bluuebunny/crossref_metadata_2025 huggingface dataset:
Health-related Quality of Life Outcomes Following Single or Bilateral Lung Transplantation: A Systematic Review
Authors: Raguragavan Aarohanan , Jayabalan Dujinthan , Saxena Akshat
Published: December 2022

Background.

Lung transplantation is the definitive treatment for end-stage lung disease. There has been uncertainty regarding whether single or bilateral lung transplantation confers patients’ greater health-related quality of life. This systematic review was performed to evaluate the impact of single lung transplantation (SLTx) against bilateral lung transplantation on short- and long-term health-related quality of life.

Methods.

A literature search was conducted on PubMed for studies matching the eligibility criteria between January 2000 and January 2022. OVID (MEDLINE), Google Scholar, EBSCOhost (EMBASE), and bibliographies of included studies were reviewed. Inclusion of studies was based on predetermined eligibility criteria. Quality appraisal and data tabulation were performed using predetermined forms. Results were synthesized by narrative review. The structure of this systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This systematic review was prospectively registered in the PROSPERO register (CRD42022344389).

Results.

Ten studies (1916 patients) were included. Within 12 mo posttransplantation, there was no evidence of the improved health-related quality of life with respect to the type of lung transplantation procedure. Bilateral lung transplantation patients reported significantly greater scores in both the physical and mental health domains of health-related quality of life. Bilateral lung transplantation offered significantly better health-related quality of life outcomes at later follow-up periods. Bilateral lung transplantation showed a significantly slower reduction in health-related quality of life physical composite scores relative to SLTx.

Conclusions.

Bilateral lung transplant (BLTx) recipients perceive the greater health-related quality of life beyond 1-y post-lung transplantation. BLTx recipients better retain their health-related quality of life long-term posttransplantation than those receiving SLTx.
Impact of Race, Ethnicity, Primary Language and Insurance on Reconstruction after Mastectomy for Patients with Breast Cancer at an Urban, Academic Safety-Net Hospital
Authors: Beaulieu-Jones Brendin R , Fefferman Ann , Woods Alison P , Shewmaker Grant , Zhang Tina , Roh Daniel S , Sachs Teviah E , Merrill Andrea , Ko Naomi Y , Cassidy Michael R
Published: December 2022

Background:

Disparities in breast reconstruction have been observed in national cohorts and single-institution studies based on race, ethnicity, insurance and language. However, little is known regarding whether safety-net hospitals deliver more or less equitable breast reconstruction care in comparison to national cohorts.

Study Design:

We performed a retrospective study of patients with either invasive breast cancer or ductal carcinoma in situ (DCIS) diagnosed and treated at our institution (1/1/09-12/31/14). The rate of, timing of, and approach to breast reconstruction were assessed by race, ethnicity, insurance status and primary language among women who underwent mastectomy. Reasons for not performing reconstruction were also analyzed.

Results:

756 women with DCIS or non-metastatic invasive cancer were identified. Median age was 58.5 years, 56.2% were non-white, 33.1% were non-English-speaking, and 48.9% were Medicaid/uninsured patients. 142 (18.8%) underwent mastectomy during their index operation. 47.9% (N=68) did not complete reconstruction. Reasons for not performing reconstruction included: patient preference (N=22), contraindication to immediate reconstruction (i.e., locoregionally advanced disease prohibiting immediate reconstruction) without follow-up for consideration of delayed reconstruction (N=12), prohibitive medical risk or contraindication (i.e., morbid obesity) (N=8), and progression of disease, prohibiting reconstruction (N=7). Immediate and delayed reconstruction were completed in 43.7% and 8.5% of patients. Rate of reconstruction was inversely associated with tumor stage (OR=0.52, 95% CI: 0.31-0.88), but not race, ethnicity, insurance or language, on multivariate regression.

Conclusions:

At a safety-net hospital, we observed rates of reconstruction at or above national estimates. After adjustment for clinical attributes, rates did not vary by race, ethnicity, insurance or language. Future research is needed to understand the role of reconstruction in breast cancer care and how to advance shared decision-making among diverse patients.
Bone and joint tuberculosis in paediatrics: a 13-year retrospective study
Authors: Gouveia Catarina , Cabral Mafalda Félix , Jordão Pedro , Campagnolo João , Mineiro Jorge , Peres Helena , Conceição Carla , Silva Tiago Milheiro , Varandas Luís , Brito Maria João
Published: December 2022

Introduction. Bone and joint tuberculosis (BJTB) is rare in developed countries, particularly in the paediatric population.

Hypothesis/Gap Statement. The clinical features and sequelae of paediatric BJTB in Europe are not well characterized and should be assessed to achieve a better approach.

Aim. To assess the management and outcomes of paediatric BJTB.

Methodology. Longitudinal observational study of all paediatric patients (0–17 years old) diagnosed with BJTB between 2008 to 2020 in a tertiary-care hospital.

