Monitoring SARS-CoV-2 variants in wastewater of Dhaka City, Bangladesh: approach to complement public health surveillance systems.

BACKGROUND: Wastewater-based epidemiological surveillance has been considered a powerful tool for early detection and monitoring of the dynamics of SARS-CoV-2 and its lineages circulating in a community. This study is aimed to investigate the complexity of SARS-CoV-2 infection dynamics in Dhaka city by examining its genetic variants in wastewater. Also, the study seeks to determine a connection between the SARS-CoV-2 variations detected in clinical testing and those found in wastewater samples. RESULTS: Out of 504 samples tested in RT-qPCR, 185 (36.7%) tested positive for SARS-CoV-2 viral RNA. The median log10 concentration of SARS-CoV-2 N gene copies/Liter of wastewater (gc/L) was 5.2, and the median log10 concentration of ORF1ab was 4.9. To further reveal the genetic diversity of SARS-CoV-2, ten samples with ORF1ab real-time RT-PCR cycle threshold (Ct) values ranging from 28.78 to 32.13 were subjected to whole genome sequencing using nanopore technology. According to clade classification, sequences from wastewater samples were grouped into 4 clades: 20A, 20B, 21A, 21J, and the Pango lineage, B.1, B.1.1, B.1.1.25, and B.1.617.2, with coverage ranging from 94.2 to 99.8%. Of them, 70% belonged to clade 20B, followed by 10% to clade 20A, 21A, and 21J. Lineage B.1.1.25 was predominant in Bangladesh and phylogenetically related to the sequences from India, the USA, Canada, the UK, and Italy. The Delta variant (B.1.617.2) was first identified in clinical samples at the beginning of May 2021. In contrast, we found that it was circulating in the community and was detected in wastewater in September 2020. CONCLUSION: Environmental surveillance is useful for monitoring temporal and spatial trends of existing and emerging infectious diseases and supports evidence-based public health measures. The findings of this study supported the use of wastewater-based epidemiology and provided the baseline data for the dynamics of SARS-CoV-2 variants in the wastewater environment in Dhaka, Bangladesh.

Safety Assessment of Streptococcus salivarius UBSS-01 in Rats and Double-Blind Placebo-Controlled Study in Healthy Individuals.

Streptococcus salivarius is a common, harmless, and prevalent member of the oral microbiota in humans. In the present study, the safety of S. salivarius UBSS-01 was evaluated using in silico methods and preclinical and clinical studies. In an acute toxicity study, rats were administered with 5 g/kg (500 × 109 CFU) S. salivarius UBSS-01. The changes in phenotypic behaviors and hematological, biochemical, electrolytes, and urine analyses were monitored. No toxicity was observed at 14 days post-treatment. The no observable effects limit (NOEL) of S. salivarius UBSS-01 was >5 g/kg in rats. In a 28-day repeat dose toxicity study, rats were administered S. salivarius UBSS-01 once daily at doses of 0.1, 0.5, and 1 g/kg (10, 50, and 100 billion CFU/kg, respectively) body weight. S. salivarius UBSS-01 did not influence any of the hematology parameters and clinical chemistry parameters in plasma and serum samples after 28-day repeated administration. No structural abnormality was observed in the histological examination of organs. Whole genome analysis revealed the absence of virulence factors or genes that may transmit antibiotic resistance. In the double-blind study with 60 human participants (aged 18-60 years), consumption of S. salivarius UBSS-01 for 30 days was found to be safe and results were comparable with placebo treatment These findings indicate that S. salivarius UBSS-01 may be safe for human consumption.

Combating Cariogenic Streptococcus mutans Biofilm Formation and Disruption with Coumaric Acid on Dentin Surface.

