bluuebunny/crossref_metadata_2025 huggingface dataset:
Sinonasal cancers treatments: state of the art
Authors: Ferrari Marco , Orlandi Ester , Bossi Paolo
Published: March 2021

Purpose of review

The present review provides the reader with the state-of-the-art concepts of sinonasal oncology in view of the latest literature data.

Recent findings

Most recent publications in sinonasal oncology assessed treatment timing, centralization, surgical approach, margin status, orbit/neck management, salvage strategies, emerging surgical technologies, intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), particle radiotherapy, and neoadjuvant chemotherapy.

Indications to endoscopic surgery for sinonasal cancer have plateaued and are unlikely to further expand. Endoscopic surgery provides noninferior results compared to open surgery and best suits timing constraints imposed by multimodal treatment. Management of orbit-encroaching sinonasal cancer is remarkably improving mostly owing to optimal use of nonsurgical strategies. Prognostic value of the margin status and management of the nodal basin and recurrent sinonasal tumors are far from being fully elucidated. Most promising surgical technologies are surgical navigation, optical imaging, and radiofrequency-aided ablation. IMRT and VMAT have theoretical technical advantages that are in the process of being clinically demonstrated. Pieces of evidence are progressively confirming the physical and radiobiological advantages offered by particle radiotherapy. Systemic therapy is being tested mostly in the neoadjuvant setting with the aim of improving outcomes in locally advanced sinonasal cancers; response to induction chemotherapy could better select a further locoregional approach.
Integrated Chinese and western medicine for SLE
Authors: Cheng Xueli , Liu Jing , Zhong Zhenghong , Xu Donghan , Cha Xushan , Wu Qibiao
Published: March 2021

Background:

The efficacy and safety of integrated Chinese and western medicine in the treatment of Systemic Lupus Erythematosus (SLE) have not been systematically evaluated.

Methods:

This systematic review and meta-analysis will be performed and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We will search PubMed, Embase, Cochrane Library, Chinese Biomedical Database WangFang, VIP, and China National Knowledge Infrastructure (CNKI) for potentially eligible studies from their inception to Dec. 2020, and we will select all the eligible randomized controlled trials (RCTs) of the integrated Chinese and western medicine for Systemic Lupus Erythematosus. All the studies will be screened according to the inclusion and exclusion criteria and meta-analysis will be conducted using Review Manager V.5.3. and Stata V.12.0. The primary endpoint was the clinical efficacy rate, the secondary outcomes were SLEDAI score, adverse reaction rate, and laboratory test parameters (white blood cells, complement C3).

Results:

The results of this study will systematically evaluate the effectiveness and safety of the integrated Chinese and western medicine in the treatment of primary dysmenorrhea.

Conclusion:

The efficacy and safety of integrated Chinese and western medicine will be systematically evaluated in this paper, thus providing evidence for the clinical application of this therapy.

Ethics and dissemination:

This study is a systematic review, which is based on the published studies, so examination and agreement by the ethics committee are not required in this study. We intend to publish the study results in a journal or conference presentations.

Open Science Framework (OSF)registration number:

https://osf.io/mabxh.
Effect of Baduanjin exercise on cervical spondylosis
Authors: Zou Liang , Zhong Chongfu , Xu Xiaohui , Liu Fanjie , Wang Congan , Shi Bin
Published: March 2021

Background:

The study aims to evaluate the effectiveness and safety of Baduanjin exercise for patients with cervical spondylosis (CS).

Methods:

We will retrieve a randomized controlled trial of Baduanjin for CS from the following electronic databases establishment to May 2021: The Cochrane Library, MEDLINE, EMBASE, Web of Science, Springer, World Health Organization International Clinical Trials Registry Platform (ICTRP), China National Knowledge Infrastructure (CNKI), Wan-fang database, Chinese Scientific Journal Database (VIP), Chinese Biomedical Literature Databases (CBM), and other databases. Two independent researchers will operate article retrieval, duplication removing, screening, quality evaluation, and data analyses by Review Manager (V.5.3.5). Meta-analyses, subgroup analysis, and/or descriptive analysis will be performed based on the included data conditions.

Results:

The results of this study will provide researchers in the field of CS with a current synthesis of high-quality evidence.

Conclusion:

This conclusion of this study will provide the evidence of whether Baduanjin is an effective and safe intervention for patients with CS.

PROSPERO registration number:

CRD42020211019.
Celiac Disease Management in the United Kingdom Specialist Pediatric Gastroenterology Centers—A Service Survey
Authors: Paul Siba Prosad , Balakumar Varathagini , Gillett Peter Michael
Published: March 2021

Objectives:

The 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines on celiac disease (CD) recommended a no‐biopsy pathway (NBP) for symptomatic children with high immunoglobin A (IgA)‐based anti‐tissue transglutaminase (TGA‐IgA) titers, positive anti‐endomysial antibody and human leukocyte antigen (HLA)‐DQ2/DQ8 status. We aimed to understand variations in practice amongst specialist pediatric gastroenterology centers (SPGIC) in the United Kingdom (UK).

