complexes.

One-Sentence Summary

Raf kinase complexes are degraded by the UFD-2 ubiquitin ligase and CDC-48 unfoldase during Raf-MEK-ERK signal transduction.
Differential genetic strategies ofBurkholderia vietnamiensisandParaburkholderia kururiensisfor root colonization ofOryza sativassp.japonicaand ssp.indica, as revealed by Tn-seq
Authors: Wallner Adrian , Busset Nicolas , Lachat Joy , Guigard Ludivine , King Eoghan , Rimbault Isabelle , Mergaert Peter , Béna Gilles , Moulin Lionel
Published: April 2022

Burkholderia vietnamiensisLMG10929 (Bv) andParaburkholderia kururiensisM130 (Pk) are bacterial rice growth-promoting models. Besides this common ecological niche, species of theBurkholderiagenus are also found as opportunistic human pathogens whileParaburkholderiaare mostly environmental and plant-associated species. Here, we compared the genetic strategies used byBvandPkto colonize two subspecies of their common host,Oryza sativa ssp. japonica(cv. Nipponbare) andssp. indica(cv. IR64). We used high-throughput screening of transposon insertional mutant libraries (Tn-seq) to infer which genetic elements have the highest fitness contribution during root surface colonization at 7 days post inoculation. Overall, we detected twice more genes inBvinvolved in rice roots colonization compared toPk, including genes contributing to the tolerance of plant defenses, which suggests a stronger adverse reaction of rice towardsBvcompared toPk. For both strains, the bacterial fitness depends on a higher number of genes when colonizingindicarice compared tojaponica. These divergences in host pressure on bacterial adaptation could be partly linked to the cultivar’s differences in nitrogen assimilation. We detected several functions commonly enhancing root colonization in both bacterial strains e.g., Entner-Doudoroff (ED) glycolysis. Less frequently and more strain-specifically, we detected functions limiting root colonization such as biofilm production inBvand quorum sensing inPk.The involvement of genes identified through the Tn-seq procedure as contributing to root colonization i.e., ED pathway, c-di-GMP cycling and cobalamin synthesis, was validated by directed mutagenesis and competition with WT strains in rice root colonization assays.

Importance

Burkholderiaceae are frequent and abundant colonizers of the rice rhizosphere and interesting candidates to investigate for growth promotion. Species ofParaburkholderiahave repeatedly been described to stimulate plant growth. However, the closely relatedBurkholderiagenus hosts both beneficial and phytopathogenic species, as well as species able to colonize animal hosts and cause disease in humans. We need to understand to what extent the bacterial strategies used for the different biotic interactions differ depending on the host and if strains with agricultural potential could also pose a threat towards other plant hosts or humans. To start answering these questions, we used here transposon sequencing to identify genetic traits inBurkholderia vietnamiensisandParaburkholderia kururiensisthat contribute to the colonization of two different rice varieties. Our results revealed large differences in the fitness gene sets between the two strains and between the host plants, suggesting a strong specificity in each bacterium-plant interaction.
COVID-19 vaccine effectiveness against SARS-CoV-2 infection in the United States prior to the Delta and Omicron-associated surges: a retrospective cohort study of repeat blood donors
Authors: Grebe Eduard , Yu Elaine A. , Bravo Marjorie D. , Welte Alex , Bruhn Roberta L. , Stone Mars , Green Valerie , Williamson Phillip C. , Feldstein Leora R. , Jones Jefferson M. , Busch Michael P. , Custer Brian
Published: April 2022

To inform public health policy, it is critical to monitor COVID-19 vaccine effectiveness (VE), including against acquiring infection. We estimated VE using a retrospective cohort study among repeat blood donors who donated during the first half of 2021, demonstrating a viable approach for monitoring of VE via serological surveillance. Using Poisson regression, we estimated overall VE was 88.8% (95% CI: 86.2–91.1), adjusted for demographic covariates and variable baseline risk. Time since first reporting vaccination, age, race-ethnicity, region, and calendar time were statistically significant predictors of incident infection. Studies of VE during periods of Delta and Omicron spread are underway.
Can We Really Trust the Findings of the COVID-19 Research? Quality Assessment of Randomized Controlled Trials Published on COVID-19
Authors: Joshy Athira S , Thomas Christy , Surendran Saphal , Undela Krishna
Published: April 2022

Objective

To evaluate the quality of randomized controlled trials (RCTs) published on Coronavirus Disease-19 (COVID-19) and to investigate the reasons behind compromising the quality, if found.

Methods

A systematic literature search was performed in PubMed, Google Scholar, and Cochrane CENTRAL to identify the Randomized Controlled Trails published on Coronavirus Disease-19 between 1st Dec 2019 to 31st Aug 2021. Research articles met with study criteria were included in the study. Assessment of quality of randomized controlled trials was done using modified Jadad scale.