Streptococcus mutans, the primary cause of dental caries, relies on its ability to create and sustain a biofilm (dental plaque) for survival and pathogenicity in the oral cavity. This study was focused on the antimicrobial biofilm formation control and biofilm dispersal potential of Coumaric acid (CA) against Streptococcus mutans on the dentin surface. The biofilm was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assay, microtiter plate assay, production of extracellular polymeric substances (EPSs), florescence microscopy (surface coverage and biomass µm2) and three-dimensional (3D) surface plots. It was observed that CA at 0.01 mg/mL reduced bacterial growth by 5.51%, whereases at 1 mg/mL, a significant (p < 0.05) reduction (98.37%) was observed. However, at 1 mg/mL of CA, a 95.48% biofilm formation reduction was achieved, while a 73.45% biofilm dispersal (after 24 h. treatment) was achieved against the preformed biofilm. The MTT assay showed that at 1 mg/mL of CA, the viability of bacteria in the biofilm was markedly (p < 0.05) reduced to 73.44%. Moreover, polysaccharide (EPS) was reduced to 24.80 µg/mL and protein (EPS) to 41.47 µg/mL. ImageJ software (version 1.54 g) was used to process florescence images, and it was observed that the biofilm mass was reduced to 213 (µm2); the surface coverage was reduced to 0.079%. Furthermore, the 3D surface plots showed that the untreated biofilm was highly dense, with more fibril-like projections. Additionally, molecular docking predicted a possible interaction pattern of CA (ligand) with the receptor Competence Stimulating Peptide (UA159sp, PDB ID: 2I2J). Our findings suggest that CA has antibacterial and biofilm control efficacy against S. mutans associated with dental plaque under tested conditions.

Benzimidazole derivatives as tubulin polymerization inhibitors: Design, synthesis and in vitro cytotoxicity studies.

A new class of benzimidazole derivatives as tubulin polymerization inhibitors has been designed and synthesized in this study. The in vitro anticancer profile of the developed molecules was reconnoitred on selected human cancer cells. The highest cytotoxicity was illustrated by compounds 7n and 7u with IC50 values ranging from 2.55 to 17.89 µM with specificity toward SK-Mel-28 cells. They displayed 5-fold less cytotoxicity towards normal rat kidney epithelial NRK52E cells, which implies that they are not harmful to normal, healthy cells. The cellular staining procedures like AO/EB, DCFDA, and DAPI were applied to comprehend the inherent mechanism of apoptosis which displayed nuclear and morphological alterations. The Annexin V binding and JC-1 studies were executed to evaluate the extent of apoptosis and the decline in mitochondrial transmembrane potential in SK-Mel-28 cell lines. Compound 7n dose-dependently arrested the G2/M phase of the cell cycle and the target-based outcomes proposed tubulin polymerization inhibition by 7n (IC50 of 5.05±0.13 µM). Computational studies were also conducted on the tubulin protein (PDB ID: 3E22) to investigate the stabilized binding interactions of compounds 7n and 7u with tubulin, respectively.

Context-Dependent miR-21 Regulation of TLR7-Mediated Autoimmune and Foreign Antigen-Driven Antibody-Forming Cell and Germinal Center Responses.

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), although the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. In this study, using the TLR7 agonist, imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody-producing Ab-forming cells (AFCs) without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21-deficient Sle1b mice that were associated with reduced IFN, proinflammatory cytokines, and effector CD4+ T cell responses. RNA sequencing analysis on B cells from miR-21-deficient Sle1b mice revealed reduced activation and response to IFN, and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I IFN stimulation. Our findings in the B6.Sle1bYaa (Sle1b Yaa) spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and T follicular helper responses. Finally, immunization with T-dependent Ag revealed a role for miR-21 in foreign Ag-driven GC and Ab, but not AFC, responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign Ag-driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.

Spectroscopic and Density Functional Studies on the Interaction of a Naphthalene Derivative with Anions.

This article highlights the investigation of anion interactions and recognition abilities of naphthalene derivative, [(E)-1-(((4-nitrophenyl)imino)methyl)naphthalen-2-ol], (NIMO) by UV-visible spectroscopically and colorimetrically. NIMO shows selective recognition of F- ions colorimetrically, and a visual color change from yellow to pink is observed by the naked eye. The F- ions recognition is fully reversible in the presence of HSO4- ions. The limit of F- ions detection by NIMO could be possible down to 0.033 ppm-level. A paper strips-based test kit has been demonstrated to detect F- ions selectively by the naked eye, and a smartphone-based method for real sample analysis in the non-aqueous medium has also been demostrated. Spectroscopic behavior is well supported by pKa value calculation and DFT analysis, to find a correlation with receptor analyte interaction. The optical response of NIMO towards the accumulation of F- ions and, subsequently, HSO4- ions as chemical inputs provides an opportunity to construct INH and IMP molecular logic gates.

