bluuebunny/crossref_metadata_2025 huggingface dataset:
Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes
Authors: Tse Kai-Hei , Cheng Aifang , Yeung Sunny Hoi-Sang , Ng Jia-Nian , Cheng Gerald Wai-Yeung , Wang Qingyang , Zhu Beika , Cui Yong , Jiang Liwen , Kofler Julia , Herrup Karl
Published: January 2021

Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T pathology, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing and fromAtm-/-mice. In healthy human cerebellum, we confirmed the presence of ATM in white matter OLs. In A-T, a significant reduction in OL density was found along with a massive astrogliosis. This white matter pathology was recapitulated inAtm-/-mice in an age- and gene dose-dependent fashion. Activated ATM was found expressed both in the nucleus and cytoplasm of OL progenitor cells (OPC) and myelinating mature OL. Its presence in the OL lineage is associated with novel OL-specific functions of the ATM protein affecting all stages of the OL life cycle. Blockage of ATM activity with KU-60019 or inducing DNA damage induced with etoposide altered the cell cycle in self-renewing OPC and triggered ectopic cell cycle re-entry in mature OLin vitro. Further, the differentiation program of OPC is highly sensitive to DNA damage either induced directly or by blocking DNA repair. As much of the impact of ATM deficiency in OL is independent of neuronal loss, our findings have important implications for the complex neurological symptoms of human A-T.

HIGHLIGHTS

Oligodendrocytes are highly vulnerable to DNA double strand breaks

ATM regulates cell cycle control and differentiation of oligodendrocytes

Myelin-pathology in Ataxia Telangiectasia is likely the cell-autonomous consequence of ATM deficiency in oligodendrocytes
Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection
Authors: Cheemarla Nagarjuna R. , Watkins Timothy A. , Mihaylova Valia T. , Wang Bao , Zhao Dejian , Wang Guilin , Landry Marie L. , Foxman Ellen F.
Published: January 2021

The interferon response is a potent antiviral defense mechanism, but its effectiveness depends on its timing relative to viral replication. Here, we report viral replication and host response kinetics in patients at the start of SARS-CoV-2 infection and explore the impact of these kinetics experimentally. In both longitudinal patient nasopharyngeal samples and airway epithelial organoids, we found that SARS-CoV-2 initially replicated exponentially with a doubling time of ∼6hr, and induced interferon stimulated genes (ISGs) with delayed timing relative to viral replication. Prior exposure to rhinovirus increased ISG levels and blocked SARS-CoV-2 replication. Conversely, inhibiting ISG induction abrogated interference by rhinovirus and enhanced SARS-CoV-2 replication rate. These results demonstrate the importance of initial interferon-mediated defenses in determining the extent to which SARS-CoV-2 can replicate at the start of infection and indicate that biological variables that alter the airway interferon response, including heterologous induction of innate immunity by other viruses, could profoundly impact SARS-CoV-2 susceptibility and transmission.
Longevity of SARS-CoV-2 immune responses in haemodialysis patients and protection against reinfection
Authors: Clarke Candice L , Prendecki Maria , Dhutia Amrita , Edwards Claire , Prout Virginia , Lightstone Liz , Parker Eleanor , Marchesin Federica , Griffith Megan , Charif Rawya , Pickard Graham , Cox Alison , McClure Myra , Tedder Richard , Randell Paul , Greathead Louise , Guckian Mary , McAdoo Stephen P. , Kelleher Peter , Willicombe Michelle
Published: January 2021

Background

Patients with end stage kidney disease (ESKD) receiving in-centre haemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. Following infection, ICHD patients frequently develop serological evidence of infection, even with asymptomatic disease. The aim of this study is to investigate the durability and functionality of immune responses to SARS-CoV-2 infection in ICHD patients.

Methods

Three hundred and fifty-six ICHD patients were longitudinally screened for SARS-CoV-2 antibodies and underwent routine PCR-testing for symptomatic and asymptomatic infection. Patients were screened for nucleocapsid protein (anti-NP) and receptor binding domain (anti-RBD) antibodies. Patients who became seronegative at 6 months were investigated for SARS-CoV-2 specific T-cell responses.

Results

One hundred and twenty-nine (36.2%) patients had detectable antibody to anti-NP at Time 0, of which 127 (98.4%) also had detectable anti-RBD. At 6 months, of 111 patients tested, 71(64.0%) and 97 (87.4%) remained anti-NP and anti-RBD seropositive respectively, p<0.001. For patients who retained antibody, both anti-NP and anti-RBD levels reduced significantly after 6 months. Ten patients who were anti-NP and anti-RBD seropositive at Time 0, had no detectable antibody at 6 months; of which 8 were found to have SARS-CoV-2 antigen specific T cell responses.

Independent of antibody status at 6 months, patients with baseline positive SARS-CoV-2 serology were significantly less likely to have PCR confirmed infection over the following 6 months.