Results

21,259 records of randomized controlled trials were identified through database searching, out of which 90 randomized controlled trials were included in the study and, 34 (37.8%) were of high-quality, 46 (51.1%) were of moderate quality, and 10 (11.1 %) were of low-quality studies. There were 40 (44.4%), 38 (42.2%), and 12 (13.3%) randomized controlled trials published in the early, middle, and late terms with Jadad score 5.12±1.67, 5.34±1.32, and 5.68±1.50 respectively (P=0.52). When comparing the blinding status, appropriate blinding, and methods to evaluate adverse events in randomized controlled trials with modified Jadad score, a significant difference was observed (P<0.001). A significant moderate positive correlation was found between the impact factor of the journal and the modified Jadad scale score (R2= 0.48, P<0.001).

Conclusion

Findings from our study indicate that accelerated publication of Coronavirus Disease-19 researches along with the fast-track review process has resulted in lowering study quality scores. With the emergence of stronger evidence, Coronavirus Disease-19 clinical studies with lower methodological quality should be revisited.

Impacts on practice

There have been numerous sacrifices and tragedies in the clinical response to covid-19. Revising the quality of randomized controlled trials published on COVID-19 as we enter the third wave of the pandemic and beyond, will improve the evidence-based practice of medications for clinical pharmacy services.

COVID-19 Patients will benefit from evidence-based pharmaceutical care through reduced drug-related problems.
Introduction and Establishment of SARS-CoV-2 Gamma Variant in New York City in Early 2021
Authors: Vasylyeva Tetyana I. , Fang Courtney E. , Su Michelle , Havens Jennifer L. , Parker Edyth , Wang Jade C. , Zeller Mark , Yakovleva Anna , Hassler Gabriel W. , Chowdhury Moinuddin A. , Andersen Kristian G. , Hughes Scott , Wertheim Joel O.
Published: April 2022

Background

Monitoring the emergence and spread of SARS-CoV-2 variants is an important public health objective. Travel restrictions, aimed to prevent viral spread, have major economic consequences and unclear effectiveness despite considerable research. We investigated the introduction and establishment of the Gamma variant in New York City (NYC) in 2021.

Methods

We performed phylogeographic analysis on 15,967 Gamma sequences available on GISAID and sampled between March 10th through May 1st, 2021, to identify geographic sources of Gamma lineages introduced into NYC. We identified locally circulating Gamma transmission clusters and inferred the timing of their establishment in NYC.

Findings

We identified 16 phylogenetically-distinct Gamma clusters established in NYC (cluster sizes ranged 2-108 genomes). Most of the NYC clusters were introduced from Florida and Illinois; only one was introduced from outside the United States (US). By the time the first Gamma case was reported by genomic surveillance in NYC on March 10th, the majority (57%) of circulating Gamma lineages had already been established in the city for at least two weeks.

Interpretation

Despite the expansion of SARS-CoV-2 genomic surveillance in NYC, there was a substantial gap between Gamma variant introduction and establishment in January/February 2021, and its identification by genomic surveillance in March 2021. Although travel from Brazil to the US was restricted from May 2020 through the end of the study period, this restriction did not prevent Gamma from becoming established in NYC as most introductions occurred from domestic locations.
The Validity of the Parsley Symptom Index: an e-PROM designed for Telehealth
Authors: Williams Hants , Steinberg Sarah , Leon Kendall , O’Shea Catherine , Berzin Robin , Hagg Heather
Published: April 2022

Background / Purpose

The Parsley Symptom Index (PSI) is a recently developed symptom assessment for adults with chronic disease in telehealth settings. The purpose of this study was to validate the PSI against the Self-Rated Health (SRH) item.

Materials and Methods

This prospective cohort study took place from January 15, 2021 to December 15, 2021 among a sample of 10,519 adult patients at Parsley Health, a subscription based holistic medical practice. The PSI and the SRH were completed by patients via an online portal. The association between the PSI and SRH was assessed via polyserial and polychoric correlations, while weighted kappa scores provided information related to agreement between the PSI and SRH.

Results

From 22,748 responses, there were moderate levels of association (polyserial r=0.51; polychoric r=0.52) and agreement (weighted □ = 0.46) between the PSI and SRH. In total 74.2% (16865) of responses between the PSI and SRH were relatively congruent while 36.2% (8229) were literally congruent.

Conclusions

The PSI demonstrates validity with the SRH for adults with chronic disease in a telehealth setting.
Linking Genotype to Phenotype: Further Exploration of Mutations in SARS-CoV-2 Associated with Mild or Severe Outcomes
Authors: Agarwal Roshna , Leblond Tyler , McAuley Erin M , Maier Ezekiel J , Skarzynski Martin , Voss Jameson D , Sozhamannan Shanmuga
Published: April 2022

We previously interrogated the relationship between SARS-CoV-2 genetic mutations and associated patient outcomes using publicly available data downloaded from GISAID in October 2020 [1]. Using high-level patient data included in some GISAID submissions, we were able to aggregate patient status values and differentiate between severe and mild COVID-19 outcomes. In our previous publication, we utilized a logistic regression model with an L1 penalty (Lasso regularization) and found several statistically significant associations between genetic mutations and COVID-19 severity. In this work, we explore the applicability of our October 2020 findings to a more current phase of the COVID-19 pandemic.

