bluuebunny/crossref_metadata_2025 huggingface dataset:
Interracial contact differentially shapes brain networks involved in social and non-social judgments from faces: a combination of univariate and multivariate approaches
Authors: Handley Grace , Kubota Jennifer , Cloutier Jasmin
Published: July 2021

The present work explores the relationship between interracial contact and the neural substrates of explicit social and non-social judgments about both racial ingroup and outgroup targets. Convergent evidence from univariate and multivariate partial least squares (PLS) analyses reveals that contact shapes the recruitment of brain regions involved in social cognition similarly for both ingroup and outgroup targets. Results support the hypothesis that increased contact is associated with generalized changes in social cognition toward both ingroup and outgroup faces. Specifically, regardless of target race, low- and average-contact perceivers showed the typically observed increased recruitment of temporoparietal junction and dorsomedial prefrontal cortex during social compared to perceptual judgments. However, high-contact perceivers did not show selective recruitment of these brain regions for social judgments. Complimenting univariate results, multivariate PLS analyses reveal that greater perceiver contact leads to reduced co-activation in networks of brain regions associated with face processing (e.g. fusiform gyrus) and salience detection (e.g. anterior cingulate cortex and insula). Across univariate and multivariate analyses, we found no evidence that contact differentially impacted cross-race face perception. Instead, when performing either a social or a novel perceptual task, interracial contact appears to broadly shape how perceivers engage with all faces.
Homoplasy and morphological stasis revealed through multilocus phylogeny of new myrmecophilous species in Armadillidiidae (Isopoda: Oniscidea)
Authors: Recuero Ernesto , Rodríguez-Flores Paula C , García-París Mario
Published: July 2021

The terrestrial isopod family Armadillidiidae presents higher diversity in karstic areas, with fewer species present in areas with reduced suitable subterranean habitats, such as siliceous sandy soils. Myrmecophily, although not widespread in the family Armadillidiidae, can help these animals to colonize sandy substrates, as is observed in several populations of myrmecophilous Armadillidiidae species in central and southern Spain. Morphological examination and multilocus phylogenetic analyses, including mitochondrial DNA (Cox1) and nuclear DNA (18S, 28S and H3) markers, indicate that these myrmecophilous populations represent four new taxa: Iberiarmadillidium pinicola gen. & sp. nov., Iberiarmadillidium psammophilum sp. nov., Iberiarmadillidium sakura sp. nov. and Cristarmadillidium myrmecophilum sp. nov. Some of the main diagnostic characters used in the taxonomy of Armadillidiidae are not clearly apomorphic. Among head morphologies, Eluma type seems to be the ancestral state, being typical of several unrelated lineages; duplocarinate and Armadillidium types are derived states observed in unrelated lineages. The presence of a schisma is a convergent character state, because it has been identified in several taxa nested in unrelated clades. The newly described taxa present patterns of morphological stasis and homoplasy, likely to be associated with their shared myrmecophilous habits. The generic taxonomy of the family needs a deep revision including phylogenetic approaches and thorough taxon sampling.
Quantifying within-school SARS-CoV-2 transmission and the impact of lateral flow testing in secondary schools in England
Authors: Leng Trystan , Hill Edward M. , Holmes Alex , Southall Emma , Thompson Robin N. , Tildesley Michael J. , Keeling Matt J. , Dyson Louise
Published: July 2021

Background

To control within-school SARS-CoV-2 transmission in England, secondary school pupils have been encouraged to participate in twice weekly mass testing via lateral flow device tests (LFTs) from 8th March 2021, to complement an isolation of close contacts policy in place since 31st August 2020. Strategies involving the isolation of close contacts can lead to high levels of absences, negatively impacting pupils.

Methods

We fit a stochastic individual-based model of secondary schools to both community swab testing data and secondary school absences data. By simulating epidemics in secondary schools from 31st August 2020 until 21st May 2021, we quantify within-school transmission of SARS-CoV-2 in secondary schools in England, the impact of twice weekly mass testing on within-school transmission, and the potential impact of alternative strategies to the isolation of close contacts in reducing pupil absences.

Findings

The within-school reproduction number, Rschool, has remained below 1 from 31st August 2020 until 21st May 2021. Twice weekly mass testing using LFTs have helped to control within-school transmission in secondary schools in England. A strategy of serial contact testing alongside mass testing substantially reduces absences compared to strategies involving isolating close contacts, with only a marginal increase in within-school transmission.

Interpretation

Secondary school control strategies involving mass testing have the potential to control within-school transmission while substantially reducing absences compared to an isolation of close contacts policy.
SARS-CoV-2 Antibody Lateral Flow Assay for antibody prevalence studies following vaccine roll out: a Diagnostic Accuracy Study
Authors: Cann Alexandra , Clarke Candice , Brown Jonathan , Thomson Tina , Prendecki Maria , Moshe Maya , Badhan Anjna , Elliott Paul , Darzi Ara , Riley Steven , Ashby Deborah , Willicombe Michelle , Kelleher Peter , Randell Paul , Ward Helen , Barclay Wendy S , Cooke Graham
Published: July 2021

Background

Lateral flow immunoassays (LFIAs) have the potential to deliver affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of SARS-CoV-2 vaccine.

