Distinct SARS-CoV-2 specific NLRP3 and IL-1ß responses in T cells of aging patients during acute COVID-19 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro, peripheral blood mononuclear cell (PBMC) CD4+ and CD8+ T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1ß. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1+ cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1ß expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4+ and CD8+ T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly.

Data-driven technique for disruption prediction in GOLEM tokamak using stacked ensembles with active learning.

In a tokamak, disruption is defined as losing control over a confined plasma resulting in sudden extinction of the plasma current. Machine learning offers potent solutions to classify plasma discharges into disruptive and non-disruptive classes. Evolving experimental programs reduce the performance of machine learning models, and also, the need for labeling the huge volume of data incurs more labor cost and time. This paper proposes a data-driven based machine learning technique that employs an active learning approach for labeling and classification of plasma discharges. The designed model uses 117 normally terminated shots and 70 disruptive shots with 14 labeled diagnostic signals. The stacking classifier is built over three base learners: logistic regression, reduced error pruning tree, and categorial boost algorithm, and the logistic regression technique is used at the meta-learner. An active learning approach is proposed for labeling the unlabeled dataset using a modified uncertainty sampling technique with minimal queries. The proposed model queries the unlabeled data to an oracle based on a selection strategy with uncertainty sampling using entropy metrics. The new labeled data and the class probabilities of the base classifiers are channeled to the final predictor for classifying the plasma discharge. The proposed model achieves an accuracy of 98.75% in classifying the disruptive vs non-disruptive discharges, with a minimally trained dataset, and also, it is free from aging of predictors.

Fungal Colonization and Infections-Interactions with Other Human Diseases.

Candida albicans is a commensal fungus that asymptomatically colonizes the skin and mucosa of 60% of healthy individuals. Breaches in the cutaneous and mucosal barriers trigger candidiasis that ranges from asymptomatic candidemia and mucosal infections to fulminant sepsis with 70% mortality rates. Fungi influence at least several diseases, in part by mechanisms such as the production of pro-carcinogenic agents, molecular mimicking, and triggering of the inflammation cascade. These processes impact the interactions among human pathogenic and resident fungi, the bacteriome in various organs/tissues, and the host immune system, dictating the outcomes of invasive infections, metabolic diseases, and cancer. Although mechanistic investigations are at stages of infancy, recent studies have advanced our understanding of host-fungal interactions, their role in immune homeostasis, and their associated pathologies. This review summarizes the role of C. albicans and other opportunistic fungi, specifically their association with various diseases, providing a glimpse at the recent developments and our current knowledge in the context of inflammatory-bowel disease (IBD), cancers, and COVID-19. Two of the most common human diseases where fungal interactions have been previously well-studied are cancer and IBD. Here we also discuss the emerging role of fungi in the ongoing and evolving pandemic of COVID-19, as it is relevant to current health affairs.

Can employment in a café change Clientele Attitude towards the staff when they are Persons with Mental Illness?

BACKGROUND: Clientele's attitude toward Persons with Mental Illness (PwMI) changes over a period of time. The aim of this study was to explore and understand how and whether perception about PwMI changes when they are seen working like persons without mental illness among those availing services of ROSes café at NIMHANS, Bengaluru. METHODS: The descriptive research design was adopted with purposive sampling. Community Attitude toward Mentally Ill (CAMI) a self -administered questionnaire of was administered to measure the clientele attitude towards staff with mental illness in ROSes Café (Recovery Oriented Services). A total of 256 subjects availing services from the ROSes café recruited in the study. Chi-square and Mann-Whitney U test was computed to see the association and differences on selected variables. RESULTS: The present study results showed that subjects had a positive attitude seen in health care professionals in the domains of benevolence (BE) (28.68 ± 3.00) and community mental health ideology (CMHI) (31.53 ± 3.19), whereas non-health care professionals had showed negative attitude in the domain of authoritarianism (AU) (30.54 ± 3.42) and social restrictiveness (SR) (30.18 ± 3.05). Education, employment, marital, income, and working status were significantly associated with CAMI domains. CONCLUSION: PwMI also can work like people without mental illness when the opportunities are provided. The community needs to regard mental illness in the same manner as chronic physical illness diabetes mellitus and allow PwMI to live a life of dignity by creating and offering opportunities to earn livelihood which would help them recover with their illnesses.

The Role of Dectin-1 Signaling in Altering Tumor Immune Microenvironment in the Context of Aging.

An increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1ß, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1ß, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.

IL-1ß-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging.

