Innate lymphoid cells (ILCs) are a heterogeneous family of immune regulators that protect against mucosal pathogens but can also promote intestinal pathology. Although the plasticity between ILCs populations has been described, the role of mucosal pathogens in inducing ILC conversion leading to intestinal pathology remains unclear. Here we demonstrate that IFNγ-producing ILCs are responsible for promoting intestinal pathology in a mouse model of enterocolitis caused by Campylobacter jejuni, a common human enteric pathogen. Phenotypic analysis revealed a distinct population of IFNγ-producing NK1.1-T-bet+ILCs that accumulated in the intestine of C. jejuni-infected mice. Adoptive transfer experiments demonstrated their capacity to promote intestinal pathology. Inactivation of T-bet in NKp46+ ILCs ameliorated disease. Transcriptome analysis and cell-fate mapping experiments revealed that IFNγ-producing NK1.1-ILCs correspond to ILC1 profile and develop from RORγt+ progenitors. Collectively, we identified a distinct population of NK1.1-ex-ILC3s that promotes intestinal pathology through IFNγ production in response to C. jejuni infection.

Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment.

Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo.

Long non‑coding RNAs (lncRNAs) serve a crucial role in gastric cancer (GC) progression. However, the molecular mechanism underlying lncRNA JPX transcript, XIST activator (JPX) in the tumorigenesis of GC is not completely understood. Reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting were performed to detect gene expression. A luciferase reporter gene assay was conducted to determine the relationship between microRNA (miR)‑197 and JPX or C‑X‑C motif chemokine receptor 6 (CXCR6). Cell viability, migration and invasion were determined by performing MTT, wound healing and Transwell assays, respectively. The Cancer Genome Atlas database and the RT‑qPCR results indicated that JPX expression was upregulated and miR‑197 expression was downregulated in patients with GC and in GC cells. Moreover, high JPX expression and low miR‑197 expression in patients with GC indicated poor prognosis. miR‑197 expression was directly inhibited by JPX. Compared with the short hairpin RNA (sh) negative control (NC) group, NCI‑N87 and MKN‑45 cells in the shJPX group displayed decreased cell viability and invasion, as well as a wider scratch width. NCI‑N87 and MKN‑45 cells in the shJPX + miR‑197 inhibitor group had increased viability and invasion, but a narrower scratch width compared with the shJPX group. It was also identified that miR‑197 directly inhibited CXCR6 expression. miR‑197 inhibited Beclin1 protein expression and promoted p62 protein expression. Compared with the NC group, NCI‑N87 and MKN‑45 cells in the miR‑197 mimic group had decreased cell viability and invasion, and a wider scratch width. Enhanced cell viability and invasion, and a narrower scratch width was also observed in the miR‑197 mimic + CXCR6 and miR‑197 mimic + Beclin1 groups, compared with the miR‑197 mimic group. Collectively, the results indicated that lncRNA JPX promoted GC progression by regulating CXCR6 and autophagy via inhibiting miR‑197. Furthermore, JPX knockdown regulated GC cell phenotype by promoting miR‑197.

Acute kidney injury (AKI) is a common clinical disease. Ferropotosis, a new type of regulatory cell death, serves an important regulatory role in AKI. Pachymic acid (PA), a lanostane‑type triterpenoid from Poria cocos, has been reported to be protective against AKI. However, the protective mechanism of PA in AKI is not yet fully understood. The present study aimed to investigate the effect and molecular mechanism of PA on ferroptosis in renal ischemia reperfusion injury in vivo. A total of 30 mice were intraperitoneally injected with 5, 10 and 20 mg/kg PA for 3 days. A bilateral renal pedicle clip was used for 40 min to induce renal ischemia‑reperfusion injury and establish the model. The results demonstrated that treatment with PA decreased serum creatinine and blood urea nitrogen, and ameliorated renal pathological damage. Transmission electron microscopy revealed no characteristic changes in ferroptosis in the mitochondria of the renal tissue in the high‑dose PA group, and only mild edema. Furthermore, treatment with PA increased glutathione expression, and decreased the expression levels of malondialdehyde and cyclooxygenase 2. Treatment with PA enhanced the protein and mRNA expression levels of the ferroptosis related proteins, glutathione peroxidase 4 (GPX4), solute carrier family 7 (cationic amino acid transporter, y+ system) member 11 (SLC7A11) and heme oxygenase 1 (HO‑1) in the kidney, and increased the expression levels of nuclear factor erythroid derived 2 like 2 (NRF2) signaling pathway members. Taken together, the results of the present study suggest that PA has a protective effect on ischemia‑reperfusion induced acute kidney injury in mice, which may be associated with the inhibition of ferroptosis in the kidneys through direct or indirect activation of NRF2, and upregulation of the expression of the downstream ferroptosis related proteins, GPX4, SLC7A11 and HO‑1.

