Peptide-triggered IL-12 and IFN-γ mediated immune response in CD4+ T-cells against Leishmania donovani infection.

Leishmania donovani are intracellular, human blood parasites that cause visceral leishmaniasis or kala-azar. Cell-penetrating peptides (CPPs) have been shown to modulate intracellular processes and cargo delivery, whereas host defense peptides (HDPs) promote proliferation of both naïve and antigen activated CD4+ T-cells. We report newly designed tripeptides that were able to trigger proinflammatory cytokine (IL-12 and IFN-γ) secretion by CD4+CD44+ T-cells in response to Leishmania donovani infection. These peptides can be used to induce antigen specific TH1 responses to combat obstacles of cytotoxicity and drug resistance associated with current anti-leishmanial drugs. Furthermore, these peptides can also be used as adjuvants to develop an effective immunoprophylactic approach for immunity restoration against visceral leishmaniasis.

Fasting GLP-1 Levels and Albuminuria Are Negatively Associated in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16-10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17-1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria.

Sustained Effectiveness and Safety of Therapeutic miR-10a/b in Alleviating Diabetes and Gastrointestinal Dysmotility without Inducing Cancer or Inflammation in Murine Liver and Colon.

microRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of diabetes. In this study, we elucidated the safety profile of a long-term treatment with miR-10a/b mimics in diabetic mice. Male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD) to induce diabetes and treated by five subcutaneous injections of miR-10a/b mimics for a 5 month period. We examined the long-term effects of the miRNA mimics on diabetes and GI dysmotility, including an assessment of potential risks for cancer and inflammation in the liver and colon using biomarkers. HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics on a monthly basis for 5 consecutive months exhibited a marked reduction in fasting blood glucose levels with restoration of insulin and significant weight loss, improved glucose and insulin intolerance, and restored GI transit time. In addition, the miR-10a/b mimic-treated diabetic mice showed no indication of risk for cancer development or inflammation induction in the liver, colon, and blood for 5 months post-injections. This longitudinal study demonstrates that miR-10a/b mimics, when subcutaneously administered in diabetic mice, effectively alleviate diabetes and GI dysmotility for 5 months with no discernible risk for cancer or inflammation in the liver and colon. The sustained efficacy and favorable safety profiles position miR-10a/b mimics as promising candidates in miRNA-based therapeutics for diabetes and GI dysmotility.

Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy.

Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.

Impact of ligand environment on optical, luminescence and thermometric behavior of A3 (PO4 )2 :Sm3+ (A = Ca, Sr) phosphors.

The present study investigates the impact of the ligand environment on the luminescence and thermometric behavior of Sm3+ doped A3 (PO4 )2 (A = Sr, Ca) phosphors prepared by combustion synthesis. The structural and luminescent properties of Sm3+ ions in the phosphate lattices were investigated using powder X-ray diffraction (PXRD) and photoluminescence (PL) techniques. PXRD results of the synthesized phosphors exhibit the expected phases that are in agreement with their respective standards. Fourier-transform infrared (FTIR) spectroscopy confirms the presence of PO4 vibrational bands. Upon excitation with near ultraviolet light, the PL studies indicated that Sr3 (PO4 )2 :Sm3+ phosphors exhibit a yellow light emission, whereas Ca3 (PO4 )2 :Sm3+ phosphors exhibit an emission of orange light. The PL emission results are in accordance with the CIE coordinates, with the Sr3 (PO4 )2 :Sm3+ phosphors showing coordinates of (0.56, 0.44), and the Ca3 (PO4 )2 :Sm3+ phosphors displaying coordinates of (0.60, 0.40). Thermal analysis shows improved stability of Ca3 (PO4 )2 :Sm3+ based on lower weight reduction in thermogravimetric analysis. The effect of temperature on the luminescence properties of the phosphor has been examined upon a 405 nm excitation. By using the fluorescence intensity ratio (FIR) method, the temperature responses of the emission ratios from the Sm3+ : the 4 F3/2 → 6 H5/2 transition to the 4 G5/2 → 6 H7/2 and 4 F3/2 → 6 H5/2 transition to the 4 G5/2 → 6 H9/2 emissions are characterized. The Ca3 (PO4 )2 :Sm3+ phosphors are more sensitive as compared with the Sr3 (PO4 )2 :Sm3+ phosphors. The earlier research findings strongly indicate that these phosphors hold great promise as ideal candidates for applications in non-invasive optical thermometry and solid-state lighting devices.