Results. We identified 18 patients with BJTB, with a median age of 10 years (IQR 6–14.8), 66.7 % male. Most (72 %) were diagnosed after 2015 and were foreign-born (88.9 %), mainly from Portuguese-speaking African countries, and none had HIV. The most common symptoms were pain (77.8 %), fever (50 %) and bone deformity (44.4 %). Spinal TB (STB) affected 13 (72.2 %) and extra-spinal TB (ESTB) 9 (50 %) patients, and 4 (27.7 %) had both conditions. Diagnostic positive procedures included positive nucleic acid amplification technique (NAAT) (44.4 %),

Mycobacterium tuberculosis

isolation (44.4 %) and compatible histology (33.3 %). All completed antituberculous drugs for a median of 12 months (IQR 12–13) and nine (50 %) had surgery. Overall, acute complications occurred in 16 (88.9 %) patients – 11/13 (84.6 %) with STB and 5/5 (100 %) with ESTB – and included abscesses, spinal compression, spine deformity and pathological fractures. Sequelae were still present at the 12-month follow-up in seven cases (46.7 %), and were more common in foreign-born patients sent to Portugal to receive medical treatment (66.7 vs 20 %).

Conclusions. Paediatric BJTB is difficult to diagnose and has high morbidity, requiring long-term follow-up. Over the last decade, foreign-born TB seems to be increasing, with still longer treatment courses and more acute complications and sequelae.
Hantavirus infection as a risk factor for chronic kidney disease of unknown aetiology (CKDu) and its prevalence in endemic areas of Sri Lanka since 2010 according to a retrospective serological analysis
Authors: Gamage Chandika D. , Nanayakkara Shanika , Sarathkumara Yomani D. , Muthusinghe Devinda S. , Shimizu Kenta , Arikawa Jiro , Lokupathirage Sithumini M. W. , Nanayakkara Nishantha , Gunarathne Lishanthe , Chandrajith Rohana , Harada Kouji H. , Koizumi Akio , Yoshimatsu Kumiko
Published: December 2022

Background. Chronic kidney disease of unknown aetiology (CKDu) is a major public health problem in Sri Lanka, especially among agrarian communities. Although the cause of CKDu is still unknown, hantavirus infection has been proposed as a risk factor.

Methods. This study was performed using serological samples collected from two CKDu-endemic areas, Anuradhapura (2010) and Badulla districts (2010 and 2016), and a non-endemic area, Matale (2016) district. The presence of anti-Thailand orthohantavirus IgG antibodies was investigated in serum samples. Hantavirus seroprevalence and demographic data were epidemiologically analysed.

Results. Seroprevalence was higher in CKDu patients (40.6–60.0 %) and healthy individuals in CKDu-endemic areas (17.6–25.5 %) than in healthy individuals in non-endemic areas (3.0 %). Statistically significant odds ratios (ORs) for hantavirus infection in CKDu patients were detected in CKDu-endemic areas [ORs: 3.2 and 3.1; 95 % confidence interval (CI): 1.8–5.5 and 1.8–5.2 in Anuradhapura and Badulla districts in 2010; and OR: 4.4, 95 % CI: 2.3–8.5 in 2016 in Badulla district). Furthermore, the OR for hantavirus infection in Badulla district has increased in the last decade from 3.1 (95 % CI: 1.8–5.3) to 4.4 (95 % CI: 2.3–8.5).

Conclusion. Hantavirus infection has been prevalent in two distant CKDu-endemic areas since 2010. The observed significant association of hantavirus seropositivity with CKDu indicates a possible role of hantavirus infection in CKDu pathogenesis.
miR472 deficiency enhancesArabidopsis thalianadefence without reducing seed production
Authors: Vasseur Francois , Baldrich Patricia , Jiménez-Góngora Tamara , Villar-Martin Luis , Weigel Detlef , Rubio-Somoza Ignacio
Published: December 2022

After having co-existed in plant genomes for at least 200 million years, the products of microRNA (miRNA) and Nucleotide-Binding Leucine Rich Repeat protein (NLR) genes formed a regulatory relationship in the common ancestor of modern gymnosperms and angiosperms. From then on, DNA polymorphisms occurring at miRNA target sequences within NLR transcripts must have been compensated by mutations in the corresponding mature miRNA sequence, therefore maintaining that regulatory relationship. The potential evolutionary advantage of such regulation remains largely unknown and might be related to two mutually non-exclusive scenarios: miRNA-dependent regulation of NLR levels might prevent defence mis-activation with negative effects on plant growth and reproduction; or reduction of active miRNA levels in response to pathogen derived molecules (PAMPS and silencing suppressors) might rapidly release otherwise silent NLR transcripts for rapid translation and thereby enhance defence. Here, we usedArabidopsis thalianaplants deficient for miR472 function to study the impact of releasing its NLR targets on plant growth and reproduction and on defence against the fungal pathogenPlectospharaella cucumerina. We show that miR472 regulation has a dual role, participating both in the tight regulation of plant defence and growth. MIM472 lines, with reduced active miR472, are more resistant to pathogens and, correlatively, have reduced relative growth compared to wild-type plants. However, despite MIM472 lines flower at the same time than their wild-type, the end of their reproductive phase is delayed, and they exhibit higher adult biomass, resulting in similar seed yield as the wild-type. Our study highlights how negative consequences of defence activation might be compensated by changes in phenology and that miR472 reduction is an integral part of plant defence responses.
Comparison of two multi-trait association testing methods and sequence-based fine mapping of six QTL in Swiss Large White pigs
Authors: Nosková A. , Mehrotra A. , Kadri N.K. , Lloret-Villas A. , Neuenschwander S. , Hofer A. , Pausch H.
Published: December 2022