We isolated a filamentous, thermophilic, and first anaerobic representative of the genus Thermoactinomyces, designated strain AMNI-1T, from a biogas plant in Tyrol, Austria and report the results of a phenotypic, genetic, and phylogenetic investigation. Strain AMNI-1T was observed to form a white branching mycelium that aggregates into pellets when grown in liquid medium. Cells could primarily utilize lactose, glucose, and mannose as carbon and energy sources, with acetate accelerating and yeast extract being mandatory for growth. The optimum growth temperature and pH turned out to be 55 °C and pH 7.0, respectively, with an optimum NaCl concentration of 0-2% (w/v). 16S rRNA gene sequence comparison indicated that the genetic relatedness between strain AMNI-1T and Thermoactinomyces intermedius, Thermoactinomyces khenchelensis, and Thermoactinomyces vulgaris was less than 97%. The G + C content of the genomic DNA was 44.7 mol%. The data obtained suggest that the isolate represents a novel and first anaerobic species of the genus Thermoactinomyces, for which the name Thermoactinomyces mirandus is proposed. The type strain is AMNI-1T (= DSM 110094T = LMG 31503T). The description of the genus Thermoactinomyces is emended accordingly.

Integrins are heterodimeric adhesion receptors that maintain cell-extracellular matrix (ECM) interactions in diverse tissue microenvironments. They mediate cell adhesion and signaling through the assembly of large cytoplasmic multiprotein complexes that focally connect with the cytoskeleton. Integrin adhesion complexes (IAC) are specialized by the type of integrin-ECM contact and are sensitive to mechanical forces. Thus, they encrypt context-dependent information about the microenvironment in their composition. Signals mediated through IACs modulate many aspects of cell behavior, which allows cells to adapt to their surroundings. To gain insights into their function, IACs have been isolated from cultured cells and explored by proteomics. IACs are insoluble by nature and held together by transient/weak interactions, which makes it challenging to isolate intact IACs. Usually all IACs coupled to a specified ECM, which may employ different integrins, are isolated. Here we describe an alternative method based on proximity-dependent biotin identification (BioID), where specific integrin interaction partners are labeled in live cells and isolated without the need to isolate intact IACs.

Using animals for research raises ethical concerns that are addressed in project evaluation by weighing expected harm to animals against expected benefit to society. A harm-benefit analysis (HBA) relies on two preconditions: (a) the study protocol is scientifically suitable and (b) the use of (sentient) animals and harm imposed on them are necessary for achieving the study's aims. The 3Rs (Replace, Reduce and Refine) provide a guiding principle for evaluating whether the use of animals, their number and the harm imposed on them are necessary. A similar guiding principle for evaluating whether a study protocol is scientifically suitable has recently been proposed: the 3Vs principle referring to the three main aspects of scientific validity in animal research (construct, internal and external validity). Here, we analyse the internal consistency and compatibility of these two principles, address conflicts within and between the 3Rs and 3Vs principles and discuss their implications for project evaluation. We show that a few conflicts and trade-offs exist, but that these can be resolved either by appropriate study designs or by ethical deliberation in the HBA. In combination, the 3Vs, 3Rs and the HBA thus offer a coherent framework for a logically structured evaluation procedure to decide about the legitimacy of animal research projects.

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre-and postoperative Burke-Fahn-Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty-five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median-reported follow-up was 12 months (n = 83; range: 2-180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication-refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cognitive composite scores offer a means of precisely measuring executive functioning (EF).