Methods:

A survey questionnaire was sent to all UK SPGIC (n = 29) providing endoscopy services for CD diagnosis. It was divided into four main subgroups: analyzing diagnosis of CD through adherence to the ESPGHAN (2012) guidelines, post‐diagnosis care and long‐term follow‐up and discharge from pediatric services.

Results:

All 29 responded. NBP was implemented in 28 of 29 centers. Five of 29 centers had already stopped HLA‐DQ2/DQ8 testing for NBP diagnosis. Twenty six of 29 centers were performing endoscopy on screening‐identified children (mostly asymptomatic, “at‐risk” patients). Diagnosis was communicated by a doctor in 65% SPGIC (n = 19). Most centers (n = 23) waited 6–12 months post‐diagnosis to start gluten‐free oats. Routine vitamin D supplementation was commenced by 4 of 29 centers. All centers repeated TGA‐IgA to assess normalization but at varying times post‐GFD. Follow‐up was with a combination of doctors/dieticians (n = 26). Eleven of 29 centers discharged their patient to primary care.

Conclusions:

There was excellent uptake of ESPGHAN guidelines (2012) in the UK and adherence to guidelines is generally good. Despite published evidence and pragmatic advice from the British Society of Paediatric Gastroenterology Hepatology and Nutrition and National Institute for Health and Care Excellence, significant differences remain in diagnostic and ongoing management practice and are opportunities for research and directive evidence‐based follow‐up guidance.
In-utero exposure to zidovudine-containing antiretroviral therapy and clonal hematopoiesis in HIV-exposed uninfected newborns
Authors: Lin Shu-Hong , Wang Youjin , Hartley Stephen W. , Karyadi Danielle M. , Lee Olivia W. , Zhu Bin , Zhou Weiyin , Brown Derek W. , Beilstein-Wedel Erin , Hazra Rohan , Kacanek Deborah , Chadwick Ellen G. , Marsit Carmen J. , Poirier Miriam C. , Brummel Sean S. , Chanock Stephen J. , Engels Eric A. , Machiela Mitchell J.
Published: March 2021

Objective:

Zidovudine (ZDV) has been extensively used in pregnant women to prevent vertical transmission of HIV but few studies have evaluated potential mutagenic effects of ZDV during fetal development.

Design:

Our study investigated clonal hematopoiesis in HIV-exposed uninfected (HEU) newborns, 94 of whom were ZDV-exposed and 91 antiretroviral therapy (ART)-unexposed and matched for potential confounding factors.

Methods:

Utilizing high depth sequencing and genotyping arrays, we comprehensively examined blood samples collected during the first week after birth for potential clonal hematopoiesis associated with fetal ZDV exposure, including clonal single nucleotide variants (SNVs), small insertions and deletions (indels), and large structural copy number or copy neutral alterations.

Results:

We observed no statistically significant difference in the number of SNVs and indels per person in ZDV-exposed children (adjusted ratio [95% confidence interval, CI] for expected number of mutations = 0.79 [0.50--1.22], P = 0.3), and no difference in the number of large structural alterations. Mutations in common clonal hematopoiesis driver genes were not found in the study population. Mutational signature analyses on SNVs detected no novel signatures unique to the ZDV-exposed children and the mutational profiles were similar between the two groups.

Conclusion:

Our results suggest that clonal hematopoiesis at levels detectable in our study is not strongly influenced by in-utero ZDV exposure; however, additional follow-up studies are needed to further evaluate the safety and potential long-term impacts of in-utero ZDV exposure in HEU children as well as better investigate genomic aberrations occurring late in pregnancy.
SARS-Cov-2 Seroprevalence in a French Kidney Transplant Center Located Within a “High-risk” Zone
Authors: Caillard Sophie , Benotmane Ilies , Meidinger Céline , Jegou Vanessa , Ludwiller Sandra , Rihon Anne , Desmarquets Audrey , Steinmetz Lucille , Morvan Murielle , Kedjam Karima , Bigot Amandine , Roy Danielle , Schmitt Dominique , Marx David , Bassand Xavier , Perrin Peggy , Gautier Vargas Gabriela , Cognard Noelle , Olagne Jérome , Braun Laura , Heibel Francoise , Martzloff Jonas , Moulin Bruno , Fafi Kremer Samira
Published: March 2021

Background.

Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in kidney transplant recipients (KTRs) remain rare. We sought to shed further light on this issue by conducting a single-center study in a kidney transplant center located in one of the France’s highest risk zone (Grand Est) for coronavirus disease 2019 (Covid-19) during the initial disease outbreak.

Methods.

To this aim, we used a survey approach coupled with systematic investigation of SARS-CoV-2 serology in a cohort of 1390 KTRs.

Results.

SARS-CoV-2 serologies were available for 780 survey respondents, among whom 48 had anti-SARS-CoV-2 antibodies (total seroprevalence: 6.2%). Thirty-five of the 48 seropositive KTRs had previously received a diagnosis of Covid-19, whereas the remaining 13 patients were not known to be infected (8 asymptomatic cases). Specifically, 18.7% of seropositive KTRs and 1.1% of the entire cohort were asymptomatic. Household exposure was found to markedly increase the risk of SARS-CoV-2 transmission.

Conclusions.