Conclusions

ICHD patients mount durable immune responses 6 months post SARS-CoV-2 infection, with <3% of patients showing no evidence of humoral or cellular immunity. These immune responses are associated with a reduced risk of subsequent reinfection.

SIGNIFICANCE STATEMENT

Following infection with SARS-CoV-2, patients with end stage kidney disease (ESKD) frequently develop serological evidence of infection, even with asymptomatic disease. Patients with ESKD receiving in-centre haemodialysis (ICHD) have had high rates of SARS-CoV-2 infection. What is not known is how durable the serological responses in ESKD patients are or whether evidence of prior immune responses protect patients from reinfection. In this study of 356 ICHD patients, at 6 months following the detection of SARS-CoV-2 antibodies, fewer than 3% of patients lacked evidence of either humoral or cellular immunity. Furthermore, patients with serological evidence of infection had a significantly lower risk of being diagnosed with subsequent infection or ‘reinfection’, suggesting functional immune protection.
Strategic Treatment Optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C
Authors: Cooke Graham S. , Pett Sarah , McCabe Leanne , Jones Chris , Gilson Richard , Verma Sumita , Ryder Stephen D , Collier Jane D , Barclay Stephen T. , Ala Aftab , Bhagani Sanjay , Nelson Mark , Ch’Ng Chinlye , Stone Ben , Wiselka Martin , Forton Daniel , McPherson Stuart , Halford Rachel , Nguyen Dung , Smith David , Ansari Azim , Dennis Emily , Hudson Fleur , Barnes Eleanor J , Walker Ann Sarah
Published: January 2021

Background

The WHO has identified the need for a better understanding of which patients can be cured with ultrashort course hepatitis C (HCV) therapy

Methods

202 individuals with chronic HCV were randomised to fixed-duration shortened therapy (8 weeks) vs variable-duration ultrashort strategies (VUS1/2). Participants not cured following first-line treatment were retreated with 12 weeks’ sofosbuvir/ledipasvir/ribavirin. Primary outcome was sustained virological response 12 weeks (SVR12) after first-line treatment and retreatment. Participants were factorially randomised to receive ribavirin with first-line treatment.

Results

All evaluable participants achieved SVR12 overall (197/197, 100%[95%CI 98-100]) demonstrating non-inferiority between fixed-duration and variable-duration strategies (difference 0% [95%CI −3.8%,+3.7%], 4% pre-specified non-inferiority margin). First-line SVR12 was 91%[86%-97%] (92/101) for fixed-duration vs 48%[39%-57%] (47/98) for variable-duration, but was significantly higher for VUS2 (72% [56%-87%] (23/32)) than VUS1 (36% [25%-48%] (24/66)). Overall first-line SVR12 was 72%[65%-78%] (70/101) without ribavirin and 68%[61%-76%] (69/98) with ribavirin (p=0.48). At treatment failure, the emergence of viral resistance was lower with ribavirin (12% [2%-30%] (3/26)) than without (38% [21%-58%] (11/29), p=0.01).

Conclusions

Unsuccessful first-line short-course therapy did not compromise retreatment with sofosbuvir/ledipasvir/ribavirin (100% SVR12). SVR12 rates were significantly increased when ultrashort treatment varied between 4-7 weeks rather than 4-6 weeks. Ribavirin significantly reduced resistance emergence in those failing first-line therapy.

Registration

ISRCTN 37915093.

Funding

National Institutes of Health Research.
Two original observations concerning bacterial infections in COVID-19 patients hospitalized in intensive care units during the first wave of the epidemic in France
Authors: d’Humières Camille , Patrier Juliette , Lortat-Jacob Brice , Tran-dinh Alexy , Chemali Lotfi , Maataoui Naouale , Rondinaud Emilie , Ruppé Etienne , Burdet Charles , Ruckly Stéphane , Montravers Philippe , Timsit Jean-François , Armand-Lefevre Laurence
Published: January 2021

Among 197 COVID-19 patients hospitalized in ICU, 88 (44.7%) experienced at least one bacterial infection, with pneumonia (39.1%) and bloodstream infections (15,7%) being the most frequent. Unusual findings include frequent suspicion of bacterial translocations originating from the digestive tract as well as bacterial persistence in the lungs despite adequate therapy.
A Genetic Risk Score for Glioblastoma Multiforme Based on Copy Number Variations
Authors: Ko Charmeine , Brody James P.
Published: January 2021

Glioblastoma multiforme is the most common form of brain cancer. Several lines of evidence suggest that glioblastoma multiforme has a genetic basis. A genetic test that could identify people who are at high risk of developing glioblastoma multiforme could improve our understanding of this form of brain cancer.

Using the Cancer Genome Atlas (TCGA) dataset, we found common germ line DNA copy number variations in the TCGA population. We tested whether different sets of these germ line DNA copy number variations could effectively distinguish patients with glioblastoma multiforme from others in the TCGA dataset. We used a gradient boosting machine, a machine learning classification algorithm, to classify TCGA patients solely based on a set of germline DNA copy number variations.

