bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of a FAD-Linked Oxidase RSc0454 for Expression of the Type III Secretion System and Pathogenicity in Ralstonia solanacearum
Authors: Chen Min , Chen Nan , Wang Jiwu , Zhou YuJian , Han Liangliang , Shi Xiaojun , Hikichi Yasufumi , Ohnishi Kouhei , Li Jing , Zhang Yong
Published: August 2021

Ralstonia solanacearum RSc0454 is predicted as a FAD-linked oxidase based on protein homologies, while it contains distinct domains of lactate dehydrogenase and succinate dehydrogenase. A previous study demonstrated that RSc0454 exhibits lactate dehydrogenase activity using pyruvate and NADH as substrates, and is essential for pathogenicity of R. solanacearum. Here, we genetically characterized involvement of RSc0454 on bacterial growth and expression of genes for the type III secretion system (T3SS, a pathogenicity determinant) in R. solanacearum. The RSc0454 mutant grew normally in rich medium but grew faintly in host plants, and failed to grow in minimal medium. Supplementary succinate but not lactate could substantially restore some phenotypes of RSc0454 mutants, including faint growth in host plants, diminished growth in the minimal medium, and lost pathogenicity toward host plants. Expression of T3SS genes is directly controlled by a master regulator, HrpB, and hrpB expression is positively regulated by HrpG and PrhG in parallel ways. Deletion of RSc0454 substantially reduced expression levels of hrpB and T3SS both in vitro and in planta. Moreover, RSc0454 is revealed to be required for the T3SS expression via HrpG and PrhG, although through some novel pathway, and impaired expression of these genes was not due to growth deficiency of RSc0454 mutants. RSc0454 is suggested to be important for redox balance inside cells, and supplementary NADH partially restored diminished growth of the RSc0454 mutant in the minimal medium only in the presence of succinate at some moderate concentrations, indicating that the unbalanced redox in the RSc0454 mutant might be responsible for its diminished growth in the minimal medium. Taken together, these results provide novel insights into the understanding of various biological functions of this FAD-linked oxidase RSc0454 and involvement of the redox balance on expression of the T3SS in R. solanacearum.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Basophil activation test in food allergy: is it ready for real-time?
Authors: Keswani Tarun , Patil Sarita U.
Published: August 2021

Purpose of review

Utilization of basophil activation in the diagnosis and monitoring of food allergy has gained increasing recognition. An ex-vivo functional assay, basophil activation reflects clinical reactivity, thereby providing clinically relevant insights. Moreover, as a biomarker of reactivity and tolerance, basophil activation testing (BAT) may provide a useful tool for management of food allergies. Despite its utility, significant limitations of BAT have prevented widespread use. Addressing these limitations will increase the future application and adoption of BAT in food allergy.

Recent findings

A number of clinical trials in the past few years have demonstrated the use of BAT in the diagnosis and treatment of food allergy. Specifically, BAT has been found to be a biomarker of tolerance.

Basophil activation testing is an effective biomarker for diagnosis and monitoring of food allergy.
Clinical Application of Platelet-Rich Fibrin in Dermatology
Authors: Wu Qing-Yun , Zhang Qian , Fang Fang , Bu Wen-Bo
Published: August 2021

Platelet-rich fibrin (PRF) is a second-generation platelet concentrate obtained from autologous blood. PRF is composed of abundant platelets, leucocytes, and a high concentration of various growth factors and fibrinogen. The composition and three-dimensional structure of PRF enable it to effectively make cells migrate and proliferate, playing an important role in tissue repair. Furthermore, the easy preparation and low cost of PRF make it a good treatment option. Numerous articles have been published about the application of PRF in clinical practice, however, the application of PRF in dermatology has not been comprehensively reviewed. The objective of this review article was to discuss various applications of PRF in dermatology, including healing chronic wounds, treating androgenic alopecia, skin rejuvenation, autologous fat transplantation, and treating vitiligo. PRF is a promising dermatologic treatment, but lacks a standardized protocol regarding its methods of attainment and use, which needs more investigations.
Use of xenografts and allografts in scalp reconstruction
Authors: Poonia Seerat K. , Harris Brianna N.
Published: August 2021

Purpose of review

Scalp reconstruction requires a full array of reconstructive options given the complex anatomy and protection of vital structures. Not all patients qualify for advanced reconstructive options and therefore rely on short, effective procedures with minimal morbidity. This review aims to focus on xenografts and allografts to achieve an adequate reconstruction while minimizing morbidity.

Recent findings

Although bovine xenografts have been used for many decades, there have been recent advances in porcine xenografts to aid in scalp defects. Similarly, new allogenic materials have emerged as additional tools in the armamentarium to promote wound healing.

