Search

Transfer RNA-derived small RNAs (tsRNAs) - categorized as tRNA-derived fragments (tRFs), tRNA-derived stress-induced RNAs (tiRNAs) and internal tRF (itRF) - are small non-coding RNAs that participate in various cellular processes such as translation inhibition and responses to cellular stress. We here identified tsRNA profiles within susceptible tissues in animal models of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) to pinpoint disease-specific tsRNAs and those shared across neurodegenerative diseases. We performed small RNA sequencing in the SOD1G93A and TDP43A315T mouse models of ALS (spinal cord), the TauP301S model of FTD (hippocampus), and the parkin/POLG model of PD (substantia nigra). Bioinformatic analysis showed higher expression of 5' tiRNAs selectively in the two ALS models, lower expression of 3' tRFs in both the ALS and FTD mouse models, and lower expression of itRF Arg in the PD model. Experimental validation confirmed the expression of tsRNAs. Gene Ontology analysis of targets associated with validated 3' tRFs indicated functions in the regulation of synaptic and neuronal pathways. Our profiling of tsRNAs indicates disease-specific fingerprints in animal models of neurodegeneration, which require validation in human disease., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: This study aimed to compare extracorporeal shock wave therapy (ESWT) with the use of stabilization splint in nonsurgical temporomandibular disorders treatments, and to evaluate the effects., Methods: In this study, individuals, who are diagnosed with disc displacements with reduction according to the diagnostic criteria for temporomandibular disorder examination criteria. The patients in the first control group (n = 36) were applied a medical treatment + stabilization splint. The second group (n = 25) was applied the ESWT (2 days a week for 4 weeks) + medical treatment + stabilization splint. Visual Analog Scale scores, painless maximum painless mouth opening, and passive-forced mouth opening measurements were recorded for the first and second weeks., Results: The ESWT application significantly contributed to pain-reducing (Visual Analog Scale) in patients at short notice (P = .030) in the second group. There were statistically significant differences between the groups in painless maximum active mouth opening (P = .009) and passive forced measurements (P = .004) in the second week., Conclusion: This pilot study showed that short-term ESWT addition to stabilization splint and medical treatment may yield satisfactory outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

A high-performance and affordable peanut shell-derived biochar was employed for the efficient removal of Rhodamine B (RhB) from aqueous solutions. The properties of peanut shell biochar (PSB) were investigated through Fourier transform infrared (FTIR) spectroscopy and Brunauer-Emmett-Teller surface area measurements. The FTIR analysis revealed numerous active sites and functional groups for the binding of dye molecules, while the BET surface area was determined to be 351.11 m 2 g -1 . Four different isotherms and kinetic models were applied to determine the equilibrium adsorption of RhB, and the results indicated that the Freundlich isotherm was the most appropriate model. A maximum dye removal rate of 94.0% occurred at a pH of 3 with an adsorbent dose of 0.325 g L -1 . The prepared adsorbent showed excellent sorbent behaviour and can be reused multiple times after regeneration, with the surface area decreasing from 351.11 m 2 g -1 to 140.13 m 2 g -1 after the third cycle. The negative Gibbs free energy ΔG o at all applied temperatures suggested that spontaneous adsorption occurred and RhB adsorption on the PSB was found exothermic, as evidenced by the negative value of ΔH o . The regenerated PSB can be utilized as an efficient, environmentally friendly, and cost-effective sorbent for the removal of dyes at temperatures lower than ambient temperature, providing both technical and financial advantages for sustainable environmental management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objective: The triglyceride-glucose index (TyG) has been proposed as a marker of insulin resistance (IR) and has shown associations with cardiovascular diseases. This study aimed to investigate the relationship between the TyG and the coronary slow flow phenomenon (CSFP) and explore the index's potential as a predictor of this condition., Patients and Methods: A total of 187 patients who underwent coronary angiography were included; of these, 91 patients were diagnosed with CSFP, and 96 patients with normal coronary flow served as a control group. The TyG was calculated using fasting triglyceride and glucose levels., Results: The results showed that the TyG was significantly higher in the CSFP group compared with the control group (p < 0.001). Additionally, the TyG exhibited a moderate positive correlation with the thrombolysis-in-myocardial-infarction frame count in coronary arteries (p < 0.001). A multivariate logistic regression analysis revealed that the TyG, along with gender, ejection fraction, and uric acid, remained significant predictors of CSFP (p < 0.05)., Conclusions: This study's findings suggest that the TyG may serve as a useful marker for identifying individuals at risk of CSFP and provide insights into the potential role of IR in its pathophysiology.