We found that this machine learning algorithm could classify TCGA glioblastoma multiforme patients from the other TCGA patients with an area under the curve (AUC) of the receiver operating characteristic curve (AUC=0.875). Grouped into quintiles, the highest ranked quintile by the machine learning algorithm had an odds ratio of 3.78 (95% CI 3.25-4.40) higher than the average odds ratio and about 40 (95% CI 20-70) times higher than the lowest quintile.

The identification of an effective germ line genetic test to stratify risk of developing glioblastoma multiforme should lead to a better understanding of how this cancer forms. This result might ultimately lead to better treatments of glioblastoma multiforme.
Factors influencing nursing students’ intention to accept COVID-19 vaccination – A pooled analysis of seven countries
Authors: Patelarou Evridiki , Galanis Petros , Mechili Enkeleint A. , Argyriadi Agathi , Argyriadis Alexandros , Asimakopoulou Evanthia , Brokaj Stiliana , Bucaj Jorgjia , Carmona-Torres Juan Manuel , Cobo-Cuenca Ana Isabel , Doležel Jakub , Finotto Stefano , Jarošová Darja , Kalokairinou Athina , Mecugni Daniela , Pulomenaj Velide , Saliaj Aurela , Sopjani Idriz , Zahaj Majlinda , Patelarou Athina
Published: January 2021

Experiencing the second wave of COVID-19 pandemic, high vaccination coverage by a safe and effective vaccine globally would be a great achievement. Acceptance of vaccination by healthcare students is an important issue as they have a key role as future professionals in educating patients, informing and guiding them to the right clinical decision. The aim of this study was to explore the intention of nursing students to get vaccinated for SARS-CoV-2 infection and the factors acting either as motivators or barriers towards vaccination. A multicenter cross-sectional study was conducted in 7 countries (Greece, Albania, Cyprus, Spain, Italy, Czech Republic and Kosovo) through a web survey. In total 2249 undergraduate nursing students participated. Forty three point eight percent of students agreed to accept a safe and effective COVID-19 vaccine, while the acceptance was higher among Italian students. The factors for intention to get vaccinated were male gender (p=0.008), no working experience in healthcare facilities during the pandemic (p=0.001), vaccination for influenza in 2019 and 2020 (p<0.001), trust in doctors (p<0.001), governments and experts (p=0.012), high level of knowledge (p<0.001) and fear of COVID-19 (p<0.001). Understanding of factors that influence students’ decision to accept COVID-19 vaccination could increase the acceptance rate contributing to a management of the pandemic.

Highlights

Less than half of the sample intended to accept COVID-19 vaccination

Factors that influenced nursing students to get vaccinated against COVID-19 were male gender, no working experience in healthcare facilities during the pandemic, vaccination for influenza in 2019 and 2020, trust in doctors, governments and experts, high level of knowledge and fear of COVID-19.
Pooled Sample Testing for SARS-CoV-2 Using Rapid RT-PCR COVID-19 Tests
Authors: Hyde Bethany , Verma Prat , Berke Ethan M.
Published: January 2021

We tested an operationally efficient way to pool samples on a rapid, point-of-care PCR device and examined the limit of detection of SARS-CoV-2 for various pool sizes. Pooled testing maintained testing performance similar to individual sample PCR testing, offering the potential for scalable rapid testing at lower cost with less supplies.
Linked supergenes underlie split sex ratio and social organization in an ant
Authors: Lagunas-Robles German , Purcell Jessica , Brelsford Alan
Published: January 2021

Sexually reproducing organisms usually invest equally in male and female offspring. Deviations from this pattern have led researchers to new discoveries in the study of parent-offspring conflict, genomic conflict, and cooperation. Some social insect species exhibit the unusual population-level pattern of split sex ratio, wherein some colonies specialize in the production of future queens and others specialize in the production of males. Theoretical work focused on the relatedness asymmetries emerging from haplodiploid inheritance, whereby queens are equally related to daughters and sons, but their daughter workers are more closely related to sisters than to brothers, led to a series of testable predictions and spawned many empirical studies of this phenomenon. However, not all empirical systems follow predicted patterns, so questions remain about how split sex ratio emerges. Here, we sequence the genomes of 138Formica glacialisworkers from 34 male-producing and 34 gyne-producing colonies to determine whether split sex ratio is under genetic control. We identify a supergene spanning 5.5 Mbp that is closely associated with sex allocation in this system. Strikingly, this supergene is adjacent to another supergene spanning 5 Mbp that is associated with variation in colony queen number. We identify a similar pattern in a second related species,Formica podzolica.The discovery that split sex ratio is determined, at least in part, by a supergene in two species opens a new line of research on the evolutionary drivers of split sex ratio.

