bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultradeep sequencing reveals HIV-1 diversity and resistance compartmentalization during HIV-encephalopathy
Authors: Giatsou Eleni , Abdi Basma , Plu Isabelle , Desire Nathalie , Palich Romain , Calvez Vincent , Seilhean Danielle , Marcelin Anne-Geneviève , Jary Aude
Published: July 2020

Objectives:

To examine viral diversity and resistance mutations in different brain areas in cases of HIV-encephalopathy.

Design:

Twelve postmortem brain areas from three cases of possible or certain HIV-encephalopathy were analyzed.

Methods:

After amplification of the reverse transcriptase and the V3 loop region of the gp120 protein, ultradeep sequencing was performed with Illumina technology. Phylogenetic analysis was performed with Fastree v2.1 using the generalized time-reversible (GTR) model. Identification of resistant viral variants was performed on Geneious software, according to HIV-1 genotypic drug resistance interpretation's algorithms, 2018 administered by the French Agency for Research on AIDS and Viral Hepatitis.

Results:

Phylogenetic analysis revealed significant inter-regional and intra-regional diversity reflecting persistent HIV-1 viral replication in the different brain areas. Although some cerebral regions shared HIV-variants, most of them harbored a specific HIV-subpopulation reflecting HIV compartmentalization in the central nervous system. Furthermore, proportion and distribution of resistance mutations to nucleoside and non-nucleoside reverse transcriptase inhibitors differed among different brain areas of the same case suggesting that penetration of antiretroviral treatment may differ from one compartment to another.

Conclusion:

This study, performed with a powerful sequencing technique, confirmed HIV compartmentalization in the central nervous system already shown by classical sequencing, suggesting that there are several reservoirs within the brain.
Higher frequencies of functional HIV-envelope-specific memory B cells are associated with nonprogressive HIV infection in Indian population
Authors: Dhande Jayshree R. , Saikia Kasturi , Singh Dharmendra P. , Bagul Rajani D. , Kulkarni Smita S. , Ghate Manisha V. , Thakar Madhuri R.
Published: July 2020

Objective:

The HIV-1-specific antibodies are being considered for prevention and therapy in HIV infection. For effective antibody response, presence of functionally competent memory B cells (MEBs) is important; however, HIV-infection is known to alter the B-cell functionality. Very limited data are available on the HIV-specific memory B-cell population in HIV-infected Indian population.

Methods:

In this study, the frequencies of HIV-gp140-specific MEBs were measured in individuals with nonprogressive [long-term-nonprogressors (LTNPs), N = 20] and progressive (N = 19) HIV infection using multicolor flow cytometry. The activation and functional status of these MEBs were assessed as frequencies and mean fluorescence intensity (MFI) of the CD38 and CD40 expression, respectively.

Results:

The percentages of gp140 + MEBs were higher in LTNPs than seen in progressors (P = 0.0475) and associated with higher CD4+ cell count (P = 0.0312, r = 0.2833). As compared with the progressors, LTNPs also showed higher functional (CD40+) gp140 + MEBs both frequencies (P < 0.0001) and CD40 MFI (P = 0.0222), whereas the frequencies (<0.0001) and the MFI (P = 0.0047) of CD38 expression was significantly lower. Higher CD4+ cell counts and lower plasma viral load values were associated with higher frequencies of CD40+ gp140 + MEBs (P < 0.0001, r = 0.4962) (P = 0.0036, r = −0.4202) and lower frequencies (P = 0.0008, r = −0.4231) and CD38 expression (MFI) (P = 0.004, r = −0.3719) (P = 0.0066, r = 0.4033).

Conclusion:

Our study suggests that LTNPs have functional HIV-specific memory B-cell compartment with reduced activation that may lead to effective HIV-specific humoral immune responses contributing to their nondisease progression status. These findings would help in better understanding of the characteristics of the HIV-specific memory B-cell population in nonprogressive HIV infection.
Population attributable fractions of mortality in people living with HIV: roles of delayed antiretroviral therapy, hepatitis coinfections and social factors
Authors: Santos Melina E. , Protopopescu Camelia , Ribero Rachel A. , Benzaken Adele S. , Pereira Gerson F.M. , Stevens Antony , Nishimwe Marie L. , Yaya Issifou , Carrieri Patrizia , Araújo Wildo N.
Published: July 2020

Objectives:

Despite free access to antiretroviral therapy (ART) from 1996 onward, and treatment for all people living with HIV (PLWHIV) from 2013, mortality in Brazil has not homogeneously decreased. We investigated to what extent delayed ART, hepatitis coinfections and sociodemographic factors predict all-cause mortality in Brazilian PLWHIV.

Design:

We included PLWHIV at least 18 years, with complete CD4+ cell count data, followed up between 2007 and 2015 in Brazil.

Methods:

After multiple imputation, an extended Cox model helped estimate the effects of fixed and time-varying covariates on mortality.

Results:

The study population (n = 411 028) were mainly male (61%), white (55%), 40 years or less (61%), heterosexually HIV infected (71%), living in the Southeast region (48%) and had basic education (79%). Hepatitis C virus and hepatitis B virus coinfection prevalences were 2.5 and 1.4%, respectively. During a 4-year median follow-up, 61 630 deaths occurred and the mortality rate was 3.45 (95% confidence interval: 3.42–3.47) per 100 person-years. Older age, male sex, non-white ethnicity, illiteracy/basic education and living outside the Southeast and Central-West regions were independently associated with increased mortality. The main modifiable predictors of mortality were delayed ART (i.e. CD4+ cell count <200 cells/μl at ART initiation) (adjusted population attributable fraction: 14.20% [95% confidence interval: 13.81–14.59]), being ART-untreated (14.06% [13.54–14.59]) and ART-treated with unrecorded CD4+ at ART initiation (5.74% [5.26–6.21]). Hepatitis C virus and hepatitis B virus coinfections accounted for 2.44 [2.26–2.62] and 0.42% [0.31–0.53] of mortality, respectively.