Background: Fibroblast growth factor receptor 3 (FGFR3) alterations are oncogenic drivers of urothelial carcinoma (UC). Pemigatinib is a selective, oral inhibitor of FGFR1-3 with antitumor activity. We report the efficacy and safety of pemigatinib in the open-label, single-arm, phase II study of previously treated, unresectable or metastatic UC with FGFR3 alterations (FIGHT-201; NCT02872714)., Patients and Methods: Patients ≥18 years old with FGFR3 mutations or fusions/rearrangements (cohort A) and other FGF/FGFR alterations (cohort B) were included. Patients received pemigatinib 13.5 mg once daily continuously (CD) or intermittently (ID) until disease progression or unacceptable toxicity. The primary endpoint was centrally confirmed objective response rate (ORR) as per RECIST v1.1 in cohort A-CD. Secondary endpoints included ORR in cohorts A-ID and B, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: Overall, 260 patients were enrolled and treated (A-CD, n = 101; A-ID, n = 103; B, n = 44; unconfirmed FGF/FGFR status, n = 12). All discontinued treatment, most commonly due to progressive disease (68.5%). ORR [95% confidence interval (CI)] in cohorts A-CD and A-ID was 17.8% (10.9% to 26.7%) and 23.3% (15.5% to 32.7%), respectively. Among patients with the most common FGFR3 mutation (S249C; n = 107), ORR was similar between cohorts (A-CD, 23.9%; A-ID, 24.6%). In cohorts A-CD/A-ID, median (95% CI) DOR was 6.2 (4.1-8.3)/6.2 (4.6-8.0) months, PFS was 4.0 (3.5-4.2)/4.3 (3.9-6.1) months, and OS was 6.8 (5.3-9.1)/8.9 (7.5-15.2) months. Pemigatinib had limited clinical activity among patients in cohort B. Of 36 patients with samples available at progression, 6 patients had 8 acquired FGFR3 secondary resistance mutations (V555M/L, n = 3; V553M, n = 1; N540K/S, n = 2; M528I, n = 2). The most common treatment-emergent adverse events overall were diarrhea (44.6%) and alopecia, stomatitis, and hyperphosphatemia (42.7% each)., Conclusions: Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements., Competing Interests: Disclosures AN received honoraria from Astellas, AstraZeneca, BMS, Foundation Medicine, Janssen, MSD, and Roche; served as a consultant and/or advisor to AstraZeneca, Basilea Pharmaceutica, Bayer, Bicycle Therapeutics, BMS, Catalym, Clovis Oncology, GlaxoSmithKline, Incyte, Janssen, MSD, Rainier Therapeutics, Roche, and Seattle Genetics/Astellas; received research funding paid to the institution from AstraZeneca, Gilead, Ipsen, and MSD; received payments for travel and accommodations from AstraZeneca, Janssen, MSD, Pfizer, Rainer Therapeutics, and Roche; and reports that his spouse is an employee and shareholder of Bayer. DP received research grants paid to his institution from AstraZeneca, BMS, Merck Sharp & Dohme, Roche, and Seattle Genetics; received honoraria from AstraZeneca, Astellas Pharma, BMS, Ipsen, MSD Oncology, and Pfizer/Astellas; served as a consultant for Astellas Pharma, BMS/Medarex, Merck, MSD Oncology, and Pfizer; and received payments for travel and accommodations from AstraZeneca and Pfizer. RL received honoraria from AstraZeneca, Bayer, BMS, Isotopia, Janssen, MSD, Pfizer, and Roche; served as a consultant and/or advisor for Astellas Medivation, AstraZeneca, Bayer, Immunai, Kamada, NeoPharm, Oncohost, Pfizer, and Sanofi; received travel support from Janssen and Pfizer; and served as a principal investigator on studies from BMS, Eisai, Incyte, Janssen, MSD, and Pfizer. SG received research funding from Acrotech, Astellas, AstraZeneca, BMS, Clovis Oncology, Daiichi Sankyo/Lilly, Five Prime Therapeutics, Hoosier Cancer Research Network, Immunocore, Incyte, LSK BioPharma, MedImmune, Merck, Mirati Therapeutics, Novartis, Pfizer, QED Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, and Viralytics. AF received honoraria from Astellas, Janssen, Merck, MSD, Pfizer, and Seagen. JGD received researching funding from Astellas, BMS, GSK, Ipsen, Janssen, Pfizer, Roche, and Sanofi and honoraria for serving as a speaker for AstraZeneca, BMS, Janssen, and Roche. MAB has acted as a paid consultant for and/or as a member of the advisory boards of AstraZeneca, Bayer, BMS, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, Sanofi, and SeaGen and has received grants to his institution from AAA, AstraZeneca, Bayer, BMS, Genentech/Roche, Genome & Company, Incyte, Merck, Nektar, Peloton Therapeutics, Pfizer, SeaGen, Tricon Pharmaceuticals, and Xencor for work carried out as outside of the current study. PRD received grants to institution from Pfizer; received consulting fees for participation on advisory boards from BMS, Ipsen, Merck, and Pfizer; received honoraria for lectures from Bayer; received travel support from Janssen; serves as a substitute board member for the Clinical Trials College, Federal Public Service, Kingdom of Belgium; and holds stock or stock options in Alkermes and Biocartis Group NV. MIM received research grants paid to his institution from Alliance for Clinical Trials in Oncology, Alliance Foundation Trials, ALX Oncology, Arvinas, BMS, Clovis Oncology, G1 Therapeutics, Hoosier Cancer Research Network, Incyte, Loxo, Merck, Mirati Therapeutics, Roche/Genentech, and Seagen; served as a consultant for Loxo/Lilly; owns stock in Gilead Sciences, Merck, and Pfizer; and reports a relationship with Elsevier, Research to Practice, and Medscape. TF received honoraria and payments for travel and accommodations from Astellas; had a consulting or advisory role for AADi Therapeutics, Basilea Pharmaceutica, and Seagen/Astellas; and received research funding paid to the institution from BMS, Roche/Genentech, Seagen, and Trishula. MM served as a consultant and/or advisor to Alfasigma, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Incyte, Merck Serono, Merck Sharpe & Dohme, Pierre Fabre, Roche, Sanofi, and Sciclone and owns shares in Epigen Therapeutics and Theravance. AG, XL, and MLV are employees and shareholders of Incyte. YL received honoraria from AstraZeneca, Astellas, BMS, Gilead, Janssen, Merck KGaA, MSD, and Pfizer and received payments for travel and accommodations from Astellas, BMS, Janssen, Merck KGaA, MSD, Pfizer, and Roche., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The novel bacterial strain Marseille-P4005 T was isolated from the stool sample of a healthy donor. It is a Gram-stain negative, non-motile, non-spore-forming rod. It grew optimally at 37 °C and at pH 7.0 on 5% sheep blood-enriched Columbia agar after preincubation in a blood-culture bottle supplemented with rumen and blood. This strain does not ferment monosaccharides (except D-tagatose), disaccharides, or polymeric carbohydrates. The major cellular fatty acids were hexadecenoic (24.6%), octadecanoic (22.8%), and tetradecanoic (20.1%) acids. Next-generation sequencing revealed a genome size of 3.2 Mbp with a 56.4 mol% G + C. Phylogenetic analysis based on the 16S rRNA gene highlighted Agathobaculum desmolans strain ATCC 43058 T as the closest related strain. The OrthoANI, AAI, and digital DNA-DNA hybridization values were below the critical thresholds of 95%, 95-96%, and 70%, respectively, to define a novel bacterial species. Antibiotic resistance genes APH(3')-IIIa, erm(B), and tet(W) were detected with high identity percentages of 100%, 98.78%, and 97.18% for each gene, respectively. The APH(3')-IIIa gene confers resistance to amikacin, erm(B) gene confers resistance to erythromycin, lincomycin, and clindamycin, while tet(W) gene confers resistance to doxycycline and tetracycline. Based on KEGG BlastKOALA analyses, the annotation results showed that our strain could use glucose to produce L-lactate and pyruvate but not acetate or ethanol. Also, strain Marseille-P4005 T was predicted to use phenylalanine to produce indole, a major intercellular signal molecule within the gut microbial ecosystem. Through having a gene coding for tryptophan synthase beta chain (trpB), strain Marseille-P4005 T could produce L-tryptophan (an essential amino acid) from indole. Strain Marseille-P4005 T showed its highest prevalence in the human gut (34.19%), followed by the reproductive system (17.98%), according to a query carried out on the Integrated Microbial NGS (IMNGS) platform. Based on phylogenetic, phenotypic, and genomic analyses, we classify strain Marseille-P4005 T (= CSUR P4005 = CECT 9669), a novel species within the genus Agathobaculum, for which the name of Agathobaculum massiliense sp. nov. is proposed., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The circadian system synchronizes behavior and physiology to the 24-h light- dark (LD) cycle. Timing of food intake and fasting periods provide strong signals for peripheral circadian clocks regulating nutrient assimilation, glucose, and lipid metabolism. Mice under 12 h light:12 h dark (LD) cycles exhibit behavioral activity and feeding during the dark period, while fasting occurs at rest during light. Disruption of energy metabolism, leading to an increase in body mass, was reported in experimental models of circadian desynchronization. In this work, the effects of chronic advances of the LD cycles (chronic jet-lag protocol, CJL) were studied on the daily homeostasis of energy metabolism and weight gain., Methods: Male C57 mice were subjected to a CJL or LD schedule, measuring IPGTT, insulinemia, microbiome composition and lipidemia., Results: Mice under CJL show behavioral desynchronization and feeding activity distributed similarly at the light and dark hours and, although feeding a similar daily amount of food as compared to controls, show an increase in weight gain. In addition, ad libitum glycemia rhythm was abolished in CJL-subjected mice, showing similar blood glucose values at light and dark. CJL also generated glucose intolerance at dark in an intraperitoneal glucose tolerance test (IPGTT), with increased insulin release at both light and dark periods. Low-density lipoprotein (LDL) cholesterolemia was increased under this condition, but no changes in HDL cholesterolemia were observed. Firmicutes/Bacteroidetes ratio was analyzed as a marker of circadian disruption of microbiota composition, showing opposite phases at the light and dark when comparing LD vs. CJL., Discussion: Chronic misalignment of feeding/fasting rhythm leads to metabolic disturbances generating nocturnal hyperglycemia, glucose intolerance and hyperinsulinemia in a IPGTT, increased LDL cholesterolemia, and increased weight gain, underscoring the importance of the timing of food consumption with respect to the circadian system for metabolic health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Trebucq, Lamberti, Rota, Aiello, Borio, Bilen, Golombek, Plano and Chiesa.)