Significance Statement

Some social insects exhibit split sex ratio, wherein some colonies produce future queens and others produce males. This phenomenon spawned many influential theoretical studies and empirical tests, both of which have advanced our understanding of parent-offspring conflicts and cooperation. However, some empirical systems did not follow theoretical predictions, indicating that researchers lack a comprehensive understanding of the drivers of split sex ratio. Here, we show that split sex ratio is associated with a large genomic region in two ant species. The discovery of a genetic basis for sex allocation in ants provides a novel explanation for this phenomenon, particularly in systems where empirical observations deviate from theoretical predictions.
Sequence-based prediction of protein-protein interactions: a structure-aware interpretable deep learning model
Authors: Sledzieski Samuel , Singh Rohit , Cowen Lenore , Berger Bonnie
Published: January 2021

Protein-protein interaction (PPI) networks have proven to be a valuable tool in systems biology to facilitate the discovery and understanding of protein function. Unfortunately, experimental PPI data remains sparse in most model organisms and even more so in other species. Existing methods for computational prediction of PPIs seek to address this limitation, and while they perform well when sufficient within-species training data is available, they generalize poorly to new species or often require specific types and sizes of training data that may not be available in the species of interest. We therefore present D-SCRIPT, a deep learning method for predicting a physical interaction between two proteins given just their sequences. Compared to existing methods, D-SCRIPT generalizes better to new species and is robust to limitations in training data size. Our approach encodes the intuition that for two proteins to physically interact, a subset of amino acids from each protein should be in contact with the other. The intermediate stages of D-SCRIPT directly implement this intuition; the penultimate stage in D-SCRIPT is a rough estimate of the inter-protein contact map of the protein dimer. This structurally-motivated design enables interpretability of our model and, since structure is more conserved evolutionarily than sequence, improves generalizability across species. We show that a D-SCRIPT model trained on 38,345 human PPIs enables significantly improved functional characterization of fly proteins compared to the state-of-the-art approach. Evaluating the same D-SCRIPT model on protein complexes with known 3-D structure, we find that the inter-protein contact map output by D-SCRIPT has significant overlap with the ground truth. Our work suggests that recent advances in deep learning language modeling of protein structure can be leveraged for protein interaction prediction from sequence. D-SCRIPT is available athttp://dscript.csail.mit.edu.
Genetic overlap between Alzheimer’s disease and depression mapped onto the brain
Authors: Sánchez Jennifer Monereo , Schram Miranda T. , Frei Oleksandr , O’Connell Kevin , Shadrin Alexey A. , Smeland Olav B. , Westlye Lars T. , Andreassen Ole A. , Kaufmann Tobias , Linden David E.J. , van der Meer Dennis
Published: January 2021

Background

Alzheimer’s disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterizing their genetic overlap may provide etiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects.

Methods

We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n=79,145) and depression (n=450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (mean age 57.21 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data.

Results

MiXer estimated 98 causal genetic variants overlapping between the two disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B=-0.002, p=9.1×10−4) and depression (B=0.007, p=3.2×10−9) in the UK Biobank. This SNP was also associated with several regions of the corpus callosum volume anterior (B>0.024, p<8.6×10−4), third ventricle volume ventricle (B=-0.025, p=5.0×10−6), and inferior temporal gyrus surface area (B=0.017, p=5.3×10−4).

Discussion

Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.
Opportunistic Assessment of Ischemic Heart Disease Risk Using Abdominopelvic Computed Tomography and Medical Record Data: a Multimodal Explainable Artificial Intelligence Approach
Authors: Zambrano Chaves Juan M , Chaudhari Akshay S , Wentland Andrew L , Desai Arjun D , Banerjee Imon , Boutin Robert D , Maron David J , Rodriguez Fatima , Sandhu Alexander T , Jeffrey R Brooke , Rubin Daniel , Patel Bhavik
Published: January 2021

Current risk scores for predicting ischemic heart disease (IHD) risk—the leading cause of global mortality—have limited efficacy. While body composition (BC) imaging biomarkers derived from abdominopelvic computed tomography (CT) correlate with IHD risk, they are impractical to measure manually. Here, in a retrospective cohort of 8,197 contrast-enhanced abdominopelvic CT examinations undergoing up to 5 years of follow-up, we developed improved multimodal opportunistic risk assessment models for IHD by automatically extracting BC features from abdominal CT images and integrating these with features from each patient’s electronic medical record (EMR). Our predictive methods match and, in some cases, outperform clinical risk scores currently used in IHD risk assessment. We provide clinical interpretability of our model using a new method of determining tissue-level contributions from CT along with weightings of EMR features contributing to IHD risk. We conclude that such a multimodal approach, which automatically integrates BC biomarkers and EMR data can enhance IHD risk assessment and aid primary prevention efforts for IHD.
Attention Deficit and Hyperactivity Disorder and Enuresis co-occurrence in the pediatric population: a systematic review and meta-analysis
Authors: de Sena Oliveira Ana Cecília , da Silva Athanasio Bruno , de Carvalho Mrad Flávia Cristina , de Almeida Vasconcelos Monica Maria , Rodrigues Maicon Albuquerque , de Miranda Débora Marques , Simões e Silva Ana Cristina
Published: January 2021

Background

Attention Deficit and Hyperactivity/Impulsivity Disorder (ADHD) and Enuresis are common behavioral disorders in childhood, impacting in adolescence and adult life.