Methods

This is a prospective diagnostic accuracy study.

Setting

Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Laboratory analyses were performed across Imperial College London sites and university facilities.

Participants

Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following SARS-CoV-2 vaccine booster, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination, and 21 day follow up. A total of 186 paired samples were collected.

Interventions

During the participants visit, capillary blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG were detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA.

Main outcome measures

The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay.

Results

Using the threshold value for positivity on serological testing of ≥7.10 BAU/ml, the overall performance of the test produces an estimate of sensitivity of 91.94% (95% CI 85.67% to 96.06%) and specificity of 93.55% (95% CI 84.30% to 98.21%) using the Abbott assay as reference standard.

Conclusions

Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveys, but does not meet criteria for individual testing.
SARS-CoV-2 variants of concern, Gamma (P.1) and Delta (B.1.617), sensitive detection and quantification in wastewater employing direct RT-qPCR
Authors: Yaniv Karin , Ozer Eden , Kushmaro Ariel
Published: July 2021

SARS-CoV-2 variants of concern present a worldwide threat. Demonstrating higher infection rate and durability to antibodies when compared to the original SARS-CoV-2 virus, the variants of concern are responsible for continuing global outbreaks. Prompt identification of the infecting SARS-CoV-2 variant is essential for pandemic assessment and containment. However, variant identification is mainly being performed using expensive, time-consuming next generation sequencing. Rapid identification methodology for variants of concern is of great need and various variant-specific assays are being developed. Amongst the variants of concern that have recently appeared, the Gamma variant (P.1, Brazilian) and Delta variant (B.1.617, Indian) are the most prominent. Here we describe the development of a sensitive RT-qPCR assay for the quick direct detection of the Gamma and Delta variants as part of a methodical characterization and detection in municipal wastewater.
London Ramadan Fasting Study (LORANS): Rationale, design, and methods
Authors: Al-Jafar Rami , Elliott Paul , Tsilidis Konstantinos K. , Dehghan Abbas
Published: July 2021

Background

Hundreds of millions of Muslims fast during the month of Ramadan. The London Ramadan Fasting Study (LORANS) aims to assess the lifestyle changes during this month and investigate the effect of Ramadan fasting on health.

Methods

LORANS is an observational study of participants that follow religious fasting in Ramadan. We advertised, recruited, and visited participants in five mosques in London, United Kingdom. In total, 146 individuals were recruited before Ramadan in May 2019 of which 85 participated in the follow up visit after Ramadan. The study protocol was approved by the ethics committee affiliated to Imperial College London. A written informed consent was signed by all the participants. Every participant completed a questionnaire, a physical examination, and gave blood samples at each visit. Moreover, they completed a 3-day food diary before Ramadan and once again during Ramadan to record dietary changes during the month of fasting.

Results

The mean age of participants was 45.6± 15.9 years. 47.1% of the participants were females, 25.5% were obese, 4.7% were smokers, 14% were diabetic, 24% were hypertensive, and 5.2% had cardiovascular diseases. Data collection covered demographics, lifestyle, food intake, blood pressure, anthropometric measurements, body composition, and metabolic biomarker profiling.

Conclusion

By engaging with mosques, proper introduction of the study aims and convenient recruitment in the mosque, we were able to recruit a balanced population regarding age and sex and collected valuable data on Ramadan fasting using high-quality techniques.
Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults
Authors: Sumazin Pavel , Peters Tricia L. , Sarabia Stephen F. , Kim Hyunjae R. , Urbicain Martin , Hollingsworth Emporia Faith , Alvarez Karla R. , Perez Cintia R. , Pozza Alice , Panah Mohammad Javad Najaf , Elswood Jessica L. , Scorsone Kathy , Katzenstein Howard , O’Neal Allison , Meyers Rebecka , Tiao Greg , Geller Jim , Ranganathan Sarangarajan , Rangaswami Arun A. , Woodfield Sarah E. , Goss John A. , Vasudevan Sanjeev A. , Heczey Andras , Roy Angshumoy , Fisher Kevin E. , Alaggio Rita , Patel Kalyani R. , Finegold Milton J. , López-Terrada Dolores H.
Published: July 2021