Since the global pandemic of SARS-CoV-2, people's health and the economic support of their countries have been seriously affected. It was necessary to develop a low-cost and faster diagnostic tool that allows the evaluation of symptomatic patients. Point-of-care testing and point-of-need testing systems have been recently developed to solve these drawbacks, providing accurate and rapid diagnostics at field level or at the site of outbreaks. In this work, a bio-photonic device has been developed for the diagnosis of COVID-19. The device is used with an isothermal system (Easy Loop Amplification based) for the detection of SARS-CoV-2. The performance of the device was evaluated in the detection of a SARS-CoV-2 RNA sample panel, showing an analytical sensitivity comparable to the reference method of quantitative reverse transcription polymerase chain reaction used commercially. In addition, the device was mainly built with simple and low-cost components; therefore, it is possible to obtain a high-efficiency and low-cost instrument. The device excites the sample to be analyzed with a semiconductor laser with a specific wavelength, thus triggering spontaneous emission of the fluorophore bound to the specific probe. The emitted fluorescence is suitably managed by using interferential filters. Under these conditions, a signal is registered and, depending on this level, defines the case as positive or negative. All the analysis is done autonomously inside the developed device through an integrated control system, and it is connected to a portable device to show the results wirelessly.

Aims: A subset of patients with urothelial carcinoma (UCa) and lamina propria (LP) invasion in bladder biopsies/transurethral resections (TURs) are at significant risk for recurrence and have increased rates of progression to UCa with muscularis propria (MP) invasion. The clinicopathologic features of this patient population has not been well characterised in the Pathology literature., Methods: We performed a search through our urologic pathology files and expert consult cases of the senior author for bladder biopsies/TURs of UCa with LP invasion and variant/divergent histology from 2014 to 2020. Patients with a prior diagnosis of UCa with MP invasion or upper tract UCa were excluded. Clinicopathologic data were obtained., Results: Ninety-five patients with at least one biopsy/TUR of UCa with LP invasion and variant/divergent histology were identified. Mean patient age was 72 years (range: 46-92 years) with a male predominance 2.3:1. Initial variant/divergent histologies identified were: glandular (35.8%), squamous (23.2%), micropapillary (20%), clear cell/lipid rich (12.6%), diffuse/signet ring/plasmacytoid (10.5%), nested (9.5%), sarcomatoid (6.3%), poorly differentiated/anaplastic (4.2%), small cell (2.1%), lymphoepithelioma-like (2.1%), osteoclast-like giant cells (1.1%) and tumour giant cells (1.1%). Two or more variant histologies were identified in 18.9% of these cases. The rate of micropapillary UCa was significantly higher in multifocal tumours compared with unifocal tumours (37% vs 7.1%)., Conclusions: In our cohort of patients undergoing early repeat biopsy/TUR, 75% of patients had persistent UCa. Additionally, almost 25% of patients had a prior diagnosis of UCa without a variant/divergent histology identified. Our findings highlight the critical role of repeat biopsy/TUR especially in a subset of patients who have variant/divergent histology, even in the absence of MP invasion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to dementia. The hippocampus, which is one of the sites where neural stem cells reside and new neurons are born, exhibits the most significant neuronal loss in AD. A decline in adult neurogenesis has been described in several animal models of AD. However, the age at which this defect first appears remains unknown. To determine at which stage, from birth to adulthood, the neurogenic deficits are found in AD, we used the triple transgenic mouse model of AD (3xTg). We show that defects in neurogenesis are present as early as postnatal stages, well before the onset of any neuropathology or behavioral deficits. We also show that 3xTg mice have significantly fewer neural stem/progenitor cells, with reduced proliferation and decreased numbers of newborn neurons at postnatal stages, consistent with reduced volumes of hippocampal structures. To determine whether there are early changes in the molecular signatures of neural stem/progenitor cells, we perform bulk RNA-seq on cells sorted directly from the hippocampus. We show significant changes in the gene expression profiles at one month of age, including genes of the Notch and Wnt pathways. These findings reveal impairments in neurogenesis very early in the 3xTg AD model, which provides new opportunities for early diagnosis and therapeutic interventions to prevent neurodegeneration in AD., (© 2023. The Author(s).)

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear., Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS)., Results: Fifty-two patients with metastatic TRCC treated in the participating centers and evaluable for response were included. Median age at metastatic diagnosis was 40 years (IQR 28.5-53). Patients' IMDC risk groups at diagnosis were favorable (9/52), intermediate (35/52), and poor (8/52). Eleven (21.2%) patients received cabozantinib as frontline therapy, 15 (28.8%) at second line, and 26 (50%) at third line and beyond. The proportion of patients who achieved an objective response was 17.3%, including 2 complete responses and 7 partial responses. For 26 (50%) patients, stable disease was the best response. With a median follow-up of 25.1 months (IQR 12.6-39), median PFS was 6.8 months (95%CI 4.6-16.3) and median OS was 18.3 months (95%CI 17.0-30.6). No difference of response was identified according to fusion transcript features., Conclusion: This real-world study provides evidence of the activity of cabozantinib in TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: Health care workers (HCWs) are disproportionately exposed to infectious diseases and play a role in nosocomial transmission, making them a key demographic for vaccination. HCW vaccination rates are not optimal in many countries; hence, compulsory vaccination policies have been implemented in some countries. Although these policies are effective and necessary under certain conditions, resolving HCWs' hesitancies and misconceptions about vaccines is crucial. HCWs have the advantage of direct contact with patients; hence, they can respond to safety concerns, explain the benefits of vaccination, and counter antivaccine campaigns that escalate during pandemics, as has been observed with COVID-19., Method: A short survey was carried out in May-June 2020 on the vaccination status of HCWs working with pediatric patients with COVID-19. The survey inquired about their vaccination status (mumps/measles/rubella [MMR], varicella, influenza, and diphtheria/tetanus [dT]) and willingness to receive hypothetical future COVID-19 vaccines. The respondents were grouped according to gender, age, occupation, and region., Results: In total, 4927 HCWs responded to the survey. Most were young, healthy adults. The overall vaccination rates were 57.8% for dT in the past 10 years, 44.5% for MMR, 33.2% for varicella, and 13.5% for influenza. Vaccination rates were the highest among physicians. The majority of HCWs (81%) stated that they would be willing to receive COVID-19 vaccines., Conclusion: Although vaccination rates for well-established vaccines were low, a majority of HCWs were willing to receive COVID-19 vaccines when available. Education and administrative trust should be enhanced to increase vaccination rates among HCWs.

