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The gut microbiota harbors a complex ecosystem of bacteria that govern host health homeostasis. Alterations to the intestinal environment, known as gut dysbiosis, is associated with several diseases. Targeting the gut with microbiome-engineered therapeutics, such as probiotics, is a promising approach to restore microbial homeostasis and host health. Probiotics can effectively improve the gut environment, although strain-specific mechanisms remain largely unknown. Thus, this study aims to identify beneficial action of select probiotics to modulate the gut environment through antioxidative and anti-inflammatory properties. To this end, we tested the interaction among three probiotic strains – Lactobacillus gasseri A237 (LgA237), Lactobacillus plan-tarum WCFS1 (LpWCFS1) and Lactobacillus fermentum NCIMB 5221 (Lf5221) – and a human intestinal epithelial cell line, HT-29, for adhesion properties, radical scavenging abilities and anti-inflammatory activities. All three probiotics adhere well to HT-29 cells, indicating proper gut colonization. LpWCFS1 demonstrated the greatest adhesion capacity (68.3%), followed by LgA237 (35.5%) and Lf5221 (25.9%). The probiotics also exhibit excellent antioxidant properties via DPPH radical scavenging activity, comparable to quercetin, a known and potent antioxidant. Moreover, LgA237, LpWCFS1 and Lf5221 decrease interleukin-8 expression in lipopolysaccharide (LPS)-damaged HT-29 cells (41.19, 34.53 and 14.80% reduction, respectively), compared to non-treated cells. Further investigation of LpWCFS1 and LgA237 revealed a significant (p

PURPOSESquamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, with approximately 225,419 new cases with over 125,000 deaths annually in India. This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients with recurrent locoregional or metastatic SCCHN.METHODSThis phase III trial is a multicenter, randomized, double-blind and parallel group study performed in Indian patients with recurrent locoregional or metastatic SCCHN. Patients were randomly assigned in 2:1 ratio to receive biosimilar cetuximab and IC in combination with cisplatin and fluorouracil via intravenous infusions. The primary end points were disease control rate (DCR) and overall response rate (ORR) as per response evaluation criteria in solid tumors version 1.1. The secondary end points included pharmacokinetics (PK), immunogenicity, safety, and tolerability.RESULTSOf 180 patients enrolled, 120 patients received biosimilar cetuximab and 60 patients received IC treatment. No significant statistical difference was observed in the primary outcomes between two groups. Treatment difference in DCR and ORR response was found to be –5.21 (90% CI, –8.94 to –1.48) and –4.79 (90% CI, –19.42 to 9.84), respectively, indicating noninferiority to reference product. The incidence of treatment-emergent adverse events (AEs; biosimilar cetuximab: 89.2% v IC: 91.7%; P = .8364) and serious AEs (biosimilar cetuximab: 23.3% v IC: 13.3%; P = .0603) and PK parameters were comparable between treatment groups. The immunogenicity findings showed higher incidence of anticetuximab antibodies in the biosimilar cetuximab group compared with the IC group at the end of Study.CONCLUSIONThe findings of this study demonstrated noninferiority along with comparable PK, safety, and immunogenicity of biosimilar cetuximab and IC in patients with recurrent or metastatic SCCHN.

AbstractIn this study, non-toxic mercury nanoparticle was synthesized as per “Prakash theory of metal drugs” and nanoparticle’s characters has been demonstrated by employing several nanotechnological tools including XPS, XRD, EDAX. The size of the Prakasine nanoparticles (PRK-NP) ranged from 90–100 nm, confirmed using TEM, SEM, DLS and along with zeta potential of −29.5 mV before storage and −8.5 mV after storage. The FTIR provided information regarding the nanoparticle capping and functional groups. The study was further elaborated for determining PRK-NPs toxicity, genotoxicity, in-vivo toxicity, immunological anti-tumour activity, immunogenicity potential, gene expression profiling and confirmed by MTT and apoptosis assays, cancer zebrafish model studies and WBC proliferation assay. PRK-NPs revealed no cytotoxicity where cell viability was observed 99% in L6 mouse fibroblasts and 99% in MCF-7 cell lines. Also, the cell viability was to be 89.47% at a very high concentration of 320 µg/ml in HEK 293 cells. The PRK-NPs significantly reduced the tumour in zebrafish at dose of 90 μg/g by up regulating IL-1α, IL-1β, IL-2-ITK, IL-6, IL-8, IL-12, TNF-α and IFN-γ, and down regulating IL-4, IL-5, IL-10 and TGF-β compared to untreated controls without any adverse effects and toxicity. Thus, the current study beholds anticipation PRK-NPs may play a vital role in therapeutic.