Here we first test our previous models on newer GISAID data downloaded in October 2021 to evaluate the classification ability of each model on expanded datasets. The October 2021 dataset (n=53,787 samples) is approximately 15 times larger than our October 2020 dataset (n=3,637 samples). We show limitations in using a supervised learning approach and a need for expansion of the feature sets based on progression of the COVID-19 pandemic, such as vaccination status. We then re-train on the newer GISAID data and compare the performance of our two logistic regression models. Based on accuracy and Area Under the Curve (AUC) metrics, we find that the AUC of the re-trained October 2021 model is modestly decreased as compared to the October 2020 model. These results are consistent with the increased emergence of multiple mutations, each with a potentially smaller impact on COVID-19 patient outcomes. Bioinformatics scripts used in this study are available at https://github.com/JPEO-CBRND/opendata-variant-analysis. As described in Voss et al. 2021, machine learning scripts are available at https://github.com/Digital-Biobank/covid_variant_severity.
Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice
Authors: Carvalho Adriana Lelis , Brooks Daniel J , Barlow Deborah , Langlais Audrie L. , Morrill Breanna , Houseknecht Karen L. , Bouxsein Mary L. , Lian Jane B , King Tamara , Farina Nicholas H , Motyl Katherine J
Published: April 2022

Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. While the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Our aim was to develop a model of opioid-induced bone loss to understand bone turnover and identify candidate miRNA-mediated regulatory mechanisms. We evaluated the effects of sustained morphine treatment on the skeleton, metabolism, and body composition of male and female C57BL/6J mice by treating with vehicle (0.9% saline) or morphine (18 mg/kg) using subcutaneous osmotic minipumps for 25 days. Morphine-treated mice had higher energy expenditure and respiratory quotient, indicating a shift toward carbohydrate metabolism. Microcomputed tomography (µCT) analysis indicated that male mice treated with morphine had reduced trabecular bone volume fraction (Tb.BV/TV) (15%) and Tb. bone mineral density (BMD) (14%) in the distal femur compared to vehicle. Conversely, bone microarchitecture was not changed in females after morphine treatment. Histomorphometric analysis demonstrated that in males, morphine reduced bone formation rate compared to vehicle, but osteoclast parameters were not different. Furthermore, morphine reduced bone formation marker gene expression in the tibia of males (Bglap and Dmp1). Circulating miRNA profile changes were evident in males, with 14 differentially expressed miRNAs associated with morphine treatment. Target analysis indicated hypoxia inducible factor (HIF) signaling pathway was targeted by miR-223-3p and fatty acid metabolism by miR-484, - 223-3p, and -328-3p. In summary, we have established a model where morphine leads to a lower trabecular bone formation in males. Further, understanding the mechanisms of bone loss from opioid treatment will be important for improving management of the adverse effects of opioids on the skeleton.
A Genome-Scale Metabolic Model of Marine HeterotrophVibrio splendidussp. 1A01
Authors: Iffland-Stettner Arion , Okano Hiroyuki , Gralka Matti , Guessous Ghita , Amarnath Kapil , Cordero Otto X. , Hwa Terence , Bonhoeffer Sebastian
Published: April 2022

While theVibrio splendidusspecies is best known as an opportunistic pathogen in oysters, theVibrio splendidussp. 1A01 strain was first identified as an early colonizer of synthetic chitin particles incubated in seawater. To gain a better understanding of its metabolism, a genome-scale metabolic model (GSMM) ofV. splendidussp. 1A01 was reconstructed. GSMMs enable us to simulate all metabolic reactions in a bacterial cell using Flux Balance Analysis. A draft model was built using an automated pipeline from BioCyc. Manual curation was then performed based on experimental data, in part by gap-filling metabolic pathways and tailoring the model’s biomass reaction toV. splendidussp. 1A01. The challenges of building a metabolic model for a marine microorganism likeV. splendidussp. 1A01 are described.
Probing neuronal functions with precise and targeted laser ablation in the living cortex: reply
Authors: Cheng Zongyue , Lin Jianian , Han Yiyong , Wei Bowen , Lai Baoling , Li Baoming , Cui Meng , Gan Wen-Biao
Published: April 2022

In the comment on the article [Optica 8, 12 (2021)], the authors performed theoretical calculation to show that with a 1.1 NA objective and 140 fs laser pulses with single pulse energy of 2.2 nJ, and 80 MHz repetition rate, the focal point temperature rises 0.3 K and reaches equilibrium after 100 μs in water. They suggest that the damage to brain tissue by laser could not be caused by thermal effects but rather by plasma-mediated chemical effects. To quantify the thermal accumulation due to the fs laser illumination in living animals, we used a thermocouple sensor to measure the temperature change in the vicinity of the laser focus at a depth of 300 μm in the adult mouse cortex. Our results show that at 930 nm wavelength, 25 μm from the laser focus, 19-300 mW laser can all lead to a brain tissue temperature rise of more than 0.3 K at 1 second and the maximum equilibrium temperature rise of more than 28 K. These experimental measurements are significantly higher than theoretically calculated values in the comment. These results suggest that the thermal accumulation effect of focused low-energy pulses from fs laser oscillators could contribute significantly to the collateral damage in the living brain.
rox: A statistical model for regression with missing values
Authors: Buyukozkan Mustafa , Benedetti Elisa , Krumsiek Jan
Published: April 2022