The human microbiota has been extensively studied over the past decade to describe its role in health and diseases. Numerous studies showed the presence of bacterial imbalance in a variety of human health conditions, suggesting great potential for the development of bacteriotherapies. Identifying mechanisms involving the human microbiota has been very challenging due to the complex data generated by molecular approaches and the limited number of organisms isolated by culture and described. This review summarizes the efforts done to describe the human microbiota through culturomics and the advancements in culturing the organisms residing at different body sites., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The Microbial Culturomics Project aiming to discover several bacterial species made it possible to isolate the strain Marseille-P4308 T from a stool sample of a healthy indigenous Congolese volunteer. Strain Marseille-P4308 T is a Gram-positive coccus shaped bacterium that optimally grows at 37 °C. The 16S rRNA gene sequence of the strain has a 96.2% sequence similarity to Peptostreptococcus anaerobius strain NCTC 11460 T (GenBank accession number: NR&#95;042847.1). In addition, the average nucleotide identity of strain Marseille-P4308 T with its closest related species was 71.1%, which was far below the recommended threshold (>95-96%). The genome of the strain Marseille-P4308 T has a length of 2.14 Mbp with G + C content of 30.4 mol%. Based on phenotypic, biochemical, genomic and phylogenetic analysis, strain Marseille-P4308 T (= CSUR P4308 = CECT 9960) clearly appears to be a new species for which the name Peptostreptococcus faecalis sp. nov., is proposed., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

Using microbial culturomics, we were able to isolate strain Marseille-P3078 from a stool sample of a healthy 50-year-old Saudi Arabian woman. To this end, we used taxonogenomics that combines phenotypic, biochemical and genomic analyses, to describe this bacterium. Cells from strain Marseille-P3078 are anaerobic and Gram-negative rods that are motile and unable to sporulate. Its genome size is 3,377,914-bp-long with a 66.33 mol% G + C content. Based on its phenotypic and genomic features, including a 94.6% 16S rRNA similarity with Paraeggerthella hongkongensis strain JCM 14552, its closest phylogenetic neighbor withstanding in nomenclature, we propose that strain Marseille-P3078T (= CSUR P3078 = DSM 104007) is the representative strain of a new genus for which we propose the name Arabiibacter massiliensis gen. nov., sp. nov., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Strains Marseille-P2265 T (=CSUR P2265 T  =DSM 102082  T ) and Marseille-P3890 T (=CSUR P3890 T  =CCUG 72341  T ) were isolated from stool samples using the culturomics approach. The 16S rRNA gene sequences of both strains were sequenced and compared by BLASTn to the NCBI database. Strains Marseille-P2265 T and Marseille-P3890 T were most closely related to Acutalibacter muris with identities of 94.3% and 91.5%, respectively. Between the two strains, the 16S rRNA gene sequence identity was 91.5%. Both strains are anaerobic Gram-positive, oxidase- and catalase-negative. The major fatty acid methyl esters (> 10%) in both strains are C 16:0 and anteiso-C 15:0 . Additionally, strain Marseille-P2265 T has iso-C 15:0 and C 14:0 , and strain Marseille-P3890 T , iso-C 14:0 . Strain Marseille-P2265 T has a genome size of 3,671,396-bp with a G + C content of 52.8%. As for strain Marseille-P3890 T , the genome is 2,702,024-bp-long with a 39.8% G + C content. The genomic comparison of closely related species with strains Marseille-P2265 T and Marseille-P3890 T showed that all digital DNA-DNA hybridization (dDDH), orthologous average nucleotide identity (OrthoANI) and average amino acid identity (AAI) values were lower than the published species thresholds (70% for dDDH, 95-96% for OrthoANI/AAI). Based on these results, it was concluded that strains Marseille-P2265 T and Marseille-P3890 T belong to two new genera in the family Oscillospiraceae. For these two genera, the names Neglectibacter gen. nov. and Scatolibacter gen. nov. were proposed, with strains Marseille-P2265 T and Marseille-P3890 T being the type strains of Neglectibacter timonensis gen. nov., sp. nov. and Scatolibacter rhodanostii gen. nov., sp. nov., respectively., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Understanding SARS-CoV-2 seroprevalence among health care personnel is important to explore risk factors for transmission, develop elimination strategies and form a view on the necessity and frequency of surveillance in the future., Methods: We enrolled 4927 health care personnel working in pediatric units at 32 hospitals from 7 different regions of Turkey in a study to determine SARS Co-V-2 seroprevalence after the first peak of the COVID-19 pandemic. A point of care serologic lateral flow rapid test kit for immunoglobulin (Ig)M/IgG was used. Seroprevalence and its association with demographic characteristics and possible risk factors were analyzed., Results: SARS-CoV-2 seropositivity prevalence in health care personnel tested was 6.1%. Seropositivity was more common among those who did not universally wear protective masks (10.6% vs 6.1%). Having a COVID-19-positive co-worker increased the likelihood of infection. The least and the most experienced personnel were more likely to be infected. Most of the seropositive health care personnel (68.0%) did not suspect that they had previously had COVID-19., Conclusions: Health surveillance for health care personnel involving routine point-of-care nucleic acid testing and monitoring personal protective equipment adherence are suggested as important strategies to protect health care personnel from COVID-19 and reduce nosocomial SARS-CoV-2 transmission., Competing Interests: Conflict of interest All contributing authors declare no conflict of interest. The study is not funded by any organization. The study is approved by Hacettepe University Ethics Committee (Approval No: 2020/11-57)., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Thanks to its ability to isolate previously uncultured bacterial species, culturomics has dynamized the study of the human microbiota. A new bacterial species, Gemella massiliensis Marseille-P3249 T , was isolated from a sputum sample of a healthy French man. Strain Marseille-P3249 T is a facultative anaerobe, catalase-negative, Gram positive, coccus, and unable to sporulate. The major fatty acids were C 16:0 (34%), C 18:1n9 (28%), C 18:0 (15%) and C 18:2n6 (13%). Its 16S rRNA sequence exhibits a 98.3% sequence similarity with Gemella bergeri strain 617-93 T , its phylogenetically closest species with standing in nomenclature. Its digital DNA-DNA hybridization (dDDH) and OrthoANI values with G. bergeri of only 59.7 ± 5.6% and 94.8%, respectively. These values are lower than the thresholds for species delineation (> 70% and > 95%, respectively). This strain grows optimally at 37 °C and its genome is 1.80 Mbp long with a 30.5 mol% G + C content. Based on these results, we propose the creation of the new species Gemella massilienis sp. nov., strain Marseille-P3249 T (= CSUR P3249 = DSMZ 103940)., (© 2021. The Author(s).)

COVID-19 spread globally and caused over 97 million cases with more than 2 million deaths. There is still ongoing discussion on the duration of infectious interval SARS-CoV-2 infection. Symptomatic children had longer virus shedding and there are some reports of prolonged infectious virus shedding in adults particularly patients having an immunocompromised status. A missense mutation, D614G, in the spike protein of SARS-CoV-2, which has emerged as a predominant clade in Europe and is spreading worldwide that can result in higher viral loads in patients. Herein, we described the longest infectious virus shedding in a previously healthy child infected with SARS-CoV-2 expressing spike D614G substitution., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Strain Marseille-P2012 T was described to represent a new bacterial genus belonging to the phylum Firmicutes using the taxonogenomics concept. It was isolated from stool samples of a healthy 2-year-old Senegalese boy in a study of the human gut microbiota. This strain is a Gram-positive, anaerobic, non-motile and coccus-shaped bacterium. The 16S rRNA gene sequence of strain Marseille-P2012 exhibited 90.5% similarity with Finegoldia magna strain ATCC 29,328, the phylogenetically closest species with standing in nomenclature. The genome of strain Marseille-P2012 T is 1,832,315 bp-long with 32.46 mol% of G + C content. With regard to its phenotypic, biochemical and genomic characteristics, this bacterium was classified as a new bacterial genus and species, Lagierella massiliensis gen. nov., sp. nov., with strain Marseille-P2012 T (= CSUR P2012 = DSM100854) as type strain.