Conclusion:

The current study demonstrates that besides early ART and coinfection control, actions targeting males, non-whites and illiterate people and those with basic education are important to reduce avoidable deaths among Brazilian PLWHIV.
Advanced HIV disease in the Botswana combination prevention project: prevalence, risk factors, and outcomes
Authors: Lebelonyane Refeletswe , Mills Lisa A. , Mogorosi Chipo , Ussery Faith , Marukutira Tafireyi , Theu Joe , Kapanda Max , Matambo Stembile , Block Lisa , Raizes Elliot , Makhema Joseph , Lockman Shahin , Bachanas Pamela , Moore Janet , Jarvis Joseph N.
Published: July 2020

Objective(s):

To determine the proportion of individuals linking to HIV-care with advanced HIV-disease (CD4+ cell counts ≤200 cells/μl) in the Botswana Combination Prevention Project, describe the characteristics of these individuals, and examine treatment outcomes.

Design:

A subanalysis of a cluster-randomized HIV-prevention trial. HIV status was assessed in 16–64-year-olds through home and mobile testing. All HIV-positive persons not on antiretroviral therapy were referred to local Ministry of Health and Wellness clinics for treatment.

Methods:

Analysis was restricted to the 15 intervention clusters. The proportion of individuals with advanced HIV disease was determined; associations between advanced HIV disease and sex and age explored; and rates of viral suppression determined at 1-year. Mortality and retention in care were compared between CD4+ strata (CD4+ cell counts ≤200 vs. >200 cells/μl).

Results:

Overall, 17.2% [430/2499; 95% confidence interval (CI) 15.7–18.8%] of study participants had advanced HIV disease (CD4+ cell counts ≤200 cells/μl) at time of clinic linkage. Men were significantly more likely to present with CD4+ cell counts 200 cells/μl or less than women [23.7 vs. 13.4%, adjusted odds ratio 1.9, 95% CI 1.5–2.3]. The risk of advanced HIV disease increased with increasing age (adjusted odds ratio 2.2, 95% CI 1.4–3.2 >35 vs. <25 years). Patients with CD4+ cell counts 200 cells/μl or less had significantly higher rates of attrition from care during follow-up (hazards ratio 1.47, 95% CI 1.1–2.1).

Conclusion:

Advanced HIV disease due to late presentation to or disengagement from antiretroviral therapy care remains common in the Treat All era in Botswana, calling for innovative testing, linkage, and treatment strategies to engage and retain harder-to-reach populations in care.
Computed Tomography Coronary Plaque Characteristics Predict Ischemia Detected by Invasive Fractional Flow Reserve
Authors: Velangi Pratik S. , Maharaj Valmiki , Athwal Satyajit S. , Bartos Jason A. , Markowitz Jeremy , Duval Sue , Nijjar Prabhjot S.
Published: July 2020

Purpose:

Coronary computed tomography angiography (CCTA) plaque quantification has been proposed to be of incremental value in the prediction of ischemia, although prior studies have shown conflicting results. We aimed to determine whether CCTA plaque features assessed on a commercial vendor platform predict invasive fractional flow reserve (FFR)/instantaneous wave-free ratio (IFR).

Methods:

Consecutive patients who underwent CCTA for evaluation of suspected stable coronary artery disease followed by invasive coronary physiology testing within 60 days at a single academic center were identified retrospectively. Semiautomated plaque quantification of the vessel proximal to the location of FFR/IFR measurement was carried out in TeraRecon, along with simple visual assessment for high-risk plaque features of positive remodeling, spotty calcification, low-attenuation plaque (LAP), and lesion length. Ischemia was defined by FFR ≤0.80 or IFR ≤0.89.

Results:

A total of 134 patients (62% male, mean age 62±10 y) were included in this study. On univariate logistic regression, the following visual plaque analysis parameters were predictive of ischemia: positive remodeling (odds ratio [OR] with 95% confidence interval [CI]: 4.96; 2.25-10.95; P<0.001), lesion length (OR for every 1 mm with 95% CI: 1.24; 1.14-1.34; P<0.001), spotty calcification (OR with 95% CI: 6.67; 1.67-26.64; P=0.007), and LAP (OR with 95% CI: 30; 3.78-246; P=0.001). None of the semiautomated plaque quantification parameters, such as noncalcified plaque volume or LAP volume, were predictive of ischemia. On stepwise multivariable logistic regression, lesion length (OR with 95% CI: 1.25; 1.14-1.37; P<0.0001) and LAP (OR with 95% CI: 43; 4.4-438; P=0.001) were significant predictors of ischemia, improving the area under the curve of CCTA from 0.53 to 0.87.