Both xenografts and allografts offer viable options for complex scalp reconstruction.
Use of advanced cardiac imaging in congenital heart disease: growth, indications and innovations
Authors: Steele Jeremy M. , Moore Ryan A. , Lang Sean M.
Published: August 2021

Purpose of review

Significant improvements in the diagnosis and management of patients with congenital heart disease (CHD) have led to improved survival. These patients require life-long noninvasive evaluation. The use of advanced imaging such as cardiac magnetic resonance imaging (CMR) and cardiac computed tomography (CCT) has increased to support this need. The purpose of this review is to discuss the basics of advanced cardiac imaging, indications and review the recent innovations.

Recent findings

Recent literature has demonstrated the increasing reliance of advanced imaging for CHD patients. In addition, research is focusing on CMR techniques to shorten scan time and address previous limitations that made imaging younger and sicker patients more challenging. CCT research has involved demonstrating high-quality images with low radiation exposure. Advances in digital technology have impacted the interactivity of 3D imaging through the use of virtual and augmented reality platforms. With the increased reliance of advanced imaging, appropriate use criteria have been developed to address possible under or over utilization.

The utilization of advanced cardiac imaging continues to increase. As CMR and CCT continue to grow, increased knowledge of these modalities and their usage will be necessary for clinicians caring for CHD patients.
Age disparities in transplantation
Authors: Melandro Fabio , Del Turco Serena , Ghinolfi Davide
Published: August 2021

Purpose of review

The aim of this review is to outline disparities in liver and kidney transplantation across age spectrum. Disparities do not involve only recipients whose age may severely affect the possibility to access to a potentially life-saving procedure, but donors as well. The attitude of transplant centers to use older donors reflects on waiting list mortality and drop-out. This review examines which age categories are currently harmed and how different allocation systems may minimize disparities.

Recent findings

Specific age categories suffer disparities in the access to transplantation. A better understanding of how properly evaluate graft quality, a continuous re-evaluation of the most favorable donor-to-recipient match and most equitable allocation system are the three key points to promote ‘justice and equality’ among transplant recipients.

The duty to protect younger patients waiting for transplantation and the request of older patients to have access to potentially life-saving treatment urge the transplant community to use older organs thus increasing the number of available grafts, to evaluate new allocation systems with the aim to maximize ‘utility’ while respecting ‘equity’ and to avoid ‘futility’ thus minimizing waiting list mortality and drop-out, and improving the survival benefits for all patients requiring a transplant.

Video abstract

http://links.lww.com/COOT/A9
Mental Health Impact in Latin American Pediatric Rheumatologists During the COVID-19 Pandemic
Authors: Kozu Kátia T. , Casella Caio B. , Strabelli Claudia A.A. , Aikawa Nadia E. , Campos Lucia M.A. , Elias Adriana M. , Miguel Eurípedes C. , Polanczyk Guilherme V. , Silva Clovis A.
Published: August 2021

Objective

The aim of this study was to assess mental health in Latin American pediatric rheumatologists (LAPRs) during the COVID-19 pandemic.

Methods

A cross-sectional study was performed with 318 LAPRs based on an online, self-rated survey about clinical practice/mental health impacts during the COVID-19 pandemic. Validated self-reported scales for anxiety (Generalized Anxiety Disorder [GAD-7]) and depression (Patient Health Questionnaire [PHQ-9]) were evaluated.

Results

The response rate was 126 of 318 (40%), including 13 of 20 (65%) Latin American countries. Working on the COVID-19 frontline was reported by 27% of LAPRs. Anxiety and moderate/severe depression were observed in 49% and 25%, respectively. No LAPRs reported previous mental health disorders. Deaths of childhood-onset systemic lupus erythematosus and juvenile idiopathic arthritis patients with confirmed/suspected COVID-19 were reported by 8% and 2% of LAPRs, respectively. Further analysis of LAPRs revealed that the median current age was significantly lower in LAPRs with anxiety than in those without anxiety (39 [29–43] vs 45 [30–70] years, p = 0.029). Working on the frontline of COVID-19 (37% vs 17%, p = 0.015), feeling helpless (39% vs 17%, p = 0.009), and experiencing burnout (39% vs 11%, p = 0.0001) were factors significantly higher in LAPRs with anxiety. Median nighttime sleep abnormalities measured by the visual analog scale (VAS) (8 [0–10] vs 4 [0–10], p = 0.009) were significantly higher in the anxiety group, whereas the physical activity VAS was lower (0.5 [0–10] vs 3 [0–10], p = 0.005). A positive Spearman correlation was shown between the GAD-7 score and nighttime sleep abnormality VAS score (r = +0.348, p < 0.001), and a negative correlation was shown between the GAD-7score and physical activity VAS score (r = −0.192, p = 0.031).