Background

Genetic correlations between complex traits suggest that pleiotropic variants contribute to trait variation. Genome-wide association studies (GWAS) aim to uncover the genetic underpinnings of traits. Multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS enable detecting variants associated with multiple phenotypes. In this study, we used array-derived genotypes and phenotypes for 24 reproduction, production, and conformation traits to explore differences between the two methods and used imputed sequence variant genotypes to fine-map six quantitative trait loci (QTL).

Results

We considered genotypes at 44,733 SNPs for 5,753 pigs from the Swiss Large White breed that had deregressed breeding values for 24 traits. Single-trait association analyses revealed eleven QTL that affected 15 traits. Multi-trait association testing and the meta-analysis of the single-trait GWAS revealed between 3 and 6 QTL, respectively, in three groups of traits. The multi-trait methods revealed three loci that were not detected in the single-trait GWAS. Four QTL that were identified in the single-trait GWAS, remained undetected in the multi-trait analyses. To pinpoint candidate causal variants for the QTL, we imputed the array-derived genotypes to the sequence level using a sequenced reference panel consisting of 421 pigs. This approach provided genotypes at 16 million imputed sequence variants with a mean accuracy of imputation of 0.94. The fine-mapping of six QTL with imputed sequence variant genotypes revealed four previously proposed causal mutations among the top variants.

Conclusions

Our findings in a medium-size cohort of pigs suggest that multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS provide very similar results. Although multi-trait association methods provide a useful overview of pleiotropic loci segregating in mapping populations, the investigation of single-trait association studies is still advised, as multi-trait methods may miss QTL that are uncovered in single-trait GWAS.
Engineering Xylose Fermentation in an Industrial Yeast: Continuous Cultivation as a Tool for Selecting Improved Strains
Authors: Basso Thalita Peixoto , Procópio Dielle Pierotti , Petrin Thais Helena Costa , Giacon Thamiris Guerra , Jin Yong-Su , Basso Thiago Olitta , Basso Luiz Carlos
Published: December 2022

Production of second-generation ethanol from lignocellulosic residues should be fueling the energy matrix in the near future. Lignocellulosic feedstock has received much attention as an alternative energy resource for biorefineries toward reducing the demand for fossil resources, contributing to a future sustainable bio-based economy. Fermentation of lignocellulosic hydrolysates poses many scientific and technological challenges as the drawback ofSaccharomyces cerevisiae’sinability in fermenting pentose sugars (derived from hemicellulose). To overcome the inability ofS. cerevisiaeto ferment xylose and increase yeast robustness in the presence of inhibitory compound-containing media, the industrialS. cerevisiaestrain SA-1 was engineered using CRISPR-Cas9 with the oxidoreductive xylose pathway fromScheffersomyces stipitis(encoded byXYL1, XYL2, andXYL3). The engineered strain was then cultivated in a xylose-limited chemostat under increasing dilution rates (for 64 days) to improve its xylose consumption kinetics under aerobic conditions. The evolved strain (DPY06) and its parental strain (SA-1 XR/XDH) were evaluated under anaerobic conditions in complex media. DPY06 consumed xylose faster, exhibiting an increase of 70% in xylose consumption rate at 72h of cultivation compared to its parental strain, indicating that laboratory evolution improved xylose uptake of SA-1 XR/XDH.

GRAPHICAL ABSTRACT
A complex reach direction rule that delays reaction time causes alternating excitation and inhibition in express muscle responses and corticospinal excitability
Authors: Divakar Rechu , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J.
Published: December 2022