Conclusions:

Simple visual plaque assessment for high-risk plaque features improved the performance of CCTA to predict ischemia. Semiautomated plaque quantification performed on a commercial vendor platform was not predictive of ischemia.
The evolving options in metastatic castration-sensitive prostate cancer
Authors: Hamilou Zineb
Published: July 2020

Purpose of review

Leading trials CHAARTED, STAMPEDE, GETUG-AFU15 and LATITUDE established docetaxel and abiraterone acetate addition to androgen deprivation therapy (ADT) as a treatment guideline for patients with metastatic castration-sensitive prostate cancer.

Recent findings

Two recent combinations, enzalutamide with ADT and apalutamide with ADT were tested in metastatic castration-sensitive prostate cancer in three randomized controlled trials. Both combinations provided survival gain, expanding our options of treatment. Moreover, additional evidence behind radiotherapy for the primary tumor in metastatic prostate cancer is emerging.

In this updated article, we review the data of these trials and highlight the distinctions between these therapies, in order to better personalize the care for patients with metastatic prostate cancer.
Use of short-acting opioids in the management of breathlessness: an evidence-based review
Authors: Hui David , Bruera Eduardo
Published: July 2020

Purpose of review

To provide an evidence-based review on the use of short-acting opioids for management of breathlessness in patients with advanced diseases.

Recent findings

We identified 28 randomized controlled trials that examined the effect of short-acting opioids on breathlessness under three study settings: as a prophylactic dose given prior to exertion; as a rescue dose for treatment of breathlessness at rest or episodic breathlessness; or as a scheduled medication for overall reduction of breathlessness. These trials varied widely in regard to patient population (opioid naive or tolerant), opioid (formulation, dose, timing of administration, and scheduling) and control intervention. Taken together, there is good evidence to support that short-acting opioids can reduce breathlessness and improve activity level when given before exertion. There is some evidence that parenteral opioids are efficacious for the as needed treatment of episodic breathlessness or breathlessness at rest. However, there is only limited evidence to support scheduled short-acting opioids for overall relief of breathlessness.

There is evidence to support that short-acting opioids have a pharmacologic effect on breathlessness. More research is needed to clarify how opioids can be prescribed to optimize breathlessness relief, function, and quality of life.
Motor Performance and Quality of Life in a Community Exercise Program for Parkinson Disease
Authors: Stiles Elizabeth A. , Jaffe Karen M. , Schwartz Catherine E. , Rossi Benjamin M. , Riley David E.
Published: July 2020

We investigated the effect of a comprehensive community program composed of exercise, mindfulness practice, and education on motor function and quality of life in individuals with Parkinson disease (PD). Thirty-six participants completed physical and quality-of-life assessments independently at baseline and 12 months. Physical assessments showed stability or improvement in functional mobility, integrated strength, and walking ability over the 1-year interval. PDQ-39 measures showed improvement in 6 of 8 indices: mobility, activities of daily living, emotional well-being, stigma reduction, social support, and bodily discomfort. Our results demonstrate the effectiveness of exercise, mindfulness, and education in community and group settings.
Analysis of Auditory Function of Patients With Parkinson Disease Based on Mandarin
Authors: Liu Jie , Huang Zhaoming , Zhao Hang , Fu Yicheng , Ding Zhongbing , Yu Bo
Published: July 2020

Objective:

This study aimed to assess hearing loss and speech recognition impairment in patients with Parkinson disease (PD) based on Mandarin through pure-tone audiometry and speech audiometry.

Methods:

In total, 32 PD patients and 32 age-matched normal controls were enrolled for pure-tone audiometry and speech audiometry using a GSI arrow audiometer together with the BOSCH Chinese speech audiometry system.

Results:

The results of pure-tone audiometry showed that PD patients exhibited more severe low-, medium-, or high-frequency hearing loss than normal controls, especially at higher frequencies, and there were significant differences in gender. In addition, the results of speech audiometry showed that the speech recognition threshold of PD patients was significantly higher than that of normal controls. Furthermore, at any of the 3 hearing levels of 70, 50, and 30 dB HL, the recognition rates of initials, finals, and tones were successively decreased in PD patients, especially initials.

Conclusion:

PD patients exhibited significant hearing loss and speech recognition impairment. The initial recognition was more dependent on the hearing levels.
Donald Lynden-Bell. 5 April 1935— 6 February 2018
Authors: Wyn Evans Neil
Published: July 2020

Donald Lynden-Bell's many contributions to astrophysics encompass general relativity, galactic dynamics, telescope design and observational astronomy. In the 1960s, his papers on stellar dynamics led to fundamental insights into the equilibria of elliptical galaxies, the growth of spiral patterns in disc galaxies and the stability of differentially rotating, self-gravitating flows. Donald introduced the ideas of ‘violent relaxation’ and ‘the gravothermal catastrophe’ in pioneering work on the thermodynamics of galaxies and negative heat capacities. He shared the inaugural Kavli Prize in Astrophysics in 2008 for his contributions to our understanding of quasars. His prediction that dead quasars or supermassive black holes may reside in the nuclei of nearby galaxies has been confirmed by multiple pieces of independent evidence. His work on accretion discs led to new insights into their workings, as well as the realization that the infrared excess in T Tauri stars was caused by protostellar discs around these young stars. He introduced the influential idea of monolithic collapse of a gas cloud as a formation mechanism for the Milky Way Galaxy. As this gave way to modern ideas of merging and accretion as drivers of galaxy formation, Donald was the first to realize the importance of tidal streams as measures of the past history and present-day gravity field of the Galaxy. Though primarily a theorist, Donald participated in one of the first observational programmes to measure the large-scale streaming of nearby galaxies. This led to the discovery of the ‘Great Attractor’. The depth and versatility of his contributions mark Donald out as one of the most influential and pre-eminent astronomers of his day.
Craterilacuibacter sinensis gen. nov. sp. nov., isolated from a crater lake in China
Authors: Liu Zi-Xuan , Phurbu Dorji , Liu Hong-Can , Zhou Yu-Guang , Li Ai-Hua
Published: July 2020