Abstract

High-dimensional omics datasets frequently contain missing data points, which typically occur due to concentrations below the limit of detection (LOD) of the profiling platform. The presence of such missing values significantly limits downstream statistical analysis and result interpretation. Two common techniques to deal with this issue include the removal of samples with missing values, and imputation approaches which substitute the missing measurements with reasonable estimates. Both approaches, however, suffer from various shortcomings and pitfalls. In this paper, we present “rox”, a novel statistical model for the analysis of omics data with missing values without the need for imputation. The model directly incorporates missing values as “low” concentrations into the calculation. We show the superiority of rox over common approaches on simulated data and on six metabolomics datasets. Fully leveraging the information contained in LOD-based missing values, rox provides a powerful tool for the statistical analysis of omics data.
Cross-activation of the FGF, TGF-β and WNT pathways constrains BMP4-mediated induction of the Totipotent state in mouse embryonic stem cells
Authors: Meharwade Thulaj , Joumier Loïck , Parisotto Maxime , Huynh Vivian , da Rocha Edroaldo Lummertz , Malleshaiah Mohan
Published: April 2022

Cell signaling induced cell fate determination is central to stem cell and developmental biology. Embryonic stem cells (ESC) are an attractive model for understanding the relationship between cell signaling and cell fates. Cultured mouse ESCs can exist in multiple cell states resembling distinct stages of early embryogenesis, such as Totipotent, Pluripotent, Primed and Primitive Endoderm. The signaling mechanisms regulating the Totipotent state acquisition and coexistence of these states are poorly understood. Here we identify BMP4 as an inducer of the Totipotent state. However, we discovered that BMP4-mediated induction of the Totipotent state is constrained by the cross-activation of FGF, TGF-β and WNT pathways. We exploited this finding to enhance the proportion of Totipotent cells in ESCs by rationally inhibiting these cross-activated pathways using small molecules. Single-cell mRNA-sequencing further revealed that induction of the Totipotent state is accompanied by the suppression of both the Primed and Primitive Endoderm states. Furthermore, the reprogrammed Totipotent cells generated in culture have a molecular and functional resemblance to Totipotent cell stages of preimplantation embryos. Our findings reveal a novel BMP4 signaling mechanism in ESCs to regulate multiple cell states, potentially significant for managing stem cell heterogeneity in differentiation and reprogramming.
Dopamine release at the time of a predicted aversive outcome causally controls the trajectory and expression of conditioned behavior
Authors: Kutlu Munir Gunes , Tat Jennifer , Zachry Jennifer E. , Calipari Erin S.
Published: April 2022

Background

The inability to predict when aversive stimuli will and will not occur in is a hallmark of anxiety and stress disorders. Dopamine release in the nucleus accumbens (NAc) is sufficient and necessary for aversive learning and has been linked to both anxiety and stress disorder symptomatology. Thus, understanding how dopamine controls associative learning in response to aversive stimuli is critical to understanding the role of dopamine in behavior in health and disease.

Methods

Using an optical dopamine sensor combined with in-vivo fiber photometry in the NAc core of male and female C57BL/6J mice (N=38), we recorded dopamine responses to expected and omitted aversive outcomes during learning. We derived predictions from a theory-driven model of associative learning (Kutlu-Calipari-Schmajuk, KCS model) and tested the causality of these predictions using optogenetics.

Results

Dopamine release was evoked by the predicted omission of aversive stimuli in a fashion that cannot be explained by dopamine as a reward-based prediction signal. The magnitude of the dopamine response during omissions scaled with predictions about the probability of their occurrence; however, dopamine did not track the associative value of predictive cues. Finally, we showed that the observed effects are causal to learned behavior and can only be explained by dopamine signaling the perceived saliency of predicted aversive events.

Conclusions

We elucidate the role of NAc core dopamine signaling in aversive learning in a theory-based and stimulus-specific fashion and offer potential avenues for understanding the neural mechanisms involved in anxiety and stress disorders.
Growing up unloved: the enduring consequence of childhood emotional neglect on the qualia of memory and imagination
Authors: Mullally Sinéad L. , Grafton-Clarke Désirée , Mawson Eleanor R , Unwin Matthew , Stapleton Molly , Webber Kat , Dodd Alyson L , Pepper Gillian V , Cokal Derya , Robinson Lucy J , Gallagher Peter , Watson Stuart
Published: April 2022