The dynamics of muscle activation during fast visually guided reaching are suggestive of two neural control signals; an early signal that acts at “express” latencies in response to the visual stimulus, and a longer latency signal that executes a strategic reach plan. Here we developed a task designed to temporally isolate the express visuomotor response from the longer latency muscle response, and to characterize the time course of corticospinal excitability changes in the express response time window when the late voluntary response is delayed. We tested this by measuring electromyograms (EMG) and changes in Motor Evoked Potential (MEP) amplitudes following Transcranial Magnetic Stimulation (TMS) of the motor cortex, as participants reached either towards or away from visual targets. Crucially, the information about the task rule was provided by the luminance of the target itself, and so was unknown to the subject until the instant of target presentation. This feature delayed reaction times, likely because additional (presumably cortical) processing was required to interpret and apply the rule before formation of a goal directed reach plan. The earliest EMG responses to target presentation occurred with a 70-105 ms time window, and were oriented to bring the hand toward the location of the target. However, there was also a slightly later response that was also time-locked to target appearance in a 105-140 ms time window. This second response was “reciprocal” to the first, such that it was oriented to take the hand in the direction opposite from the target. In some participants, additional oscillating cycles were apparent after the first two target-related responses. These multiphasic express visuomotor responses were nearly identical in both pro- and anti-reach conditions. These muscle activity responses were generally reflected in the temporal pattern of corticospinal excitability modulations in experiment two. Indeed, the MEP and background EMG responses showed an alternating pattern similar to that in experiment one, although the effect was clearer in the anti-reach than the pro-reach condition. Overall, the data show that the express and voluntary responses are indeed distinct neural control signals, which supports the hypothesis that at least two separate neural pathways (one slow and one fast) contribute to the control of visually guided reaching. The properties of the fast pathway are consistent with a tecto-reticulospinal pathway, while those of the slow pathway are consistent with a transcortical loop.
Performance characteristics allow for confinement of a CRISPR toxin-antidote gene drive designed for population suppression
Authors: Zhang Shijie , Champer Jackson
Published: December 2022

Gene drives alleles that can bias their own inheritance are a promising way to engineer populations for control of disease vectors, invasive species, and agricultural pests. Recent advancements in the field have yielded successful examples of powerful suppression type drives and confined modification type drives, but developing confined suppression drives has proven more difficult. This is because the necessary power for strong suppression is often incompatible with the characteristics needed for drive confinement. However, one type of CRISPR toxin-antidote drive may be strong enough and confined, the TADE (Toxin-Antidote Dominant Embryo) suppression drive. By disrupting a haplolethal target gene and a haplosufficient female fertility gene, this drive quickly eliminates wild-type alleles and eventually induces population suppression. It has been shown to perform effectively in panmictic populations. However, confinement in spatial scenarios may be substantially different. Here, we use a reaction-diffusion model to assess the performance of TADE suppression drive in continuous space. We measure the drive wave advance speed while varying several performance parameters and find that moderate fitness costs or embryo cutting (from maternally deposited nuclease) can eliminate the drive’s ability to form a wave of advance. We assess the release size required for the drive to propagate, and finally, we investigate migration corridor scenarios. Depending on the corridor size and dispersal, it is often possible for the drive to suppress one population and then persist in the corridor without invading the second population. This prevents re-invasion by wild-type, which may be a particularly desirable outcome in some scenarios. Thus, even imperfect variants of TADE suppression drive may be excellent candidates for confined population suppression.
Extending the breeder’s equation to take aim at the Target Population of Environments
Authors: Cooper Mark , Powell Owen , Gho Carla , Tang Tom , Messina Carlos
Published: December 2022

1)

A major focus for genomic prediction has been on improving trait prediction accuracy using combinations of algorithms and the training data sets available from plant breeding multi-environment trials (METs). Any improvements in prediction accuracy are viewed as pathways to improve traits in the reference population of genotypes and product performance in the target population of environments (TPE). To realise these breeding outcomes there must be a positive MET-TPE relationship that provides consistency between the trait variation expressed within the MET data sets that are used to train the genome-to-phenome (G2P) model for applications of genomic prediction and the realised trait and performance differences in the TPE for the genotypes that are the prediction targets. The strength of this MET-TPE relationship is usually assumed to be high, however it is rarely quantified. To date investigations of genomic prediction methods have not given adequate attention to quantifying the structure of the TPE and the MET-TPE relationship and its potential impact on training theG2Pmodel for applications of genomic prediction to accelerate breeding outcomes for the on-farm TPE. We provide a perspective on the importance of the MET-TPE relationship as a key component for the design of genomic prediction methods to realize improved rates of genetic gain for the target yield, quality, stress tolerance and yield stability traits in the on-farm TPE.
Understanding anaemia and stunting among young women in a rural setting of Indonesia
Authors: Okinarum Giyawati Yulilania , Hardiningsih  , Yunita Fresthy Astrika , Fauziah Afroh , Hardhantyo Muhammad
Published: December 2022

Background

Indonesian Ministry of Health stated that around 80% of Indonesian women aged between 15-24 years are anaemic, and 30% of children are stunted. The leading cause of this problem is poor quality food, including poor micronutrient quality, low dietary diversity and low intake of animal-source foods. Preconceptional young women who are anaemic and stunted have a risk of giving birth to stunted children later in life if their nutrition is not immediately improved. This study aims to have a deeper understanding of anaemia and stunting conditions among young women in the rural setting of Indonesia.

Methods

Twenty young women with the anaemic and stunting condition aged between 15 - 19 years were recruited through the randomly selected patient in the outpatient department of Public Health Center (Puskesmas) in the rural area of Gunungkidul, Yogyakarta from October to November 2022. Focus Group Discussion (FGD) was conducted with the following area early marriage, cause and effect of anaemia and stunting, and women health-seeking behavior. Interviews were audio-recorded, transcribed, translated, and analyzed thematically.