Two bacterial strains, designated B2N2-7T and B2N2-12, were isolated from Buteha crater lake in the Greater Khingan Mountain of China. The two strains were Gram-stain-negative, non-spore-forming, motile with a single polar flagellum, short rod-shaped bacteria. They were catalase- and oxidase-positive. Optimal growth occurred at 20–25 ℃, at pH 7.5–8.0 and with 0–1.0 % (w/v) NaCl. Based on phylogenomic analysis, strains B2N2-7T and B2N2-12 were assigned to the family

Neisseriaceae

, and their 16S rRNA gene sequences showed the highest similarities to that of

Aquitalea denitrificans

5YN1-3T (<94.2 %). The predominant cellular fatty acids were C16 : 0 and summed feature 3 (comprising C16 : 1ω7c/C16 : 1
ω6c). The major respiratory quinone was ubiquinone 8 (Q-8). The polar lipids were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), two unidentified aminophospholipids (APL) and some unidentified lipids (L). The genomic DNA G+C content of strain B2N2-7T was 59.4 mol% according to the genomic sequencing result. Based on the phylogenetic, genotypic and chemotaxonomic analyses, the two strains are proposed to represent a novel species of a new genus in the family

Neisseriaceae

, named Craterilacuibacter sinensis gen. nov., sp. nov. The type strain of Craterilacuibacter sinensis is B2N2-7T (=CGMCC 1.17189T=KCTC 73735T); B2N2-12 (=CGMCC 1.17190=KCTC 72734) is a second strain of the species.
Comparative genomic insights into Yersinia hibernica – a commonly misidentified Yersinia enterocolitica-like organism
Authors: Nguyen Scott Van , Muthappa Dechamma Mundanda , Eshwar Athmanya K. , Buckley James F. , Murphy Brenda P. , Stephan Roger , Lehner Angelika , Fanning Séamus
Published: July 2020

Food-associated outbreaks linked to enteropathogenic

Yersinia enterocolitica

are of concern to public health. Pigs and their meat are recognized risk factors for transmission of

Y. enterocolitica

. This study aimed to describe the comparative genomics of

Y. enterocolitica

along with a number of misclassified

Yersinia

isolates, now constituting the recently described

Yersinia hibernica

. The latter was originally cultured from an environmental sample taken at a pig slaughterhouse. Unique features were identified in the genome of Y. hibernica, including a novel integrative conjugative element (ICE), denoted as ICE
Yh-1
contained within a 255 kbp region of plasticity. In addition, a zebrafish embryo infection model was adapted and applied to assess the virulence potential among

Yersinia

isolates including

Y. hibernica

.
STAKEHOLDER ENGAGEMENT IN A COMPARATIVE EFFECTIVENESS/IMPLEMENTATION STUDY TO PREVENT CA-MRSA INFECTION RECURRENCE: CA-MRSA Project (CAMP2)
Authors: D’Orazio Brianna , Ramachandran Jessica , Khalida Chamanara , Gonzalez Johana , Kost Rhonda G. , Vasquez Kimberly S. , Evering Teresa H. , Hassen Getaw Worku , Hammock Regina , Nguyen Rosalee , Davis Ronette , Millan Keenan , Parola Claude , Coller Barry S. , Tobin Jonathan N.
Published: July 2020

Background

Methicillin-Resistant (MRSA) or Methicillin-Sensitive (MSSA) Staphylococcus aureus skin and soft tissue infections (SSTIs) pose serious clinical and public health challenges. Few protocols exist for outpatient education, decolonization and decontamination.

Objectives

This trial implemented infection prevention protocols in homes via Community Health Workers/promotoras.

Methods

We engaged clinicians, patients, clinical and laboratory researchers, New-York-based Federally Qualified Health Centers and community hospital Emergency Departments. The Clinician and Patient Stakeholder Advisory Committee (CPSAC) convened in-person and remotely for shared decision-making and trial oversight.

Results

The trial consented 186 and randomized 119 participants with SSTIs with MRSA (n=59) or MSSA (n=59), completed home visits, obtained surveillance cultures from index patients and household members and sampled household environmental surfaces at baseline and three months.

Lessons Learned

The retention of the CPSAC during the trial demonstrated high levels of engagement.

Conclusions

CPSAC was highly effective throughout design and execution by troubleshooting recruitment and home visit challenges.
Surges in COVID-19 are led by lax government interventions in initial outbreaks
Authors: Yuan Hsiang-Yu , Wu Lindsey , Wang Dong-Ping
Published: July 2020

Sharp increases in COVID-19 cases occurred after reopening in the United States. We show that the post-intervention effective reproduction number is a strong predictor of the surge in late June. Lax interventions in the early stages coupled with elevated virus spread are primarily responsible for surges in most affected states.
BioContainers Registry: searching for bioinformatics tools, packages and containers
Authors: Bai Jingwen , Bandla Chakradhar , Guo Jiaxin , Alvarez Roberto Vera , Vizcaíno Juan Antonio , Bai Mingze , Moreno Pablo , Grüning Björn A. , Sallou Olivier , Perez-Riverol Yasset
Published: July 2020