Our findings demonstrate that the overall SARS-CoV-2 seroprevalence in KTRs living in one of the France’s highest risk zone for Covid-19 during the first French lockdown was as low as 6.3%. Rapid and strict implementation of protective measures could have significantly mitigated virus spread even in an area of high virus circulation.
The secreted hypersensitive response inducing protein 1 fromBotrytis cinereadisplays non-canonical PAMP-activity
Authors: Jeblick Tanja , Leisen Thomas , Steidele Christina E. , Müller Jonas , Mahler Florian , Sommer Frederik , Keller Sandro , Hückelhoven Ralph , Hahn Matthias , Scheuring David
Published: March 2021

According to their lifestyle, plant pathogens are divided into biotrophic and necrotrophic organisms. While biotrophic pathogens establish a relationship with living host cells, necrotrophic pathogens rapidly kill host cells and feed on the cell debris. To this end, the necrotrophic ascomycete fungusBotrytis cinereasecretes large amounts of phytotoxic proteins and cell wall degrading enzymes. However, the precise role of these proteins during the infection process is unknown. Here we report on the identification and characterization of the previously unknown toxic protein hypersensitive response inducing protein 1 (Hip1), which induces plant cell death. We found the adoption of a folded protein structure to be a prerequisite for Hip1 to exert its necrosis-inducing activity inNicotiana benthamiana. Localization and the induction of specific plant responses by Hip1 indicate recognition as pathogen-associated molecular pattern at the plant plasma membrane. Our results demonstrate that recognition of Hip1, even in the absence of obvious enzymatic or poreforming activity, induces strong plant defense reactions eventually leading to plant cell death.
Corticosteroids and mortality in patients with severe Covid-19 who have autoantibodies
Authors: Cui Zhu , Roth Maxwell , Averbukh Yelena , Assa Andrei , Ani Azal Al , Southern William , Gil Morayma Reyes , Arora Shitij
Published: March 2021

Auto-reactivity in COVID-19 is increasingly being recognized and may identify a group of patients with inflammation severe enough to result in loss of self-tolerance. Corticosteroids are potent anti-inflammatory agents and now the standard of care for patients with severe Covid-19 requiring oxygen support/mechanical ventilation. We studied the outcomes of COVID-19 patients who demonstrated clinically identifiable auto-reactivity and received corticosteroid treatment.

In this retrospective cohort study, we included 51 COVID-19 patients admitted between March 10, 2020 and May 2, 2020 who received corticosteroid treatment and also had serum sample in our institution bio-bank available for ANA and RF ELISA. Twelve patients (23.5%) had positive ANA or RF. Mortality rate among patients with positive autoantibodies was significantly higher than those without (9/12 or 75% versus 13/39 or 33.3%, p= 0.02). The high mortality rate in patients with auto-reactivity warrants further investigation and may be the subgroup where additional immunomodulation is effective.
No support for oxytocin modulation of reward-related brain function in autism: evidence from a randomized controlled trial
Authors: Mayer Annalina V. , Preckel Katrin , Ihle Kristin , Piecha Fabian A. , Junghanns Klaus , Reiche Stefan , Rademacher Lena , Kamp-Becker Inge , Stroth Sanna , Roepke Stefan , Küpper Charlotte , Engert Veronika , Singer Tania , Kanske Philipp , Paulus Frieder M. , Krach Sören
Published: March 2021

Autism spectrum disorder (ASD) is characterized by difficulties in social communication and interaction, which have been related to atypical neural processing of rewards, especially in the social domain. Since intranasal oxytocin has been shown to modulate activation of the brain’s reward circuit, oxytocin could be a useful tool to ameliorate the processing of social rewards in ASD and thus improve social difficulties. In this randomized, double-blind, placebo-controlled, crossover fMRI study, we examined effects of a 24 IU dose of intranasal oxytocin on reward-related brain function in 37 men with an ASD diagnosis and 37 age- and IQ-matched control participants. Participants performed an incentive delay task that allows the investigation of neural activity associated with the anticipation and receipt of monetary and social rewards. Apart from a specific interaction effect in a single voxel within the left amygdala during the receipt of rewards, oxytocin did not influence neural processes related to the anticipation or consumption of social or monetary rewards in either group. Exploratory analyses suggested that oxytocin may increase ventral striatum sensitivity to monetary, but not social rewards, in individuals with high levels of self-reported anxiety, depression, alexithymia, and autistic traits irrespective of an ASD diagnosis. There were no significant differences in reward-related brain function between the two groups under placebo. Overall, our results do not support the hypothesis that intranasal oxytocin generally enhances activation of reward-related neural circuits in men with and without ASD without intellectual impairment. How and if oxytocin can be beneficial in the treatment of social difficulties in ASD needs to be addressed by examining moderating influences of individual differences and context on reward-related oxytocin effects.
A Differential Equation for Mutation Rates in Environmental Coevolution
Authors: Neal-Sturgess C E
Published: March 2021

