Reduced Incretin Receptor Trafficking upon Activation Enhances Glycemic Control and Reverses Obesity in Diet-Induced Obese Mice.

Activation of incretin receptors by their cognate agonists augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a non-acylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic beta cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity.

Effectiveness of ayurvedic formulation, NAOQ19 along with standard care in the treatment of mild-moderate COVID-19 patients: A double blind, randomized, placebo-controlled, multicentric trial.

BACKGROUND: Medicines in indigenous systems such as Ayurveda have strong antimicrobial activity but double-blind randomized control trials are infrequent in this system of medicine. The efficacy of a new ayurvedic formulation was evaluated during the pandemic. METHODS: 150 mild-moderate COVID-19 patients were enrolled and randomized in 1:1 to NAOQ19 and placebo group. RT-PCR was done on Day 3, 5 and 7. CBC, CRP, LFT, and KFT were assessed at baseline and exit. Duration of hospital stay was noted and clinical assessment was also performed. RESULT: The results demonstrated more people turning RT-PCR negative in the NAOQ19 group compared to the placebo group on day 3 (p-value = 0.033). The mean time duration to turn RT-PCR negative was significantly lower in the NAOQ19 group (4.6 days) compared to placebo group (5.2 days) (p-value = 0.018). There was significant reduction in hospital stay among patients in the NAOQ19 arm who were discharged earlier (5.6 days) compared to placebo group (6.4 days) (p-value = 0.046). Patients in NAOQ19 arm did not show any adverse life-threatening events. CONCLUSION: The ayurvedic preparation given along with standard of care therapy reduced the duration of hospital stay and there was earlier conversion to RT-PCR negative.The integrated approach can help to reduce patient workload in the hospitals as well as limit the transmission of the virus in the community. STUDY REGISTRATION: CTRI/2021/05/033790.

Unravelling blood-based epigenetic mechanisms: the impact of hsa-miR-146a and histone H3 acetylation in lead-induced inflammation among occupational workers.

BACKGROUND: Occupational and environmental exposure to lead (Pb) is a persistent health problem majorly in developing countries and has been implied to cause epigenetic alterations. Its effect on histone post-translational modifications is not explored in human population. MicroRNAs are epigenetic modulators reported to be differentially expressed under Pb exposure. The present study was targeted to find plausible association between the role of hsa-miR-146a and global histone (H3) acetylation in Pb-induced inflammation in occupationally exposed workers. MATERIALS AND METHODS: A total of 100 occupationally exposed individuals working in different industries were recruited for the study and divided into 2 groups based on the median Pb levels [low Pb group (Pb < 5 µg/dL) and High Pb group (Pb > 5 µg/dL)]. The Pb levels were measured in whole blood using atomic absorption spectrometry to confirm Pb exposure. Histone H3 acetylation and serum interleukin-6 (IL-6) levels were measured using colorimetric methods and enzyme-linked immunosorbent assay (ELISA), respectively. MicroRNA-146a expression was quantified using TaqMan assay. RESULTS: The median BLL of the study population was 5 µg/dL. BLL, IL-6, and Histone (H3) acetylation increased significantly with the duration of exposure. BLL level showed a significant positive correlation with IL-6 and histone H3 acetylation level. We also found that hsa-miR-146a exhibited significantly increased expression in the high Pb group compared to the low Pb group (Fold change: 2.56; P = 0.014). The linear regression model suggested that BLL has significantly predicted histone H3 acetylation, hsa-miR-146a, and IL-6 in the study subjects. CONCLUSION: The finding that hsa-miR146a was significantly upregulated in individuals with high BLL and had a significant negative correlation with serum IL-6 suggests that Pb-induced oxidative stress likely activates H3 acetylation, which then releases inflammatory cytokines like IL-6.

Forecasting User Interests Through Topic Tag Predictions in Online Health Communities.