1

BioContainers is an open-source project that aims to create, store, and distribute bioinformatics software containers and packages. The BioContainers community has developed a set of guidelines to standardize the software containers including the metadata, versions, licenses, and/or software dependencies. BioContainers supports multiple packaging and containers technologies such as Conda, Docker, and Singularity. Here, we introduce the BioContainers Registry and Restful API to make containerized bioinformatics tools more findable, accessible, interoperable, and reusable (FAIR). BioContainers registry provides a fast and convenient way to find and retrieve bioinformatics tools packages and containers. By doing so, it will increase the use of bioinformatics packages and containers while promoting replicability and reproducibility in research.
Neural Stem Cells Secreting Bispecific T Cell Engager to Induce Selective Anti-Glioma Activity
Authors: Pituch Katarzyna C. , Zanikou Markella , Ilut Liliana , Xiao Ting , Chastkofsky Michael , Sukhanova Madina , Bertolino Nicola , Procissi Daniele , Amidei Christina , Horbinski Craig M. , Aboody Karen S. , James Charles D. , Lesniak Maciej S. , Balyasnikova Irina V.
Published: July 2020

Glioblastoma (GBM) is the most lethal primary brain tumor in adults. There is no treatment that provides durable relief for the vast majority of GBM patients. In this study, we’ve tested a bispecific antibody comprised of single-chain variable regions (scFvs) against T cell CD3ε and GBM cell interleukin 13 receptor alpha 2 (IL13Rα2). We demonstrate that this BiTE (BiTELLON) engages peripheral and tumor-infiltrating lymphocytes harvested from patient’s tumors, and in so doing exerts anti-GBM activityex vivo. The interaction of BiTELLONwith T cells and engagement of IL13Rα2-expressing GBM cells stimulates T cell proliferation as well as production of pro-inflammatory cytokines INFγ and TNFα. We have modified neural stem cells (NSCs) to produce and secrete the BiTE (NSCsLLON). When injected intracranially in mice with brain tumor, NSCsLLONshow tropism for tumor, secrete BiTELLON, and remain viable for several days. When injected directly into tumor, NSCLLONprovide significant survival benefit to mice bearing IL13Rα2+ GBM. Our results support further investigation and development of this therapeutic for clinical translation.
rTASSEL: an R interface to TASSEL for association mapping of complex traits
Authors: Monier Brandon , Casstevens Terry M. , Bradbury Peter J. , Buckler Edward S.
Published: July 2020

The need for efficient tools and applications for analyzing genomic diversity is essential for any genetics research program. One such tool, TASSEL (Trait Analysis by aSSociation, Evolution and Linkage), provides many core methods for genomic analyses. Despite its efficiency, TASSEL has limited means to use scripting languages for reproducible research and interacting with other analytical tools. Here we present an R package rTASSEL, a front-end to connect to a variety of highly used TASSEL methods and analytical tools. The goal of this package is to create a unified scripting workflow that exploits the analytical prowess of TASSEL in conjunction with R’s popular data handling and parsing capabilities without ever having the user to switch between these two environments. By implementing this workflow, we can achieve performances ranging from approximately 2 to 20 times faster than other widely used R packages for various functionalities.

Availability and implementation

rTASSEL is implemented in R using core TASSEL methods written in Java. The source code for rTASSEL can be found athttps://bitbucket.org/bucklerlab/rtassel/src/master/. The source code for TASSEL can be found athttps://bitbucket.org/tasseladmin/tassel-5-source/src/master/.

Supplemental information

The rTASSEL user manual and tutorials are freely available athttps://maize-genetics.github.io/rTASSEL/. Supplemental material for this manuscript regarding performance metrics can be found in the attached file.
T cells are present in non-diabetic islets and accumulate during aging
Authors: Denroche Heather C. , Miard Stéphanie , Sallé-Lefort Sandrine , Picard Frédéric , Verchere C. Bruce
Published: July 2020

Background

The resident immune population of pancreatic islets has roles in islet development, beta cell physiology, and the pathology of diabetes. These roles have largely been attributed to islet macrophages, comprising 90% of islet immune cells (in the absence of islet autoimmunity), and, in the case of type 1 diabetes, to infiltrating autoreactive T cells. In adipose, tissue-resident and recruited T and B cells have been implicated in the development of insulin resistance during diet-induced obesity and aging, but whether this is paralleled in the pancreatic islets is not known. Here, we investigated the non-macrophage component of resident islet immune cells in islets isolated from C57BL/6J male mice during aging (3 to 24 months of age) and following diet-induced obesity (12 weeks 60% high fat diet). Immune cells were also examined by flow cytometry in cadaveric non-diabetic human islets.

Results

Immune cells comprised 2.7 ± 1.3% of total islet cells in non-diabetic mouse islets, and 2.3 ± 1.7% of total islet cells in non-diabetic human islets. In 3-month old mice on standard diet, B and T cells each comprised approximately 2-4% of the total islet immune cell compartment, and approximately 0.1% of total islet cells. A similar amount of T cells were present in non-diabetic human islets. Islet T cells were comprised of CD8-positive, CD4-positive, and regulatory T cells. Interestingly, while islet B cells and macrophage numbers were unaltered by age, the number of islet T cells increased linearly (R2=0.9902) with age from 0.10 ± 0.05% (3 months) to 0.38 ±0.11% (24 months) of islet cells. This increase was uncoupled from body weight, and was not phenocopied by a degree similar weight gain induced by high fat diet in mice.