Background: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC., Methods: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses., Results: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification., Conclusions: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC., Competing Interests: Disclosure TKC reports grants received from Pfizer during the conduct of the study; personal fees received from Agensys, Alexion, Alligent, American Society of Clinical Oncology, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Celldex, Cerulean, Clinical Care Options, Corvus, Dana-Farber Cancer Institute, EMD Serono, Inc., Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Harborside Press, Heron, Ipsen, Kidney Cancer Association, Kidney Cancer Journal, Lpath, Lancet Oncology, Lilly, Merck & Co., Michael J. Hennessy Associates, National Comprehensive Cancer Network, Navinata Health, New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus Laboratories, Sanofi, Seattle Genetics/Astellas, and UpToDate outside the conduct of the study; grants received from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Ipsen, Merck & Co., Novartis, Peloton Therapeutics, Pfizer, Prometheus Laboratories, Takeda, and TRACON outside the conduct of the study; and medical writing and editorial assistance provided by ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel, funded by pharmaceutical companies. JL reports personal fees from Eisai, EUSA Pharma, GSK, Kymab, Pierre Fabre, Roche/Genentech, and Secarna and grants and personal fees from Bristol Myers Squibb, Merck & Co., Novartis, and Pfizer outside the submitted work. SP reports personal fees from Astellas Pharma and Novartis and personal fees and grants from Medivation. RJM reports serving as a consultant or advisor for and research funding from Pfizer, Novartis, Eisai, and Genentech/Roche, serving as a consultant or advisor for Exelixis, Lilly, Merck & Co., and Incyte, and receiving travel, accommodation, and expenses and research funding from Bristol Myers Squibb outside the submitted work. BIR reports grants and personal fees from AVEO Oncology, Bristol Myers Squibb, Genentech/Roche, Merck & Co., and Pfizer; grants from AstraZeneca; and personal fees from 3D Medicines, Alkermes, Arravive, Inc., Compugen, Corvus Pharmaceuticals, Exelixis, Merck & Co., Novartis, Peloton, Surface Oncology, and Synthorx. BV reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck & Co. and Pfizer, and grants from Merck & Co. during the conduct of the study; and personal fees from EUSA Pharma, Ipsen, and Janssen outside the submitted work. BA reports personal fees from Amgen and Ferring, grants and personal fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck & Co., Pfizer, Roche, and Sanofi, and grants from Ipsen outside the submitted work. GG reports receiving travel, accommodation, and expenses from Astellas, Bristol Myers Squibb, Ipsen, Janssen Oncology, and Pfizer. MAB reports grants from AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Incyte, Peleton Therapeutics, Pfizer, and TRACON; personal fees from EMD Serono, Inc., Exelixis, Genomic Health, and Sanofi; and grants and personal fees from Nektar. AC reports employment at Pfizer at the time when the study was conducted. SH, KAC, XJM, MM, PBR, BH, AdiP report employment at Pfizer. LA reports consulting fees compensated to their institution from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus Pharmaceuticals, Exelixis, Ipsen, Merck KGaA, Merck & Co., Novartis, Peloton Therapeutics, Roche, and Pfizer outside the submitted work. HM has declared no conflicts of interest. Data sharing Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (i) for indications that have been approved in the USA and/or EU or (ii) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies., Patients and Methods: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients)., Results: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality., Conclusions: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies., Clinical Trial Identifier: NCT04354701., Competing Interests: Disclosure JDA reports research funding to the institution from Tesaro, outside the submitted work. ZB reports nonfinancial support from Bristol Myers Squibb and grants from Genentech/imCORE, outside the submitted work. BB reports research funding to the institution from Boehringer Ingelheim, Bicycle Therapeutics, Syros Pharmaceuticals, and Ikena Oncology, all outside the submitted work. TB-S reports research funding to the institution from Agios, Arys, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Novartis, Mirati, Merus, AbGenomics, Incyte, Pfizer, BMS; consulting (to institution) for Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; consulting (to self) for AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daiichi Sankyo, Natera, Treos Bio, Celularity, Exact Science, Sobi, BeiGene, Xilis, Astra Zeneca, and Foundation Medicine; serving on Independent Data Monitoring Committee/Data and Safety Monitoring Board (to self) for AstraZeneca, Exelixis, Lilly, PanCAN, and 1Globe; positions on Scientific Advisory Board for Imugene, Immuneering, and Sun Biopharma; and inventions/patents (WO/2018/183488 and WO/2019/055687), all outside the submitted work. SB reports being on advisory boards for Bristol Meyers Squibb and Seattle Genetics. MAB reports personal fees from Exelixis, Bristol-Myers Squibb, Bayer, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar, and Sanofi; grants from Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peloton Therapeutics, and Pfizer, outside the submitted work. NB reports honoraria from Novartis, Pfizer, Roche, and Lilly, outside the submitted work. DWB reports research funding to the institution from Exelixis, Ayala, Merck, and Elevar, all outside the submitted work. DDC declares consulting or advisory role with Exelixis, outside the submitted work. TKC reports institutional and personal research support from Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon; consulting/honoraria or advisory role with Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date; CME-related events (e.g. OncLive, PVI, MJH Life Sciences); stock ownership in Pionyr, Tempest; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; fees for travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; and no speaker's bureau; also supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. DBD reports consulting for Ipsen, Boehringer Ingelheim; ASCO Young Investigator Award from Conquer Cancer Foundation, outside the submitted work. AE reports grant support from AstraZeneca, outside the submitted work. DF reports research funding to the institution from Viracor-Eurofins and Astellas, all outside the submitted work. LAF reports clinical trial funding to the institution from BMS, EMD Serono, Pfizer, Merck KGaA, Array, Kartos, Merck, and Incyte, ECOG-ACRIN study funding from Array; and personal fees from Elsevier and Via Oncology, outside the submitted work. DBF reports honoraria from Castle Biosciences. SMG reports Honoraria from AstraZeneca, Merck, Genentech/Roche; consulting or advisory role with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Xcovery, Boehringer Ingelheim, Novocure, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Blueprint Medicines, Eli Lilly, Pfizer, Janssen Oncology; research funding (to self) from Merck, AstraZeneca; research funding (to institution) from Genentech/Roche, Merck, Blueprint Medicines, ARIAD/Takeda, Astellas Pharma, Lycera, Daiichi Sankyo, IMAB, Nektar, AstraZeneca, Pfizer, Amgen; travel, accommodations, expenses from Genentech/Roche, Merck; and other relationship from AstraZeneca, all outside the submitted work. MDG reports personal fees from Genentech, Pfizer, Astra Zeneca, Merck, Bristol Myers Squib, Dragonfly, Dracen, Seattle Genetics, and Astellas, outside the submitted work. PG reports consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Dyania Health, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Heron Therapeutics, Immunomedics, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, Seattle Genetics, QED Therapeutics; research funding to institution from Merck, Mirati Therapeutics, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Debiopharm, Bristol-Myers Squibb, QED Therapeutics, GlaxoSmithKline, and Kure It Cancer Research, all outside the submitted work. SG reports research funding to the institution from AstraZeneca and consulting/advisory role with Puma Biotechnology. SG reports consultancy fees from BMS, Merck, AstraZeneca, Seattle Genetics, Pfizer; and speaker fees from Seattle Genetics and Janssen, all outside the submitted work. TRH reports consulting or advisory role with Curium, ScioScientific, TERUMO, Lexicon, Ipsen, Advanced Accelerator; research funding from Ipsen, ArQule, Agios, Thermo Fisher Scientific, Basilea. BH reports research funding to the institution from Amgen, AbbVie, BI, Mirati, Merck, Eli-Lilly, AstraZeneca, BMS, Novartis, GSK, Pfizer, Advaxis, and Guardant Health; consulting/advisory role with Merck, BMS, Genentech, AstraZeneca, Amgen, Novartis, TPT, VI, Guardant Health; and honoraria from PER and OncLive, all outside the submitted work. JEH reports research funding from Regeneron and Dendreon; and travel, accommodations, and expenses from Genzyme. CH reports funding from the Henry Ford Cancer Institute supporting the current work; research funding to institution from Merck, Exelixis, Bayer, AstraZeneca, Genentech, Dendreon and Bausch; personal fees from Sanofi/Genzyme, Dendreon, Exelixis, Bristol Myers Squibb, Astellas, Medivation, Bayer, and Janssen Scientific, all outside the submitted work; and stock ownership by an immediate family member in Johnson and Johnson. DBJ reports advisory board participation for Array