Objective

We systematically search the literature to verify the relationship between ADHD and enuresis and how these conditions can modify each other during development.

Method

Using PRISMA guidelines, we tried to answer the following question: How frequent is ADHD and Enuresis comorbidity?

Results

Twenty-five studies were fully read and show similar rates of ADHD in the Enuretic group than the frequency of Enuresis in the ADHD group. There is a two-times higher risk to have both conditions simultaneously.

Conclusion

Enuresis and ADHD seems to happen as a continuous of the same spectrum. Further studies are necessary to evaluate if gender, age, course and presence of comorbidities are similar in patients with both conditions in comparison to those with only one of these conditions.
TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis
Authors: Collins Jeffrey M. , Jones Dean P. , Sharma Ashish , Khadka Manoj , Liu Ken , Kempker Russell R. , Prideaux Brendan , Maner-Smith Kristal , Tukvadze Nestani , Shah N. Sarita , Brust James C.M. , Sekaly Rafick P. , Gandhi Neel R. , Blumberg Henry M. , Ortlund Eric , Ziegler Thomas R.
Published: January 2021

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the pro-inflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates are important drivers of IL-1β-mediated proinflammatory eicosanoid signaling in humans with pulmonary TB disease. Host-directed therapies that mitigate such metabolic reprograming have potential to limit pulmonary inflammation and tissue damage.

Graphical Abstract

One Sentence Summary

Remodeling of the tricarboxylic acid cycle, characterized by increases in the proinflammatory metabolite succinate and decreased itaconate, mediates proinflammatory eicosanoids signaling in humans with pulmonary tuberculosis through induction of IL-1β.
Assessing the impact of static and fluctuating ocean acidification on the behavior ofAmphiprion percula
Authors: Vaughan Matthew A. , Dixson Danielle L.
Published: January 2021

Coral reef organisms are exposed to both an increasing magnitude ofpCO2, and natural fluctuations on a diel scale. For coral reef fishes, one of the most profound effects of ocean acidification is the impact on ecologically important behaviors. Previous behavioral research has primarily been conducted under staticpCO2conditions and have recently come under criticism. Recent studies have provided evidence that the negative impacts on behavior may be reduced under more environmentally realistic, fluctuating conditions. We investigated the impact of both present and future day, static (500 and 1000 μatm) and diel fluctuating (500 ± 200 and 1000 ± 200 μatm)pCO2on the lateralization and chemosensory behavior of juvenile anemonefish,Amphiprion percula. Our static experimental comparisons support previous findings that under elevatedpCO2, fish become un-lateralized and lose the ability to discriminate olfactory cues. Diel-fluctuatingpCO2may aid in mitigating the severity of some behavioral abnormalities such as the chemosensory response, where a preference for predator cues was significantly reduced under a future diel-fluctuatingpCO2regime. This research aids in ground truthing earlier findings and contributes to our growing knowledge of the role of fluctuating conditions.
Cellular crowd control: overriding endogenous cell coordination makes cell migration more susceptible to external programming
Authors: Shim Gawoon , Devenport Danelle , Cohen Daniel J.
Published: January 2021

As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, pre-existing collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue—electrical stimulation and electrotaxis—to primary mouse skin monolayers where we can tune cell-cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell-cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing pre-existing coordination in the tissue by specifically inhibiting E-cadherin-dependent cell-cell adhesion, either by disrupting the formation of cell-cell junctions with E-cadherin specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control to demonstrate accelerated wound closurein vitro. These results are in keeping with those from diverse, non-cellular systems, and confirm that endogenous collectivity should be considered as a key, quantitative design variable when optimizing external control of collective migration.
Molecular Dynamics Simulations of Phytopthora sojae Avirulence Factor 5, PsAvh5, Define Membrane Binding, Inositolphosphate-3’-phosphate Interactions and Protein Mechanics
Authors: Watkins Stephan L.
Published: January 2021