Malignant hepatocellular cancers are the most common primary liver malignancies in children, and hepatoblastomas (HBs) account for more than two-thirds of these cases. While most HBs respond to chemotherapy and have favorable outcomes, the 3-year overall survival rate for high-risk HBs is below 50% and guidelines for their classification and treatment are still evolving. HB risk-stratification efforts using clinical, histological, and molecular parameters have been reported to help identify patients that require more or less aggressive therapies in retrospective studies, and are being validated in clinical trials. However, risk assessment is particularly challenging for cancers with certain histologies, including tumors in the recently proposed provisionalhepatocellular neoplasm not otherwise specified(HCN NOS) category. HCN NOSs exhibit either intermediate or combined HB and hepatocellular carcinoma (HCC) histological features, and while neoplasms with such features were observed over a decade ago, only a handful have been characterized and little is known about their biology and clinical features. Here, we molecularly characterized a series of clinically annotated HCN NOSs that demonstrated either intermediate HB/HCC histology or distinct coexisting areas with HB and HCC histological features. In addition, molecular profiling of HBs demonstrating focal pleomorphism or anaplasia (HB FPA) revealed underlying biological features previously observed in HCCs. Our study suggested that HCN NOSs and HB FPAs are aggressive tumors, irrespective of patient age or resectability. Consequently, we designated them collectively asHBs with carcinoma features(HBCs) and outlined histological and molecular characteristics for their diagnosis and treatment. In our single-institution study, transplanted HBC patients were significantly and more than twice as likely to have good outcomes, highlighting the importance of molecular testing and aggressive early intervention.
Unravelling the puzzle of anthranoids metabolism in living plant cells using spectral imaging coupled to mass spectrometry
Authors: Chevalier Quentin , Gallé Jean-Baptiste , Wasser Nicolas , Mazan Valérie , Villette Claire , Mutterer Jérôme , Elustondo Maria M. , Girard Nicolas , Elhabiri Mourad , Schaller Hubert , Hemmerlin Andréa , Vonthron-Sénécheau Catherine
Published: July 2021

Vismione H (VH) is a fluorescent prenylated anthranoid produced by plants from the Hypericaceae family, with antiprotozoal activities against malaria and leishmaniosis. Little is known about its biosynthesis and metabolism in plants or its mode of action against parasites. When VH is isolated from Psorospermum glaberrimum, it is rapidly converted into madagascine anthrone and anthraquinone, which are characterized by markedly different fluorescent properties. To locate the fluorescence of VH in living plant cells and discriminate it from that of the other metabolites, an original strategy combining spectral imaging (SImaging), confocal microscopy and non-targeted metabolomics using mass spectrometry, was developed. Besides VH, structurally related molecules including madagascine, emodin, quinizarin as well as lapachol and fraxetin were analyzed. This strategy readily allowed a spatiotemporal characterization and discrimination of spectral fingerprints from anthranoids-derived metabolites and related complexes with cations and proteins. In addition, our study validates the capability of plant cells to metabolize VH into madagascine anthrone, anthraquinones and unexpected metabolites, leading to new hypotheses on the metabolism of anthranoids in plants.
Identification of a novel Candida metapsilosis isolate suggests ongoing hybridization.
Authors: O'Brien Caoimhe E. , Zhai Bing , Ola Mihaela , Ó Cinnéide Eoin , O'Connor Ísla , Rolling Thierry , Miranda Edwin , Babady N. Esther , Hohl Tobias M , Butler Geraldine
Published: July 2021

Candida metapsilosis is a member of the C. parapsilosis species complex, a group of opportunistic human pathogens. Of all the members of this complex, C. metapsilosis is the least virulent, and accounts for a small proportion of invasive Candida infections. Previous studies established that all C. metapsilosis isolates are hybrids, originating from a single hybridization event between two lineages, parent A and parent B. Here, we use MinION and Illumina sequencing to characterize a C. metapsilosis isolate that originated from a separate hybridization. One of the parents of the new isolate is very closely related to parent A. However, the other parent (parent C) is not the same as parent B. Unlike C. metapsilosis AB isolates, the C. metapsilosis AC isolate has not undergone introgression at the Mating Type-like Locus. In addition, the A and C haplotypes are not fully collinear. The C. metapsilosis AC isolate has undergone Loss of Heterozygosity (LOH) with a preference for haplotype A, indicating that this isolate is in the early stages of genome stabilization.
Visualizing Amino Acid Substitutions in a Physicochemical Vector Space
Authors: Nemzer Louis R.
Published: July 2021

A three-dimensional representation of the twenty proteinogenic amino acids in a physicochemical space is presented. Vectors corresponding to amino acid substitutions are classified based on whether they are accessible via a single-nucleotide mutation. It is shown that the standard genetic code establishes a “choice architecture” that permits nearly independent tuning of the properties related with size and those related with hydrophobicity. This work sheds light on the non-arbitrary benefits of evolvability that may have shaped the development standard genetic code to increase the probability that adaptive point mutations will be generated. Illustrations of the usefulness of visualizing amino acid substitutions in a 3D physicochemical space are shown using recent datasets collected regarding the SARS-CoV-2 receptor binding domain. First, the substitutions most responsible for antibody escape are almost always inaccessible via single nucleotide mutation, and change multiple properties concurrently. Second, it is shown that assays of ACE2 binding by sarbecovirus variants, including the viruses responsible for SARS and COVID-19, are more easily understood when plotted with this method. The results of this research can extend our understanding of certain hereditary disorders caused by point mutations, as well as guide the development of rational protein and vaccine design.
Ultraviolet screening by slug tissue and tight packing of plastids protect photosynthetic sea slugs from photoinhibition
Authors: Havurinne Vesa , Aitokari Riina , Mattila Heta , Käpylä Ville , Tyystjärvi Esa
Published: July 2021

One of the main unsolved questions regarding photosynthetic sea slugs is how the slug plastids handle photoinhibition of Photosystem II. Photoinhibition has not been studied in detail in these animals although resilience against photoinhibition might obviously explain the longevity of plastids inside animal cytosol.