Biopharma, BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, and OncoSec, and receives research funding from BMS and Incyte, all outside the submitted work. AK reports support to his institution from TESARO, Halozyme, Geistlich Pharma, Astellas Pharma, and Rafael Pharmaceuticals; and honoraria from OncLive, outside the submitted work. ARK (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Merck, Sanofi, and BMS. VSK reports personal fees from Pfizer, Janssen, Dendreon, AstraZeneca, Seattle Genetics, and Clovis; grants (for institution) from Nektar, Novartis/Endocyte, Janssen, Clovis, and Prostate Cancer Foundation, all outside the submitted work. NMK reports personal fees from G1 Therapeutics, Invitae, Beyond Spring, Spectrum, BMS, Janssen, and Total Health, all outside the submitted work. PEL reports consulting/advisory role with Pfizer, Merck, Teva, BI, and Astra Zeneca, all outside the submitted work. AL-B reports personal fees from PSI CRO, Bayer, Blueprint, Astra-Zeneca, Medidata, Taiho, QED, Cardinal Health, BrightInsight, The Lynx Group, Boston Biomedical, Amgen, Bayer, Guardant, Natera, Eisai, Ipsen, and Merck; and stock options from Massive Bio, outside the submitted work. GdLL reports honoraria from Boehringer Ingelheim; consulting or advisory role for Pfizer and AstraZeneca; research funding from AstraZeneca; funding to his institution from Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, NOVARTIS, G1 Therapeutics, Adaptimmune, BMS, GSK, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, and Janssen; travel, accommodations, and expenses from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen. GHL reports grants from AMGEN (institution); personal fees from G1 Therapeutics, TEVA, Samsung Bioepis, Beyond Spring, and Merck, outside the submitted work. RRM reports research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion; and serves on the molecular tumor board at Caris. RAM grants from Incyte, CTI, AbbVie, and Celgene; personal fees from Novartis, Genentech, Sierra Oncology, La Jolla, and Samus, outside the submitted work. VM has currently or during the past 2 years employment and stock or other ownership interest with Johnson & Johnson, all outside the submitted work. GN reports research funding to the institution from Novartis, all outside the submitted work. JN reports personal fees from AstraZeneca, Clovis Oncology; all outside the submitted work. CAP (or an immediate family member) has currently or during the past 2 years owned stock or held an ownership interest in Pfizer, Epizyme, Inovio, OPKO Health Inc, Roche. JMP reports grant from Dana-Farber/Harvard Cancer Center Breast SPORE Program, outside the submitted work. PP reports receiving payment for speakers' bureau from Novartis, Daichi Sankyo, Genentech, Seattle Genetics, and Pfizer, all outside the submitted work. NAP reports personal fees from Eli Lilly, Merck, BMS, Genentech, AstraZeneca, Inivata, and Regeneron, outside the submitted work. SP reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, and Takeda; nonfinancial support from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Meyers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, and Sanofi; and personal fees from BioInvent (all fees to institution), outside the submitted work. DYR reports consulting/advisory role with and coverage of travel/accommodation expenses by Castle Biosciences, all outside the submitted work. BIR reports grants, personal fees, and nonfinancial support from Merck; grants and personal fees from BMS, Pfizer, Aveo, and Genentech; grants from Astra Zeneca; personal fees from Synthorx, 3D Medicines, Aravive, Surface Oncology, and Arrowhead Therapeutics; and other from PTC Therapeutics, outside the submitted work. RPR reports research grants to her institution from BMS and Janssen and has worked as a consultant/advisor and received honoraria from BMS and Janssen, all of which are outside the scope of submitted work. ALS reports travel support provided by Pfizer and Astellas. GKS reports personal fees from Apexigen, Array, Epizyme, GenCirq, Daiichi Sankyo, Fortress, Iovance Biotherapeutics, Bayer Pharmaceuticals, Pfizer Oncology, Array Advisory Board, Oncogenuity, Puretech, PTC Therapeutics, Ellipses Pharma, Concarlo; advisory board for Bionaut; grants from Astex; stock ownership in Pfizer, all outside the submitted work. SS reports stock and other ownership interests in Grand Rounds, Janssen, and Natera. YS reports honoraria from Boehringer Ingelheim, AstraZeneca, Novartis, and Eisai; consulting or advisory role with Pfizer, AstraZeneca, Novartis, Roche, Genentech, and Janssen, all outside the submitted work. MAT reports travel support from Syapse, Royalties from UpToDate, Connect MDS/AML Registry in Celgene (now owned by BMS), Myeloma Registry in Takeda; stock ownership in Doximity; personal fees from VIA Oncology (now owned by Elsevier ClinicalPath), Adaptive Advisory Board, and GSK; he is the local PI for Clinical Trials in AbbVie, BMS, CRAB CTC, Denovo, Research Network, Eli Lilly, LynxBio, Strata Oncology, and TG Therapeutics, all outside the submitted work. AKV reports research funding to the institution from BMS, MedPacto, Prelude, iOnctura, and Janssen; honoraria from Acceleron and Novartis; consulting/advisory role with Stelexis and Janssen; stock or other ownership in Stelexis; and an immediate family member with employment/leadership with CereXis, all outside the submitted work. DCV reports honoraria and speakers' bureau fees from CSL Behring, Merck Canada, Novartis Canada, Takeda, and UCB Biosciences GmbH, and travel accommodations from CSL Behring, and Avir Pharma, all outside the submitted work. He is supported by the Fonds de la recherche en santé du Québec (FRQS) Clinician-Scientist Junior 2 program. JLW reports grants from the National Cancer Institute during the conduct of the study; personal fees from Westat and IBM Watson Health; and other from HemOnc.org LLC, outside the submitted work. TMW-D reports stock and other ownership interests in High Enroll; honoraria from Physicians' Education Resource; consulting or advisory roles with Shattuck Labs, Rakuten Medical, Exicure; research funding from Merck, AstraZeneca/MedImmune, Bristol-Myers Squibb, GlaxoSmithKline, Caris Life Sciences, GlaxoSmithKline; travel, accommodations, expenses from Merck, Bristol-Myers Squibb, Bexion, AstraZeneca/MedImmune, Caris Life Sciences, Lilly, and Tesaro, all outside the submitted work. EW-B reports work in a consultant/advisor role for Astellas and BMS; funding support from Pfizer Global Medical Grants; other for Exelixis; and an immediate family member with stock ownership in Immunomedics and Nektar, all outside the submitted work. TZ reports research funding (to Duke) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Regeneron; consulting/speaking role with Genentech Roche, Exelixis, Genomic Health, and Sanofi Aventis; and serves on the consulting/advisory board for AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Amgen, BMS, Calithera, Dendreon, and MJH Associates; stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics, and Nanorobotics. AYZ has currently or during the past 2 years owned stock or held an ownership interest in Gilead Sciences. LZ reports personal fees from MERCK, outside the submitted work. All others have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: 18F-Fluciclovine is an amino acid-based radiopharmaceutical used primarily for PET imaging of patients with biochemical recurrence of prostate cancer. We report a case of a 66-year-old man with recently diagnosed metastatic castrate-resistant prostate cancer and a left supraclavicular lymph node with incidental radiotracer uptake on 18F-fluciclovine PET/CT. Left neck core needle biopsy confirmed high-grade, poorly differentiated carcinoma with neuroendocrine features positive for synaptophysin and chromogranin, and negative for prostate markers., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Screening critical congenital heart disease in neonates with 24-48 h of age could be made by oxygen saturation determination. Perfusion index may be used as an adjunct to pulse oximetry screening to detect non-cyanotic critical congenital heart disease cases such as a left heart outflow obstruction. We evaluate the results of combined screening for oxygen saturation and peripheral perfusion index at high altitudes. The study included 501 neonates older than gestational week 35. The mean oxygen saturation was lower than at sea level, and the screening test was positive in a total of 21 (4.2%) babies. Critical congenital heart diseases were not detected in any patient. A total of 10 (2%) babies were detected with PDA, nine (1.8%) of whom recorded a positive screening test. The prevalence of PDA was significantly higher in the positive screening test group when compared with those who underwent echocardiography due to clinical findings.Conclusion: The median peripheral perfusion index at high altitude was not lower than at sea level, while the mean oxygen saturation, in contrast, was lower than at sea level. The low partial oxygen pressure found at high altitudes leads to a variation in postnatal adaptation and an increased prevalence of PDA. Accordingly, oxygen saturation screening may serve to identify babies with PDA at high altitudes. What is Known: • Oxygen saturation is known to be low at high altitudes, and thus the rates of false positivity are high when screening for critical congenital heart disease. • High altitudes are also associated with an increased prevalence of simple congenital heart disease. What is New: • The peripheral perfusion index at high altitude is not lower than at sea level. • The prevalence of PDA is significantly higher in those with false positive screening results.