Synthesis and cytotoxicity evaluation of DNA-interactive ß-carboline indolyl-3-glyoxamide derivatives: Topo-II inhibition and in silico modelling studies.

In a quest for effective cancer targeted drug therapy, a series of new ß-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC50 < 10 µM) on human cancer cell lines like HCT116, A549, SK-MEL-28, and MCF7. Precisely, compound 12x expressed the best cytotoxic potential against melanoma cancer cell line (SK-MEL-28) with an IC50 value of 4.37 µM. In addition, cytotoxicity evaluation against normal kidney cell line (NRK52E) entrenched the cytospecificity and selectivity index of 12x. The traditional apoptosis assays advised morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented nuclei, and generation of ROS. The flow cytometric analysis revealed significant early and slight late-stage induction of apoptosis. The target-based physiochemical assays indicated the ability of compound 12x to bind with DNA and inhibition of Topoisomerase II. Moreover, molecular modeling studies affirm the excellent DNA intercalation potential and stabilized interactions of 12x with DNA base pairs. In silico prediction of physicochemical parameters revealed the promising drug-like properties of the synthesized derivatives.

Insight into potent TLR2 inhibitors for the treatment of disease caused by Mycoplasma pneumoniae based on machine learning approaches.

Mycoplasma pneumoniae (MP) is one of the most common pathogens that causes acute respiratory tract infections. Children experiencing MP infection often suffer severe complications, lung injury, and even death. Previous studies have demonstrated that Toll-like receptor 2 (TLR2) is a potential therapeutic target for treating the MP-induced inflammatory response. However, the screening of natural compounds has received more attention for the treatment of bacterial infections to reduce the likelihood of bacterial resistance. Herein, we screened compounds by combining molecular docking and machine learning approaches to find potential lead compounds for treating MP infection. First, all compounds were docked with the TLR2 receptor protein to screen for potential candidates. To predict drug bioactivity, a machine learning model (random forest) was trained for TLR2 inhibitors to obtain the predictive model. The model achieved significant squared correlation coefficient (R2) values for the training set (0.85) and validation set (0.84) of compounds. The developed machine learning model was then used to predict the pIC50 values of the top 50 candidates from the Traditional Chinese compounds and Discovery Diversity sets of compounds. As a result, these compounds are capable of inhibiting the inflammatory response induced by MP. However, prior to bringing these compounds to market, it is necessary to verify these results with additional biological testing, including preclinical and clinical studies. Moreover, the present study provides a theoretical basis for the use of natural compounds as potential candidates to treat pneumonia caused by MP.

Multinomial classification of NLRP3 inhibitory compounds based on large scale machine learning approaches.

The role of NLRP3 inflammasome in innate immunity is newly recognized. The NLRP3 protein is a family of nucleotide-binding and oligomerization domain-like receptors as well as a pyrin domain-containing protein. It has been shown that NLRP3 may contribute to the development and progression of a variety of diseases, such as multiple sclerosis, metabolic disorders, inflammatory bowel disease, and other auto-immune and auto-inflammatory conditions. The use of machine learning methods in pharmaceutical research has been widespread for several decades. An important objective of this study is to apply machine learning approaches for the multinomial classification of NLRP3 inhibitors. However, data imbalances can affect machine learning. Therefore, a synthetic minority oversampling technique (SMOTE) has been developed to increase the sensitivity of classifiers to minority groups. The QSAR modelling was performed using 154 molecules retrieved from the ChEMBL database (version 29). The accuracy of the multiclass classification top six models was found to fall within ranges of 0.99 to 0.86, and log loss ranges of 0.2 to 2.3, respectively. The results showed that the receiver operating characteristic curve (ROC) plot values significantly improved when tuning parameters were adjusted and imbalanced data was handled. Moreover, the results demonstrated that SMOTE offers a significant advantage in handling imbalanced datasets as well as substantial improvements in overall accuracy of machine learning models. The top models were then used to predict data from unseen datasets. In summary, these QSAR classification models exhibited robust statistical results and were interpretable, which strongly supported their use for rapid screening of NLRP3 inhibitors.