Adjuvantation of whole-killed Leishmania vaccine with anti-CD200 and anti-CD300a antibodies potentiates its efficacy and provides protection against wild-type parasites.

One of the major reasons behind the limited success of vaccine candidates against all forms of leishmaniasis is the inability of parasitic antigens to induce robust cell-mediated immunity and immunological memory. Here we find, for the first time, that the adjuvantation of whole-killed Leishmania vaccine (Leishvacc) with anti-CD200 and anti-CD300a antibodies enhances CD4+ T cells mediated immunity in vaccinated mice and provides protection against wild-type parasites. The antibody adjuvantation, either alone or with a TLR4 agonist monophosphoryl A (MPL-A), induced the production of pro-inflammatory cytokines viz., IFN-γ, TNF-α, and IL-2 by antigen experienced CD4+ T cells, and also enhanced their rate of conversion into their memory phenotypes against Leishvacc antigens. The antibody adjuvanted vaccine also promoted the generation of IgG2a-mediated protective humoral immunity in vaccinated mice. Further, the mice vaccinated with antibodies adjuvanted vaccine showed strong resilience against metacyclic forms of L. donovani parasites as we observed reduced clinical features such as splenomegaly, hepatomegaly, granulomatous tissues in the liver, and parasitic load in their spleen. The findings of this study demonstrate that the anti-CD200 and anti-CD300a antibodies have potential to increase the protective efficacy of the whole-killed Leishmania vaccine, and opens up a new gateway to diversify the roles of immune checkpoints in vaccine development against leishmaniasis.

Salmonella infection among the pediatric population at a tertiary care children's hospital in central Nepal: a retrospective study.

Background: Typhoid fever, an infective bacterial disease, is capable of causing fatal systemic infection in humans, and in an era of antimicrobial resistance, it has become of public health importance. This study aimed to investigate the laboratory diagnosis of Salmonella bloodstream infection, its serotype, antimicrobial resistance pattern, and seasonal variation at a tertiary care children's hospital. Methods: We undertook a retrospective, cross-sectional study by reviewing hospital-based laboratory records of patients whose blood culture samples were submitted from the outpatient department to the laboratory of a tertiary care children's hospital in Kathmandu, Nepal, from January 2017 to January 2019. Results: Among the total blood culture samples obtained (n = 39,771), bacterial isolates (n = 1,055, 2.65%) belonged either to the Genus Enterobacteriaceae or Genus Acinetobacter. Altogether (n = 91, 8.63%), isolates were positive for Salmonella spp., which were further identified as Salmonella enterica subsp. enterica ser. Typhi (n = 79, 7.49%), Salmonella enterica subsp. enterica ser. Paratyphi A (n = 11, 1.04%), and Salmonella enterica subsp. enterica ser. Paratyphi B (n = 1, 0.1%). The median age of patients was 6 years (IQR: 4-9), with male and female patients constituting (n = 53, 58.24%; OR, 1.0; 95% CI, 0.60-1.67) and (n = 38, 41.76%; OR, 0.98; 95% CI, 0.49-2.05) cases, respectively. The disease was observed throughout the year, with a high prevalence toward the spring season (March-May). An antibiogram showed resistance more toward nalidixic acid with S. Typhi, comprising half the isolates (n = 52, 65.82%; p = 0.11). Resistance toward ß-lactams with ß-lactamase inhibitors (amoxicillin/clavulanate; 1.27%) was seen in a single isolate of S. Typhi. The multidrug resistance pattern was not pronounced. The multiple antibiotic resistance (MAR) index was in the range between 0.14 and 0.22 in S. Typhi and 0.22 and 0.23 in S. Paratyphi. Conclusion: Salmonella Typhi was the predominant ser. Infection was common among children between 1 and 5 years of age, showing male predominance and with the spring season contributing to a fairly higher number of cases. Antimicrobial susceptibility testing of S. Typhi showed more resistance toward nalidixic acid, with only a single isolate resistant to ß-lactamase inhibitors (amoxicillin/clavulanate). Alarming multidrug resistance patterns were not observed. The MAR index in this study indicates the importance of the judicious use of antimicrobials and hospital infection prevention and control practices.

Lack of awareness of neurogastroenterology and motility within medical education: Time to fill the gap.