Conclusions

Anxiety and depression were relevant to the experience of LAPRs during the COVID-19 pandemic, impacting their mental health. Reporting information about mental health is essential to planning future preventive and health promotion strategies.
Effects of gelling agents and sugar substitutes on the quality
characteristics of carrot jelly
Authors: Park Jong Jin , Olawuyi Ibukunoluwa Fola , Park Gwang Deok , Lee Won Young
Published: August 2021

In this study, the quality characteristics of carrot jellies prepared using
different gelling agents (gelatin and carrageenan) and sugar substitutes
(sucrose, sorbitol, and xylitol) were evaluated. The effects of gelling agents
and sugar substitutes on the pH, °Brix, color, syneresis, melting-down
rate, textural properties, and sensory acceptance of the jellies were
determined. Textural analysis indicated that gelatin-based jellies containing
sugar substitutes sorbitol and xylitol showed higher hardness than that of
gelatin-based jelly containing sucrose. Among all samples, jellies containing
1.5% (w/v) carrageenan showed higher hardness, cohesiveness, and chewiness than
those of other jellies, regardless of the sugar substitute. The pH and
°Brix of carrageenan-based jellies were lower than those of gelatin-based
jellies. The instrumental color values of jellies containing gelatin decreased
with an increase in gelatin concentration. Gelatin-based jellies (3 and 5 %)
containing sucrose and gelatin-based jelly (5%) containing xylitol showed lower
syneresis than that in other jellies. Jelly containing 5% gelatin content had a
lower melting-down rate compared with that containing 3% gelatin content.
Moreover, carrageenan-based jellies showed a lower melting-down rate than that
of gelatin-based jellies Carrot jellies containing 3% gelatin and xylitol showed
a high score for sensory acceptance. Based on the results, the utilization of 3%
gelatin and xylitol as a sugar substitute is suitable for producing carrot
jellies showing high sensory preference and stability.
Full vaccination against COVID-19 suppresses SARS-CoV-2 delta variant and spike gene mutation frequencies and generates purifying selection pressure
Authors: Yeh Ting-Yu , Contreras Gregory P.
Published: August 2021

COVID-19 vaccination resistance has become a major challenge to prevent global SARS-CoV-2 transmission. Here we report that the vaccination coverage rate is inversely correlated to the mutation frequency of the full genome (R2=0.878) and spike gene (R2=0.829) of SARS-CoV-2 delta variants in 16 countries, suggesting that full vaccination against COVID-19, with other mitigation strategies, is critical to suppress emergent mutations. Neutrality analysis of DH and Zeng E tests suggested that directional selection was the major driving force of delta variant evolution. To eliminate the homogenous effects (population expansion, selective sweep etc.), the synonymous (Dsyn) and nonsynonymous (Dnonsyn) polymorphisms of the delta variant spike gene were estimated with Tajima D statistic. Both D ratio (Dnonsyn/Dsyn) and deltaD (Dsyn-Dnonsyn) have positive correlation with the full vaccination rate (R2= 0.723 and 0.505, respectively) in 19 countries, indicating that purifying selection pressure of SARS-CoV-2 spike gene increased as the vaccination coverage rate increased. Taken together, our data suggests that vaccination plays an important role in the purifying selection force of spike protein of SARS-CoV-2 delta variants.
IGF-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit
Authors: Hayes Cellas A. , Ashmore Brandon G. , Vijayasankar Akshaya , Marshall Jessica P. , Ashpole Nicole M.
Published: August 2021

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.
Antibody response in individuals affected with Sars-Cov-2 infection: temporal trends and qualitative and quantitative differences in symptomatic and asymptomatic subjects. A Cross Sectional Analysis. Ab-Covid Study
Authors: Abraha Iosief , Germani Antonella , Pasquarelli Erica , Pascolini Sofia , Antonietti Rossana , Argenti Sandro , Fioravanti Alessandra , Martini Elisa , Aristei Luana , Mancinelli Paola , Ottaviani Maria Letizia , Roselli Martina , Barzacca Milena , Belardinelli Erika , Micheli Marta
Published: August 2021