Light response and action spectrum of photoinhibition were measured from the slug Elysia timida and its prey alga Acetabularia acetabulum. Plastid packing in the slugs and algae was compared with spectroscopic and microscopic methods. The importance of plastid concentration was also estimated by measuring photoinhibition from starved slugs.

Compared to A. acetabulum, E. timida is highly resistant against photoinhibition. The resilience of the slugs is even more pronounced in the UV-region, as the slug tissue screens UV radiation. The plastids in the slug tissue are tightly packed, and the outer plastids protect the inner ones from photoinhibition.

The sea slug E. timida protects its plastids from photoinhibition by screening UV radiation and packing the plastids tightly in its tissues. Both mechanisms enhance the longevity of the plastids in slug cytosol and ameliorate the need for repair of photoinhibited Photosystem II.
Cellular translational enhancer elements that recruit eukaryotic initiation factor 3
Authors: Koubek Jiří , Niederer Rachel O. , Stanciu Andrei , Aitken Colin Echeverría , Gilbert Wendy V.
Published: July 2021

Translation initiation is a highly regulated process which broadly affects eukaryotic gene expression. Eukaryotic initiation factor 3 (eIF3) is a central player in canonical and alternative pathways for ribosome recruitment. Here we have investigated how direct binding of eIF3 contributes to the large and regulated differences in protein output conferred by different 5′-untranslated regions (5′-UTRs) of cellular mRNAs. Using an unbiased high-throughput approach to determine the affinity of budding yeast eIF3 for native 5′-UTRs from 4,252 genes, we demonstrate that eIF3 binds specifically to a subset of 5′-UTRs that contain a short unstructured binding motif, AMAYAA. eIF3 binding mRNAs have higher ribosome density in growing cells and are preferentially translated under certain stress conditions, supporting the functional relevance of this interaction. Our results reveal a new class of translational enhancer and suggest a mechanism by which changes in core initiation factor activity enact mRNA-specific translation programs.
Structural basis for protein glutamylation by the Legionella pseudokinase SidJ
Authors: Adams Michael , Sharma Rahul , Colby Thomas , Weis Felix , Matic Ivan , Bhogaraju Sagar
Published: July 2021

Legionella pneumophila (LP) avoids phagocytosis by secreting nearly 300 effector proteins into the host cytosol. SidE family of effectors (SdeA, SdeB, SdeC and SidE) employ phosphoribosyl serine ubiquitination to target an array of host Rab GTPases and innate immune factors. To suppress the deleterious toxicity of SidE enzymes in a timely manner, LP employs a metaeffector named SidJ. Upon activation by host Calmodulin (CaM), SidJ executes an ATP-dependent glutamylation to modify the catalytic residue Glu860 in the mono-ADP-ribosyl transferase (mART) domain of SdeA. SidJ is a unique glutamylase that adopts a kinase-like fold but contains two nucleotide-binding pockets. There is a lack of consensus about the substrate recognition and catalytic mechanism of SidJ. Here, we determined the cryo-EM structure of SidJ in complex with its substrate SdeA in two different states of catalysis. Our structures reveal that both phosphodiesterase (PDE) and mART domains of SdeA make extensive contacts with SidJ. In the pre-glutamylation state structure of the SidJ-SdeA complex, adenylylated E860 of SdeA is inserted into the non-canonical (migrated) nucleotide-binding pocket of SidJ. Structure-based mutational analysis indicates that SidJ employs its migrated pocket for the glutamylation of SdeA. Finally, using mass spectrometry, we identified several transient autoAMPylation sites close to both the catalytic pockets of SidJ. Our data provide unique insights into the substrate recognition and the mechanism of protein glutamylation by the pseudokinase SidJ.
Accurate Direct PCR with Arabidopsis and rice
Authors: Lynagh Peter , Osuna-Kleist Paul , Wang Bohai , Malagon Edgar , Anleu Gil Maria Ximena , Comai Luca
Published: July 2021

Plant sampling methods for PCR that avoid costly and time-consuming plant DNA purification can be accurate but have not been widely adopted, partly because the efficacy of the methods is unclear. Here, we introduce new sampling methods for Direct PCR in Arabidopsis and rice and compare them to previously published methods. CutTip, stabbing a pipette tip into a plant and depositing the tip of the pipette tip into the reaction buffer, yielded high accuracy for genotyping Arabidopsis and rice. This did not require visible tissue fragments in the reactions. We found that using short thin segments of fishing line, called Line-PCR, to be even more practical and highly accurate. Compared to traditional and other Direct PCR preparation methods, Line-PCR is faster, inexpensive, easier, uses less plastic and chemicals, and causes the least tissue damage. CutTip and Line-PCR require no modified PCR reagents. Line-PCR particularly lacks any complicated steps. Probably, the most difficult step in Line-PCR is a wipe of the tweezer between samples. These methods can help address the challenge of genotyping at different scales with high accuracy. CutTip and Line-PCR also simplify the application of PCR in the field.
A single de novo substitution in SARS-CoV-2 spike informs enhanced adherence to human ACE2
Authors: Erausquin Elena , López-Sagaseta Jacinto
Published: July 2021