Childhood Adversity (CA) is one of the strongest factors associated with the onset of Major Depressive Disorder (MDD), and both CA and MDD have been linked to altered hippocampal structure/function. The current study aimed to explore the relationships between retrospectively reported childhood emotional neglect (CEN), current wellbeing and depressive symptoms, and a range of hippocampal-dependent cognitive functions i.e., anterograde learning and memory, episodic memory recollection, and imagination (episodic future thinking and scene construction). In two-wave recruitment periods at undergraduate intake 2014-15 (Cohort 1) and 2016-17 (Cohort 2), a combined cohort of n=1485 university students completed online surveys, with n=64 further participating in experimental testing session. As anticipated, higher CEN ratings consistently correlated with poorer current wellbeing and higher depressive symptoms. However, whilst the anticipated relationships between CEN, current wellbeing, and subjectively reported estimates of hippocampal-dependent cognitions were observed in the data reported in the online survey, an unexpectedly circumscribed pattern was observed on formal in-person examination of these cognitive functions. More specifically, higher CEN related to less vivid and less detailed imagined future/scene constructions and with an attenuated sense of presence and emotional valence during these simulations. A similar pattern was not evidence when participants simulated experienced past events (i.e. episodic memories). Current depression scores did not consistently correlate with vividness, detail, or emotional valence. In addition, and contrary to expectation, no relationship between CEN, depressive symptoms, and the spatial coherence of imagined or recollected events was seen. Moreover, neither CEN nor depressive symptoms correlated with many key measures of anterograde memory. Hence, we observed a highly specific constellation of impairment related to CEN when explored on a simulation per simulation basis, that was not obviously linked to altered hippocampal function, indicating that the relationship between CEN, hippocampal function, and subsequent psychopathology may not readily explained by either spatial or mnemonic hippocampal- related deficits. We consider whether the observed experiential differences in the qualia of imagined simulations may represent an important therapeutic target to decrease a CEN-driven latent vulnerability to MDD.
The impact of HIV on women living with HIV and their families in low- and middle-income countries: A systematic review
Authors: Fauk Nelsensius Klau , Mwanri Lillian , Hawke Karen , Mohammadi Leila , Ward Paul Russell
Published: April 2022

HIV infection adds a significant burden to women in low- and middle-income countries (LMICs), often leading to severe detrimental impact, not only on themselves, but also on their families and communities. Given that more than half of all people living with HIV globally are females (53%), this review seeks to understand the impact of HIV infection on women living with HIV (WLHIV) and their families in LMICs, and the interrelationships between one impact and another. A systematic review was conducted to find literature using the following databases: Medline, PsycINFO, CINAL, Emcare, Scopus and ProQuest. Research articles were included if they met the following inclusion criteria: conducted in LMICs, published in English language between January 1st 1990 and October 31st 2021, had full text available, involved WLHIV (married and unmarried), and focused on the impact of HIV on these women and their families. Critical appraisal tools developed by Joanna Briggs Institute (JBI) were used to assess the methodological quality of the studies and thematic narrative synthesis was used to analyse the findings. A total of 22 articles met the inclusion criteria. The review showed that HIV has a range of negative consequences on WLHIV and their families including: (i) psychological impact, (ii) poor physical health and intimate partner violence, (iii) social impact, and (iv) economic impact. The findings indicate the need for targeted interventions, specific to WLHIV, that address the inequity and discrimination they face. These interventions should also incorporate education and sustainable support structures for WLHIV and their families.
A Kinetic Map of the Influence of Biomimetic Lipid Membrane Models on Aβ42Aggregation
Authors: Baumann Kevin N. , Sanguanini Michele , Rimon Oded , Šneiderienė Greta , Greer Heather , Thacker Dev , Schneider Matthias , Linse Sara , Knowles Tuomas P. J. , Vendruscolo Michele
Published: April 2022

The aggregation of the amyloid β peptide (Aβ) is one of the major molecular hallmarks of Alzheimer’s disease. Although Aβ deposits have been mostly observed extracellularly, various studies have reported the presence of also intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of Alzheimer’s disease, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein (APP), from which Aβ is derived by proteolytic cleavage. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of the 42-residue form of Aβ (Aβ42). By using small unilamellar vesicles modelling cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the endoplasmic reticulum (ER), and the Golgi apparatus, we show that Aβ42aggregation is inhibited by the ER and Golgi membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation, and suggest the presence of an evolutionary optimization of lipid composition to prevent the intracellular aggregation of Aβ.
SATINN: An automated neural network-based classification of testicular sections allows for high-throughput histopathology of mouse mutants
Authors: Yang Ran , Stendahl Alexandra , Vigh-Conrad Katinka A. , Held Madison , Lima Ana C. , Conrad Donald F.
Published: April 2022

Motivation

The mammalian testis is a complex organ with a hierarchical organization that changes smoothly and stereotypically over time in normal adults. While testis histology is already an invaluable tool for identifying and describing developmental differences in evolution and disease, methods for standardized, digital image analysis of testis are needed to expand the utility of this approach.