Objectives To describe clinical characteristics and treatment used in subjects who had Sars-Cov-2 infection during the first pandemic and to assess the correlation between serological titers and clinical characteristics; to evaluate the persistence of anti-Sars-Cov-2 titers over a follow-up of 12.
Design Cross-sectional study.
Setting Residents in Azienda USL Umbria 2.
Participants Consecutive subjects aged 15 to 75 who from February, 2020, to March 2021 were discharged with the diagnosis of Sars-Cov-2 from the hospitals of the AUSL Umbria 2, or resulted positive to a PCR test for Sars-Cov-2 infection with or without symptoms. Participants were classified according to clinical findings. SARS-CoV-2 serologic testing for antibodies targeting the Nucleocapside and Spike proteins were determined.
Results Of 184 eligible subjects, 149 were available for evaluation: 17 were classified as Oligo/asymptomatic, 107 as Symptomatic (with no hospital admission), 25 as Hospital. While fever resulted common to all the groups, headache or musculoskeletal pain was common to symptomatic participants whereas cough and dyspnea was present in all the hospital admitted. Participants with significant signs and symptoms were more likely to use antibiotics, hydroxychloroquine, heparin and steroids.
Compared to Oligo/asymptomatic participants, Symptomatic and Hospital admitted participants had higher levels of anti-S titers at every follow-up (median titer at 12 month follow-up: 29 vs 94 vs 116 respectively; P < 0.001). At 12 months follow-up, anti-S titers persisted above the threshold for at least 12 months in all Hospital admitted participants, in 90% of the Symptomatic participants and 83% in the oligo/asymptomatic participants; in 30% of participants the titer raised significantly probably due to reinfection. Anti-N antibody titer tended to decrease over time and in 62% of the entire cohort resulted negative.
None of the participants reported clinical reinfection with Sars-Cov-2 virus.
Conclusion - Anti-S and anti-N antibody titers correlates well with disease severity. While anti-N decline overtime, anti-S antibodies persist for at least one year and most probably provide protection from reinfection.
Immune enhancement to prevent infected pancreatic necrosis: A double-blind randomized controlled trial
Authors: Ke Lu , Zhou Jing , Mao Wenjian , Chen Tao , Zhu Yin , Pan Xinting , Mei Hong , Singh Vikesh , Buxbaum James , Doig Gordon , He Chengjian , Gu Weili , Lu Weihua , Tu Shumin , Ni Haibin , Zhang Guoxiu , Zhao Xiangyang , Sun Junli , Chen Weiwei , Song Jingchun , Shao Min , Tu Jianfeng , Xia Liang , He Wenhua , Zhu Qingyun , Li Kang , Yao Hongyi , Wu Jingyi , Fu Long , Jiang Wendi , Zhang He , Lin Jiajia , Li Baiqiang , Tong Zhihui , Windsor John , Liu Yuxiu , Li Weiqin ,   Chinese Acute Pancreatitis Clinical Trials Group (CAPCTG)
Published: August 2021

BACKGROUND&AIMS

Infected pancreatic necrosis (IPN) is a highly morbid complication of acute pancreatitis (AP). Since there is evidence of immunosuppression in the early phase of AP, immune enhancement using Thymosin alpha 1 (Tα1), which stimulates both innate and adaptive immunity, may be a therapeutic strategy to prevent IPN. Our aim was to assess the efficacy of early Tα1 treatment on the development of IPN.

METHODS

We conducted a multicenter, randomized, double-blind, placebo-controlled trial in patients with predicted severe acute necrotizing pancreatitis (ANP). ANP patients with an APACHE II score≥8 admitted within seven days of the advent of symptoms were considered eligible. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg, every 12 hours for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebo (normal saline). The primary outcome was the development of IPN during the index admission.

RESULTS

From Mar 2017 through Dec 2020, 508 patients were randomized at 16 hospitals, of whom 254 were assigned to receive Tα1 and 254 placebo. During the index admission, 40/254 (15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95%CI -7.4% to 5.0%]; p=0.47). The results were similar in four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15.0%; p=0.15), bleeding (6.3% vs. 3.5%; p=0.15), and gastrointestinal fistula (2.0% vs. 2.4%; p=0.75) during the index admission.

CONCLUSIONS

The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

Trial registration

Clinicaltrials.gov registry: NCT02473406.
Schwann cells contribute to keloid formation
Authors: Direder Martin , Weiss Tamara , Copic Dragan , Vorstandlechner Vera , Laggner Maria , Mildner Caterina Selina , Klas Katharina , Bormann Daniel , Haslik Werner , Radtke Christine , Farlik Matthias , Shaw Lisa , Golabi Bahar , Tschachler Erwin , Hötzenecker Konrad , Ankersmit Hendrik Jan , Mildner Michael
Published: August 2021

Keloids are disfiguring, hypertrophic scars with yet poorly understood pathomechanisms, which could lead to severe functional impairments. Here we analyzed the characteristics of keloidal cells by single cell sequencing and discovered the presence of an abundant population of Schwann cells that persisted in the hypertrophic scar tissue after wound healing. In contrast to normal skin, keloidal Schwann cells possess a repair-like phenotype and high cellular plasticity. Our data support the hypothesis that keloidal Schwann cells contribute to the formation of the extracellular matrix and are able to affect M2 polarization of macrophages. Indeed, we show that macrophages in keloids predominantly display a M2 polarization and produce factors that inhibit Schwann cell differentiation. Our data suggest a contribution of this cross-talk to the continuous expansion of keloids, and that targeting Schwann cells might represent an interesting novel treatment option for keloids.
Symptoms that predict positive COVID-19 testing and hospitalization: an analysis of 9,000 patients
Authors: Jalalizadeh Mehrsa , Leme Patricia A. F. , Buosi Keini , Dionato Franciele A. V. , Giacomelli Cristiane F. , Col Luciana S.B. Dal , Ferrari Karen L. , Pagliarone Ana Carolina , Gon Lucas M. , Cezar Douglas F.O. , Esfahani Akbar A. , Reis Leonardo O.
Published: August 2021