In their paper Natural selection for least action (Kaila and Annila 2008) they depict evolution as a process conforming to the Principle of Least Action (PLA). From this concept, together with the Coevolution model of Lewontin, an equation of motion for environmental coevolution is derived which shows that it is the time rate (frequency) of evolutionary change of the organism (mutations) that responds to changes in the environment. It is not possible to compare the theory with viral or bacterial mutation rates, as these are not measured on a time base. There is positive evidence from population level avian studies where the coefficient of additive evolvability (Cav) and its square (IA) change with environmental favourability in agreement with this model. Further analysis shows that the time rate of change of the coefficient of additive evolvability (Cav) and its square (IA) are linear with environmental favourability, which could help in defining the Lagrangian of the environmental effects.
Passive clearing and 3D lightsheet imaging of the intact and injured spinal cord in mice
Authors: McCreedy Dylan A. , Jalufka Frank L. , Platt Madison E. , Min Sun Won , Kirchhoff Megan A. , Manlapaz Ron , Mihaly Eszter , Butts Jessica C. , Iyer Nisha R. , Sakiyama-Elbert Shelly E. , Crone Steven A. , McDevitt Todd C.
Published: March 2021

The spinal cord contains a diverse array of sensory and motor circuits that are essential for normal function. Spinal cord injury (SCI) permanently disrupts neural circuits through initial mechanical damage, as well as a cascade of secondary injury events that further expand the spinal cord lesion, resulting in permanent paralysis. Tissue clearing and 3D imaging have recently emerged as promising techniques to improve our understanding of the complex neural circuitry of the spinal cord and the changes that result from damage due to SCI. However, the application of this technology for studying the intact and injured spinal cord remains limited. Here we optimized the passive CLARITY technique (PACT) to obtain gentle and efficient clearing of the murine spinal cord without the need for specialized equipment. We demonstrate that PACT clearing enables 3D imaging of multiple fluorescent labels in the spinal cord to assess molecularly defined neuronal populations, acute inflammation, long-term tissue damage, and cell transplantation. Collectively, these procedures provide a framework for expanding the utility of tissue clearing to enhance the study of spinal cord neural circuits, as well as cellular- and tissue-level changes that occur following SCI.
Spatiotemporal variations of surface water microplastics near Kyushu, Japan: A quali-quantitative analysis
Authors: Kobayashi Tsunefumi , Yagi Mitsuharu , Kawaguchi Toshiya , Hata Toshiro , Shimizu Kenichi
Published: March 2021

Microplastics in the ocean are threatening marine ecosystems. Although plastic contaminants are ubiquitous from rivers to polar oceans, their distribution is thought to be heterogeneous, implying that both spatial and temporal variability exist. Here, we elucidate the significant spatial and temporal (seasonal) variations in the quanti-qualitative characteristics of microplastics off the west coast of Kyushu, Japan in the East China Sea. Six surveys across nine stations (n = 54) were conducted over a 14-month period, and a total of 6131 plastic items were identified. The average microplastic abundance (items ·m-3) and size (mm) ± S.D. were 0.49 ± 0.92 (n = 54), and 1.71 ± 0.93 (n = 6131), respectively. Differences between the highest and lowest abundances were 50-fold among monthly means (1.97 ± 1.49, n = 9; 0.04 ± 0.03, n = 9), and 550-fold across all net tows (5.50; 0.01). With respect to colour, polymer type, and shape, white and transparent (68.5%), polyethylene (80%) fragments (76.0%) were the dominant composition. There were statistically significant differences for each of the analytical microplastic parameters among survey months (p < 0.02). Our results provide baseline data, and lead to a more comprehensive understanding of the spatiotemporal characteristics of microplastic pollution.

Highlights

Significant spatiotemporal variability in microplastic litter was detected based on the quali-quantitative analyses.

Average (± S.D.) microplastic abundance was 0.49 ± 0.92 (items ·m-3) and size was 1.71 ± 0.93 (mm).

Differences between highest and lowest abundances were 50-fold among monthly means, and 550-fold across all net tows.

White and transparent polyethylene fragments were the dominant composition.
Evolution of mechanisms controlling epithelial morphogenesis across animals: new insights from dissociation - reaggregation experiments in the sponge Oscarella lobularis.
Authors: Vernale Amelie , Prunster Maria Mandela , Marchiano Fabio , Debost Henry , Brouilly Nicolas , Rocher Caroline , Massey Harroche Dominique , RENARD Emmanuelle , Le Bivic Andre , Habermann Bianca H , Borchiellini Carole
Published: March 2021

Background: The ancestral presence of epithelia in Metazoa is no longer debated. Even though Porifera seem to be the best candidates to be the sister group to all other Metazoa, hardly anything is known about the proteins involved in the composition of cell-cell junctions or about the mechanisms that regulate epithelial morphogenetic processes in this phylum. Results: To get insights into the early evolution of epithelial morphogenesis, we focused on morphogenic characteristics of the homoscleromorph sponge Oscarella lobularis. Homoscleromorpha are a sponge class with a typical basement membrane and adherens-like junctions unknown in other sponge classes. We took advantage of the dynamic context provided by cell dissociation-reaggregation experiments to explore morphogenetic processes in epithelial cells in an early lineage by combining fluorescent and electronic microscopy observations and RNA sequencing approaches at key time-points of the dissociation and reaggregation processes. Conclusions: Our results show that part of the molecular toolkit involved in the loss and restoration of epithelial features such as cell-cell and cell-matrix adhesion is conserved between Homoscleromorpha and Bilateria, suggesting their common role in the last common ancestor of animals. In addition, Sponge-specific genes are differently expressed during the dissociation and reaggregation processes, calling for future functional characterization of these genes.
Chimpanzees communicate to coordinate a cultural practice
Authors: Goldsborough Zoë , Schel Anne Marijke , van Leeuwen Edwin J. C.
Published: March 2021