SARS-CoV-2 initiates colonization of host cells by binding to cell membrane ACE2 receptor. This binding is mediated by the viral spike receptor binding domain (RBD). The COVID-19 pandemic has brought devastating consequences at a clinical, social and economical levels. Therefore, anticipation of potential novel SARS-causing species or SARS-CoV-2 variants with enhanced binding to ACE2 is key in the prevention of future threats to come. We have characterized a de novo single substitution, Q498Y, in SARS-CoV-2 RBD that confers stronger adherence to ACE2. While the SARS-CoV-2 β variant, which includes three simultaneous amino acid replacements, induces a 4-fold stronger affinity, a single Q498Y substitution results in 2.5-fold tighter binding, compared to the Wuhan-Hu-1 SARS-CoV-2 2019 strain. Additionally, we crystallized RBDQ498Y complexed with ACE2 and provide here the structural basis for this enhanced affinity. These studies inform a rationale for prevention of potential SARS-causing viruses to come.
Obsessive Compulsive Disorder and Response Inhibition: Meta-analysis of the Stop-Signal Task
Authors: Mar Kendall , Townes Parker , Pechlivanoglou Petros , Arnold Paul , Schachar Russell
Published: July 2021

This systematic review and meta-analysis updates evidence pertaining to deficient response inhibition in obsessive-compulsive disorder (OCD) as measured by the stop-signal task (SST). We conducted a meta-analysis of the literature to compare response inhibition in patients with OCD and healthy controls, meta-regressions to determine relative influences of age and sex on response inhibition impairment, and a risk of bias assessment for included studies using the Newcastle-Ottawa Scale (NOS). Stop-signal reaction time (SSRT), which estimates the latency of the stopping process deficit, was significantly longer in OCD samples than in controls, reflecting inferior inhibitory control (Raw mean difference = 23.43ms; p = <0.001; 95% CI = [17.42, 29.45]). We did not observe differences in mean reaction time (MRT) in OCD compared to controls (Raw mean difference = 2.51ms; p = 0.755; 95% CI = [−13.27, 18.30]). Age impacted effect size of SSRT, indicating a greater deficit in older patients than younger ones. We did not observe a significant effect of sex on SSRT or MRT scores.

General Scientific Summary

Difficulty inhibiting responses is an hypothesized deficit in Obsessive-Compulsive Disorder (OCD). The results of this systematic review and meta-analysis of studies using the Stop Signal Task support the notion of deficient response inhibition in OCD and indicate that older individuals with OCD show greater impairments than younger ones.
Efficient Estimation of Indirect Effects in Case-Control Studies Using a Unified Likelihood Framework
Authors: Satten Glen A. , Curtis Sarah W. , Solis-Lemus Claudia , Leslie Elizabeth J. , Epstein Michael P.
Published: July 2021

Mediation models are a set of statistical techniques that investigate the mechanisms that produce an observed relationship between an exposure variable and an outcome variable in order to deduce the extent to which the relationship is influenced by intermediate mediator variables. For a case-control study, the most common mediation analysis strategy employs a counterfactual framework that permits estimation of indirect and direct effects on the odds ratio scale for dichotomous outcomes, assuming either binary or continuous mediators. While this framework has become an important tool for mediation analysis, we demonstrate that we can embed this approach in a unified likelihood framework for mediation analysis in case-control studies that leverages more features of the data (in particular, the relationship between exposure and mediator) to improve efficiency of indirect effect estimates. One important feature of our likelihood approach is that it naturally incorporates cases within the exposure-mediator model to improve efficiency. Our approach does not require knowledge of disease prevalence and can model confounders and exposure-mediator interactions, and is straightforward to implement in standard statistical software. We illustrate our approach using both simulated data and real data from a case-control genetic study of lung cancer.
Transcriptomic analysis of mdx mouse muscles reveals a signature of early human Duchenne muscular dystrophy
Authors: Ralston Evelyn , Gutierrez-Cruz Gustavo , Kenea Aster , Brooks Stephen R.
Published: July 2021