Purpose

To develop a reliable tool that predicts which patients are most likely to be COVID-19 positive and which ones have an increased risk of hospitalization.

Methods

From February 2020 to April 2021, trained nurses recorded age, gender, and symptoms in an outpatient COVID-19 testing center. All positive patients were followed up by phone for 14 days or until symptom-free. We calculated the symptoms odds ratio for positive results and hospitalization and proposed a “random forest” machine-learning model to predict positive testing.

Results

A total of 8,998 patients over 16 years old underwent COVID-19 RT-PCR, with 1,914 (21.3%) positives. Fifty patients needed hospitalization (2.6% of positives), and three died (0.15%). Most common symptoms were: cough, headache, sore throat, coryza, fever, myalgia (57%, 51%, 44%, 36%, 35%, 27%, respectively). Cough, fever, and myalgia predicted positive COVID-19 test, while others behaved as protective factors. The best predictors of positivity were fever plus anosmia/ageusia (OR=6.31), and cough plus anosmia/ageusia (OR=5.82), both p<0.0001. Our random forest model had an ROC-AUC of 0.72 (specificity=0.70, sensitivity=0.61, PPV=0.38, NPV=0.86). Having steady fever during the first days of infection and persistent dyspnea increased the risk of hospitalization (OR=6.66, p<0.0001 and OR=3.13, p=0.003, respectively), while anosmia-ageusia (OR=0.36, p=0.009) and coryza (OR=0.31, p=0.014) were protective.

Conclusion

Present study and algorithm may help identify patients at higher risk of having SARS-COV-2 (online calculator http://wdchealth.covid-map.com/shiny/calculator/), and also disease severity and hospitalization based on symptoms presence, pattern, and duration, which can help physicians and health care providers.
Using Novel, Agent-Based Periodic Mobility Model with Super Spreaders to Analyze Vaccination Strategies for COVID-19
Authors: Jacob Mathew , Guo Eva Xueyao
Published: August 2021

The authors have withdrawn this manuscript because there have been a number of mutations of COVID-19, since the manuscript was posted, as well as changes in virus behavior, such as increased transmissibility. As a result, both the vaccination strategies and parameters used during the simulation are less applicable to the current situation, and thus the results from the simulations may be incorrect for the current situation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Efficient and Rapid generation of anti-aging neural stem cells by direct conversion Fibroblasts with A Single microRNA
Authors: Li Yuanyuan , Sun Jing , Xu Tingting , Weng Xiaobin , Zhang Yanan , Rasmussen Theodore P. , Dai Bo , Wang Yuesi
Published: August 2021

Neural stem cells (NSCs) have great potential in the application of neurodegenerative disease therapy, drug screening and disease modeling. NSC can be generated by reprogramming from terminally differentiated cells with transcription factors or small molecules. However, current methods for producing NSCs involve the danger of integrating foreign genes into the genome and the problem of low efficiency. Here, we report an efficient method to generate NSCs from human skin-derived fibroblasts with microRNA (mir-302a) in 2-3 days. The induced NSCs (iNSCs) have more than 90% of purity. Their morphology is similar to regular NSCs, expressing key markers including Nestin, Pax6 and Sox2, and can be expanded for more than 20 passages in vitro. They can also differentiate into functional neuron progeny, astrocytes and oligodendrocytes as well. Those cells can elicit action potential, can be xeno-transplanted into the brain of immune-deficient mice, and can survive and differentiate in vivo without tumor formation. This study shows that a single part of pluripotency-inducing mir-302 cluster can drive fibroblasts reprogramming, providing a general platform for high-efficiency generation of individual-specific human NSCs for studies of neuron system development and regenerative cell therapy.
Marine gregarine genomes reveal the breadth of apicomplexan diversity and provide new insights on gliding motility
Authors: Boisard Julie , Duvernois-Berthet Evelyne , Duval Linda , Schrével Joseph , Guillou Laure , Labat Amandine , Le Panse Sophie , Prensier Gérard , Ponger Loïc , Florent Isabelle
Published: August 2021