Results

Young women with anaemic and stunting condition are having powerlessness where they are unable in determining daily diet, arise from a low-income family and have no choice in their life course. They are suffering from financial difficulties and food insecurity, resulting in inadequate nutrition and stunting. They also believe that early marriage is a viable option for their own and their children’s well-being.

Conclusion

This study is the evidence of young women powerlessness in the rural area of Indonesia. The understanding could contribute to develop evidence-based, effective, and efficient policies and regulations. The existing health system needs to reinforce the support for young women to reduce risks in early life and improve their health across the life course. The intervention could include promoting access to nutritious foods, good hygiene, family planning education, and access to health facilities and services.
Establishing Causality in the Relationship between Sleep and Migraine in a Global Sample: A Bayesian Approach
Authors: Stanyer Emily C. , Brookes Jack , Pang Jia Rong , Urani Alexandre , Holland Philip R. , Hoffmann Jan
Published: December 2022

Background

There is a bidirectional link between sleep and migraine, however causality is difficult to determine. Previous studies rely on retrospective questionnaires, and small samples to support their findings. This study aimed to overcome this by teasing apart this relationship using sleep assessment and concomitant migraine data collected from a smartphone application using Bayesian modelling.

Methods

Anonymized self-reported data on sleep and migraine from 11,166 global users (aged 18-81 years, mean: 41.21, standard deviation: 11.49) were collected from the Migraine Buddy application (Healint Pte. Ltd.) between 30thJune and 31stDecember 2021. Measures included: demographics, start and end times of each sleep episode and migraine attack, and the pain intensity for each migraine attack (visual analogue scale 0-10). Bayesian regression models were used to predict occurrence of a migraine attack the next day based on users’ deviations from mean monthly sleep, number of sleep interruptions, and hours slept the night before in those reporting ≥ 4 and <25 migraine attacks on average per month. Conversely, we modelled whether attack occurrence and pain intensity could predict hours slept that same night.

Results

Once exclusion criteria were applied, there were 724 users (129 males, 412 females, 183 unknown) with an average age of 41.88 years (SD= 11.63), with a mean monthly number of attacks of 9.94. A greater number of sleep interruptions (95% Highest Density Interval (95% HDI [0.112 – 0.205]) and deviation from a user’s mean sleep the night before (95% HDI [0.040 – 0.080]) were significant predictors of a next day migraine attack. Total hours slept was not a significant predictor (95% HDI [-0.04 – 0.04]). Pain intensity, but not attack occurrence was a positive predictor of hours slept.

Discussion

Sleep fragmentation and deviation from typical sleep are the main drivers of the relationship between sleep and migraine, whereas overall sleep duration is not. Conversely, simply having a migraine attack does not predict sleep duration, it is the pain associated with an attack which alters sleep. This study has shed light on the causal mechanisms of sleep and migraine and highlights sleep hygiene as crucial in migraine management.
The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming
Authors: Oger Frédérik , Moreno Maeva , Derhourhi Mehdi , Thiroux Bryan , Berberian Lionel , Bourouh Cyril , Durand Emmanuelle , Amanzougarene Souhila , Badreddine Alaa , Blanc Etienne , Molendi-Coste Olivier , Pineau Laurent , Pasquetti Gianni , Rolland Laure , Carney Charlène , Bornaque Florine , Courty Emilie , Gheeraert Céline , Eeckhoute Jérôme , Dombrowicz David , Kerr-Conte Julie , Pattou François , Staels Bart , Froguel Philippe , Bonnefond Amélie , Annicotte Jean-Sébastien
Published: December 2022

Objective

The pancreatic islets of Langerhans contain distinct cell subtypes including insulin-producing β cells. Although their cell-specific gene expression pattern defines their identity, the underlying molecular network driving this transcriptional specificity is not fully understood. Among the numerous transcriptional regulators, histone deacetylases (HDAC) enzymes are potent chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone proteins. The precise molecular mechanisms underlying HDAC effects on cellular plasticity and β-cell identity are currently unknown.

Methods

The pharmacological inhibition of HDAC activity by trichostatin A (TSA) was studied in the mouse Min6 and human EndocBH1 cell lines, as well as primary mouse sorted β cells and human pancreatic islets. The molecular and functional effects of treating these complementary β-cell models with TSA was explored at the epigenomic and transcriptomic level through next-generation sequencing of chromatin immunoprecipitation (ChIP) assays (ChIP-seq) and RNA sequencing (RNA-seq) experiments, respectively.

Results

We showed that TSA alters insulin secretion associated with β-cell specific transcriptome programming in both mouse and human β-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative β-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers.