CD4+Foxp3+Tregs maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3+ cells altered their function and resulted in increased fungal burden and immunopathology during oral Candida albicans (CA) challenge. Excessive inflammation due to the absence of MyD88 in Tregs coincided with a reduction of the unique population of IL-17A expressing Foxp3+ cells (Treg17) and an increase in dysfunctional IFN-γ+/Foxp3+ cells (TregIFN-γ) in infected mice. Failure of MyD88-/- Tregs to regulate effector CD4+ T cell functions correlated with heightened levels of IFN-γ in CD4+ T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1ß/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of Treg17 cells. In the absence of IL-1 receptor signaling, Treg17 cells were reduced, but IL-6-driven expansion of TregIFN-γ cells was increased. This mechanism was physiologically relevant during Candida infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3+ cells, loss of p-mTORhighTreg17 cells and reduced levels of IL-1ß in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with Treg dysfunction, aging was associated with increased CD4+ T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa in vivo. Taken together, our data identify IL-1ß/MyD88/Treg axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.

Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa.

Mammals co-exist with resident microbial ecosystem that is composed of an incredible number and diversity of bacteria, viruses and fungi. Owing to direct contact between resident microbes and mucosal surfaces, both parties are in continuous and complex interactions resulting in important functional consequences. These interactions govern immune homeostasis, host response to infection, vaccination and cancer, as well as predisposition to metabolic, inflammatory and neurological disorders. Here, we discuss recent studies on direct and indirect effects of resident microbiota on regulatory T cells (Tregs) and Th17 cells at the cellular and molecular level. We review mechanisms by which commensal microbes influence mucosa in the context of bioactive molecules derived from resident bacteria, immune senescence, chronic inflammation and cancer. Lastly, we discuss potential therapeutic applications of microbiota alterations and microbial derivatives, for improving resilience of mucosal immunity and combating immunopathology.

Mitotic phosphorylation of SUN1 loosens its connection with the nuclear lamina while the LINC complex remains intact.

At the onset mitosis in higher eukaryotes, the nuclear envelope (NE) undergoes dramatic deconstruction to allow separation of duplicated chromosomes. Studies have shown that during this process of nuclear envelope breakdown (NEBD), the extensive protein networks of the nuclear lamina are disassembled through phosphorylation of lamins and several inner nuclear membrane (INM) proteins. The LINC complex, composed of SUN and nesprin proteins, is involved in multiple interactions at the NE and plays vital roles in nuclear and cellular mechanics by connecting the nucleus to the cytoskeleton. Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. In mitotic cells, SUN1 loses its interaction with N-terminal domain binding partners lamin A/C, emerin, and short nesprin-2 isoforms. Furthermore, a triple phosphomimetic SUN1 mutant displays increased solubility and reduced retention at the NE. In contrast, the central LINC complex interaction between the SUN1 C-terminus and the KASH domain of nesprin-2 is maintained during mitosis. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. At the same time, our data add to an emerging picture that the core LINC complex plays an active role in NEBD.

Case Series of Umbilical and Extra-umbilical Port Site Herniae.

Trocar site hernia or port site hernia (PSH) is a type of incisional hernia occurring at the trocar sites after laparoscopic surgeries. This is a rare but a potentially dangerous complication, as it can lead to considerable morbidity requiring surgical intervention. Various factors have been implicated for its development and various methods are also suggested for its prevention. We present here five cases of port site herniae.

Metachronous colorectal malignancies.

Colorectal cancers (CRC) diagnosed 6 months after primary surgery for colorectal tumors are defined as metachronous CRC. Colonoscopy is the only reliable investigation for diagnosis. Favourable prognosis and survival is seen after conservative resection for metachronous CRCs. Clear guidelines are available for identification of CRCs after primary resection, and many questions remain unanswered regarding the development, management and prevention of CRC. We report here two cases of CRCs.

Multiple metachronous malignancies, one patient with three primary malignancies.

Development of a primary cancer after treatment of the first with radiotherapy or chemotherapy is well documented, but it is common with hematological malignancies. Variety of reasons are suggested by various researchers, but a conclusive evidence is not yet available. Excepting a few correlations like the tamoxifen therapy and endometrial cancer, angiosarcoma of the breast following radiotherapy, occurrence of other metachronous malignancies seem to be dependent on genetic and environmental factors. A patient with three primary malignancies is presented here.

Synovial sarcoma of anterior abdominal wall.

Sarcomas are connective tissue tumours, and can arise in any part of the body, more commonly in the extremities. Histological types and clinical presentation of truncal sarcomas are similar to those seen in any other anatomic locations. Radiological investigations may be contributory, but biopsy is conclusive. Surgical resection with wide margins is the initial standard treatment, however a multimodal approach including radiotherapy and chemotherapy is often favoured. Because of the high recurrence rate regardless of therapy, close follow-up is imperative. We present a case of synovial sarcoma of the anterior abdominal wall.