Human culture thrives by virtue of communication, yet whether communication plays an influential role in the cultural lives of other animals remains understudied. Here, we investigated whether chimpanzees use communication to engage in a cultural practice by analyzing grooming handclasp (GHC) interactions – a socio-cultural behavior requiring inter-individual coordination for its successful execution. Previous accounts attributed GHC initiations to behavioral shaping whereby the initiator physically molds the partner’s arm into the desired GHC posture. Using frame-by-frame analysis and matched-control methodology, we find that chimpanzees do not only shape their partner’s posture (22%), but also use gestural communication to initiate GHC (44%), which requires an active and synchronized response from the partner. Moreover, in a third (34%) of the GHC initiations, the requisite coordination was achieved by seemingly effortless (i.e., no shaping or communication) synchrony. Lastly, using a longitudinal approach, we find that communication occurs more frequently than shaping in experienced dyads and less in mother-offspring dyads. These findings are consistent with the theory of ontogenetic ritualization, thereby reflecting the first documentation of learned communication in a cultural context. We conclude that chimpanzees show situation-contingent interactional flexibility in the socio-cultural domain, opening the possibility that the interplay between communication and culture is rooted in our deep evolutionary history.
Do exercise-associated genes explain phenotypic variance in the three components of fitness? A Systematic review & Meta-analysis
Authors: Chung Henry C , Keiller Don R , Roberts Justin D , Gordon Dan A
Published: March 2021

The aim of this systematic review and meta-analysis was to identify a list of common, candidate genes associated with the three components of fitness, specifically cardiovascular fitness, muscular strength, and anaerobic power, and how these genes are associated with exercise response phenotype variability, in previously untrained participants. A total of 3,969 potentially relevant papers were identified and processed for inclusion. After eligibility and study selection assessment, 24 studies were selected for meta-analysis, comprising a total of 3,012 participants. Meta-Essentials spreadsheet 1.4 (Microsoft Excel) was used in creating the forest plots and meta-analysis. IBM SPSS statistics V24 was implemented for the statistical analyses and the alpha was set atp≤ 0.05. 13 candidate genes and their associated alleles were identified, which were associated with the phenotypes of interest. Analysis of training group data showed significant differential phenotypic responses. Subgroup analysis showed; 44%, 72% and 10% of the response variance in aerobic, strength and power phenotypes, respectively, were explained by genetic influences. This analysis established that genetic variability explained a significant proportion of the adaptation differences across the three components of fitness in the participants post-training. The results also showed the importance of analysing and reporting specific gene alleles. Information obtained from these findings has the potential to inform and influence future exercise-related genes and training studies.
Individualized Spatial Network Predictions Using Siamese Convolutional Neural Networks: A Resting-State fMRI Study of over 11,000 Unaffected Individuals
Authors: Hassanzadeh Reihaneh , Silva Rogers F. , Abrol Anees , Salman Mustafa , Bonkhoff Anna , Du Yuhui , Fu Zening , DeRamus Thomas , Damaraju Eswar , Baker Bradley , Calhoun Vince D.
Published: March 2021

Individuals can be characterized in a population according to their brain measurements and activity, given the inter-subject variability in brain anatomy, structure-function relationships, or life experience. Many neuroimaging studies have demonstrated the potential of functional network connectivity patterns estimated from resting functional magnetic resonance imaging (fMRI) to discriminate groups and predict information about individual subjects. However, the predictive signal present in the spatial heterogeneity of brain connectivity networks is yet to be extensively studied. In this study, we investigate, for the first time, the use of pairwise-relationships between resting-state independentspatial mapsto characterize individuals. To do this, we develop a deep Siamese framework comprising three-dimensional convolution neural networks for contrastive learning based on individual-level spatial maps estimated via a fully automated fMRI independent component analysis approach. The proposed framework evaluates whether pairs of spatial networks (e.g., visual network and auditory network) are capable of subject identification and assesses the spatial variability in different network pairs’ predictive power in an extensive whole-brain analysis. Our analysis on nearly 12,000 unaffected individuals from the UK Biobank study demonstrates that the proposed approach can discriminate subjects with an accuracy of up to 88% for a single network pair on the test set (best model, after several runs), and 82% average accuracy at the subcortical domain level, notably the highest average domain level accuracy attained. Further investigation of our network’s learned features revealed a higher spatial variability in predictive accuracy among younger brains and significantly higher discriminative power among males. In sum, the relationship among spatial networks appears to be both informative and discriminative of individuals and should be studied further as putative brain-based biomarkers.
Failure of the brain glucagon-like peptide-1-mediated control of intestinal redox homeostasis in a rat model of sporadic Alzheimer’s disease
Authors: Homolak Jan , Perhoc Ana Babic , Knezovic Ana , Barilar Jelena Osmanovic , Salkovic-Petrisic Melita
Published: March 2021