Conclusions

Taken together, our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
A Cancer-Associated Fibroblast Classification Framework for Single-Cell Data
Authors: Cords Lena , Tietscher Sandra , Anzeneder Tobias , Langwieder Claus , Rees Martin , de Souza Natalie , Bodenmiller Bernd
Published: December 2022

Cancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on tumour evolution and patient prognosis. To define CAF phenotypes, we analysed a single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours of 14 breast cancer patients, based on which we defined and functionally annotated nine CAF phenotypes and one class of pericytes. We validated this classification system in four additional cancer types and used highly multiplexed imaging mass cytometry on matched breast cancer samples to confirm our defined CAF phenotypes at the protein level and to analyse their spatial distribution within tumours. This general CAF classification scheme will allow comparison of CAF phenotypes across studies, facilitate analysis of their functional roles, and potentially guide development of new treatment strategies in the future.
Phase transitions in a simple model of focal stroke imitate recovery and suggest neurorehabilitation strategies
Authors: Carballo-Castro Alba , Seoane Luís F
Published: December 2022

A stroke is a brain insult that can take offline (often permanently) extended regions of the brain. As a consequence, cognitive tasks or representations implemented by the affected circuitry lose their computational substrate (they becomeorphan). The brain must adapt to attempt retaining such functions. The existing clinical literature offers a complex picture, often with conflicting observations, about how the brain gets reorganized after stroke. It also does little use of the few mathematical works on the topic. Can a minimal mathematical model of cortical plasticity shed light on this complex phenomenology? Here we explore such minimal model, and find a specific phenomenology: a lasting perilesional reorganization for small injuries, and a temporary contralesional reorganization for large injuries that is not always reverted to ipsilesional. We furthermore show the mechanisms behind these dynamics in our model: a second order phase transition with a critical point, as well as a delayed engagement of perilesional reorganization in large injuries. These dynamics emerge out of a fairly minimal modeling of plasticity, and they reproduce the story put together from clinical observations. We further explore neurorehabilitation strategies, and argue that increased tissue susceptibility (a property that diverges at critical points) can be crucial to manipulate plasticity in beneficial ways.
CAAStools: a toolbox to identify and test Convergent Amino Acid Substitutions
Authors: Barteri Fabio , Valenzuela Alejandro , Farré Xavier , de Juan David , Muntané Gerard , Esteve-Altava Borja , Navarro Arcadi
Published: December 2022

Background

Coincidence of Convergent Amino Acid Substitutions (CAAS) with phenotypic convergences allow pinpointing genes and even individual mutations that are likely to be associated with trait variation within their phylogenetic context. Such findings can provide useful insights into the genetic architecture of complex phenotypes. Here we introduce CAAStools, a set of bioinformatics tools to identify and validate CAAS in orthologous protein alignments for pre-defined groups of species representing the phenotypic values targeted by the user.

Implementation and availability

CAAStools source code is available athttp://github.com/linudz/caastools, along with documentation and examples.

Supplementary information

Supplementary data are available.
MSL2 targets histone genes inDrosophila virilis
Authors: Xie Mellisa , Hodkinson Lauren J. , Comstra H. Skye , Diaz-Saldana Pamela P. , Gilbonio Hannah E. , Gross Julia L. , Chavez Robert M. , Puckett Gwyn L. , Aoki Tsutomu , Schedl Paul , Rieder Leila E.
Published: December 2022

Histone genes are amongst the most evolutionary conserved in eukaryotic genomes, yetcis-regulatory mechanisms of histone gene regulation differ considerably amongst species. InDrosophila melanogaster, an interaction between GA-richciselements in theH3/H4promoter and the GA-binding transcription factor CLAMP is important for promoting histone gene regulation and factor recruitment to the locus. CLAMP also participates in male dosage compensation by recruiting the Male Specific Lethal Complex (MSLc) to the X-chromosome. We discovered that the male-specific protein of MSLc, MSL2, is recruited to the autosomal major histone locus inD. virilisbut not to the minor locus or to the single histone locus in other species. While the histone coding sequences are well conserved between species, the critical GA-richciselements in theH3/H4promoter are poorly conserved betweenD. melanogasterandD. virilis. We show that CLAMP still targets the twoD. virilishistone lociin vivo. Further, CLAMP interacts with theD. virilis H3/H4promoterin vitro, even when the poorly-conserved GA-richciselements are deleted, indicating that the protein interacts differently with theD. virilispromoter than it does with theD. melanogasterpromoter. Since CLAMP and MSL2 directly interact inD. melanogaster, we propose thatD. virilisCLAMP recruits MSL2 to an ectopic autosomal site through interaction with X-likeciselements. Further, localization of MSL2 to one of theD. virilishistone loci suggests that the loci are regulated differently and that males and females have different requirements for histone gene regulation.
3D-printed polymeric scaffolds with optimized architecture to repair a sheep metatarsal critical-size bone defect
Authors: Garot Charlotte , Schoffit Sarah , Monfoulet Cécile , Machillot Paul , Deroy Claire , Roques Samantha , Vial Julie , Vollaire Julien , Renard Martine , Ghanem Hasan , El-Hafci Hanane , Decambron Adeline , Josserand Véronique , Bordenave Laurence , Bettega Georges , Durand Marlène , Manassero Mathieu , Viateau Véronique , Logeart-Avramoglou Delphine , Picart Catherine
Published: December 2022