Partial blood replacement ameliorates middle cerebral artery occlusion generated neurological aberrations by intervening TLR4 and NLRP3 cascades in rats.

Acute ischemic stroke is a catastrophic medical condition that causes severe disability and mortality if the sufferer escapes treatment within a stipulated timeframe. While timely intervention with clot-bursting agents like tissue-plasminogen activators abrogates some post-stroke neurologic deficits, no neuroprotective therapy is yet promisingly addresses the post-recanalization neuroinflammation in post-stroke survivors. Herein, we investigated the effect of partial blood replacement therapy (BRT), obtained from healthy and treadmill-trained donor rats, on neurological deficits, and peripheral and central inflammatory cascades using the ischemia-reperfusion animal paradigm. The cerebral ischemia-reperfusion was induced in rats by occlusion of the middle cerebral artery (MCAO) for 90 min, followed by reperfusion. Rats underwent MCAO surgery displayed remarkable sensorimotor and motor deficits in rotarod, foot fault, adhesive removal, and paw whisker tests till 5 days post-surgery. These behavior abnormalities were ameliorated in the BRT-recipient MCAO rats. BRT also reduced the infarct volume and neuronal death in the ipsilateral hemisphere revealed by TTC and cresyl violet staining compared to the MCAO group. Rats received BRT infusion exhibited the reduced expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule-1 (Iba-1), and MyD88 on day 5 post-MCAO in immunohistochemistry and immunofluorescent assays. Moreover, elevated levels of toll-like receptor 4 (TLR4) and mRNA expression of IL-1ß, TNF-α, matrix metalloproteinase-9 and NLRP3, and decreased levels of zonula occludens-1 in MCAO rats, were reversed following BRT. These findings suggest that the partial BRT may rescind MCAO-induced neurological dysfunctions and cerebral injury by intervening in the TLR4 and NLRP3 pathways in rats.

Oxyberberine an oxoderivative of berberine confers neuroprotective effects in controlled-cortical impact mouse model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is known as a silent epidemic that causes many deaths and disabilities worldwide. We examined the response of oxyberberine (OBB) in lipopolysaccharide-stimulated BV2 microglial cells and a controlled-cortical impact (CCI) mouse model of TBI. METHODS: We synthesized OBB from berberine, and also prepared OBB-nanocrystals (OBB-NC). Male C57BL/6 mice were used for CCI surgery, and post-CCI neurobehavioral deficits were assessed from 1 h after injury through 21 days post-injury (dpi). RESULTS: OBB treatment reduced the lipopolysaccharide-triggered elevated levels of reactive oxygen species, nitric oxide, and nuclear factor kappa B (NF-κB) in BV2 microglial cells, indicating a neuroprotective potential. CCI-operated mice exhibited significant neurological deficits on 1, 3, and 5 dpi in neurological severity scoring and rotarod assay. OBB (25 and 50 mg/kg/day) and OBB-NC (3 mg/kg/day) ameliorated these neurological aberrations. Mice subjected to CCI surgery also displayed anxiogenic- and depression-like behaviours, and cognitive impairments in forced-swimming test and elevated-zero maze, and novel object recognition task, respectively. Administration of OBB reduced these long-term neuropsychiatric complications, and also levels of toll-like receptor 4 (TLR4), high-motility group protein 1 (HMGB1), NF-κB, tumour necrosis factor-alpha and interleukin 6 cytokines in the ipsilateral cortex of mice. CONCLUSION: We suggest that the administration of OBB offers neuroprotective effects via inhibition of HMGB1-mediated TLR4/NFκB pathway.

Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity.

TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-γ signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-γ signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-γ reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-γ. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-γR indicates that TLR7-induced IFN-γ activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-γ signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-γ and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.

Serine Phosphorylation of the STAT1 Transactivation Domain Promotes Autoreactive B Cell and Systemic Autoimmunity Development.

Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag-driven GC and Tfh responses in B6.Sle1b mice. By generating B cell-specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell-intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727-mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.