Disorders of gut-brain interaction (DGBI), previously referred to as functional gastrointestinal disorders, affect 40.3% of adults in the general population and are diagnosed in 34.9% of new adult referrals to secondary care gastroenterology services. Despite their high prevalence, studies published in this issue of Neurogastroenterology and Motility by investigators based in Germany, the UK, and the USA demonstrate a mismatch between the clinical burden of DGBI and their representation in medical school and postgraduate curricula. This review outlines the salient findings of these studies and explores why and how negative perceptions toward DGBI exist, including factors related to misinformation and internalized stigma. The authors propose a selection of strategies to ameliorate physicians' attitudes toward and knowledge of neurogastroenterology and motility including linking trainees with dedicated clinician mentors with an interest in motility, exposing trainees to expert patients who can enhance empathy, extending Balint groups into gastroenterology training, and offering motility apprenticeships in specialist units. Urgent improvements to medical school and postgraduate curricula are required to ensure the longevity of this subspecialty field in gastroenterology, and to ensure the needs of a sizeable proportion of gastroenterology patients are appropriately met.

miR-10b-5p rescues leaky gut linked with gastrointestinal dysmotility and diabetes.

BACKGROUND/AIM: Diabetes has substantive co-occurrence with disorders of gut-brain interactions (DGBIs). The pathophysiological and molecular mechanisms linking diabetes and DGBIs are unclear. MicroRNAs (miRNAs) are key regulators of diabetes and gut dysmotility. We investigated whether impaired gut barrier function is regulated by a key miRNA, miR-10b-5p, linking diabetes and gut dysmotility. METHODS: We created a new mouse line using the Mb3Cas12a/Mb3Cpf1 endonuclease to delete mir-10b globally. Loss of function studies in the mir-10b knockout (KO) mice were conducted to characterize diabetes, gut dysmotility, and gut barrier dysfunction phenotypes in these mice. Gain of function studies were conducted by injecting these mir-10b KO mice with a miR-10b-5p mimic. Further, we performed miRNA-sequencing analysis from colonic mucosa from mir-10b KO, wild type, and miR-10b-5p mimic injected mice to confirm (1) deficiency of miR-10b-5p in KO mice, and (2) restoration of miR-10b-5p after the mimic injection. RESULTS: Congenital loss of mir-10b in mice led to the development of hyperglycemia, gut dysmotility, and gut barrier dysfunction. Gut permeability was increased, but expression of the tight junction protein Zonula occludens-1 was reduced in the colon of mir-10b KO mice. Patients with diabetes or constipation- predominant irritable bowel syndrome, a known DGBI that is linked to leaky gut, had significantly reduced miR-10b-5p expression. Injection of a miR-10b-5p mimic in mir-10b KO mice rescued these molecular alterations and phenotypes. CONCLUSIONS: Our study uncovered a potential pathophysiologic mechanism of gut barrier dysfunction that links both the diabetes and gut dysmotility phenotypes in mice lacking miR-10b-5p. Treatment with a miR-10b-5p mimic reversed the leaky gut, diabetic, and gut dysmotility phenotypes, highlighting the translational potential of the miR-10b-5p mimic.

Preclinical Evaluation of a New Series of Albumin-Binding 177Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(ß)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, ß-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2-177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.

Preclinical Development in Radiopharmaceutical Therapy for Prostate Cancer.