Phytopthora Avirulence proteins are a primary target for development of rational chemical and biological control of some of the most devastating plant pathogens. Despite the sequencing of entire genomes, and characterization of many of these proteins at the chemical level, many questions remain regarding actual chemical and biological interactions involved. In addition, disputed roles of ligands, such as Inositolphosphate-3’-phosphate and amino acids of important function remain unclear. To address some of these issues, we developed molecular models from structural elements and published data for Phytopthora sojae avirulence protein 5. Molecular dynamics simulations are used to study protein function, interactions involved primarily with lipids and membranes, and inositol derivatives. Our findings indicate that the protein is stable as a monomer, and in a dimeric form. Also, that these proteins interact with Inositolphosphate-3’phosphate as a necessary membrane element, in binding. We identified several amino acids of importance, additional to defining the mechanical features of the protein within the binding process to different membranes. A high affinity, comparable to other membrane surface binding molecules of −219.54 Kcal for the dimer, and −176.61 for the monomer were determined. With either form, we found the inositolphosphate-3’-phosphate to be essential in the membrane binding process. Our findings answer some of the debated questions while creating a point to further test avirulence proteins in general for functional aspects. Additionally, the structures and data can be utilized to provide a better starting point for rational design approaches to control this pathogen.
From zero to infinity: minimum to maximum diversity of the planet by spatio-parametric Rao’s quadratic entropy
Authors: Rocchini Duccio , Marcantonio Matteo , Da Re Daniele , Bacaro Giovanni , Feoli Enrico , Foody Giles M. , Furrer Reinhard , Harrigan Ryan J. , Kleijn David , Iannacito Martina , Lenoir Jonathan , Lin Meixi , Malavasi Marco , Marchetto Elisa , Meyer Rachel S. , Moudrý Vítězslav , Payne Davnah , Schneider Fabian D. , Šímová Petra , Thornhill Andrew H. , Thouverai Elisa , Vicario Saverio , Wayne Robert K. , Ricotta Carlo
Published: January 2021

Aim

The majority of work done to gather information on Earth diversity has been carried out by in-situ data, with known issues related to epistemology (e.g., species determination and taxonomy), spatial uncertainty, logistics (time and costs), among others. An alternative way to gather information about spatial ecosystem variability is the use of satellite remote sensing. It works as a powerful tool for attaining rapid and standardized information. Several metrics used to calculate remotely sensed diversity of ecosystems are based on Shannon’s Information Theory, namely on the differences in relative abundance of pixel reflectances in a certain area. Additional metrics like the Rao’s quadratic entropy allow the use of spectral distance beside abundance, but they are point descriptors of diversity, namely they can account only for a part of the whole diversity continuum. The aim of this paper is thus to generalize the Rao’s quadratic entropy by proposing its parameterization for the first time.

Innovation

The parametric Rao’s quadratic entropy, coded in R, i) allows to represent the whole continuum of potential diversity indices in one formula, and ii) starting from the Rao’s quadratic entropy, allows to explicitly make use of distances among pixel reflectance values, together with relative abundances.

Main conclusions

The proposed unifying measure is an integration between abundance- and distance-based algorithms to map the continuum of diversity given a satellite image at any spatial scale.
Towards a unifying framework for diversity and dissimilarity coefficients
Authors: Ricotta Carlo , Szeidl László , Pavoine Sandrine
Published: January 2021

Diversity and dissimilarity within and between species assemblages have now been studied for more than half a century by community ecologists in relation to their connections with ecosystem functioning. However, a generalized framework that puts diversity and dissimilarity coefficients under the same formal umbrella is still lacking. In this paper, we show that generalized means represent an effective tool to develop a unifying formulation for the construction of a large array of parametric diversity and dissimilarity measures. These measures include some of the classical diversity coefficients, such as the Shannon entropy, the Gini-Simpson index or the parametric diversity of Patil and Taillie, together with a large number of dissimilarity coefficients of the Bray-Curtis family and can be further extended to the measurement of functional and phylogenetic differences within and between plots.
Mycorrhizal dominance reduces forest-tree species diversity
Authors: Carteron Alexis , Vellend Mark , Laliberté Etienne
Published: January 2021

Ectomycorrhizas and arbuscular mycorrhizas, the two most widespread plant-fungal symbioses, are thought to differentially influence tree species diversity, with positive plant-soil feedbacks favoring locally abundant ectomycorrhizal tree species and negative feedbacks promoting species coexistence and diversity in arbuscular mycorrhizal forests. While seedling recruitment studies and cross-biome patterns of plant diversity and mycorrhizal dominance support this hypothesis, it remains to be tested at the forest stand level over continental scales. Here, we analyze ∼85,000 forest plots across the United States to show that both ectomycorrhizal-dominated and arbuscular mycorrhizal-dominated forests show relatively low tree diversity, while forests with a mixture of mycorrhizal strategies support a higher number of tree species. Our findings suggest that mycorrhizal dominance, rather than mycorrhizal type, shapes tree diversity in forests.
LSTrAP-Kingdom: an automated pipeline to generate annotated gene expression atlases for kingdoms of life
Authors: Goh William , Mutwil Marek
Published: January 2021

There are now more than two million RNA sequencing experiments for plants, animals, bacteria and fungi publicly available, allowing us to study gene expression within and across species and kingdoms. However, the tools allowing the download, quality control and annotation of this data for more than one species at a time are currently missing. To remedy this, we present the Large-Scale Transcriptomic Analysis Pipeline in Kingdom of Life (LSTrAP-Kingdom) pipeline, which we used to process 134,521 RNA-seq samples, achieving ~12,000 processed samples per day. Our pipeline generated quality-controlled, annotated gene expression matrices that rival the manually curated gene expression data in identifying functionally-related genes.