Our current view of the evolutionary history, coding and adaptive capacities of Apicomplexa, protozoan parasites of a wide range of metazoan, is currently strongly biased toward species infecting humans, as data on early diverging apicomplexan lineages infecting invertebrates is extremely limited. Here, we characterized the genome of the marine eugregarinePorospora gigantea, intestinal parasite of Lobsters, remarkable for the macroscopic size of its vegetative feeding forms (trophozoites) and its gliding speed, the fastest so far recorded for Apicomplexa. Two highly syntenic genomes named A and B were assembled. Similar in size (~9 Mb) and coding capacity (~5300 genes), A and B genomes are 10.8% divergent at the nucleotide level, corresponding to 16-38 My in divergent time. Orthogroup analysis across 25 (proto)Apicomplexa species, includingGregarina niphandrodes, showed that A and B are highly divergent from all other known apicomplexan species, revealing an unexpected breadth of diversity. Phylogenetically these two species branch sister to Cephaloidophoroidea, and thus expand the known crustacean gregarine superfamily. The genomes were mined for genes encoding proteins necessary for gliding, a key feature of apicomplexans parasites, currently studied through the molecular model called glideosome. Sequence analysis shows that actin-related proteins and regulatory factors are strongly conserved within apicomplexans. In contrast, the predicted protein sequences of core glideosome proteins and adhesion proteins are highly variable among apicomplexan lineages, especially in gregarines. These results confirm the importance of studying gregarines to widen our biological and evolutionary view of apicomplexan species diversity, and to deepen our understanding of the molecular bases of key functions enabling parasitism, such as the glideosome.
Increasing temporal variance leads to stable species range limits
Authors: Benning John W. , Hufbauer Ruth A. , Weiss-Lehman Christopher
Published: August 2021

What prevents populations of a species from adapting to the novel environments outside the species’ geographic distribution? Previous models highlighted how gene flow across spatial environmental gradients determines species expansion vs. extinction and the location of species range limits. However, space is only one of two axes of environmental variation — environments also vary in time, and we know temporal environmental variation has important consequences for population demography and evolution. We used analytical and individual-based evolutionary models to explore how temporal variation in environmental conditions influences the spread of populations across a spatial environmental gradient. We find that temporal variation greatly alters our predictions for range dynamics compared to temporally static environments. When temporal variance is equal across the landscape, the fate of species (expansion vs. extinction) is determined by the interaction between the degree of temporal autocorrelation in environmental fluctuations and the steepness of the spatial environmental gradient. When the magnitude of temporal variance changes across the landscape, stable range limits form where this variance increases maladaptation sufficiently to prevent local persistence. These results illustrate the pivotal influence of temporal variation on the likelihood of populations colonizing novel habitats and the location of species range limits.
Phased Mutations and Complex Rearrangements in Human Prostate Cancer Cell Lines through Linked-Read Whole Genome Sequencing
Authors: Pham Minh-Tam , Gupta Harshath , Gupta Anuj , Vaghasia Ajay , Skaist Alyza , Garrison McKinzie A. , Coulter Jonathan B. , Haffner Michael C. , Isaacs William B. , Wheelan Sarah J. , Nelson William G. , Yegnasubramanian Srinivasan
Published: August 2021

A limited number of cell lines have fueled the majority of preclinical Prostate cancer (PCa) research. Despite tremendous effort in characterizing their molecular profiles, comprehensive whole genome sequencing with allelic phasing of somatic genome alterations has not been undertaken to date. Here, we utilized whole genome Linked-read sequencing to obtain haplotype information from the seven most commonly used PCa cell lines (PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b), four castrate resistant (CR) subclones (LNCaP_Abl, LNCaP_C42b, VCaP-CR, LAPC4-CR), and an immortalized prostate epithelial line RWPE-1. Phasing of mutations allowed derivation of “Gene-level Haplotype” to assess whether a gene harbored heterozygous mutations in one or both alleles, providing a comprehensive catalogue of mono or bi-allelically inactivated genes. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy, with breakpoints occurred across a single allele, providing further evidence that complex SVs occurred in a concerted event, rather than through accumulation of multiple independent rearrangements. Additionally, comparison of parental and CR subclones revealed previously known and novel genomic alterations associated with the CR clones. This study therefore comprehensively characterized phased genomic alterations in the commonly used PCa cell lines and provided a useful resource for future cancer research.
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
Authors: Gawish Riem , Starkl Philipp , Pimenov Lisabeth , Hladik Anastasiya , Lakovits Karin , Oberndorfer Felicitas , Cronin Shane J.F. , Ohradanova-Repic Anna , Wirnsberger Gerald , Agerer Benedikt , Endler Lukas , Capraz Tümay , Perthold Jan W. , Hagelkruys Astrid , Montserrat Nuria , Mirazimi Ali , Boon Louis , Stockinger Hannes , Bergthaler Andreas , Oostenbrink Chris , Penninger Josef M. , Knapp Sylvia
Published: August 2021