Results

We developed SATINN (Software for Analysis of Testis Images with Neural Networks), a multi-level framework for automated analysis of multiplexed immunofluorescence images from mouse testis. This approach uses a convolutional neural network (CNN) to classify nuclei from seminiferous tubules into 7 distinct cell types with an accuracy of 94.2%. These cell classifications are then used in a second-level tubule CNN, which places seminiferous tubules into one of 7 distinct tubule stages with 90.4% accuracy. We further describe numerous cell- and tubule-level statistics that can be derived from wildtype testis. Finally, we demonstrate how the classifiers and derived statistics can be used to rapidly and precisely describe pathology by applying our methods to image data from two mutant mouse lines. Our results demonstrate the feasibility and potential of using computer-assisted analysis for testis histology, an area poised to evolve rapidly on the back of emerging, spatially-resolved genomic and proteomic technologies.

Availability and implementation

Scripts to apply the methods described here are available from http://github.com/conradlab/SATINN.
Acute kidney injury in patients with non-valvular atrial fibrillation treated with rivaroxaban or warfarin: a population-based study from the United Kingdom
Authors: González-Pérez Antonio , Balabanova Yanina , Sáez María E , Brobert Gunnar , Garcia Rodriguez Luis A
Published: April 2022

Acute kidney injury (AKI) has been associated with use of oral anticoagulants (OACs) in patients with non-valvular atrial fibrillation (NVAF). We aimed to compare AKI risk among users of rivaroxaban vs. warfarin. We identified two cohorts of NVAF patients who initiated rivaroxaban (15/20 mg/day, N=6436) or warfarin (N=7129) excluding those without estimated glomerular filtration rate values recorded in the year before OAC initiation and those with a history of end-stage renal disease or AKI. We used two methods to define AKI during follow-up (mean 2.5 years): coded entries (method A), and the Aberdeen AKI phenotyping algorithm (method B), using recorded renal function laboratory values during the study period to identify a sudden renal deterioration event. Cox regression was used to calculate hazard ratios (HRs) for AKI with rivaroxaban vs. warfarin use, adjusted for confounders. The number of identified incident AKI cases was 249 (method) A and 723 (method B). Of the latter, 104 (14.4%) were also identified by method A. After adjusting for age, sex, baseline renal function and comorbidity, HRs (95% CIs) for AKI were 1.20 (0.93–1.55; p=0.16) using method A, and 0.80 (0.68–0.93; p<0.01) using method B. Estimates stratified by baseline level of chronic kidney disease were largely consistent with the main estimates. In conclusion, our results support a beneficial effect of rivaroxaban over warfarin in terms of AKI occurrence in patients with NVAF. More research into how best to define AKI using primary care records would be valuable for future studies.
Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis
Authors: Ouidja Mohand Ouidir , Biard Denis S.F. , Chantepie Sandrine , Laffray Xavier , Douaron Gael Le , Huynh Minh-Bao , Rebergue Nicolas , Maïza Auriane , Rubio Karla , González-Velasco Oscar , Barreto Guillermo , De Las Rivas Javier , Papy-Garcia Dulce
Published: April 2022

Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.
Prognostic Significance of WT1 Expression Level Thershold in Acute Myeloid Leukemia Patients Receiving Hematopoietic Stem Cell Transplantation: Meta-Analysis
Authors: Wang Dandan , Qin Ling , Li Boya , Li Tong
Published: April 2022

Objective

The WT1 gene is considered as a poor prognostic factor for acute myeloid leukemia (AML) after Allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, the effect of the expression threshold of WT1 on the prognosisis controversial, which is evaluated in this meta-analysis.

Methods

Relevant studies about the expression threshold of WT1 on the prognosis of AML after Allo-HSCT were searched in online databases. Data were extracted from them and analyzed by Stata16.0 software.

Results

Five studies involving 739 patients were screened out, including 433 cases experimental group and 306 cases control group. The experimental group and control group were compared for 1-year disease-free survival rate (DFS) [RR=1.19, 95%CI (1.03, 1.38), P =0.02] and 4-year DFS [RR= 1.18, 95%CI (0.98, 1.42), P =0.09]. The experimental group was lower than the control group in 1-year DFS, and there was no statistical significance in 4-year DFS. 1-year overall survival rate (OS) [RR=1.06, 95%CI (0.92, 1.23), P =0.40] and 4-year OS [RR= 1.16, 95%CI (1.03, 1.32), P =0.02], suggesting that the experimental group had a lower 4-year OS than the control group, and 1-year OS had no statistical significance.