The increasing reliance on online communities for healthcare information by patients and caregivers has led to the increase in the spread of misinformation, or subjective, anecdotal and inaccurate or non-specific recommendations, which, if acted on, could cause serious harm to the patients. Hence, there is an urgent need to connect users with accurate and tailored health information in a timely manner to prevent such harm. This article proposes an innovative approach to suggesting reliable information to participants in online communities as they move through different stages in their disease or treatment. We hypothesize that patients with similar histories of disease progression or course of treatment would have similar information needs at comparable stages. Specifically, we pose the problem of predicting topic tags or keywords that describe the future information needs of users based on their profiles, traces of their online interactions within the community (past posts, replies) and the profiles and traces of online interactions of other users with similar profiles and similar traces of past interaction with the target users. The result is a variant of the collaborative information filtering or recommendation system tailored to the needs of users of online health communities. We report results of our experiments on two unique datasets from two different social media platforms which demonstrates the superiority of the proposed approach over the state of the art baselines with respect to accurate and timely prediction of topic tags (and hence information sources of interest).

Association of circulatory Klotho levels and its expression with miRNA- 339 in patients with schizophrenia.

Schizophrenia is one of the major neuropsychiatric disorders affecting 1% of the population worldwide. Neuroinflammation, neurodevelopment, and oxidative stress are some of the crucial factors that can contribute to the pathogenesis of Schizophrenia. Klotho gene is an antiaging gene whose dysregulated expression can lead to Schizophrenia and aging-like symptoms in patients. Klotho gene expression is regulated by miRNA- 339, which might lead to expression changes of the klotho gene in schizophrenia patients. This study aimed to determine the Role of miRNA- 339-5p in the Regulation of Klotho Gene Expression and its Circulatory Levels in Schizophrenia. In this study total of 60 cases, schizophrenia patients and 30 healthy controls were recruited, and written informed consent was obtained from all the study subjects. The klotho gene and miRNA - 339-5p expressions were done using a reverse transcription polymerase chain reaction. And relative fold change expression was calculated by Livaak's method, that is 2^-double delta ct. It was found that the klotho gene is around 2.08 times upregulated as compared to healthy control, and miRNA- 339-5p was downregulated and showed an inverse relationship. The present study is the first to evaluate the klotho gene expression and correlate it with miRNA- 339-5p. Further confirmation of the results study should be planned with a large sample size and with drug naïve patients.

Role of Klotho Protein in Neuropsychiatric Disorders: A Narrative Review.

Neuropsychiatric disorders are comprised of diseases having both the neurological and psychiatric manifestations. The increasing burden of the disease on the population worldwide makes it necessary to adopt measures to decrease the prevalence. The Klotho is a single pass transmembrane protein that decreases with age, has been associated with various pathological diseases, like reduced bone mineral density, cardiac problems and cognitive impairment. However, multiple studies have explored its role in different neuropsychiatric disorders. A comprehensive search was undertaken in the Pubmed database for articles with the keywords "Klotho" and "neuropsychiatric disorders". The available literature, based on the above search strategy, has been compiled in this brief narrative review to describe the emerging role of Klotho in various neuropsychiatric disorders. The Klotho levels were decreased in various neuropsychiatric disorders except for bipolar disorder. A suppressed Klotho protein levels induced oxidative stress and incited pro-inflammatory conditions significantly contributing to the pathophysiology of neuropsychiatric disorder. The increasing evidence of altered Klotho protein levels in cognition-decrement-related disorders warrants its consideration as a biomarker in various neuropsychiatric diseases. However, further evidence is required to understand its role as a therapeutic target.