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modelling revealed how Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

Key points

The mouse-adapted SARS-CoV-2 strain maVie16 causes fatal disease in BALB/c mice and substantial inflammation, pneumonia and immunity in C57BL/6 mice

TNFα/IFNγ blockade ameliorates maVie16-induced immunopathology

MaVie16 infection depends on ACE2 and soluble ACE2 inhalation can prevent disease
Evaluating the impact ofin silicopredictors on clinical variant classification
Authors: Wilcox Emma H. , Sarmady Mahdi , Wulf Bryan , Wright Matt W. , Rehm Heidi L. , Biesecker Leslie G. , Abou Tayoun Ahmad N.
Published: August 2021

Background

In silicoevidence is important to consider when interpreting genetic variants. According to the ACMG/AMP,in silicoevidence is applied at the supporting strength level using the PP3 and BP4 criteria, for pathogenic and benign evidence, respectively. While PP3 has been determined to be one of the most commonly applied criteria, less is known about the effect of these two criteria on variant classification outcomes.

Methods

In this study, a total of 727 missense variants curated by Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEPs) were analyzed to determine how often PP3 and BP4 were applied and how often they influenced final variant classifications. The current categorical system of variant classification was compared with a point-based system being developed by the ClinGen Sequence Variant Interpretation Working Group. In addition, the performance of fourin silicotools (REVEL, VEST, FATHMM, and MPC) was assessed by using a gold set of 237 variants (classified as benign or pathogenic independent of PP3 or BP4) to calculate pathogenicity likelihood ratios.

Results

Collectively, the PP3 and BP4 criteria were applied by ClinGen VCEPs to 55% of missense variants in this data set. Removingin silicocriteria from variants where they were originally applied caused variants to change classification from pathogenic to likely pathogenic (14%), likely pathogenic to variant of uncertain significance (VUS) (24%), or likely benign to VUS (64%). The proportion of downgrades with the categorical classification system was similar to that of the point-based system, though the latter resolved borderline classifications. REVEL and VEST performed at a level consistent with moderate strength towards either benign or pathogenic evidence, while FATHMM performed at the supporting level.

Conclusions

Overall, this study demonstrates thatin silicocriteria PP3 and BP4 are commonly applied in variant classification and often affect the final classification. Our results suggest that when sufficient thresholds forin silicopredictors are established, PP3 and BP4 may be appropriate to use at a moderate strength. However, further calibration with larger datasets is needed to optimize the performance of currentin silicotools given the impact they have on clinical variant classification.
OTUs clustering should be avoided for defining oral microbiome
Authors: Regueira-Iglesias A , Vázquez-González L , Balsa-Castro C , Blanco-Pintos T , Arce VM , Carreira MJ , Tomás I
Published: August 2021

This in silico investigation aimed to: 1) evaluate a set of primer pairs with high coverage, including those most commonly used in the literature, to find the different oral species with 16S rRNA gene amplicon similarity/identity (ASI) values ≥97%; and 2) identify oral species that may be erroneously clustered in the same operational taxonomic unit (OTU) and ascertain whether they belong to distinct genera or other higher taxonomic ranks.

Thirty-nine primer pairs were employed to obtain amplicon sequence variants (ASVs) from the complete genomes of 186 bacterial and 135 archaeal species. For each primer, ASVs without mismatches were aligned using BLASTN and their similarity values were obtained. Finally, we selected ASVs from different species with an ASI value ≥97% that were covered 100% by the query sequences. For each primer, the percentage of species-level coverage with no ASI≥97% (SC-NASI≥97%) was calculated.

Based on the SC-NASI≥97% values, the best primer pairs were OP_F053-KP_R020 for bacteria (65.05%), KP_F018-KP_R002 for archaea (51.11%), and OP_F114-KP_R031 for bacteria and archaea together (52.02%). Eighty percent of the oral-bacteria and oralarchaea species shared an ASI≥97% with at least one other taxa, including Campylobacter, Rothia, Streptococcus, and Tannerella, which played conflicting roles in the oral microbiota. Moreover, around a quarter and a third of these two-by-two similarity relationships were between species from different bacteria and archaea genera, respectively. Furthermore, even taxa from distinct families, orders, and classes could be grouped in the same cluster.