The mdx mouse (C57BL/10ScSn-DMDmdx/J) is the oldest model of Duchenne muscular dystrophy (DMD). Mdx remains popular and has not been replaced by newer mouse models, despite criticisms that mdx has a nearly normal lifespan and mild pathology while DMD remains a severe, fatal disease. At some point we noticed that the absence of mdx RNA-seq data limited our ability to assess the results of physiological work on the mouse model and to compare these results to human genetic data [1]. We carried out RNA-seq analysis of wild-type and mdx mice of 2 and 5 months of age, using three hindlimb muscles per mouse: the flexor digitorum brevis (FDB), the extensor digitorum longus (EDL) and the soleus (SOL), with a total of 55 samples. We then mined the data and found that each of the three muscles is a valid experimental model for DMD-related mouse work, even the FDB, despite a delayed pathology development. We also show that the mdx mouse muscles are enriched in metabolic, developmental, regenerational and structural pathways that have been found to be the “disease signature” of DMD in young and presymptomatic subjects [38, 39]. Additionally, we show that healthy human muscle fiber microtubules present the grid-like organization found in control rodents but perturbed in the mdx mouse. We conclude that the mdx mouse appropriately mimics the early stages of DMD, with its microtubule defects signaling fiber regeneration [35]. We hope that these results may contribute to a better understanding of the failure of regeneration as DMD progresses.
A long non-coding RNA in the let-7 complex acting as a potent and specific death effector of cancer cells
Authors: Birbaumer Tosca , Schlumpf Tommy Beat , Seimiya Makiko , Jiang Yanrui , Paro Renato
Published: July 2021

The let-7 complex in Drosophila encodes three evolutionarily conserved microRNAs: miR-100, let-7, and miR-125. These act as heterochronic genes in regulating developmental timing in response to the steroid hormone ecdysone and play important roles in cell differentiation. Here we identify two additional long non-coding RNAs in the let-7 complex, we named let-A and let-B. Both are transcribed in the large first intron of the primary RNA encoding the microRNAs. We show these RNAs to be sequentially expressed in early pupal stages in response to ecdysone signaling, albeit exhibiting a different expression pattern compared to the microRNA let-7. Surprisingly, ectopic expression of let-A in Drosophila cancer cells induces rapid cell death. Dead cells further release RNA molecules in the medium that is becoming toxic to other cancer cells. In vivo grown tumors lose their tumorigenicity after being incubated in the let-A induced medium. Moreover, feeding flies carrying transplanted tumor cells with such induced medium leads to reduced growth of tumors in a subset of hosts. Our results uncover a new lncRNA which can act as a potent and specific cell death effector for Drosophila tumor cells.
Long-term ecosystem nitrogen limitation from foliar δ15N data and a land surface model
Authors: Caldararu Silvia , Thum Tea , Yu Lin , Kern Melanie , Nair Richard , Zaehle Sönke
Published: July 2021

The effect of nutrient availability on plant growth and the terrestrial carbon sink under climate change and elevated CO2 remains one of the main uncertainties of the terrestrial carbon cycle. This is partially due to the difficulty of assessing nutrient limitation at large scales over long periods of time. Consistent declines in leaf nitrogen (N) content and leaf δ15N have been used to suggest that nitrogen limitation has increased in recent decades, most likely due to the concurrent increase in atmospheric CO2. However, such datasets are often not straightforward to interpret due to the complex factors that contribute to the spatial and temporal variation in leaf N and isotope concentration. We use the land surface model QUINCY, which has the unique capacity to represent N isotopic processes, in conjunction with two large datasets of foliar N and N isotope content. We run the model with different scenarios to test whether foliar δ15N isotopic data can be used to infer large scale nitrogen limitation and if the observed trends are caused by increasing atmospheric CO2, changes in climate or changes in sources of anthropogenic N deposition. We show that while the model can capture the observed change in leaf N content and predicts widespread increases in N limitation, it does not capture the pronounced, but very spatially heterogeneous, decrease in foliar δ15N observed in the data across the globe. The addition of an observed temporal trend in isotopic composition of N deposition leads to a more pronounced decrease in simulated leaf δ15N. Our results show that leaf δ15N observations should not, on their own, be used to assess global scale N limitation and that using such a dataset in conjunction with a land surface model can reveal the drivers behind the observed patterns.
Gut regulatory T cells mediate immunological tolerance inSalmonella-infected superspreader hosts by suppressing cytotoxic activity of T cells
Authors: Massis LM , Ruddle S , Brewer SM , Schade R , Narasimhan R , Honeycutt JD , Pham THM , McKenna JA , Brubaker SW , Chairatana P , Klein JA , Margalef-Català M , Amieva MR , Vilches-Moure JG , Monack DM
Published: July 2021

Superspreader hosts carry out most pathogen transmission events and are often disease tolerant since they remain asymptomatic despite high pathogen burdens. Here we describe the superspreader immune state that allows for disease tolerance. In a model ofSalmonellainfection, superspreader mice develop colitis with robust CD4+and CD8+T-cell responses, however, they remain asymptomatic. We found that superspreaders have significantly more regulatory T cells (Tregs) in the distal gut compared to non-superspreader infected hosts. Surprisingly, the depletion of Tregs did not induce pathogen clearance but rather exacerbated weight loss, increased gut inflammation, and compromised epithelial intestinal barrier. This loss of tolerance correlated with dramatic increases in cytotoxic CD4+and CD8+T cells. Interestingly, CD4 neutralization in Tregs-depleted superspreaders was sufficient to rescue tolerance. Our results indicate that Tregs play a crucial role in maintaining immunologic tolerance in the guts of superspreader mice by suppressing cytotoxic CD4+and CD8+T-cell activities.