The Mid-Term Outcomes of Cone Repair or Replacement of Tricuspid Valve in Patients with Ebstein's Anomaly: Our Experience.

BACKGROUND: Cone repair of the tricuspid valve (TV) is a contemporary reproducible technique for surgical reconstruction of Ebstein's anomaly. Different authorities have shown that this technique restores excellent tricuspid valve function. In Bangladesh, this technique still is unfamiliar to many. We hereby present a case series of cone repair and TV replacement with the mid-term outcome (one year to six years) at the National Heart Foundation Hospital & Research Institute, Dhaka, Bangladesh. METHODS: We prospectively studied 21 patients, who underwent surgical intervention (cone repair or tricuspid valve replacement) for Ebstein's anomaly of TV from March 2014 to June 2020. We divided the total patient population into the cone repair and TV replacement groups. Preoperative, postoperative, and follow-up data were collected from the hospital records, telephone conversations, and clinic visits. All collected data statistically were analyzed. RESULTS: Our patients showed there were statistically significant improvements after surgical intervention with regard to tricuspid regurgitation (TR) (P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (P < 0.001), right ventricular (RV) function (P < 0.001), and New York Heart Association (NYHA) class (P < 0.001). These developments were sustained throughout the follow-up period. CONCLUSION: Cone repair should be offered to the symptomatic patients of Ebstein's anomaly because symptoms relief, reduction of morbidity, and survival benefits are excellent. Above all, the cone reconstruction shows fantastic results and may well become the surgical technique for patients with Ebstein's anomaly. We hope that new valve repair programs may provide extended longevity and restored quality of life to the patient of Ebstein's anomaly (EA) with the appropriate measures. In case of failed repair, valve replacement is an encouraging option.

SDN-IoT empowered intelligent framework for industry 4.0 applications during COVID-19 pandemic.

The industrial ecosystem has been unprecedentedly affected by the COVID-19 pandemic because of its immense contact restrictions. Therefore, the manufacturing and socio-economic operations that require human involvement have significantly intervened since the beginning of the outbreak. As experienced, the social-distancing lesson in the potential new-normal world seems to force stakeholders to encourage the deployment of contactless Industry 4.0 architecture. Thus, human-less or less-human operations to keep these IoT-enabled ecosystems running without interruptions have motivated us to design and demonstrate an intelligent automated framework. In this research, we have proposed "EdgeSDN-I4COVID" architecture for intelligent and efficient management during COVID-19 of the smart industry considering the IoT networks. Moreover, the article presents the SDN-enabled layer, such as data, control, and application, to effectively and automatically monitor the IoT data from a remote location. In addition, the proposed convergence between SDN and NFV provides an efficient control mechanism for managing the IoT sensor data. Besides, it offers robust data integration on the surface and the devices required for Industry 4.0 during the COVID-19 pandemic. Finally, the article justified the above contributions through particular performance evaluations upon appropriate simulation setup and environment.

Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises.

New developments implicating IL-21 in autoimmune disease.

Elevated interleukin (IL)-21 is a common finding in the tissues and/or sera of patients with autoimmune disease. CD4 T cells are the primary producers of IL-21; often the IL-21 producing CD4 T cells will express molecules associated with follicular helper cells (TFH). Recent work has shown that the CD4 T cell-derived IL-21 is able to promote effector functions and memory differentiation of CD8 T cells in chronic infections and cancer. Autoimmunity has similarities to chronic infections and cancer. However, CD4 T cell-derived IL-21:IL21R signaling in CD8 T cells has not been fully appreciated in the context of autoimmunity. In this review, we assess the current knowledge regarding CD4 T cell-derived IL-21 and IL21R signaling within CD8 T cells and evaluate what implications it has within several autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis, juvenile idiopathic arthritis, type 1 diabetes mellitus, psoriasis, Sjögren's syndrome, vitiligo, antiphospholipid syndrome, pemphigus, and giant cell arteritis.

Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer.