Conclusions

High WT1 expression is unfavorable to the prognosis of AML patients undergoing Allo-HSCT. A threshold of 250 copies/104ABL of WT1 may be the best value for predicting the poor prognosis in these patients.
Extracellular matrix assembly stress drives Drosophila central nervous system morphogenesis
Authors: Serna-Morales Eduardo , Sánchez-Sánchez Besaiz J. , Marcotti Stefania , Bhargava Anushka , Dragu Anca , Hirvonen Liisa M. , Díaz-de-la-Loza María-del-Carmen , Mink Matyas , Cox Susan , Rayfield Emily , Stramer Brian M.
Published: April 2022

The forces controlling tissue morphogenesis are attributed to cellular-driven activities and any role for extracellular matrix (ECM) is assumed to be passive. However, all polymer networks, including ECM, can theoretically develop autonomous stresses during their assembly. Here we examine the morphogenetic function of an ECM prior to reaching homeostatic equilibrium by analyzing de novo ECM assembly during Drosophila ventral nerve cord (VNC) condensation. Asymmetric VNC shortening and a rapid decrease in surface area correlate with exponential assembly of Collagen-IV (Col4) surrounding the tissue. Concomitantly, a transient developmentally-induced Col4 gradient leads to coherent long-range flow of ECM, which equilibrates the Col4 network. Finite element analysis and perturbation of Col4 network formation through the generation of dominant Col4-truncations that affect assembly, reveals that VNC morphodynamics is driven by a sudden increase in ECM-driven surface tension. These data highlight that ECM assembly stress and associated network instabilities can actively participate in tissue morphogenesis.
Benchmarking the accuracy of structure-based binding affinity predictors on Spike-ACE2 Deep Mutational Interaction Set
Authors: Ozden Burcu , Şamiloğlu Eda , Özsan Atakan , Erguven Mehmet , Koşaca Mehdi , Oktayoğlu Melis , Yükrük Can , Arslan Nazmiye , Karakülah Gökhan , Barlas Ayşe Berçin , Savaş Büşra , Karaca Ezgi
Published: April 2022

Since the start of COVID-19 pandemic, a huge effort has been devoted to understanding the Spike (SARS-CoV-2)-ACE2 recognition mechanism. To this end, two deep mutational scanning studies traced the impact of all possible mutations across Receptor Binding Domain (RBD) of Spike and catalytic domain of human ACE2. By concentrating on the interface mutations of these experimental data, we benchmarked six commonly used structure-based binding affinity predictors (FoldX, EvoEF1, MutaBind2, SSIPe, HADDOCK, and UEP). These predictors were selected based on their user-friendliness, accessibility, and speed. As a result of our benchmarking efforts, we observed that none of the methods could generate a meaningful correlation with the experimental binding data. The best correlation is achieved by FoldX (R = -0.51). Also, when we simplified the prediction problem to a binary classification, i.e., whether a mutation is enriching or depleting the binding, we showed that the highest accuracy is achieved by FoldX with 64% success rate. Surprisingly, on this set, simple energetic scoring functions performed significantly better than the ones using extra evolutionary-based terms, as in Mutabind and SSIPe. Furthermore, we also demonstrated that recent AI approaches, mmCSM-PPI and TopNetTree, yielded comparable performances to the force field-based techniques. These observations suggest plenty of room to improve the binding affinity predictors in guessing the variant-induced binding profile changes of a host-pathogen system, such as Spike-ACE2. To aid such improvements we provide our benchmarking data athttps://github.com/CSB-KaracaLab/RBD-ACE2-MutBenchwith the option to visualize our mutant models athttps://rbd-ace2-mutbench.github.io/
Restoration and resilience to sea level rise of a salt marsh affected by dieback events in Charleston, SC
Authors: Rolando JL , Hodges M , Garcia KD , Krueger G , Williams N , Carr J , Robinson J , George A , Morris J , Kostka JE
Published: April 2022

The frequency of salt marsh dieback events has increased over the last 25 years with unknown consequences to the resilience of the ecosystem to accelerated sea level rise (SLR). Salt marsh ecosystems impacted by sudden vegetation dieback events were previously thought to recover naturally within a few months to years. In this study, we provide evidence that approximately 14% of total marsh area has not revegetated 10-years after a dieback event in Charleston, SC. Dieback onset coincided with a severe drought in 2012, and a second dieback event occurred in 2016 after a historic flood influenced by Hurricane Joaquin in October of 2015, with unvegetated zones reaching nearly 30% of total marsh area in 2017. Most affected areas were associated with lower elevation zones in the interior of the marsh (midmarsh). During the 2013 dieback event, we estimate that unvegetated midmarsh area expanded by 300%. Grass planting was shown to be an effective restoration practice, with restored plants having greater aboveground biomass than relict sites after two years of transplanting. A positive restoration outcome indicated that the stressors that caused the initial dieback are no longer present. Despite that, many dieback areas have not recovered naturally even as they are located within the typical elevation range of a healthy vegetated marsh. A mechanistic modelling approach was used to assess the effects of vegetation dieback on salt marsh resilience to SLR. Predictions indicate that a highly productive restored marsh (2000 g m-2y-1) would persist at a moderate SLR rate of 60 cm 100 y-1, whereas a non- restored mudflat would lose all of its elevation capital after 100 years. Thus, rapid restoration of marsh dieback is critical to avoid further degradation. Also, failure to incorporate the increasing frequency and intensity of extreme climatic events which trigger irreversible marsh diebacks underestimates salt marsh vulnerability to climate change. At an elevated SLR rate of 122 cm 100 y-1, most likely an extreme climate change scenario, even highly productive ecosystems augmented by sediment placement would not keep pace with SLR. Thus, climate change mitigation actions are also urgently needed to preserve present-day marsh ecosystems.
Transcriptome-guided annotation and functional classification of long non-coding RNAs in Arabidopsis thaliana
Authors: Corona-Gomez Jose Antonio , Coss-Navarrete Evelia Lorena , Garcia-Lopez Irving Jair , Pérez-Patiño Jaime Alejandro , Fernandez-Valverde Selene L.
Published: April 2022