AUTHOR SUMMARY

Superspreader hosts are the main cause of disease transmission and a very important public health concern. Here, we evaluated the immunological tolerance of theSalmonellainfected superspreaders in a mouse model. By manipulating Tregs, we demonstrated the immunological mechanism from the host to maintain health status and high pathogen burden. Tregs depletion in the superspreaders led to severe disease, with damage of the intestinal epithelia, and high morbidity without having any effect on shedding and systemicSalmonellaburden. Furthermore, we demonstrated that the damage of the intestinal epithelia was related to cytotoxic activity of T cells. When Tregs were depleted, CD8+T cells produced high levels of granzyme B and perforin. CD8+T cells neutralization in Tregs depleted mice led to increased cytotoxic CD4+T cells. Interestingly, neutralization of CD4+T cells in the Tregs depleted mice led to a reduction in the CD8+T cells producing granzyme B and it was sufficient to rescue host tolerance in this model. We demonstrate for the first time that cytotoxic CD4+T cells damage the epithelial intestinal barrier and contribute to loss of tolerance in the context of a superspreader host. These findings open new perspectives to understand mechanisms of tolerance in the intestine of a superspreader host.
Non-genetic maternal effects shape individual differences in cortisol phenotypes in wild chimpanzees
Authors: Tkaczynski Patrick J. , Mafessoni Fabrizio , Girard-Buttoz Cédric , Samuni Liran , Ackermann Corinne Y. , Fedurek Pawel , Gomes Cristina , Hobaiter Catherine , Löhrich Therese , Manin Virgile , Preis Anna , Valé Prince D. , Wessling Erin G. , Wittiger Livia , Zommers Zinta , Zuberbuehler Klaus , Vigilant Linda , Deschner Tobias , Wittig Roman M. , Crockford Catherine
Published: July 2021

Glucocorticoids, such as cortisol, mediate homeostatic processes, allowing individuals to adjust to fluctuating environments. The regulation of circadian cortisol responses, a key homeostatic function, has been shown to be heritable. However, to understand better the role of parental care in shaping physiological functioning in long-lived mammals with protracted parental care, there is a need to disentangle genetic and non-genetic parental contributions to variation in glucocorticoid phenotypes. We used a dataset of 6,123 cortisol measures from urine samples from 170 wild chimpanzees spanning 18 years of data collection. We found consistent inter-individual differences in circadian cortisol phenotypes, with differences most apparent when considering average cortisol levels given the effect of time of day. Maternal effects explained around 10% (2-18%) variation in these average cortisol levels, while variation attributable to genetic factors was not distinguishable from zero. Our results indicate, relative to genetic effects, a qualitatively stronger influence of mothers, whether via epigenetic processes or via behavioral priming for coping with stressors, in shaping cortisol phenotypes in this species. This provides novel insight into the vital role of mothers in the developmental plasticity of long-lived mammals and, more generally, the selective pressures shaping physiological plasticity.
Potentialities of biotechnological recovery of hydrogen and short- and medium-chain organic acids from the co-fermentation of cheese whey and Yerba Mate (Ilex paraguariensis) waste
Authors: Ferraz Júnior Antônio Djalma Nunes , Fuentes Laura , de la Sovera Victoria , Bovio-Winkler Patricia , Eng Felipe , Garcia Mariángeles , Etchebehere Claudia
Published: July 2021

Co-fermentation of cheese whey (CW) and thermal-alkaline pre-treated Yerba Mate (Ilex paraguariensis) waste (YMW) was performed aiming to produce biohydrogen and/or short- and medium-chain organic acids. Central Composite Designs (CCD) was chosen as the experimental design for evaluating the combinations of three independent variables namely YMW concentration, pH and inoculum concentration in hydrogen yield (H2Y; response variable). The increase of inoculum and YMW concentrations had positive effect in biohydrogen production and yield (H2Ymaxof 1.35 mMH2.g-1VSadded) whereas the initial pH had no significant effect on it. Hydrogen was produced as a coproduct to butyrate mainly. Acetate from homoacetogenesis was accounted in all conditions evaluated. The CCD also indicated operating conditions to produce moderate-to-high concentrations of short and medium-chain organic acids such as butyrate (~135 mM), caproate (~45 mM) and lactate (~140 mM). 16S rRNA gene sequences analysis revealed five groups of microorganisms related to hydrogen, lactate and caproate production, ethanol-hydrogen co-production and hydrogen consumption.

Highlights

Co-fermentation improved hydrogen production in up 7.5-folds compared to the sole CW-fed system.

The initial pH had no effect on hydrogen-producing batch reactors.

Hydrogen was produced as a coproduct to butyrate.