The gastrointestinal system may be involved in the etiopathogenesis of the insulin-resistant brain state (IRBS) and Alzheimer’s disease (AD). Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is being explored as a potential therapy as activation of brain GLP-1 receptors (GLP-1R) exerts neuroprotection and controls peripheral metabolism. Intracerebroventricular administration of streptozotocin (STZ-icv) is used to model IRBS and GLP-1 dyshomeostasis seems to be involved in the development of neuropathological changes. The aim was to explore i) gastrointestinal homeostasis in the STZ-icv model ii) assess whether the brain GLP-1 is involved in the regulation of gastrointestinal redox homeostasis and iii) analyze whether brain-gut GLP-1 axis is functional in the STZ-icv animals. Acute intracerebroventricular treatment with exendin-3(9-39)amide was used for pharmacological inhibition of brain GLP-1R in the control and STZ-icv rats, and oxidative stress was assessed in plasma, duodenum and ileum. Acute inhibition of brain GLP-1R increased plasma oxidative stress. TBARS were increased, and LMWT, SH, and superoxide dismutase (SOD) were decreased in the duodenum, but not in the ileum of the controls. In the STZ-icv, TBARS and CAT were increased, LMWT and SH were decreased at baseline, and no further increment of oxidative stress was observed upon central GLP-1R inhibition. The presented results indicate that i) oxidative stress is increased in the duodenum of the STZ-icv rat model of AD, ii) brain GLP-1R signaling is involved in systemic redox regulation, iii) brain-gut GLP-1 axis regulates duodenal, but not ileal redox homeostasis, and iv) brain-gut GLP-1 axis is dysfunctional in the STZ-icv model.
The multi-functional reovirus σ3 protein is a virulence factor that suppresses stress granule formation to allow viral replication and myocardial injury
Authors: Guo Yingying , Hinchman Meleana , Lewandrowski Mercedes , Cross Shaun , Sutherland Danica M. , Welsh Olivia L. , Dermody Terence S. , Parker John S. L.
Published: March 2021

The mammalian orthoreovirus double-stranded (ds) RNA binding protein σ3 is a multifunctional protein that promotes viral protein synthesis and facilitates viral entry and assembly. The dsRNA-binding capacity of σ3 correlates with its capacity to prevent dsRNA-mediated activation of protein kinase R (PKR). However, the effect of σ3 binding to dsRNA during viral infection remains largely unknown. To identify functions of σ3 dsRNA-binding activity during reovirus infection, we engineered a panel of 13 σ3 mutants and screened them for the capacity to bind dsRNA. Six mutants were defective in dsRNA binding, and mutations in these constructs cluster in a putative dsRNA-binding region on the surface of σ3. Two recombinant viruses expressing these σ3 dsRNA-binding mutants, K287T and R296T, display strikingly different phenotypes. In a cell-type dependent manner, K287T, but not R296T, replicates less efficiently than wild-type (WT) virus. In cells in which K287T virus demonstrates a replication deficit, PKR activation occurs and abundant stress granules (SGs) are produced at late times post-infection. In contrast, the R296T virus retains the capacity to suppress activation of PKR and does not form SGs at late times post-infection. These findings indicate that σ3 inhibits PKR independently of its capacity to bind dsRNA. In infected mice, K287T produces lower viral titers in the spleen, liver, lungs, and heart relative to WT or R296T. Moreover, mice inoculated with WT or R296T viruses develop myocarditis, whereas those inoculated with K287T do not. Overall, our results indicate that σ3 functions to suppress PKR activation and subsequent SG formation during viral infection and that these functions correlate with virulence in mice.
Computational Structure Prediction Provides a Plausible Mechanism for Electron Transfer by the Outer Membrane Protein Cyc2 fromAcidithiobacillus ferrooxidans
Authors: Jiang Virginia , Khare Sagar D. , Banta Scott
Published: March 2021

Cyc2 is the key protein in the outer membrane ofAcidithiobacillus ferrooxidansthat mediates electron transfer between extracellular inorganic iron and the intracellular central metabolism. This cytochrome c is specific for iron and interacts with periplasmic proteins to complete a reversible electron transport chain. A structure of Cyc2 has not yet been characterized experimentally. Here we describe a structural model of Cyc2, and associated proteins, to highlight a plausible mechanism for the ferrous iron electron transfer chain. A comparative modeling protocol specific for trans membrane beta barrel (TMBB) proteins in acidophilic conditions (pH ~2) was applied to the primary sequence of Cyc2. The proposed structure has three main regimes: extracellular loops exposed to low-pH conditions, a TMBB, and a N-terminal cytochrome-like region within the periplasmic space. The Cyc2 model was further refined by identifying likely iron and heme docking sites. This represents the first computational model of Cyc2 that accounts for the membrane microenvironment and the acidity in the extracellular matrix. This approach can be used to model other TMBBs which can be critical for chemolithotrophic microbial growth.