The human microbiota gained a big interest among the scientific community with numerous studies being performed to better understand its role in health and diseases. Even with all the success achieved in studying the bacterial populations at the different body sites and its interaction among each other and with the host, some links remain missing and might have therapeutic benefits. In this review, we summarize the main means used for bacterial identification, human microbiota description and the role of culturomics in leading the way towards the development of new bacterio-therapeutic approaches., (Copyright © 2020. Published by Elsevier Ltd.)

Rationale: Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic behaviors associated with depression has not been deciphered., Objective: The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress., Methods: Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the behavior of mice was assessed using social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots., Results: Met did not modulate anxiety-like behaviors, but rather promoted resilience to chronic stress, rescued social avoidance behaviors and reversed the increase in the cortical expression levels of N-methyl-D-aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue social avoidance behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3)., Conclusions: Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation.

Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the anti-apoptotic role for Mcl1 is well characterized, the protective function of MCL-1 Matrix remains poorly understood. Here, we show MCL-1 OM and MCL-1 Matrix prevent neuronal death through distinct mechanisms. We report that MCL-1 Matrix functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1 Matrix protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1 Matrix may confer neuroprotection under stress conditions involving loss of mitochondrial function.

An obligate aerobic, Gram-positive, non-sporulating, rod-shaped bacterium designated Marseille P3888 T was isolated from the stool sample of a healthy male pygmy. We described its main characteristics, and sequenced and annotated its genome. The 16S rRNA analysis revealed 98.10% sequence similarity with Corynebacterium terpenotabidum, the phylogenetically closest species with standing in nomenclature. The genome had a size of 3142051 bp with a guanine + cytosine content of 66.83%. We proposed the creation of the new Corynebacterium neomassiliense sp. nov. strain Marseille-P3888 T ., (© 2020 The Author(s).)

Anaerosphaera massiliensis strain Marseille-P4592 T (= CSURP4592 T ; = CCUG72452 T ) is a new species isolated from the stool of a 39-year-old male Pygmy from the Democratic Republic of Congo., (© 2019 The Authors.)

The interest in studying gut microbiota has been rekindled with the advent of molecular techniques, in particular, metagenomics. Culturomics (high throughput microbial culture with identification of the colonies by Maldi-TOF) has demonstrated its complementarity with metagenomics for comprehensive study of the microbiota. The main metagenomic studies have revealed an increase in biodiversity, with in particular an increase of Spirochaetes and Prevotella in subjects of African origin compared with Western subjects. Studies on malnutrition have shown a reduction of all bacteria and in particular of anaerobic bacteria and methanogenic archaea. Of the 1,162 bacteria isolated by culturomics studies, 476 were isolated only from non-African samples, 445 were isolated in African and non-African groups, and 241 bacteria were isolated from samples of African origin including 68 new species. Further studies of African microbiota by culturomics and metagenomics will make it possible to assess whether some bacteria have particular specificities and if these might play a role in certain pathologies such as malnutrition.

Enterococcus mediterraneensis strain Marseille-P4358 T (= CSURP4358 T ) is a new species isolated from the stool of a 39-year-old male Pygmy from the Democratic Republic of Congo., (© 2019 The Author(s).)

Culturomics has allowed the isolation of a significant number of new bacterial species from the human gut microbiota and proved to be a valuable complement to culture-independent techniques. Using this culture-based approach, a new bacterial species has been isolated from a stool sample of a 39-year-old healthy Pygmy male and described using the taxonogenomic strategy. Cells of strain Marseille-P4356 T are Gram-stain negative cocci. The strain grows optimally at 37 °C and is catalase positive but oxidase negative. Its 16S rRNA gene sequence exhibited 92.96% sequence similarity with Dysgonomonas gadei strain JCM 16698T (NR&#95;113134.1), currently its phylogenetically closest species that has been validly named. The genome of strain Marseille-P4356 T is 3,472,011 bp long with 37.3 mol% G+C content. Phenotypic, biochemical, proteomic, genomic and phylogenetic analyses, clearly demonstrate that strain Marseille-P4356 T (= CCUG 71356 T  = CSUR P4356 T ) represents a new species within the genus Dysgonomonas, for which we propose the name Dysgonomonas massiliensis sp. nov.