Consequently, irrespective of the primer pair used, OTUs constructed with a 97% similarity provide an inaccurate description of oral-bacterial and oral-archaeal species, greatly affecting microbial diversity parameters. As a result, clustering by OTUs impacts the credibility of the associations between some oral species and certain health and disease conditions. This limits significantly the comparability of the microbial diversity findings reported in oral microbiome literature.
On the relationships between rarity, uniqueness, distinctiveness, originality and functional/phylogenetic diversity
Authors: Pavoine Sandrine , Ricotta Carlo
Published: August 2021

Rarity reflects the low abundance of a species while distinctiveness reflects its quality of being easy to recognize because it has unique functional characteristics and/or an isolated phylogenetic position. As such, the assemblage-level rarity of a species’ functional and phylogenetic characteristics (that we name ‘effective originality’) results from both the rarity and the distinctiveness of this species. The functional and phylogenetic diversity of an assemblage then results from a compromise between the abundances and the effective originalities of the species it contains. Although the distinctiveness of a species itself depends on the abundance of the other species in the assemblage, distinctiveness indices that are available in the ecological literature scarcely consider abundance data. We develop a unifying framework that demonstrates the direct connections between measures of diversity, rarity, distinctiveness and effective originality. While developing our framework, we discovered a family of distinctiveness indices that permit a full control of the influence one wants to give to the strict uniqueness of a species (=its smallest functional or phylogenetic distance to another species in the assemblage). Illustrating our framework with bat phylogenetic diversity along a disturbance gradient in Mexico, we show how each component of rarity, distinctiveness and originality can be controlled to obtain efficient indicators for conservation. Overall our framework is aimed to improve conservation actions directed towards highly diverse areas and/or towards species whose loss would considerably decrease biodiversity by offering flexible quantitative tools where the influence of abundant versus rare, and ordinary versus original, species is understood and controlled.
Regulation of sexually dimorphic abdominal courtship behaviors in Drosophila by the Tlx/tailless-like nuclear receptor, Dissatisfaction
Authors: Duckhorn Julia C. , Cande Jessica , Metkus Mary C. , Song Hyeop , Altamirano Sofia , Stern David L. , Shirangi Troy R.
Published: August 2021

Sexually dimorphic courtship behaviors in Drosophila melanogaster develop from the activity of the sexual differentiation genes, doublesex (dsx) and fruitless (fru), functioning with other regulatory factors that have received little attention. The dissatisfaction gene (dsf) encodes an orphan nuclear receptor homologous to vertebrate Tlx and Drosophila tailless that is critical for the development of several aspects of female- and male-specific sexual behaviors. Here, we report the pattern of dsf expression in the central nervous system and show that the activity of sexually dimorphic abdominal interneurons that co-express dsf and dsx is necessary and sufficient for vaginal plate opening in virgin females, ovipositor extrusion in mated females, and abdominal curling in males during courtship. We find that dsf activity results in different neuroanatomical outcomes in females and males, promoting and suppressing, respectively, female development and function of these neurons depending upon the sexual state of dsx expression. We posit that dsf and dsx interact to specify sex differences in the neural circuitry for dimorphic abdominal behaviors.
Does the evolution of division of labour require accelerating returns from individual specialisation?
Authors: Cooper Guy Alexander , Frost Hadleigh , Liu Ming , West Stuart Andrew
Published: August 2021

Recent theory has overturned the assumption that accelerating returns from individual specialisation are required to favour the evolution of division of labour. Yanni et al. (2020) showed that topologically constrained groups, where cells cooperate with only direct neighbours such as for filaments or branching growths, can evolve a reproductive division of labour even with diminishing returns from individual specialisation. We developed a conceptual framework and specific models to investigate the factors that can favour the initial evolution of reproductive division of labour. We found that selection for division of labour in topologically constrained groups: (1) is not a single mechanism to favour division of labour – depending upon details of the group structure, division of labour can be favoured for different reasons; (2) always involves an efficiency benefit at the level of group fitness; and (3) requires a mechanism of coordination to determine which individuals perform which tasks. Given that such coordination is unlikely to evolve before division of labour, this limits the extent to which topological constraints could have favoured the initial evolution of division of labour. We conclude by suggesting experimental designs that could determine why division of labour is favoured in the natural world.
Intraguild predation does not necessarily have negative effects on pest biological control: insights from a multiple consumer–multiple resource food web population model
Authors: Costa Michel Iskin da S. , dos Anjos Lucas
Published: August 2021

We develop a food web population dynamical based on an experimental pest biocontrol setup consisting of thrips and aphids (pests) being consumed by two agentsMacrolophus pygmaeusandOrius laevigatus, and withO. laevigatusbeing an intraguild predator ofM. pygmaeus. By means of numerical simulations, we show that pest biocontrol disruption can be avoided depending on initial population densities of pests and agents, despite the intraguild predation (IGP) ofO. laevigatusuponM. pygmaeus. This possible avoidance of pest biocontrol disruption is in accordance with the referred experimental setup and moreover, the proposed model corroborates the importance of initial densities of pests and agents in the determination of the failure or success of pest biocontrol found in this and other biocontrol experimental setups.