LLKL, a new traditional Chinese medicine formula containing Edgeworthia gardneri (Wall.) Meisn., Sibiraea angustata and Crocus sativus L. (saffron), was designed to ameliorate type 2 diabetes mellitus. Despite the therapeutic benefits of LLKL, its underlying mechanisms remain elusive. This study evaluated the LLKL anti-diabetic efficacy and its effect on gut microbiota to elucidate its mechanism of action in Zucker diabetic fatty rats. We found that administration of different LLKL concentrations (4.68, 2.34 and 1.17 g/kg/d) improved several diabetic parameters after a 6-week treatment. Moreover, LLKL modulated gut microbiota dysbiosis, increased the expression of occluding and maintained intestinal epithelial homeostasis, leading to a reduction in LPS, TNF-α and IL-6 levels. Hepatic transcriptomic analysis showed that the Toll-like receptor signalling pathway was markedly enriched by LLKL treatment. RT-qPCR results validated that LLKL treatment decreased the expressions of TLR4, MyD88 and CTSK. Furthermore, a gene set enrichment analysis indicated that LLKL enhanced the insulin signalling pathway and inhibited glycerolipid metabolism and fatty acid metabolism, which were verified by the liver biochemical analysis. These findings demonstrate that LLKL ameliorates hyperglycaemia, modulates the gut microbiota and regulates the gut-liver axis, which might contribute to its anti-diabetic effect.

Nipple-areola complex reconstruction (NAR) most commonly represents the finishing touch to breast reconstruction (BR). Nipple presence is particularly relevant to the patient's psyche, beyond any shadow of doubt. Many reconstructive options have been described in time. Surgery is easy, but final result is often disappointing on the long run.

Serologic tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provide information on past infection and immune response. To better understand the persistence of immune response and the proportion of the population who can develop one, the authors assessed patterns of immunoglobulin G (IgG) positivity over time in individuals tested for SARS-CoV-2 RNA or IgG at a large national reference laboratory. More than 2.4 million SARS-CoV-2 IgG serology (initiated April 21, 2020) and 6.6 million nucleic acid amplification testing (NAAT) (initiated March 9, 2020) results on persons from across the United States as of July 10, 2020 were analyzed. Additional IgG serology results through August 11, 2020 were used for one household analysis. SARS-CoV-2 IgG positivity was observed in 91% (19,434/21,452) of individuals tested after a positive NAAT result and in 10% (7,831/80,968) after a negative NAAT result. Factors associated with seropositivity include age, region of patient residence, and interval between NAAT and IgG serology. The probability of persistent IgG seropositivity declined from 98.6% after 1 week to 74.3% after 2 months, less so in individuals ages ≥55 years than in younger groups. Specimens within 2 days from pairs of same-household members showed 92% IgG antibody concordance. Household adults were more frequently IgG positive prior to household children testing positive (36% versus 8%). IgG serology testing can identify an immune response to SARS-CoV-2 that varies based on age, sex, and duration since exposure. Loss of detectable IgG seropositivity occurs, in some patients, over weeks or months. Adults may be infecting household children.

Facial attractiveness has been reported to be influenced by visual features such as facial shape and the colour and texture of the skin. However, no empirical studies have examined the effects of facial skin radiance on facial attractiveness. The present study investigated whether types of skin reflection (i.e. radiant, oily and shiny, and matte) and the position of the reflection on the face influence facial attractiveness and other affective impressions.

The most frequent variant of multiple sclerosis (MS) is the relapsing-remitting form, characterized by symptomatic phases followed by periods of total/partial recovery. Hence, it is possible that these patients can benefit from endogenous agents that control the inflammatory process and favor spontaneous remyelination. In this context, there is increasing interest in the role of myeloid-derived suppressor cells (MDSCs) during the clinical course of experimental autoimmune encephalomyelitis (EAE). MDSCs speed up infiltrated T-cell anergy and apoptosis. In different animal models of MS, a milder disease course is related to higher presence/density of MDSCs in the periphery, and smaller demyelinated lesions in the central nervous system (CNS). These observations lead us to wonder whether MDSCs might not only exert an anti-inflammatory effect but might also have direct influence on oligodendrocyte precursor cells (OPCs) and remyelination. In the present work, we reveal for the first time the relationship between OPCs and MDSCs in EAE, relationship that is guided by the distance from the inflammatory core. We describe the effects of MDSCs on survival, proliferation, as well as potent promoters of OPC differentiation toward mature phenotypes. We show for the first time that osteopontin is remarkably present in the analyzed secretome of MDSCs. The ablation of this cue from MDSCs-secretome demonstrates that osteopontin is the main MDSC effector on these oligodendroglial cells. These data highlight a crucial pathogenic interaction between innate immunity and the CNS, opening ways to develop MDSC- and/or osteopontin-based therapies to promote effective myelin preservation and repair in MS patients.