The reconstruction of critical-size bone defects in long bones remains a challenge for clinicians. We developed a new bioactive medical device for long bone repair by combining a 3D-printed architectured cylindrical scaffold made of clinical-grade polylactic acid (PLA) with a polyelectrolyte film coating delivering the osteogenic bone morphogenetic protein 2 (BMP-2). This film-coated scaffold was used to repair a sheep metatarsal 25-mm long critical-size bone defect.In vitroandin vivobiocompatibility of the film-coated PLA material were proved according to ISO standards. Scaffold geometry was found to influence BMP-2 incorporation. Bone regeneration was followed using X-ray scans, µCT scans, and histology. We showed that scaffold internal geometry, notably pore shape, influenced bone regeneration, which was homogenous longitudinally. Scaffolds with cubic pores of ∼870 µm and a low BMP-2 dose of ∼120 µg/cm3induced the best bone regeneration without any adverse effects. The visual score given by clinicians during animal follow-up was found to be an easy way to predict bone regeneration. This work opens perspectives for a clinical application in personalized bone regeneration.
Numerical study of the formation and stability of a pair of particles of different sizes in inertial microfluidics
Authors: Thota Krishnaveni , Owen Benjamin , Krüger Timm
Published: December 2022

The formation of pairs and trains of particles in inertial microfluidics is an important consideration for device design and applications, such as particle focussing and separation. We study the formation and stability of linear and staggered pairs of nearly rigid spherical particles of different sizes in a pressure-driven flow through a straight duct with rectangular cross-section under mild inertia. An in-house lattice-Boltzmann-immersed-boundary-finite-element code is used for the simulations. We find that the stability and properties of pairs of heterogeneous particles strongly depends on the particle sizes and their size ratio, while the formation of the pairs is also determined by the initial lateral position and the axial order of the particles. Our findings imply that perturbations of particle trajectories caused by other particles, as they are expected to happen even in dilute suspensions, can be important for the formation of stable pairs in inertial microfluidics.
Monitoring RNA restructuring in a human cell-free extract reveals eIF4A-dependent and eIF4A-independent unwinding activity
Authors: O’Sullivan Mattie H. , Fraser Christopher S.
Published: December 2022

The canonical DEAD-box helicase, eIF4A, unwinds 5’ UTR secondary structures to promote mRNA translation initiation. Growing evidence has indicated that other helicases, such as DHX29 and DDX3/ded1p, also function to promote the scanning of the 40S subunit on highly structured mRNAs. It is unknown how the relative contributions of eIF4A and other helicases regulate duplex unwinding on an mRNA to promote initiation. Here, we have adapted a real-time fluorescent duplex unwinding assay to precisely monitor helicase activity in the 5’ UTR of a reporter mRNA that can be translated in a cell-free extract in parallel. We monitored the rate of 5’ UTR-dependent duplex unwinding in the absence or presence of Hippuristanol, a dominant negative eIF4A (eIF4A-R362Q), or a mutant eIF4E (eIF4E-W73L) that can bind the m7G cap but not eIF4G. Our experiments reveal that roughly 50% of the duplex unwinding activity in the cell-free extract can be attributed to an eIF4A-dependent mechanism, while the remaining 50% of duplex unwinding activity is attributed to an eIF4A-independent mechanism. Importantly, we show that the robust eIF4A-independent duplex unwinding is not sufficient for translation. We also show that the m7G cap structure, and not the poly(A) tail, is the primary mRNA modification responsible for promoting duplex unwinding in our cell-free extract system. Overall, the fluorescent duplex unwinding assay provides a precise method to investigate how eIF4A-dependent and eIF4A-independent helicase activity regulates translation initiation in cell-free extracts. We anticipate that potential small molecule inhibitors could be tested for helicase inhibition using this duplex unwinding assay.
Probing the Biology of Zinc Alpha2-Glycoprotein and the role it plays in cachexia
Authors: Pandit Parth , Panigrahi Subrat
Published: December 2022

Cachexia is a metabolic disease that results in drastic weight loss and muscle wasting. 20% of total cancer patients will die due to cachexia related complications. ZAG contributes to the regulation of weight and body fat through lipid and glucose metabolism. In healthy individuals, ZAG exerts a homeostasis effect by inducing lipolysis of adipose tissue to help reduce fat storage and overall weight. ZAG is upregulated in various carcinomas and cancer patients with upregulated ZAG are observed to lose weight rapidly. The mutants of ZAG which are the 4 amino acids Tryptophan 148, Arginine 73, Phenylalanine 101, Isoleucine 76 have all been mutated to Alanine. The effect of mutants and the wild type ZAG can also be found out by conducting experiments. ZAG has a potential lipid binding site that could be imperative to the function of ZAG. A lipolysis colorimetric kit allows us to measure the ZAG variants effects on 3T3 adipose cells to determine what β-adrenoreceptor signaling pathways are being utilized in its lipolytic effect. The Tryptophan-Alanine mutant showed increased lipolysis after 1h treatment than other variants. The time period is also a rate limiting step which can play major factor in lipolysis. The ultimate goal is to identify the ligand(s) and the interactions between them and ZAG. The design of a therapeutic would give patients options of treatments brought about by attenuating the weight loss. With this, it would offer a better prognosis for patients and provide them with a greater quality of life.
Genomic loci involved in sensing environmental cues and metabolism affect seasonal coat shedding inBos taurusandBos indicuscattle
Authors: Durbin Harly J. , Yampara Helen , Rowan Troy N. , Schnabel Robert D. , Koltes James E. , Powell Jeremy G. , Decker Jared E.
Published: December 2022