As part of the culturomics project aiming at describing the human microbiota, we report in this study the description of the new bacterial genus Raoultibacter gen. nov. that includes two new species, that is, R. massiliensis sp. nov. and R. timonensis sp. nov. The R. massiliensis type strain Marseille-P2849 T was isolated from the fecal specimen of a healthy 19-year-old Saudi Bedouin, while R. timonensis type strain Marseille-P3277 T was isolated from the feces of an 11-year-old pygmy female living in Congo. Strain Marseille-P2849 T exhibited 91.4% 16S rRNA sequence similarity with Gordonibacter urolithinfaciens, its phylogenetic closest neighbor with standing in nomenclature. As well, strain Marseille-P3277 T exhibited 97.96% 16S rRNA similarity with strain Marseille-P2849 T . Both strains were Gram-positive, motile, nonspore-forming rod and form transparent microcolonies on blood agar in both anaerobic and microaerophilic atmospheres. The genome sizes of strain Marseille-P2849 T and strain Marseille-P3277 T were 3,657,161 bp and 4,000,215 bp, respectively. Using a taxono-genomic approach combining the phenotypic, biochemical, and genomic characteristics, we propose the genus Raoultibacter gen. nov., which contains strains Marseille-P2849 T (= CSUR P2849 T , = DSM 103407 T ) and Marseille-P3277 T (=CCUG 70680 T , =CSUR P3277 T ) as type strains of the species R. massiliensis sp. nov., and R. timonensis sp. nov., respectively., (© 2019 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Chronic stress promotes depression in some individuals, but has no effect in others. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas resilient individuals live normally. Exercise counteracts the effects of stress. Our objective was to examine whether lactate, a metabolite produced during exercise and known to reproduce specific brain exercise-related changes, promotes resilience to stress and acts as an antidepressant. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. On the 11th day, mice were subjected to behavioral tests. Mice received lactate before each defeat session. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Lactate promoted resilience to stress and rescued social avoidance and anxiety by restoring hippocampal class I histone deacetylase (HDAC) levels and activity, specifically HDAC2/3. To determine whether lactate is an antidepressant, mice only received lactate from days 12-25 and a second set of behavioral tests was conducted on day 26. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. On the contrary, HDAC2/3 inhibition was antidepressant-like. This indicates that lactate mimics exercise's effects and rescues susceptibility to stress by modulating HDAC2/3 activity and suggests that HDAC2/3 play opposite roles before and after establishment of susceptibility to stress.

With the aim of describing the human microbiota by the means of culture methods, culturomics was developed in order to target previously un-isolated bacterial species and describe it via the taxono-genomics approach. While performing a descriptive study of the human gut microbiota of the pygmy people, strain Marseille-P4678 T has been isolated from a stool sample of a healthy 39-year-old pygmy male. Cells of this strain were Gram-positive cocci, spore-forming, non-motile, catalase-positive and oxidase-negative, and grow optimally at 37°C under anaerobic conditions. Its 16S rRNA gene sequence exhibited 89.69% of sequence similarity with Parvimonas micra strain 3119B T (NR 036934.1), its phylogenetically closest species with standing in nomenclature. The genome of strain Marseille-P4678 T is 2,083,161 long with 28.26 mol% of G+C content. Based on its phenotypic, biochemical, genotypic and proteomic profile, this bacterium was classified as a new bacterial genus and species Miniphocibacter massiliensis gen. nov., sp. nov. with the type strain Marseille-P4678 T ., (© 2018 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Culturomics has recently allowed the isolation and description of previously uncultured bacteria from the human microbiome at different body sites. As part of a project aiming to describe the human gut microbiota by culturomics, Phoenicibacter congonensis strain Marseille-P3241 T was isolated from the gut of a 45 years old Pygmy female. In the present work, we aim to describe this strain via the taxonogenomics approach. The major phenotypic, genomic and biochemical characteristics of this strain were analysed. Strain Marseille-P3241 T is an anaerobic, Gram-positive and motile coccobacillus that grows optimally at 37 °C. The genome of strain Marseille-P3241 T is 1,447,956 bp long with 43.44% GC content and its 16S rRNA gene sequence exhibited 89% sequence similarity with that of Denitrobacterium detoxificans strain NPOH1 T , the phylogenetically closest related species with current standing in nomenclature. After performing a phylogenetic and genomic analysis, we conclude that strain Marseille-P3241 T (= CCUG 70681 T  = CSUR P3241 T ) represents the type species of a new genus, for which we propose the name Phoenicibacter congonensis gen. nov., sp. nov.

[This corrects the article DOI: 10.1016/j.nmni.2017.04.003.].

Background: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma., Methods: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment., Findings: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status., Interpretation: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Intensive efforts have been made to describe the human microbiome and its involvement in health and disease. Culturomics has been recently adapted to target formerly uncultured bacteria and other unclassified bacterial species. This approach enabled us to isolate in the current study a new bacterial species, Parabacteroides timonensis strain Marseille-P3236 T , from a stool sample of a healthy 39-year-old pygmy male. This strain, is an anaerobic, gram-negative, nonspore-forming motile rod. Its genome is made up of 6,483,434 bp with 43.41% G+C content, 5046 protein-encoding genes, and 84 RNA genes. We herein provide the full description of Parabacteroides timonensis strain Marseille-P3236 T through the taxonogenomic approach., (© 2018 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted. SIGNIFICANCE STATEMENT It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill.", (Copyright © 2019 the authors 0270-6474/19/392369-14$15.00/0.)

Enterococcus timonensis sp. nov., strain Marseille-P2817 T , is a facultatively anaerobic, motile and non-spore-forming Gram-positive coccus which was isolated from the sputum of a healthy adult man in Marseilles. We present herein its phenotypic description together with MALDI-TOF (matrix-assisted laser-desorption/ionization time-of-flight) mass spectrometry analysis and genome sequencing and comparison. The genome of Enterococcus timonensis is 2 123 933 bp long with 38.46 mol% of G+C content, and it contains 1983 protein-coding genes and 65 RNA genes (including nine rRNA genes).

Introduction: Erectile dysfunction (ED) is associated with various comorbidities and an early diagnosis and treatment is necessary to avoid the development of these comorbidities. Unfortunately, there is no biochemical marker that can be used for early diagnosis of ED. Nitric oxide (NO) is released by nerve and endothelial cells in the corpora cavernosa of the penis and is believed to be the main vasoactive chemical mediator of penile erection. Adropin is a regulatory peptide which has effects on NO bioavailability and energy homeostasis. We hypothesized that adropin may contribute to the pathogenesis of ED because of the presence of both metabolic effects and the influence on NO bioavailability. To confirm this hypothesis, we investigated the relationship between ED and serum adropin and NO levels., Material and Methods: Seventy-five ED patients were enrolled for this study and the patients were divided into two groups according to angiographic scoring. Serum NO and adropin levels were measured by the Griess reaction and ELISA method, respectively., Results: Serum adropin and NO levels were found to be lower in the group which has higher angiographic score and the difference in NO was statistically significant. Also, adropin has a significant correlation between IIEF scores in ED patients., Conclusions: This is the first study in the literature investigating the levels of adropin in ED patients having coronary artery disease. The adropin molecule shows a promising future in clarifying the etiopathogenesis of ED. More comprehensive and multicenter studies are needed to reveal the role of adropin in ED and the effects of treatment on this molecule., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)