Importance of work

Acidithiobacillus ferrooxidanscan oxidize both iron and reduced sulfur compounds and plays a key role in metal sulfide ore bioleaching used for the industrial recovery of metals.A. ferrooxidanshas also been explored as a potential organism for emerging technologies such as e-waste recycling and biofuel production. Synthetic biology efforts are hampered by lack of knowledge about the mechanisms of iron oxidation and reduction, which is mediated by the Cyc2 transmembrane beta barrel (TMBB) protein.
Gliding in the Amazonian canopy: adaptive evolution of flight inMorphobutterflies
Authors: Le Roy Camille , Amadori Dario , Charberet Samuel , Windt Jaap , Muijres Florian T. , Llaurens Violaine , Debat Vincent
Published: March 2021

The diversity of flying animals suggests that countless combinations of morphologies and behaviors have evolved with specific lifestyles, thereby exploiting diverse aerodynamic mechanisms. Elucidating how morphology, flight behavior and aerodynamic properties together diversify with contrasted ecologies remains however seldom accomplished. Here, we studied the adaptive co-divergence in wing shape, flight behavior and aerodynamic efficiency amongMorphobutterflies living in different forest strata, by combining high-speed videography in the field with morphometric analyses and aerodynamic modelling. By comparing canopy and understory species, we show that adaptation to an open canopy environment resulted in increased glide efficiency. Moreover, this enhanced glide efficiency was achieved by different canopy species through strikingly distinct combinations of flight behavior, wing shape and aerodynamic mechanisms, highlighting the multiple pathways of adaptive evolution.

One Sentence Summary

By combining high-speed videography, geometric morphometrics and computational aerodynamic modelling, our study of wild AmazonianMorphobutterflies reveals a strong contrast between the efficient gliding flight of canopy species and the powerful flapping flight of understory species, pointing at a combined adaptive divergence of wing shape and flight behavior among sympatric species flying in different forest strata.
Emergence of directional bias in tau deposition from axonal transport dynamics
Authors: Torok Justin , Maia Pedro D. , Verma Parul , Mezias Christopher , Raj Ashish
Published: March 2021

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer’s disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.

Author Summary

The misfolding and spread of the axonal protein tau is a hallmark of the pathology of many neurodegenerative disorders, including Alzheimer’s disease and frontotemporal lobar dementia. How tau misfolding causes disorders with distinct neuropathology and clinical presentations is the subject of ongoing research. Although current evidence suggests that the specific conformations tau adopts affect where it spreads throughout the brain, a mechanistic explanation has remained elusive. Here we propose that the conformer-specific dysregulation of axonal transport can lead to directionally biased spread, and we employ a mathematical model to explore how tau spreads between neurons in the context of this transport feedback mechanism. We find that conformation-specific feedback is flexible enough to explain bias in either direction and thoroughly explore how this bias emerges as a function of the model’s key parameters. Further, the model reproduces the temporal evolution of directionality observed in two classes ofin vivotauopathy models, demonstrating that transport feedback is sufficient to explain differential tau spread as a function of conformation.
Paraxial mesoderm organoids model development of human somites
Authors: Budjan Christoph , Liu Shichen , Ranga Adrian , Gayen Senjuti , Pourquie Olivier , Hormoz Sahand
Published: March 2021

During the development of the vertebrate embryo, segmented structures called somites are periodically formed from the presomitic mesoderm (PSM), and give rise to the vertebral column. While somite formation has been studied in several animal models, it is less clear how well this process is conserved in humans. Recent progress has made it possible to study aspects of human paraxial mesoderm development such as the human segmentation clockin vitrousing human pluripotent stem cells (hPSCs), however, somite formation has not been observed in these monolayer cultures. Here, we describe the generation of human paraxial mesoderm (PM) organoids from hPSCs (termed Somitoids), which recapitulate the molecular, morphological and functional features of paraxial mesoderm development, including formation of somite-like structuresin vitro. Using a quantitative image-based screen, we identify critical parameters such as initial cell number and signaling modulations that reproducibly yielded somite formation in our organoid system. In addition, using single-cell RNA sequencing and 3D imaging, we show that PM organoids both transcriptionally and morphologically resemble theirin vivocounterparts and can be differentiated into somite derivatives. Our organoid system is reproducible and scalable, allowing for the systematic and quantitative analysis of human spinal cord development and diseasein vitro.
Implementing QR Codes in Academia to Improve Sample Tracking, Data Accessibility, and Traceability in Multicampus Interdisciplinary Collaborations
Authors: Hernandez Cristian , Aslankoohi Elham , Frolikov Pavel , Kurniawan Sri , Rolandi Marco
Published: March 2021