Conclusions

This study reveals that T cells are a part of the normal islet immune population in mouse and human islets, and that they accumulate in islets during aging in a body weight-independent manner. Though comprising only a small subset of the immune cells within islets, islet T cells may play a role in the physiology of islet aging.
Neuronal SKN-1B Modulates Nutritional Signalling Pathways and Mitochondrial Networks to Control Satiety
Authors: Tataridas-Pallas Nikolaos , Thompson Maximillian , Howard Alexander , Brown Ian , Ezcurra Marina , Wu Ziyun , Keurten Timo , Silva Isabel Goncalves , Blackwell T. Keith , Tullet Jennifer
Published: July 2020

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. InC. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), has previously been implicated with metabolism and respiration, because can mediate the increased lifespan incurred by dietary restriction. We show that actually SKN-1B is not essential for dietary restriction longevity and instead, controls a variety of food-related behaviours. It acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. This is achieved by SKN-1B modulating endocrine signalling pathways (IIS and TGF-β), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.
Structure of Macrolide Efflux Protein (MefA/E) inStreptococcus pneumoniae: An in silico approach
Authors: Peela Sreeram Chandra Murthy , Sharma Jyoti , Sistla Sujatha
Published: July 2020

Background

Macrolides are one of the commonest antibiotics used to treat bacterial respiratory tract infections. Resistance to this class of antibiotics is on the rise and is mediated by macrolide efflux (MefA/E) protein as one of the mechanisms. Despite its importance, the structure of this protein is not known yet.

Methods

The publicly available MefA/E protein sequence was used to model the structure. Modelling was performed in I-TASSER, and the model was further refined. Its orientation in a membrane was studied using OPM server.

Results and conclusions

The structure of MefA/E resembled that of Major Facilitator Superfamily (MFS) proteins, with 13 transmembrane helices. It had a V-shaped conformation, with the wider part towards the outer membrane layer.
Mitochondrial and insulin gene expression in single cells shape pancreatic beta cells’ population divergence
Authors: Medini H. , Cohen T. , Mishmar D.
Published: July 2020

Mitochondrial gene expression is pivotal to cell metabolism. Nevertheless, it is unknown whether it diverges within a given cell type. Here, we analysed single-cell RNA-seq experiments from ∼4600 human pancreatic alpha and beta cells, as well as ∼900 mouse beta cells. Cluster analysis revealed two distinct human beta cells populations, which diverged by mitochondrial (mtDNA) and nuclear DNA (nDNA)-encoded oxidative phosphorylation (OXPHOS) gene expression in healthy and diabetic individuals, and in newborn but not in adult mice. Insulin gene expression was elevated in beta cells with higher mtDNA gene expression in humans and in young mice. Such human beta cell populations also diverged in mt-RNA mutational repertoire, and in their selective signature, thus implying the existence of two previously overlooked distinct and conserved beta cell populations. While applying our approach to alpha cells, two sub-populations of cells were identified which diverged in mtDNA gene expression, yet these cellular populations did not consistently diverge in nDNA OXPHOS genes expression, nor did they correlate with the expression of glucagon, the hallmark of alpha cells. Thus, pancreatic beta cells within an individual are divided into distinct groups with unique metabolic-mitochondrial signature.
New mechanisms of radioiodide uptake revealed via a novel high throughput drug screening approach in thyroid cancer
Authors: Read Martin L. , Brookes Katie , Thornton Caitlin E.M. , Fletcher Alice , Alshahrani Mohammed , Khan Rashida , Nieto Hannah R. , Borges de Souza Patricia , Webster Jamie R.M. , Alderwick Luke J. , Boelaert Kristien , Smith Vicki E. , McCabe Christopher J.
Published: July 2020

New combinatorial drug strategies are urgently needed to improve radioiodide (RAI) uptake and efficiently ablate thyroid cancer cells, thereby addressing recurrent and metastatic disease. Cellular iodide uptake is accomplished solely by the sodium iodide symporter (NIS), but the complexity of NIS functional regulation and a lack of amenable high-throughput screening assays has impeded progress. We utilised mutated yellow fluorescent protein (YFP) as a surrogate biosensor of intracellular iodide for ∼1200 FDA-approved drugs, allowing us to appraise the impact of 73 leading compounds at 10 doses on125I uptake in thyroid cancer cell lines. Subsequent mechanistic analysis suggests three predominant modes of drug action: Firstly, a number of drugs inhibited specific regulation of NIS function by the protein VCP. Secondly, some drugs enhanced transcriptional or post-transcriptional regulation of NIS expression. Thirdly, several drugs strongly implicated proteasomal degradation and the unfolded protein response in the cellular processing of NIS. Exploiting these mechanistic insights, multiple compounds gave striking increases in radioiodide uptake when combined with the drug SAHA. Importantly, our new drug combination strategies were also effective in human primary thyrocytes, suggesting they target endogenous NIS physiology. In patients with papillary thyroid cancer, genes involved in proteostasis were remarkably altered and predicted significantly worse outcome, but only in those patients who received RAI therapy. Collectively, we therefore propose a new model of intracellular NIS processing, and identify key nodes which may now be druggable in patients with aggressive thyroid cancer.