Increased expression of serum IL-18 and IL-18R in newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder in which genetic, sedentary lifestyle, obesity, and environmental factors come together to produce insulin resistance in target tissues, leading to hyperglycemia. Evidence reveals that inflammation may play an essential role in the pathogenesis of T2DM. Interleukin-18 (IL-18), a proinflammatory cytokine, plays a crucial role in the acute and chronic inflammatory process. The association of IL-18 levels with IL-18R expression in T2DM has not been investigated so far. The aim of this study was to compare the peripheral changes in serum IL-18 levels and its receptor (IL18R) expression in newly diagnosed T2DM and healthy controls. METHODS: A total of 35 newly diagnosed type 2 diabetic cases and 35 non-diabetic controls were enrolled after obtaining informed consent. Venous whole blood was taken under aseptic conditions. Biochemical parameters were estimated in an auto-analyzer. Serum IL-18 levels were calculated using ELISA, whereas IL-18R expression was determined via RT-PCR. GAPDH was used as an internal control. RESULTS: When compared to non-diabetic controls, the serum IL-18 levels were significantly higher in T2DM patients (P=0.010) along with a significant upregulation of IL18R (P=0.0018). Serum IL-18 levels in T2DM and non-diabetic controls were 669.5 (445) and 498.3 (404.9) pg/mL respectively, and IL-18R showed a fold change of 10.33. CONCLUSIONS: Both serum IL-18 and its receptor IL-18R is significantly higher in newly diagnosed T2DM patients.

Role of interleukin-22 in tuberculosis patients.

OBJECTIVES: Disease progression of tuberculosis (TB) depends on the balance between the microorganism's virulence and the host defense systems (mainly T cell-mediated immune response). Interleukin-22 (IL-22) helps in cell proliferation and regeneration and provides protection against microbial diseases. The IL-22-producing T cells can migrate into the granulomas during TB infection. However, disparity exists in literature regarding its role. The present study aims to compare serum IL-22 levels and its' expression in TB patients and healthy controls. METHODS: 87 TB patients and 85 healthy subjects were enrolled in the study. Under aseptic conditions, venous blood was withdrawn. Serum IL-22 levels were estimated using enzyme-linked immunosorbent assay, and its gene expression was assessed using SYBR green-based quantitative PCR technology. A statistical analysis was performed using SPSS. RESULTS: The median (interquartile range) of serum IL-22 levels was significantly lower in TB patients (18.55 (5.08) pg/mL) when compared to controls (49.38 (162.88) pg/mL) (p<0.0001). The IL-22 expression was significantly upregulated with a fold change value of 29.44 in TB patients. CONCLUSIONS: The IL-22 levels were found to be significantly decreased in patients, contradictory to its expression, which is upregulated. It plays a crucial role for the modulation of tissues in response to TB infection.

Plasma microRNA expression and immunoregulatory cytokines in an Indian population occupationally exposed to cadmium.

Following its accumulation in the body, cadmium (Cd) exposure is associated with devastating effects on multiple organ system of the human body. The immune system is one of the sensitive targets for Cd-induced toxicity. Recently, studies have demonstrated a significant role of Cd in inducing epigenetic alterations. With this background, the present study was planned to study the changes in candidate microRNA (miRNA) expression associated with immune regulation in occupationally Cd-exposed workers. One hundred individuals involved in welding and metal handicraft manufacturing, while 80 apparently healthy subjects without any prior history of occupational exposure were recruited for the study. Blood Cd level was determined by atomic absorption spectrometry. Serum cytokine levels were measured using an enzyme-linked immunosorbent assay and serum miRNA expression of candidate miRNAs (miR-146a, miR-210, and miR-222) were determined by real-time polymerase chain reaction. The median Cd level (2.40 µg/L) in the occupationally exposed workers was significantly higher than the nonexposed subjects (0.90 µg/L). Among the cytokines, interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-α) were significantly higher while IL-2 and IL-10 were significantly lower in the exposed. The expression level of miR-146a and miR-222 were significantly different between the groups with the former showing downregulation and later showing upregulation. Correlation analysis revealed a positive and negative association of miR-222 and miR-146a with blood cadmium level, IL-17 as well as TNF-α, respectively. Furthermore, the in-silico analysis revealed a significant role of the studied miRNAs in various cellular and genetic pathways. The findings of the present study demonstrate significant involvement of Cd-induced alteration in miRNAs in varied immune regulatory changes in exposed individuals.

COVID-19's impact on visitation behavior to US national parks from communities of color: evidence from mobile phone data.