Availability and implementation

LSTrAP-Kingdom is available from:https://github.com/wirriamm/plants-pipelineand is fully implemented in Python and Bash.
Adaptive immunity to human coronaviruses is widespread but low in magnitude
Authors: Tan Hyon-Xhi , Lee Wen Shi , Wragg Kathleen M , Nelson Christina , Esterbauer Robyn , Kelly Hannah G , Amarasena Thakshila , Jones Robert , Starkey Graham , Wang Bao Zhong , Yoshino Osamu , Tiang Thomas , Grayson M Lindsay , Opdam Helen , D’Costa Rohit , Vago Angela ,   The Austin Liver Transplant Perfusionist Group, Mackay Laura K , Gordon Claire L , Wheatley Adam K , Kent Stephen J , Juno Jennifer A
Published: January 2021

Endemic human coronaviruses (hCoV) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV-specific T cell memory in adults. We quantified CD4 T cell and antibody responses to hCoV spike antigens in 42 SARS-CoV-2 uninfected individuals. T cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS-CoV-2 cross-reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV-specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung draining lymph nodes. Overall, hCoV-specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus-specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS-CoV-2.
Novel COVID-19 phenotype definitions reveal phenotypically distinct patterns of genetic association and protective effects
Authors: Roberts Genevieve H.L. , Partha Raghavendran , Rhead Brooke , Knight Spencer C. , Park Danny S. , Coignet Marie V. , Zhang Miao , Berkowitz Nathan , Turrisini David A. , Gaddis Michael , McCurdy Shannon R. , Pavlovic Milos , Ruiz Luong ,   AncestryDNA Science Team, Baltzell Asher K. Haug , Guturu Harendra , Girshick Ahna R. , Rand Kristin A. , Hong Eurie L. , Ball Catherine A.
Published: January 2021

INTRODUCTION PARAGRAPH

Multiple large COVID-19 genome-wide association studies (GWAS) have identified reproducible genetic associations indicating that some infection susceptibility and severity risk is heritable.1-5 Most of these studies ascertained COVID-19 cases in medical clinics and hospitals, which can lead to an overrepresentation of cases with severe outcomes, such as hospitalization, intensive care unit admission, or ventilation. Here, we demonstrate the utility and validity of deep phenotyping with self-reported outcomes in a population with a large proportion of mild and subclinical cases. Using these data, we defined eight different phenotypes related to COVID-19 outcomes: four that align with previously studied COVID-19 definitions and four novel definitions that focus on susceptibility given exposure, mild clinical manifestations, and an aggregate score of symptom severity. We assessed replication of 13 previously identified COVID-19 genetic associations with all eight phenotypes and found distinct patterns of association, most notably related to the chr3/SLC6A20/LZTFL1 and chr9/ABO regions. We then performed a discovery GWAS, which suggested some novel phenotypes may better capture protective associations and also identified a novel association in chr11/GALNT18 that reproduced in two fully independent populations.
Chest wall abnormalities in Swiss childhood cancer survivors
Authors: Kasteler Rahel , Lichtensteiger Christa , Schindera Christina , Ansari Marc , Kuehni Claudia E. ,   for the Swiss Pediatric Oncology Group (SPOG)
Published: January 2021

Background

Chest wall abnormalities are a poorly studied complication after treatment for childhood cancer. Chest wall abnormalities are not well described in the literature, and little is known on the impact on daily life of survivors.

Methods

We investigated chest wall abnormalities in the nationwide, population-based cohort study (Swiss Childhood Cancer Survivor Study) with a questionnaire survey to describe prevalence and risk factors. We then interviewed a nested sample of survivors to understand types of chest wall abnormalities and their impact on daily life of survivors.

Results

48 of 2,382 (95%CI 2%–3%) survivors reported a chest wall abnormality. Risk factors were older age at cancer diagnosis (16–20 years; OR 2.5, 95%CI 1.0– 6.1), lymphoma (OR 3.8, 95%CI 1.2–11.4), and central nervous system tumors (OR 9.5, 95%CI 3.0–30.1) as underlying disease, and treatment with thoracic radiotherapy (OR 2.0, 95%CI 1.0–4.2), surgery to the chest (OR 4.5, 95%CI 1.8–11.5), or chemotherapy (OR 2.9, 95%CI 1.0–8.1) .The nature of the chest wall abnormalities varied and included thoracic wall deformities (30%), deformations of the spine (5%) or both (55%), and scars (10%). Chest wall abnormalities affected the daily life in two thirds (13/20) of those who reported these problems, and 15 (75%) had required chest wall abnormalities-related medical attention.