Our data identify FDA-approved drugs that enhance radioiodide uptake outside of the canonical pathways of NIS processing, leading to a new mechanistic understanding of endogenous NIS function which is subverted in cancer.
UV-A/B radiation rapidly activates photoprotective mechanisms inChlamydomonas reinhardtii
Authors: Tokutsu Ryutaro , Fujimura-Kamada Konomi , Yamasaki Tomohito , Okajima Keisuke , Minagawa Jun
Published: July 2020

Conversion of light energy into chemical energy through photosynthesis in the chloroplasts of photosynthetic organisms is essential for photoautotrophic growth. However, the conversion of excess light energy into thermal energy by non-photochemical quenching (NPQ) is important for avoiding the generation of reactive oxygen species and maintaining efficient photosynthesis. In the unicellular green algaChlamydomonas reinhardtii, NPQ is activated as a photoprotective mechanism through wavelength-specific light signaling pathways mediated by the phototropin (blue light) and UVR8 (ultra-violet light, UV) photoreceptors. NPQ-dependent photoprotection improves cell survival under high-light conditions; however, the biological significance of photoprotection being activated by light with different qualities remains poorly understood. Here, we demonstrate that NPQ-dependent photoprotection is activated more rapidly by UV than by visible light. We found that induction of gene expression and protein accumulation related to photoprotection was significantly faster and greater in magnitude under UV treatment compared to that under blue- or red-light treatment. Furthermore, the action spectrum of UV-dependent induction of photoprotective factors implied that Chlamydomonas sense relatively long-wavelength UV (including UV-A/B), whereas the model dicot plantArabidopsis thalianapreferentially senses relatively short-wavelength UV (mainly UV-B/C) for induction of photoprotective responses. Therefore, we hypothesize that Chlamydomonas developed a UV response distinct from that of land plants.

One-sentence summary

In contrast to land plants, which sense short-wave UV light, the unicellular green alga Chlamydomonas senses long-wavelength UV light for photoprotective responses.
Assessment of current taxonomic assignment strategies for metabarcoding eukaryotes
Authors: Hleap Jose S. , Littlefair Joanne E. , Steinke Dirk , Hebert Paul D. N. , Cristescu Melania E.
Published: July 2020

The effective use of metabarcoding in biodiversity science has brought important analytical challenges due to the need to generate accurate taxonomic assignments. The assignment of sequences to a generic or species level is critical for biodiversity surveys and biomonitoring, but it is particularly challenging. Researchers must select the approach that best recovers information on species composition. This study evaluates the performance and accuracy of seven methods in recovering the species composition of mock communities which vary in species number and specimen abundance, while holding upstream molecular and bioinformatic variables constant. It also evaluates the impact of parameter optimization on the quality of the predictions. Despite the general belief that BLAST top hit underperforms newer methods, our results indicate that it competes well with more complex approaches if optimized for the mock community under study. For example, the two machine learning methods that were benchmarked proved more sensitive to the reference database heterogeneity and completeness than methods based on sequence similarity. The accuracy of assignments was impacted by both species and specimen counts which will influence the selection of appropriate software. We urge the usage of realistic mock communities to allow optimization of parameters, regardless of the taxonomic assignment method used.
In SituUnzipping of Long, High Molecular Weight DNA in Solid State Nanopores
Authors: Losakul R. , Tobar D. E. , Pfeffer A.M. , Gutierrez A. , Schipper R. , Jehle W. A. , Postma H.W.Ch.
Published: July 2020

Nanopores are an established paradigm in genome sequencing technology, with remarkable advances still being made today. All efforts continually address the challenges associated with rapid, accurate, high-throughput, and low cost detection, particularly with long-read length DNA. We report on thein situmelting and unzipping oflong, high molecular weightDNA. At varying salt concentration, we directly compare the translocation conductance and speeds between SiN and graphene nanopores at sub-10 nm pore diameters. We observe the force-induced unzipping of dsDNA at higher salt concentrations than previously reported in literature. We observe free running translocation without secondary structures of ssDNA that is an order of magnitude longer than reported before. We hypothesize that the frayed single strands at the molecule’s end get captured with a higher likelihood than both ends together. In understanding this phenomena for long-read lengths, we continue to address the challenges revolving around future generations of sequencing technology.

Statement of Significance

Genome sequencing is an advancing field with applications in clinical diagnostics. However, the challenges of providing accurate identification of longer DNA molecules at low cost are still developing. While detection of long DNA molecules is established, the identification of its individual nucleotides presents its own set of challenges. By separating the hydrogen bonds between the two strands, individual nucleotides are made directly measurable. However, identification is hindered from the formation of secondary structures, where the single-stranded DNA sticks to itself. Previous studies only included short DNA molecules. We report in situ force-induced unzipping and translocation of long DNA without secondary structures almost an order of magnitude longer than reported before. Our findings present new experimental conditions and insights that progress the field towards high accuracy sequencing of individual long molecules.
Full-length annotation with multi-strategy RNA-seq uncovers transcriptional regulation of lncRNAs in diploid cottonG. arboreum1
Authors: Zheng Xiaomin , Chen Yanjun , Zhou Yifan , Li Danyang , Shi Keke , Hu Xiao , Ye Hanzhe , Zhou Yu , Wang Kun
Published: July 2020