Design of experiment indicated operating conditions to the production of lactate and caproate.
In-situ genomic prediction using low-coverage Nanopore sequencing
Authors: Lamb Harrison J. , Hayes Ben J. , Randhawa Imtiaz A. S. , Nguyen Loan T. , Ross Elizabeth M.
Published: July 2021

Most traits in livestock, crops and humans are polygenic, that is, a large number of loci contribute to genetic variation. Effects at these loci lie along a continuum ranging from common low-effect to rare high-effect variants that cumulatively contribute to the overall phenotype. Statistical methods to calculate the effect of these loci have been developed and can be used to predict phenotypes in new individuals. In agriculture, these methods are used to select superior individuals using genomic breeding values; in humans these methods are used to quantitatively measure an individual’s disease risk, termed polygenic risk scores. Both fields typically use SNP array genotypes for the analysis. Recently, genotyping-by-sequencing has become popular, due to lower cost and greater genome coverage (including structural variants). Oxford Nanopore Technologies’ (ONT) portable sequencers have the potential to combine the benefits genotyping-by-sequencing with portability and decreased turn-around time. This introduces the potential for in-house clinical genetic disease risk screening in humans or calculating genomic breeding values on-farm in agriculture. Here we demonstrate the potential of the later by calculating genomic breeding values for four traits in cattle using low-coverage ONT sequence data and comparing these breeding values to breeding values calculated from SNP arrays. At sequencing coverages between 2X and 4X the correlation between ONT breeding values and SNP array-based breeding values was > 0.92 when imputation was used and > 0.88 when no imputation was used. With an average sequencing coverage of 0.5x the correlation between the two methods was between 0.85 and 0.92 using imputation, depending on the trait. This demonstrates that ONT sequencing has great potential for in clinic or on-farm genomic prediction.

Author Summary

Genomic prediction is a method that uses a large number of genetic markers to predict complex phenotypes in livestock, crops and humans. Currently the techniques we use to determine genotypes requires complex equipment which can only be used in laboratories. However, Oxford Nanopore Technologies’ have released a portable DNA sequencer, which can genotype a range of organisms in the field. As a result of the device’s higher error rate, it has largely only been considered for specific applications, such as characterising large mutations. Here we demonstrated that despite the devices error rate, accurate genomic prediction is also possible using this portable device. The ability to accurately predict complex phenotypes such as the predisposition to schizophrenia in humans or lifetime fertility in livestock in-situ would decrease the turnaround time and ultimately increase the utility of this method in the human clinical and on-farm settings.
Darwin’s bark spider shares a spidroin repertoire with Caerostris extrusa but achieves extraordinary silk toughness through gene expression
Authors: Kono Nobuaki , Ohtoshi Rintaro , Malay Ali D , Mori Masaru , Masunaga Hiroyasu , Yoshida Yuki , Nakamura Hiroyuki , Numata Keiji , Arakawa Kazuharu
Published: July 2021

Spider silk is a protein-based material whose toughness suggests possible novel applications. A particularly fascinating example of silk toughness is provided by Darwin’s bark spider (Caerostris darwini) found in Madagascar. This spider produces extraordinarily tough silk, with an average toughness of 350 MJ/m and over 50% extensibility, and can build river-bridging webs with a size of 2.8 m2. Recent studies have suggested that specific spidroins expressed in C. darwini are responsible for the mechanical properties of its silk. Therefore, a more comprehensive investigation of spidroin sequences, silk thread protein contents, and phylogenetic conservation among closely related species is required. Here, we conducted genomic, transcriptomic, and proteomic analyses of C. darwini and its close relative Caerostris extrusa. A variety of spidroins and low-molecular-weight proteins were found in the dragline silk of these species; all of the genes encoding these proteins were conserved in both genomes, but their genes were more expressed in C. darwini. The potential to produce very tough silk is common in the genus Caerostris, and our results may suggest the existence of plasticity allowing silk mechanical properties to be changed by optimizing related gene expression in response to the environment.
Histone H3 deacetylation promotes host cell viability for efficient infection byListeria monocytogenes
Authors: Eldridge Matthew J.G. , Hamon Mélanie A.
Published: July 2021

For many intracellular bacterial pathogens manipulating host cell survival is essential for maintaining a replicative niche, and is a common strategy used to promote infection. The bacterial pathogenListeria monocytogenesis well known to hijack host machinery for its own benefit, such as targeting the host histone H3 for modification by SIRT2. However, in what way this modification benefits infection, as well as the molecular players involved, remain unknown. Here we show that SIRT2 activity supportsListeriaintracellular survival by maintaining genome integrity and host cell viability. This protective effect is dependent on H3K18 deacetylation, which safeguards the host genome by counteracting infection-induced DNA damage. Mechanistically, infection causes SIRT2 to interact with the nucleic acid binding protein TDP-43 and localise to genomic R-loops, where H3K18 deacetylation occurs. This work highlights novel functions of TDP-43 and R-loops during bacterial infection and identifies the mechanism through whichL. monocytogenesco-opts SIRT2 to allow efficient infection.
Significant Variability exists in the Toxicity of Global Methicillin-resistant Staphylococcus aureus Lineages
Authors: Laabei Maisem , Peacock Sharon J. , Blane Beth , Baines Sarah L. , Howden Benjamin P. , Stinear Timothy P. , Massey Ruth C.
Published: July 2021

Staphylococcus aureus is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant S. aureus (MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily toxin driven, leading to the suggestion that hyper-virulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the toxic activity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced toxicity. Interestingly, the majority of isolates that were attenuated in toxin production contained no mutations in the agr locus, indicating a role of other undefined genes in S. aureus toxin regulation.