H3K9 methyltransferase (G9a) and its relevant molecule GLP are the SET domain proteins that specifically add mono, di and trimethyl groups on to the histone H3K9, which lead to the transcriptional inactivation of chromatin and reduce the expression of cancer suppressor genes, which trigger growth and progress of several cancer types. Various studies have demonstrated that overexpression of H3K9 methyltransferase G9a and GLP in different kinds of tumors, like lung, breast, bladder, colon, cervical, gastric, skin cancers, hepatocellular carcinoma and hematological malignancies. Several G9a and GLP inhibitors such as BIX-01294, UNC0642, A-366 and DCG066 were developed to combat various cancers; however, there is a need for more effective and less toxic compounds. The current molecular docking study suggested that the selected new compounds such as ninhydrin, naphthoquinone, cysteamine and disulfide cysteamine could be suitable molecules as a G9a and GLP inhibitors. Furthermore, detailed cell based and preclinical animal studies are required to confirm their properties. In the current review, we discussed the role of G9a and GLP mediated epigenetic regulation in the cancers. A thorough literature review was done related to G9a and GLP. The databases used extensively for retrieval of information were PubMed, Medline, Scopus and Science-direct. Further, molecular docking was performed using Maestro Schrodinger version 9.2 software to investigate the binding profile of compounds with Human G9a HMT (PDB ID: 3FPD, 3RJW) and Human GLP MT (PDB ID: 6MBO, 6MBP).

The intervention of tert-butylhydroquinone protects ethanol-induced gastric ulcer in type II diabetic rats: the role of Nrf2 pathway.

Ethanol consumption increases the prevalence of gastric ulcer (GU) in rats with type II diabetes (T2D). Induction of GU by absolute ethanol (5 mL/kg or 3.94 g/kg) in the animal model resembles human ulcer characteristics. The aim was to investigate the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the treatment of GU in diabetic condition. The rats were exposed to absolute ethanol 1 h before sacrifice and T2D was induced by combined exposure of high-fat diet and low dose streptozotocin. Pretreatment of tert-butylhydroquinone (tBHQ) (25 and 50 mg/kg), metformin (500 mg/kg), and omeprazole (20 mg/kg) were given once daily for last three consecutive weeks. In ethanol-exposed diabetic rats, pretreatment with tBHQ, omeprazole, and metformin reduced gastric mucosal lesion, ulcer index, histological alterations, malondialdehyde level, and apoptosis. Furthermore, the intervention of tBHQ, omeprazole, and metformin improved the integrity of the stomach mucosa, glutathione, gastric pH, collagen, and goblet cells. tBHQ treatment improved ethanol-induced alterations of Nrf2, catalase, heat shock protein 70 (HSP70), NF-κB, and endothelin-1 expressions in diabetic rats. In diabetic conditions, the incidence of GU is increased due to elevated levels of reactive oxygen species, inflammatory mediators, depleted levels of cellular antioxidants, and altered gastric parameters. The tBHQ intervention could be a rational strategy to protect these changes.

Deep Transfer Learning Based Intrusion Detection System for Electric Vehicular Networks.

The Controller Area Network (CAN) bus works as an important protocol in the real-time In-Vehicle Network (IVN) systems for its simple, suitable, and robust architecture. The risk of IVN devices has still been insecure and vulnerable due to the complex data-intensive architectures which greatly increase the accessibility to unauthorized networks and the possibility of various types of cyberattacks. Therefore, the detection of cyberattacks in IVN devices has become a growing interest. With the rapid development of IVNs and evolving threat types, the traditional machine learning-based IDS has to update to cope with the security requirements of the current environment. Nowadays, the progression of deep learning, deep transfer learning, and its impactful outcome in several areas has guided as an effective solution for network intrusion detection. This manuscript proposes a deep transfer learning-based IDS model for IVN along with improved performance in comparison to several other existing models. The unique contributions include effective attribute selection which is best suited to identify malicious CAN messages and accurately detect the normal and abnormal activities, designing a deep transfer learning-based LeNet model, and evaluating considering real-world data. To this end, an extensive experimental performance evaluation has been conducted. The architecture along with empirical analyses shows that the proposed IDS greatly improves the detection accuracy over the mainstream machine learning, deep learning, and benchmark deep transfer learning models and has demonstrated better performance for real-time IVN security.