The widespread COVID-19 pandemic fundamentally changed many people's ways of life. With the necessity of social distancing and lock downs across the United States, evidence shows more people engage in outdoor activities. With the utilization of location-based service (LBS) data, we seek to explore how visitation patterns to national parks changed among communities of color during the COVID-19 pandemic. Our results show that visitation rates to national parks located closer than 347 km to individuals have increased amidst the pandemic, but the converse was demonstrated amongst parks located further than 347 km from individuals. More importantly, COVID-19 has adversely impacted visitation figures amongst non-white and Native American communities, with visitation volumes declining if these communities are situated further from national parks. Our results show disproportionately low-representations amongst national park visitors from these communities of color. African American communities display a particularly concerning trend whereby their visitation to national parks is substantially lower amongst communities closer to national parks.

Risk Factors for Lead Toxicity and its Effect on Neurobehavior in Indian Children.

Lead (Pb) is profoundly used heavy metal despite its known toxic effects. Children in particular are more susceptible to Pb toxicity. Thus, the present study was carried out to estimate the prevalence of lead toxicity in Indian children, to observe serum levels of biochemical parameters and to evaluate psychopathological implications of Pb toxicity using population specific scale-Childhood Psychopathological Measurement Schedule (CPMS) in children. Children between 9 and 15 years of age were included in the study (N = 70). Demographic details and information regarding the source of lead exposure were collected using a self-made questionnaire. All biochemical investigations were performed in Beckman Coulter Auto-analyser AU680 and Blood Lead Levels (BLL) were estimated by Graphite Furnace Atomic Absorption Spectrophotometer. The neurobehavioral state of the children was assessed by a population-specific scale i.e., CPMS, which evaluates for neurobehavior under 8 factors, titled, Low intelligence with behavioural problems, Conduct disorder, Anxiety, Depression, Psychotic symptoms, Special symptoms, Physical illness with emotional problems, and Somatization. The median BLL of the study population was 4.9 µg/dL. Habit of frequently consuming roadside food, proximity of residence to vehicular traffic and educational status of the mother were observed to be significant contributing factors for high BLL (≥ 5 µg/dL). Serum alkaline phosphatase (P = 0.02) and phosphorous levels (P = 0.04) were significantly lower in children belonging to high BLL group. A significantly high adverse neurobehavioral score was observed in high BLL group children compared to low BLL group (P < 0.05). There was high prevalence of Pb toxicity with 50% of children having BLL > 5 µg/dL. Further, certain lifestyle characteristics such as proximity of residence to vehicular traffic, frequent consumption of roadside food and lower educational status of the mother could be possible risk factors for higher Pb exposure in children. Evaluation of neurobehavior in children with high BLL revealed a high prevalence of adverse neurobehavior in them when compared to children in low BLL group.

Assessment of DHEAS, cortisol, and DHEAS/cortisol ratio in patients with COVID-19: a pilot study.

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) is observed to be decreased in sepsis and inflammatory conditions. In the present study, we assessed the levels of DHEAS and cortisol and the DHEAS/cortisol ratio and their association with inflammatory markers in patients with COVID-19. METHODS: The study recruited 76 RT-PCR-positive COVID-19-positive patients and 79 healthy controls. The blood samples were collected and were analyzed for cortisol and DHEAS. RESULTS: We observed decreased levels of DHEAS and DHEAS/cortisol ratio and increased levels of cortisol in cases when compared with controls. DHEAS and DHEAS/cortisol ratio showed a decreasing trend with the increase in disease severity. CONCLUSION: The present study is the first of its kind comparing DHEAS levels and DHEAS/cortisol ratio in COVID-19 patients and control subjects. DHEAS, with its inhibitory effect on IL6 and activation of Tregs, may play a crucial role in immune defense mechanisms against COVID-19.

Food insufficiency and Twitter emotions during a pandemic.

The COVID-19 pandemic initially caused worldwide concerns about food insecurity. Tweets analyzed in real-time may help food assistance providers target food supplies to where they are most urgently needed. In this exploratory study, we use natural language processing to extract sentiments and emotions expressed in food security-related tweets early in the pandemic in U.S. states. The emotion joy dominated in these tweets nationally, but only anger, disgust, and fear were also statistically correlated with contemporaneous food insufficiency rates reported in the Household Pulse Survey; more nuanced and statistically stronger correlations are detected within states, including a negative correlation with joy.