Prostate cancer is a leading cause of cancer death in men worldwide. Among the various treatment options, radiopharmaceutical therapy has shown notable success in metastatic, castration-resistant disease. Radiopharmaceutical therapy is a systemic approach that delivers cytotoxic radiation doses precisely to the malignant tumors and/or tumor microenvironment. Therapeutic radiopharmaceuticals are composed of a therapeutic radionuclide and a high-affinity, tumor-targeting carrier molecule. Therapeutic radionuclides used in preclinical prostate cancer studies are primarily α-, ß--, or Auger-electron-emitting radiometals or radiohalogens. Monoclonal antibodies, antibody-derived fragments, peptides, and small molecules are frequently used as tumor-targeting molecules. Over the years, several important membrane-associated proteases and receptors have been identified, validated, and subsequently used for preclinical radiotherapeutic development for prostate cancer. Prostate-specific membrane antigen (PSMA) is the most well-studied prostate cancer-associated protease in preclinical literature. PSMA-targeting radiotherapeutic agents are being investigated using high-affinity antibody- and small-molecule-based agents for safety and efficacy. Early generations of such agents were developed simply by replacing radionuclides of the imaging agents with therapeutic ones. Later, extensive structure-activity relationship studies were conducted to address the safety and efficacy issues obtained from initial patient data. Recent regulatory approval of the 177Lu-labeled low-molecular-weight agent, 177Lu-PSMA-617, is a significant accomplishment. Current preclinical experiments are focused on the structural modification of 177Lu-PSMA-617 and relevant investigational agents to increase tumor targeting and reduce off-target binding and toxicity in healthy organs. While lutetium-177 (177Lu) remains the most widely used radionuclide, radiolabeled analogs with iodine-131 (128I), yttrium-90 (89Y), copper-67 (67Cu), and terbium-161 (161Tb) have been evaluated as potential alternatives in recent years. In addition, agents carrying the α-particle-emitting radiohalogen, astatine-211 (211At), or radiometals, actinium-225 (225Ac), lead-212 (212Pb), radium-223 (223Ra), and thorium-227 (227Th), have been increasingly investigated in preclinical research. Besides PSMA-based radiotherapeutics, other prominent prostate cancer-related proteases, for example, human kallikrein peptidases (HK2 and HK3), have been explored using monoclonal-antibody-(mAb)-based targeting platforms. Several promising mAbs targeting receptors overexpressed on the different stages of prostate cancer have also been developed for radiopharmaceutical therapy, for example, Delta-like ligand 3 (DLL-3), CD46, and CUB domain-containing protein 1 (CDCP1). Progress is also being made using peptide-based targeting platforms for the gastrin-releasing peptide receptor (GRPR), a well-established membrane-associated receptor expressed in localized and metastatic prostate cancers. Furthermore, mechanism-driven combination therapies appear to be a burgeoning area in the context of preclinical prostate cancer radiotherapeutics. Here, we review the current developments related to the preclinical radiopharmaceutical therapy of prostate cancer. These are summarized in two major topics: (1) therapeutic radionuclides and (2) tumor-targeting approaches using monoclonal antibodies, small molecules, and peptides.

Mycorrhizae set the stage for plants to produce a higher production of biomolecules and stress-related metabolites: a sustainable alternative of agrochemicals to enhance the quality and yield of beetroot (Beta vulgaris L.).

Population explosions, environmental deprivation, and industrial expansion led to an imbalanced agricultural system. Non-judicial uses of agrochemicals have decreased agrodiversity, degraded agroecosystems, and increased the cost of farming. In this scenario, a sustainable agriculture system could play a crucial role; however, it needs rigorous study to understand the biological interfaces within agroecosystems. Among the various biological components with respect to agriculture, mycorrhizae could be a potential candidate. Most agricultural crops are symbiotic with arbuscular mycorrhizal fungi (AMF). In this study, beetroot has been chose to study the effect of different AMFs on various parameters such as morphological traits, biochemical attributes, and gene expression analysis (ALDH7B4 and ALDH3I1). The AMF Gm-Funneliformis mosseae (Glomus mosseae), Acaulospora laevis, and GG-Gigaspora gigantean were taken as treatments to study the effect on the above-mentioned parameters in beetroot. We observed that among all the possible combinations of mycorrhizae, Gm+Al+GG performed best, and the Al-alone treatment was found to be a poor performer with respect to all the studied parameters. This study concluded that the more the combinations of mycorrhizae, the better the results will be. However, the phenomenon depends on the receptivity, infectivity, and past nutrient profile of the soil.

Click inspired synthesis of piperazine-triazolyl sugar-conjugates as potent anti-Hela activity.

To imbibe the aim of synthesizing water-soluble and biocompatible motif, a click-inspired piperazine glycoconjugate has been devised up. In this report, we present a focused approach to design and synthesis of versatile sugar-appended triazoles through 'Click Chemistry' along with their pharmacological studies on cyclin-dependent kinases (CDKs) and cell cytotoxicity on cancer cells using in silico and in vitro approaches, respectively. The study has inclusively recognized the galactose- and mannose-derived piperazine conjugates as the promising motifs. The findings suggested that the galactosyl bis-triazolyl piperazine analogue 10b is the most CDK interactive derivative and also possess significant anticancer activity.

Leishmania donovani induces CD300a expression to dampen effector properties of CD11c+ dendritic and antigen activated CD8+ T cells.