Long non-coding RNAs (lncRNAs) are a prominent class of eukaryotic regulatory genes. Despite the numerous available transcriptomic datasets, the annotation of plant lncRNAs remains based on dated annotations that have been historically carried over. We present a substantially improved annotation of Arabidopsis thaliana lncRNAs, generated by integrating 224 transcriptomes in multiple tissues, conditions, and developmental stages. We annotate 6764 lncRNA genes, including 3772 that are novel. We characterize their tissue expression patterns and find 1425 lncRNAs are co-expressed with coding genes, with enriched functional categories such as chloroplast organization, photosynthesis, RNA regulation, transcription, and root development. This improved transcription-guided annotation constitutes a valuable resource for studying lncRNAs and the biological processes they may regulate.
NuRD independent Mi-2 activity represses ectopic gene expression during neuronal maturation
Authors: Aughey Gabriel N , Forsberg Elhana , Grimes Krista , Zhang Shen , Southall Tony D
Published: April 2022

During neuronal development, extensive changes to chromatin states occur to regulate lineage-specific gene expression. The molecular factors underlying the repression of non-neuronal genes in differentiated neurons are poorly characterised. The Mi2/NuRD complex is a multiprotein complex with nucleosome remodelling and histone deacetylase activity. Whilst NuRD has previously been implicated in the development of nervous system tissues the precise nature of the gene expression programmes that it coordinates are ill-defined. Furthermore, evidence from several species suggests that Mi-2 may be incorporated into multiple complexes that may not possess histone deacetylase activity. We show that Mi-2 activity is required for suppressing ectopic expression of germline genes in neurons independently of HDAC1/NuRD, whilst components of NuRD, including Mi-2, regulate neural gene expression to ensure proper development of the larval nervous system. We find that Mi-2 binding in the genome is dynamic during neuronal maturation and Mi-2 mediated repression of ectopic gene expression is restricted to the early stages of neuronal development, indicating that Mi-2/NuRD is required for establishing stable neuronal transcriptomes during the early stages of neuronal differentiation.
Nonstructural protein 1 (nsp1) widespread RNA decay phenotype varies among Coronaviruses
Authors: Bermudez Yahaira , Miles Jacob , Muller Mandy
Published: April 2022

Abstract

Extensive remodeling of the host gene expression environment by coronaviruses nsp1 proteins is a well-documented and conserved piece of the coronavirus-host takeover battle. However, whether and how the underlying mechanism of regulation or the transcriptional target landscape differ amongst coronaviruses remains mostly uncharacterized. In this study we use comparative transcriptomics to investigate the diversity of transcriptional targets between four different coronavirus nsp1 proteins (from MERS, SARS1, SARS2 and 229E). In parallel, we performed Affinity Purification followed by Mass-Spectrometry to identify common and divergent interactors between these different nsp1. For all four nsp1 tested, we detected widespread RNA destabilization, confirming that both α- and β-Coronavirus nsp1 broadly affect the host transcriptome. Surprisingly, we observed that even closely related nsp1 showed little similarities in the clustering of genes targeted. Additionally, we show that the RNA targeted by nsp1 from the α-CoV 229E partially overlapped with MERS nsp1 targets. Given MERS nsp1 preferential targeting of nuclear transcripts, these results may indicate that these nsp1 proteins share a similar targeting mechanism. Finally, we show that the interactome of these nsp1 proteins differ widely. Intriguingly, our data indicate that the 229E nsp1, which is the smallest of the nsp1 proteins tested here, interacts with the most host proteins, while MERS nsp1 only engaged with a few host proteins. Collectively, our work highlights that while nsp1 is a rather well-conserved protein with conserved functions across different coronaviruses, its precise effects on the host cell is virus specific.

Significance

Coronaviruses extensively co-opt their host gene expression machinery in order to quicky benefit from the host resources. The viral protein nsp1 plays a major role in this takeover as nsp1 is known to induce a widespread shutdown of the host gene expression, both at the RNA and the translational level. Previous work characterized the molecular basis for nsp1-mediated host shutdown. However, this was mostly conducted in the context of β-coronaviruses and in particular SARS-CoV1, CoV2 and MERS due to the important public health burden that these viruses represent. Here instead, we explored the impact of nsp1 on the host using a comparative approach, defining the influence of 4 nsp1 protein from α- and β-coronaviruses. We delineated the impact of these 4 nsp1 on the host transcriptome and mapped their interactome. We revealed that host target range and interactomes vary widely among different nsp1, suggesting a viral-specific targeting. Understanding how these differences shape infection will be important to better inform antiviral drug development.