Selenium Levels in Occupationally Lead Exposed Workers of Rajasthan.

Occupational and environmental exposure to Lead (Pb) has profound detrimental effects on human health. The underlying mechanism of lead toxicity is not fully understood but antioxidant imbalance is suggested to be a key player in its pathogenesis. Selenium (Se) being a vital component of antioxidant system in the body, has been linked to many health benefits in humans. Selenium levels in occupationally Pb exposed individuals has not been explored in Indian setup. The aim of the present study is to find out the association of Se with blood lead levels (BLL) in occupationally Pb exposed individuals. In the present study 91 occupationally Pb exposed workers employed in handicraft and paint industries were recruited after taking informed consent. The demographic details were noted on self-generated questionnaire. The BLL and Se were measured using GFAAS (Thermofisher Scientific, Waltham, USA). Samples were run in duplicate after ensuring quality control. The mean Pb and Se levels in the study population were 5.5 ± 5.6 µg/dl (0.42-31.76 µg/dl) and 105.5 ± 23.8 µg/dl (46.4-189.6 µg/dl) respectively. BLL was significantly higher in tobacco chewers and those occupationally exposed to Pb for more than 5 years. Significantly low Se levels were observed in individuals with high BLL. Statistically significant negative linear relationship was noted between BLL and Se. The negative correlation of Se with BLL indicates the antagonistic relationship between these metals.

Exploring Descriptions of Movement Through Geovisual Analytics.

Sensemaking using automatically extracted information from text is a challenging problem. In this paper, we address a specific type of information extraction, namely extracting information related to descriptions of movement. Aggregating and understanding information related to descriptions of movement and lack of movement specified in text can lead to an improved understanding and sensemaking of movement phenomena of various types, e.g., migration of people and animals, impediments to travel due to COVID-19, etc. We present GeoMovement, a system that is based on combining machine learning and rule-based extraction of movement-related information with state-of-the-art visualization techniques. Along with the depiction of movement, our tool can extract and present a lack of movement. Very little prior work exists on automatically extracting descriptions of movement, especially negation and movement. Apart from addressing these, GeoMovement also provides a novel integrated framework for combining these extraction modules with visualization. We include two systematic case studies of GeoMovement that show how humans can derive meaningful geographic movement information. GeoMovement can complement precise movement data, e.g., obtained using sensors, or be used by itself when precise data is unavailable. Supplementary Information: The online version contains supplementary material available at 10.1007/s42489-022-00098-3.

Effect of occupational co-exposure to lead and cadmium on selected immunomodulatory cytokines.

Occupational exposure to heavy metals like lead (Pb) and cadmium (Cd) is associated with the development of several diseases. The objective of this study was to determine the effect of occupational co-exposure to Pb and Cd on the blood levels of selected immune-modulatory cytokines related to T helper (Th), that is, Th1, interleukin-2 (IL-2), Th2, (IL-4 and IL-10), and Th17, (IL-17) cells. The study comprised 207 individuals divided into two groups: exposed (n = 110) and nonexposed (n = 97). Blood Pb and Cd were determined using Graphite Furnace Atomic Absorption Spectroscopy, and serum levels of cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The study revealed significantly higher blood Pb and Cd levels in the exposed group. A significant decrease in Th1 cytokine-IL-2 and Th2 cytokine-IL-10 was found, while IL-4 (Th2 cytokine) and IL-17 (Th17) levels were higher in the exposed group. In the mixed exposure analysis, among all the selected cytokines, IL-4 levels were significantly different between individuals having higher levels of both Pb and Cd versus lower levels of Pb and Cd. While IL-2 levels were highest among the low Pb and Cd group, the IL-17 levels were highest among individuals with higher Cd levels. The study demonstrated that co-exposure to low levels of Pb and Cd might have an immune-modulatory effect. The data suggested a metal-induced pro-inflammatory immune response.