Conclusion

It is important that during follow-up care physicians pay attention to chest wall abnormalities, which are rare late-effect of cancer treatment, but can considerably affect well-being of cancer survivors.
Nuclear cholesterol is required for transcriptional repression by BASP1
Authors: Loats Amy E. , Carrera Samantha , Fleming Anna F. , Roberts Abigail R.E. , Sherrard Alice , Toska Eneda , Medler Kathryn F. , Roberts Stefan G. E.
Published: January 2021

Lipids are present within the cell nucleus where they engage with factors involved in gene regulation. Cholesterol associates with chromatin in vivo and stimulates nucleosome packing in-vitro, but its effects on specific transcriptional responses are not clear. Here we show that the lipidated WT1 transcriptional corepressor, BASP1, interacts with cholesterol in the cell nucleus through a conserved cholesterol interaction motif. We demonstrate that BASP1 directly recruits cholesterol to the promoter region of WT1 target genes. Mutation of BASP1 to ablate its interaction with cholesterol or the treatment of cells with drugs that block cholesterol biosynthesis inhibit the transcriptional repressor function of BASP1. We find that the BASP1-cholesterol interaction is required for BASP1-dependent chromatin remodelling and the direction of transcription programs that control cell differentiation. Our study uncovers a mechanism for gene-specific targeting of cholesterol where it is required to mediate transcriptional repression.

Significance

Cholesterol is present within the cell nucleus where it associates with chromatin but to date, a direct role for cholesterol in nuclear processes has not been identified. We demonstrate that the transcriptional repressor BASP1 directly interacts with cholesterol within the cell nucleus through a consensus cholesterol interaction motif. BASP1 recruits cholesterol to the promoter region of target genes where it is required to mediate chromatin remodelling and transcriptional repression. Our work demonstrates that nuclear cholesterol plays a direct role in transcriptional regulation.
Spike-in normalization for single-cell RNA-seq reveals dynamic global transcriptional activity mediating anti-cancer drug response
Authors: Wang Xin , Frederick Jane , Wang Hongbin , Hui Sheng , Backman Vadim , Ji Zhe
Published: January 2021

The transcriptional plasticity of cancer cells promotes intercellular heterogeneity in response to anti-cancer drugs and facilitates the generation of subpopulation surviving cells. Characterizing single-cell transcriptional heterogeneity after drug treatments can provide mechanistic insights into drug efficacy. Here we used single-cell RNA-seq to examine transcriptomic profiles of cancer cells treated with paclitaxel, celecoxib, and the combination of the two drugs. By normalizing the expression of endogenous genes to spike-in molecules, we found that celluar mRNA abundance shows dynamic regulation after drug treatment. Using a random forest model, we identified gene signatures classifying single cells into three states: transcriptional repression, amplification, and control-like. Treatment with paclitaxel or celecoxib alone generally repressed gene transcription across single cells. Interestingly, the drug combination resulted in transcriptional amplification and hyperactivation of mitochondrial oxidative phosphorylation pathway linking to enhanced cell killing efficiency. Finally, we identified a regulatory module enriched with metabolism and inflammation-related genes activated in a subpopulation of paclitaxel-treated cells, the expression of which predicted paclitaxel efficacy across cancer cell lines andin vivopatient samples. Our study highlights the dynamic global transcriptional activity driving single-cell heterogeneity during drug response and emphasizes the importance of adding spike-in molecules to study gene expression regulation using single-cell RNA-seq.
Heterogeneity in PHGDH protein expression potentiates cancer cell dissemination and metastasis
Authors: Rossi Matteo , Doglioni Ginevra , Bornes Laura , Broekaert Dorien , Planque Mélanie , Fernández-García Juan , Rinaldi Gianmarco , Van Elsen Joke , Nittner David , Jauset Cristina , Rizzollo Francesca , Domingo Carla Riera , Orth Martin F , Dobrolecki Lacey E , Van Brussel Thomas , Teoh Shao Thing , Aurora Arin B , Eelen Guy , Karras Panagiotis , Sotlar Karl , Bartsch Harald , Marine Jean-Christophe , Carmeliet Peter , Morrison Sean J , Lewis Michael T , Hannon Gregory J , Mazzone Massimiliano , Lambrechts Diether , van Rheenen Jacco , Grünewald Thomas G P , Lunt Sophia Y , Fendt Sarah-Maria
Published: January 2021

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational intra-tumor heterogeneity contributes to this dynamic process. Beyond this, metabolic intra-tumor heterogeneity has also been observed, yet its role for cancer progression remains largely elusive. Here, we discovered that intra-tumor heterogeneity in phosphoglycerate dehydrogenase (PHGDH) protein expression drives breast cancer cell dissemination and metastasis formation. Specifically, we observed intra-tumor heterogeneous PHGDH expression in primary breast tumors, with low PHGDH expression being indicative of metastasis in patients. In mice, Phgdh protein, but not mRNA, expression is low in circulating tumor cells and early metastatic lesions, leading to increased dissemination and metastasis formation. Mechanistically, low PHGDH protein expression induces an imbalance in glycolysis that can activate sialic acid synthesis. Consequently, cancer cells undergo a partial EMT and show increased p38 as well as SRC phosphorylation, which activate cellular programs of dissemination. In turn, inhibition of sialic acid synthesis through knock-out of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) counteracts the increased cancer cell dissemination and metastasis induced by low PHGDH expression. In conclusion, we find that heterogeneity in PHGDH protein expression promotes cancer cell dissemination and metastasis formation.