CD8+ T cells are an important regiment of adaptive immunity that play a decisive role in elimination of many species of Leishmania parasite from the host. In visceral leishmaniasis, caused by L. donovani, the loss of CD8+ T cells function has been found associated with augmented pathogenesis. The factors determining CD8+ T cells activation and function against Leishmania antigens are largely unknown. In this study, we investigated the role of an immune inhibitory receptor, CD300a, on the effector properties of dendritic cells and CD8+ T cells. We observed that the Leishmania regulates the effectors function of CD8+ T cells by increasing CD300a expression on CD11c+ dendritic cells. The abrogation of CD300a signaling in parasites infected animals induced CD8+ T cell abilities to produce IFN-γ, TNF-α and also helped them to acquire desired multifunctionality. The CD300a receptor blocking also enhanced the number of CD8+ T cells memory phenotypes at the early days of infection, suggesting its potential beneficial role in vaccine induced immunity. We also observed significantly enhanced levels of pro-inflammatory cytokines in the spleen of CD300a blocked infected animals with concomitant reduced spleen parasite load. Additionally, the abrogation of CD300a signals in the infected animals helped in establishing Th1 type protective humoral immunity with significantly elevated levels of IgG2a antibodies. Since CD8+ T cells are an important determinant of vaccine induced immunity against leishmaniasis, the findings corroborate the potential of CD300a in vaccine induced immunity and thus require further attention.

A social profile of deaths related to sickle cell disease in India: a case for an ethical policy response.

India accounts for 14.5 percent of the global SCD newborns, roughly over 42,000 a year, second to sub-Saharan Africa. Despite the availability of cheap diagnostic and treatment options, SCD remains a largely neglected disease within healthcare policy and practice. Epidemiological modeling based on small, often dated, regional studies (largely from sub-Saharan Africa) estimate that between 50 and 90 percent of affected children will/die before the age of 5 years. This premise, coupled with targets of reducing under 5 mortality (SDG 4), privileges public health interventions for screening and prevention of new births, undermining investments in long-term health and social care. This paper presents a retrospective, descriptive analysis of the socio-demographic profile of 447 patients diagnosed with sickle cell or sickle-beta thalassemia, who died following admission at a tertiary care entre in India. We used anonymized hospital records of 3,778 sickle cell patients, admitted in pediatric and adult/medical wards between January 2016 and February 2021. A majority of hospital deaths occurred in the second and third decades of life, following a hospital admission for a week. The overall mortality during 2016-2019 was 14% with little gender difference over time. Contrary to our expectations, the number of hospital deaths did not increase during the first year of the COVID-19 pandemic, between 2020 and 2021. The conclusion highlights the importance of longitudinal, socio-demo-graphic data on deaths as providing important insights for identifying ethical policy interventions focused on improving SCD outcomes over time, reducing inequities in access to care, and preventing what might be considered "excess" deaths.

One-pot ultrasonicated synthesized lead-less hybrid perovskite nanocrystals: structural, morphological and optical analysis.

In contemporary years, hybrid lead halide perovskites nanocrystals (HPNCs) have emerged as core materials for low-cost solution-processable photovoltaic, light-emitting devices as well as in other optoelectronic fields, such as high-efficiency perovskite fluorescent quantum dots (quantum dot, QD). Although the high efficiency makes them an attractive active material, reducing the Pb-toxicity and enhancing the stability while sustaining the efficiency of the HPNCs devices is important for their successful commercialization in future. Here, we report for the first time the fabrication of excellent quality Pb-less, MAPb1-xSnxBr3(x = 0 to 0.50) perovskite NCs by one-pot ultrasonication method. Interestingly, an outstanding photoluminescence quantum yield (PLQY) of 94% and better lifetime performance than 100% Pb-based HPNCs is obtained for Pb-less HPNCs. The successful incorporation of Sn MAPb1-xSnxBr3HPNCs is confirmed by energy-dispersive x-ray (EDX) and x-ray photoelectron spectroscopy (XPS) analysis. Although the particle size for Pb-less HPNCs was different, the change in morphology and structure was minimal as confirmed by transmission electron microscopy (TEM) analysis. The optical analysis indicated bandgap tuning, which is evident by the blue shift of the band edge in absorbance spectra and photoluminescence peak after incorporating Sn2+. To the best of our knowledge, this is the highest achieved PLQY for Sn-substituted hybrid Pb-based HPNCs. The synthesis by using one pot ultrasonication method might be helpful for large-scale HPNCs production and can pave the way for future research on less-toxic and stable alternatives to Pb-based HPNCs.

Enterochromaffin Cells-Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction.

Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells produce up to 95% of total body serotonin and coordinate luminal and basolateral communication in the gastrointestinal (GI) tract. EC cells affect a broad range of gut physiological processes, such as motility, absorption, secretion, chemo/mechanosensation, and pathologies, including visceral hypersensitivity, immune dysfunction, and impaired gastrointestinal barrier function. We aim to review EC cell and serotonin-mediated physiology and pathophysiology with particular emphasis on DGBIs. We explored the knowledge gap and attempted to suggest new perspectives of physiological and pathophysiological insights of DGBIs, such as (1) functional heterogeneity of regionally distributed EC cells throughout the entire GI tract; (2) potential pathophysiological mechanisms mediated by EC cell defect in DGBIs; (3) cellular and molecular mechanisms characterizing EC cells and gut microbiota bidirectional communication; (4) differential modulation of EC cells through GI segment-specific gut microbiota; (5) uncover whether crosstalk between EC cells and (i) luminal contents; (ii) enteric nervous system; and (iii) central nervous system are core mechanisms modulating gut-brain homeostasis; and (6) explore the therapeutic modalities for physiological and pathophysiological mechanisms mediated through EC cells. Insights discussed in this review will fuel the conception and realization of pathophysiological mechanisms and therapeutic clues to improve the management and clinical care of DGBIs.

Metalloendopeptidase ADAM-like Decysin 1 (ADAMDEC1) in Colonic Subepithelial PDGFRα+ Cells Is a New Marker for Inflammatory Bowel Disease.

Metalloendopeptidase ADAM-Like Decysin 1 (ADAMDEC1) is an anti-inflammatory peptidase that is almost exclusively expressed in the gastrointestinal (GI) tract. We have recently found abundant and selective expression of Adamdec1 in colonic mucosal PDGFRα+ cells. However, the cellular origin for this gene expression is controversial as it is also known to be expressed in intestinal macrophages. We found that Adamdec1 mRNAs were selectively expressed in colonic mucosal subepithelial PDGFRα+ cells. ADAMDEC1 protein was mainly released from PDGFRα+ cells and accumulated in the mucosal layer lamina propria space near the epithelial basement membrane. PDGFRα+ cells significantly overexpressed Adamdec1 mRNAs and protein in DSS-induced colitis mice. Adamdec1 was predominantly expressed in CD45- PDGFRα+ cells in DSS-induced colitis mice, with only minimal expression in CD45+ CD64+ macrophages. Additionally, overexpression of both ADAMDEC1 mRNA and protein was consistently observed in PDGFRα+ cells, but not in CD64+ macrophages found in human colonic mucosal tissue affected by Crohn's disease. In summary, PDGFRα+ cells selectively express ADAMDEC1, which is localized to the colon mucosa layer. ADAMDEC1 expression significantly increases in DSS-induced colitis affected mice and Crohn's disease affected human tissue, suggesting that this gene can serve as a diagnostic and/or therapeutic target for intestinal inflammation and Crohn's disease.

Transcriptome profiling of subepithelial PDGFRα cells in colonic mucosa reveals several cell-selective markers.

Subepithelial platelet-derived growth factor receptor alpha (PDGFRα)+ cells found in the colonic mucosal tissue come in close contact with epithelial cells, immune cells, neurons, capillaries, and lymphatic networks. Mucosal subepithelial PDGFRα+ cells (MuPαC) are important regulators in various intestinal diseases including fibrosis and inflammation. However, the transcriptome of MuPαC has not yet been elucidated. Using Pdgfra-eGFP mice and flow cytometry, we isolated colonic MuPαC and obtained their transcriptome data. In analyzing the transcriptome, we identified three novel, and selectively expressed, markers (Adamdec1, Fin1, and Col6a4) found in MuPαC. In addition, we identified a unique set of MuPαC-enriched genetic signatures including groups of growth factors, transcription factors, gap junction proteins, extracellular proteins, receptors, cytokines, protein kinases, phosphatases, and peptidases. These selective groups of genetic signatures are linked to the unique cellular identity and function of MuPαC. Furthermore, we have added this MuPαC transcriptome data to our Smooth Muscle Genome Browser that contains the transcriptome data of jejunal and colonic smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and smooth muscle resident PDGFRα+ cells: (https://med.unr.edu/physio/transcriptome). This online resource provides a comprehensive reference of all currently known genetic transcripts expressed in primary MuPαC in the colon along with smooth muscle resident PDGFRα cells, SMC, and ICC in the murine colon and jejunum.