Seasonal shedding of winter hair at the start of summer is well studied in wild and domesticated populations. However, the genetic influences on this trait and their interactions are poorly understood. We use data from 13,364 cattle with 36,899 repeated phenotypes to investigate the relationship between hair shedding and environmental variables, single nucleotide polymorphisms, and their interactions to understand quantitative differences in seasonal shedding. Using deregressed estimated breeding values from a repeated records model in a genome-wide association analysis (GWAA) and meta-analysis of year-specific GWAA gave remarkably similar results.

These GWAA identified hundreds of variants associated with seasonal hair shedding. There were especially strong associations on chromosomes 5 and 23. Genotype-by- environment interaction GWAA identified 1,040 day length-by-genotype interaction associations and 17 apparent temperature-by-genotype interaction associations with hair shedding, highlighting the importance of day length on hair shedding. Accurate genomic predictions of hair shedding were created for the entire dataset, Angus, Hereford, Brangus, and multi-breed datasets. Loci related to metabolism and light- sensing have a large influence on seasonal hair shedding. This is one of the largest genetic analyses of a phenological trait and provides insight for both agriculture production and basic science.
Astroglial gap junctions strengthen hippocampal network activity by sustaining afterhyperpolarization via KCNQ channels
Authors: Dossi Elena , Zonca Lou , Pivonkova Helena , Vargova Lydia , Chever Oana , Holcman David , Rouach Nathalie
Published: December 2022

Throughout the brain, astrocytes form networks mediated by gap-junction channels that promote the activity of neuronal ensembles. Although their inputs on neuronal information processing are well established, how molecularly gap junction channels shape neuronal network patterns remains unclear. Here using astroglial connexin-deficient mice, in which astrocytes are disconnected and neuronal bursting patterns are abnormal, we found that astrocyte networks strengthen bursting activity via dynamic regulation of extracellular potassium levels, independently of glutamate homeostasis or metabolic support. Using a novel facilitation-depression model, we identified neuronal afterhyperpolarization as the key parameter underlying bursting patterns regulation by extracellular potassium in mice with disconnected astrocytes. We confirmed experimentally this prediction, and revealed that astroglial network-control of extracellular potassium sustains neuronal afterhyperpolarization via activation of KCNQ voltage-gated K+channels. Altogether, these data delineate how astroglial gap-junctions mechanistically strengthen neuronal population bursts, and points to approaches for controlling aberrant activity in neurological diseases.
The Challenge Dataset – simple evaluation for safe, transparent healthcare AI deployment
Authors: Sanayei James K. , Abdalla Mohamed , Ahluwalia Monish , Seyyed-Kalantari Laleh , Minotti Simona , Fine Benjamin A.
Published: December 2022

In this paper, we demonstrate the use of a “Challenge Dataset”: a small, site-specific, manually curated dataset – enriched with uncommon, risk-exposing, and clinically important edge cases – that can facilitate pre-deployment evaluation and identification of clinically relevant AI performance deficits. The five major steps of the Challenge Dataset process are described in detail, including defining use cases, edge case selection, dataset size determination, dataset compilation, and model evaluation. Evaluating performance of four chest X-ray classifiers (one third-party developer model and three models trained on open-source datasets) on a small, manually curated dataset (410 images), we observe a generalization gap of 20.7% (13.5% - 29.1%) for sensitivity and 10.5% (4.3% - 18.3%) for specificity compared to developer-reported values. Performance decreases further when evaluated against edge cases (critical findings: 43.4% [27.4% - 59.8%]; unusual findings: 45.9% [23.1% - 68.7%]; solitary findings 45.9% [23.1% - 68.7%]). Expert manual audit revealed examples of critical model failure (e.g., missed pneumomediastinum) with potential for patient harm. As a measure of effort, we find that the minimum required number of Challenge Dataset cases is about 1% of the annual total for our site (approximately 400 of 40,000). Overall, we find that the Challenge Dataset process provides a method for local pre-deployment evaluation of medical imaging AI models, allowing imaging providers to identify both deficits in model generalizability and specific points of failure prior to clinical deployment.
Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains
Authors: Cary GA , Wiley JC , Gockley J , Keegan S , Heath L , Butler RR , Mangravite LM , Logsdon BA , Longo FM , Levey A , Greenwood AK , Carter GW ,   The Emory-Sage-SGC TREAT-AD Center
Published: December 2022

Alzheimer’s disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly-funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify systems level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genomewide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive gene ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank and organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. The top AD-risk associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. This provides an objective methodology to localize risk within specific biological endophenotypes, and drill down into the most significantly associated sets of GO-terms and annotated genes for potential therapeutic targets.