Insects are the focus of many recent studies suggesting population declines, but even invaluable pollination service providers such as bees lack a modern distributional synthesis. Here, we combine a uniquely comprehensive checklist of bee species distributions and >5,800,000 public bee occurrence records to describe global patterns of bee biodiversity. Publicly accessible records are sparse, especially from developing countries, and are frequently inaccurate throughout much of the world, consequently suggesting different biodiversity patterns from checklist data. Global analyses reveal hotspots of species richness, together generating a rare bimodal latitudinal richness gradient, and further analyses suggest that xeric areas, solar radiation, and non-forest plant productivity are among the most important global drivers of bee biodiversity. Together, our results provide a new baseline and best practices for studies on bees and other understudied invertebrates.

Neuropeptides and peptide hormones are important cell-cell signaling molecules that mediate many physiological processes. Unlike classic neurotransmitters, peptides undergo cell-type-specific post-translational modifications that affect their biological activity. To enable the identification of the peptide repertoire of a genetically defined cell type, we generated mice with a conditional disruption of the gene for carboxypeptidase E (Cpe), an essential neuropeptide-processing enzyme. The loss of Cpe leads to accumulation of neuropeptide precursors containing C-terminal basic residues, which serve as tags for affinity purification. The purified peptides are subsequently identified using quantitative peptidomics, thereby revealing the specific forms of neuropeptides in cells with the disrupted Cpe gene. To validate the method, we used mice expressing Cre recombinase under the proopiomelanocortin (Pomc) promoter and analyzed hypothalamic and pituitary extracts, detecting peptides derived from proopiomelanocortin (as expected) and also proSAAS in POMC neurons. This technique enables the analyses of specific forms of peptides in any Cre-expressing cell type.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.

Mycobacteria harbor a unique class of adenylyl cyclases with a complex domain organization consisting of an N-terminal putative adenylyl cyclase domain fused to a nucleotide-binding adaptor shared by apoptotic protease-activating factor-1, plant resistance proteins, and CED-4 (NB-ARC) domain, a tetratricopeptide repeat (TPR) domain, and a C-terminal helix-turn-helix (HTH) domain. The products of the rv0891c-rv0890c genes represent a split gene pair, where Rv0891c has sequence similarity to adenylyl cyclases, and Rv0890c harbors the NB-ARC-TPR-HTH domains. Rv0891c had very low adenylyl cyclase activity so it could represent a pseudoenzyme. By analyzing the genomic locus, we could express and purify Rv0890c and find that the NB-ARC domain binds ATP and ADP, but does not hydrolyze these nucleotides. Using systematic evolution of ligands by exponential enrichment (SELEX), we identified DNA sequences that bound to the HTH domain of Rv0890c. Uniquely, the HTH domain could also bind RNA. Atomic force microscopy revealed that binding of Rv0890c to DNA was sequence independent, and binding of adenine nucleotides to the protein induced the formation of higher order structures that may represent biocrystalline nucleoids. This represents the first characterization of this group of proteins and their unusual biochemical properties warrant further studies into their physiological roles in future.

The goal of this study was to evaluate the effects of ovarian hormones on female rat ultrasonic vocalizations (USVs). Twenty (10 control and 10 ovariectomized) 3-month-old female rats were recorded in 3 recording conditions (elicitation, dyad, and isolation) over a full estrous cycle or time-matched duration. There were differences in USV acoustics (frequency and complexity parameters) across recording conditions but no differences in USV acoustics between control and ovariectomized groups. USVs produced in isolation had lower frequency and complexity parameters than elicited USVs for both control and ovariectomized rats. Additionally, for control rats, USV parameters of frequency, complexity, duration, and intensity changed depending on the estrous state. Therefore, although fluctuating hormone levels may influence USV acoustics, this variation can be controlled for by ovariectomizing female rats.