With the growing number of multicampus interdisciplinary projects in academic institutions, there is an increasing need for tracking systems that make device and sample data and associated results instantly accessible to all collaborators involved. This need has become particularly salient with the COVID pandemic and consequent travel restrictions that have hampered in person meetings and laboratory visits. We report a Quick Response (QR) code tracking system that integrates project management tools for seamless communication and tracking of materials and devices between three manufacturing sites (cleanrooms) and six research laboratories across five universities. We use this system to track the design, fabrication, and quality control of bioelectronic devices (in the cleanroom and engineering laboratories),in vitroexperimental results (in a biology laboratory), andin vivotesting (in the school of medicine). Setting up a tracking system for multisite interdisciplinary teams improves traceability, efficiency, and the quality of produced results making it easier to accomplish project milestones on a tight timeline. This tracking system is particularly useful to track device issues and ensure engineering device consistency when working with expensive biological samplesin vitroand animalsin vivoto reduce waste of biological and animal resources associated with device failure.
The Dual-Antigen Ad5 COVID-19 Vaccine Delivered as an Intranasal Plus Subcutaneous Prime Elicits Th1 Dominant T-Cell and Humoral Responses in CD-1 Mice
Authors: Rice Adrian , Verma Mohit , Shin Annie , Zakin Lise , Sieling Peter , Tanaka Shiho , Balint Joseph , Dinkins Kyle , Adisetiyo Helty , Morimoto Brett , Higashide Wendy , Taft Justin , Patel Rosheel , Buta Sofija , Martin-Fernandez Marta , Bogunovic Dusan , Spilman Patricia , Gabitzsch Elizabeth , Safrit Jeffrey T. , Rabizadeh Shahrooz , Niazi Kayvan , Soon-Shiong Patrick
Published: March 2021

In response to the need for an efficacious, thermally-stable COVID-19 vaccine that can elicit both humoral and cell-mediated T-cell responses, we have developed a dual-antigen human adenovirus serotype 5 (hAd5) COVID-19 vaccine in formulations suitable for subcutaneous (SC), intranasal (IN), or oral delivery. The vaccine expresses both the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins using an hAd5 platform with E1, E2b, and E3 sequences deleted (hAd5[E1-, E2b-, E3-]) that is effective even in the presence of hAd5 immunity. In the vaccine, S is modified (S-Fusion) for enhanced cell-surface display to elicit humoral responses and N is modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal pathway to increase MHC I and II presentation. Initial studies using subcutaneous (SC) prime and SC boost vaccination of CD-1 mice demonstrated that the hAd5 S-Fusion + N-ETSD vaccine elicits T-helper cell 1 (Th1) dominant T-cell and humoral responses to both S and N. We then compared SC to IN prime vaccination with either an SC or IN boost post-SC prime and an IN boost after IN prime. These studies reveal that IN prime/IN boost is as effective at generating Th1 dominant humoral responses to both S and N as the other combinations, but that the SC prime with either an IN or SC boost elicits greater T cell responses. In a third study to assess the power of the two routes of delivery when used together, we used a combined SC plus IN prime with or without a boost and found the combined prime alone to be as effective as the combined prime with either an SC or IN boost in generating both humoral and T-cell responses. The findings here in CD-1 mice demonstrate that combined SC and IN prime-only delivery has the potential to provide broad immunity – including mucosal immunity – against SARS-CoV-2 and supports further testing of this delivery approach in additional animal models and clinical trials.
scTenifoldKnk: an efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation
Authors: Osorio Daniel , Zhong Yan , Li Guanxun , Xu Qian , Yang Yongjian , Tian Yanan , Chapkin Robert S. , Huang Jianhua Z. , Cai James J.
Published: March 2021

Bigger Picture

Gene knockout (KO) experiments, using genetically altered animals, are a proven powerful approach to elucidate the role of a gene in a biological process. However, systematic KO experiments targeting many genes are usually prohibitive due to limited experimental and animal resources. Here, we present scTenifoldKnk, an efficient virtual KO tool that allows the systematic deletion of many genes individually. scTenifoldKnk uses single-cell RNA sequencing (scRNAseq) data from wild-type (WT) samples to predict gene function in a cell type-specific manner. We show that predictions made by scTenifoldKnk recapitulate findings from real-animal KO experiments. scTenifoldKnk has proven to be a powerful and effective approach for elucidating gene function, prioritizing KO targets, predicting experimental outcomes before real-animal KO experiments are conducted.

Highlights

scTenifoldKnk performs virtual KO experiments using scRNAseq data.

scTenifoldKnk only requires data from WT samples; no data is needed from KO samples.

Predictions made by scTenifoldKnk recapitulate findings from real-animal KO experiments.

Data Science Maturity Level

eTOC blurb

scTenifoldKnk is a machine learning workflow performing virtual KO experiments to predict gene function. It constructs gene regulatory networks using single-cell RNA sequencing data from wild-type samples and then computationally deletes target genes. Real-data applications demonstrate that scTenifoldKnk recapitulates findings of real-animal KO experiments and accurately predicts gene function in analyzed cells.

Gene knockout (KO) experiments are a proven, powerful approach for studying gene function. However, systematic KO experiments targeting a large number of genes are usually prohibitive due to the limit of experimental and animal resources. Here, we present scTenifoldKnk, an efficient virtual KO tool that enables systematic KO investigation of gene function using data from single-cell RNA sequencing (scRNAseq). In scTenifoldKnk analysis, a gene regulatory network (GRN) is first constructed from scRNAseq data of wild-type samples, and a target gene is then virtually deleted from the constructed GRN. Manifold alignment is used to align the resulting reduced GRN to the original GRN to identify differentially regulated genes, which are used to infer target gene functions in analyzed cells. We demonstrate that the scTenifoldKnk-based virtual KO analysis recapitulates the main findings of real-animal KO experiments and recovers the expected functions of genes in relevant cell types.