Long noncoding RNAs (lncRNAs) are crucial factors during plant development and environmental responses. High-throughput and accurate identification of lncRNAs is still lacking in plants. To build an accurate atlas of lncRNA in cotton, we combined Isoform-sequencing (Iso-seq), strand-specific RNA-seq (ssRNA-seq), cap analysis gene expression (CAGE-seq) with PolyA-seq and compiled a pipeline named plant full-length lncRNA (PULL) to integrate multi-omics data. A total of 9240 lncRNAs from 21 tissue samples of the diploid cottonGossypium arboreumwere identified. We revealed that alternative usage of transcription start site (TSS) and transcription end site (TES) of lncRNAs occurs pervasively during plant growth and responses to stress. We identified the lncRNAs which co-expressed or be linked to the protein coding genes (PCGs) or GWAS studied SNPs associated with ovule and fiber development. We also mapped the genome-wide binding sites of two lncRNAs with chromatin isolation by RNA purification sequencing (ChIRP-seq) and validated thetranstranscriptional regulation oflnc-Ga13g0352via virus induced gene suppression (VIGS) assay. These findings provide valuable research resources for plant community and broaden our understandings of biogenesis and regulation function of plant lncRNAs.

One sentence summary

The full-length annotation and transcriptional regulation of long noncoding RNAs in cotton.
Toxic Y chromosome: increased repeat expression and age-associated heterochromatin loss in male Drosophila with a young Y chromosome
Authors: Nguyen Alison H. , Bachtrog Doris
Published: July 2020

Sex‐specific differences in lifespan are prevalent across the tree of life and influenced by heteromorphic sex chromosomes. In species with XY sex chromosomes, females often outlive males. Males and females can differ in their overall repeat content due to the repetitive Y chromosome, and repeats on the Y might lower survival of the heterogametic sex (toxic Y effect). Here, we take advantage of the well‐assembled young Y chromosome ofDrosophila mirandato study the sex‐specific dynamics of chromatin structure and repeat expression during aging in male and female flies. MaleD. mirandahave about twice as much repetitive DNA compared to females, and live shorter than females. Heterochromatin is crucial for silencing of repetitive elements, yet oldD. mirandaflies lose H3K9me3 modifications in their pericentromere, with heterochromatin loss being more severe during aging in males than females. Satellite DNA becomes de‐repressed more rapidly in old vs. young male flies relative to females. In contrast to what is observed inD. melanogaster, we find that transposable elements (TEs) are expressed at higher levels in maleD. mirandathroughout their life. We show that epigenetic silencing via heterochromatin formation is ineffective on the large TE‐ rich neo‐Y chromosome, resulting in up‐regulation of Y‐linked TEs already in young males. This is consistent with an interaction between the age of the Y chromosome and the genomic effects of aging. Our data support growing evidence that “toxic Y chromosomes” can diminish male fitness and a reduction in heterochromatin can contribute to sex‐specific aging.
Experimental evidence for the role of natural radioactivity in influencing viability of commensal microorganisms
Authors: Ruggiero Marco
Published: July 2020

The role of natural radioactivity in influencing viability of commensal microorganisms, with particular reference to those pertaining to the human microbiota, has not been investigated in detail. The results of experiments culturing a diversified array of microorganims - probiotics - in naturally radioactive mineral water or deuterium-depleted water are here described. Culturing microorganisms in naturally radioactive mineral water yielded one order of magnitude more live microbial cells in comparison with culturing in deuterium-depleted water. Based on these experimental results, a method for co-culturing prebiotic microorganisms (cyanobacteria) that are extremely resistant to the harmful effects of radiations, together with the probiotics mentioned above, is described. The goal of this co-culture in naturally radioactive mineral water is to transfer the information from the radiation-resistant microorganisms to the probiotics whose viability is enhanced by natural radioactivity. Expression of DNA repair genes in cyanobacteria is induced by co-culturing in a medium of carbonated mineral water naturally containing the radioactive isotopes228U and226Ra. The culture medium, in addition to naturally radioactive water, contains silica from vegetal origin to enhance horizontal gene transfer. Finally, it is described the transfer of resistance to the harmful effects of radiations to human cells through a Lactococcus phage-encoded protein, ORF252, that is the evolutionary precursor of human proteins involved in DNA repair and cancer protection.
Spatial patterns in phage-Rhizobiumcoevolutionary interactions across regions of common bean domestication
Authors: Van Cauwenberghe Jannick , Santamaría Rosa I. , Bustos Patricia , Juárez Soledad , Ducci Maria Antonella , Fleming Trinidad Figueroa , Etcheverry Angela Virginia , González Víctor
Published: July 2020

Bacteriophages play significant roles in the composition, diversity, and evolution of bacterial communities. Despite their importance, it remains unclear how phage diversity and phage-host interactions are spatially structured. Local adaptation may play a key role. Nitrogen-fixing symbiotic bacteria, known as rhizobia, have been shown to locally adapt to domesticated common bean at its Mesoamerican and Andean sites of origin. This may affect phage-rhizobium interactions. However, knowledge about the diversity and coevolution of phages with their respectiveRhizobiumpopulations is lacking. Here, through the study of four phage-Rhizobiumcommunities in Mexico and Argentina, we show that both phage and host diversity is spatially structured. Cross-infection experiments demonstrated that phage infection rates were higher overall in sympatric rhizobia than in allopatric rhizobia except for one Argentinean community, indicating phage local adaptation and host maladaptation. Phage-host interactions were shaped by the genetic identity and geographic origin of both the phage and the host. The phages ranged from specialists to generalists, revealing a nested network of interactions. Our results suggest a key role of local adaptation to resident host bacterial communities in shaping the phage genetic and phenotypic composition, following a similar spatial pattern of diversity and coevolution to that in the host.