IntroductionIndole-3-carbinol (I3C) is found in cruciferous vegetables and used as a dietary supplement. It is known to act as a ligand for aryl hydrocarbon receptor (AhR). In the current study, we investigated the role of AhR and the ability of I3C to attenuate LPS-induced Acute Respiratory Distress Syndrome (ARDS).MethodsTo that end, we induced ARDS in wild-type C57BL/6 mice, Ccr2gfp/gfp KI/KO mice (mice deficient in the CCR2 receptor), and LyZcreAhRfl/fl mice (mice deficient in the AhR on myeloid linage cells). Additionally, mice were treated with I3C (65 mg/kg) or vehicle to investigate its efficacy to treat ARDS.ResultsI3C decreased the neutrophils expressing CXCR2, a receptor associated with neutrophil recruitment in the lungs. In addition, LPS-exposed mice treated with I3C revealed downregulation of CCR2+ monocytes in the lungs and lowered CCL2 (MCP-1) protein levels in serum and bronchoalveolar lavage fluid. Loss of CCR2 on monocytes blocked the recruitment of CXCR2+ neutrophils and decreased the total number of immune cells in the lungs during ARDS. In addition, loss of the AhR on myeloid linage cells ablated I3C-mediated attenuation of CXCR2+ neutrophils and CCR2+ monocytes in the lungs from ARDS animals. Interestingly, scRNASeq showed that in macrophage/monocyte cell clusters of LPS-exposed mice, I3C reduced the expression of CXCL2 and CXCL3, which bind to CXCR2 and are involved in neutrophil recruitment to the disease site.DiscussionThese findings suggest that CCR2+ monocytes are involved in the migration and recruitment of CXCR2+ neutrophils during ARDS, and the AhR ligand, I3C, can suppress ARDS through the regulation of immune cell trafficking.

Conditions affecting the upper digestive system are often seen in clinical practice and are associated with a high rate of death and disability. Histopathological confirmation is one of the foundations for good treatment planning and the definite diagnosis of illnesses of the upper gastrointestinal tract. The numerous methods employed in the diagnosis of gastrointestinal lesions have come a long way in the previous 25 years. The identification and diagnosis of gastrointestinal lesions have been substantially aided by the development of endoscopy, endoscopic biopsy, and other surgical techniques. This research aimed to examine the variety of gastrointestinal tract (GI) lesions and to draw connections between the clinical and pathological manifestations of these conditions. Materials and Methods: A two-year cross-sectional study was conducted in the Department of Pathology, from June 2018 to May 2020, which included surgical specimens of 140 cases from the upper gastrointestinal tract, of which 111 cases were biopsy, and 29 cases were resected surgical specimens. The data were analyzed using SPSS software. Furthermore, P values, sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results: This study was a two-year cross-sectional study conducted in the Department of Pathology during the period of June 2018–May 2020.

A field experiment was conducted during rainy (kharif) season of 2019–20 and summer season of 2020–21 at Byrasandra village, Karnataka to study the residual effects of integrated nitrogen management (INM) in maize (Zea mays L.) on succeeding mungbean [Vigna radiata (L.) R. Wilczek] growth, yield, and soil properties. The residual effect of treatment involving 75% recommended dose of nitrogen (RDN) + 50% recommended dose of farmyard manure (RD FYM) +25% RDN through vermicompost to kharif maize resulted in significant (P

Diabetes mellitus is one of the most concerning conditions, and its chronic consequences are almost always accompanied by infection, oxidative stress, and inflammation. Reducing excessive reactive oxygen species and the wound’s inflammatory response is a necessary treatment during the acute inflammatory phase of diabetic wound healing. Malva sylvestris extract (MS) containing nanofibers containing neomycin sulfate (NS) were synthesized for this investigation, and their impact on the healing process of diabetic wounds was assessed. Using Design Expert, the electrospinning process for the fabrication of NS nanofibers (NS-NF) was adjusted for applied voltage (X1), the distance between the needle’s tip and the collector (X2), and the feed rate (X3) for attaining desired entrapment efficacy [EE] and average nanofiber diameter (ND). The optimal formulation can be prepared with 19.11 kV of voltage, 20 cm of distance, and a flow rate of 0.502 mL/h utilizing the desirability approach. All the selected parameters and responses have their impact on drug delivery from nanofibers. In addition, M. sylvestris extracts have been added into the optimal formulation [MS-NS-NF] and assessed for their surface morphology, tensile strength, water absorption potential, and in vitro drug release studies. The NS and MS delivery from MS-NS-NF has been extended for more than 60 h. M. sylvestris-loaded nanofibers demonstrated superior antibacterial activity compared to plain NS nanofibers. The scaffolds featured a broad aspect and a highly linked porous fibrous network structure. Histomorphometry study and the in vitro scratch assay demonstrate the formulation’s efficacy in treating diabetic wound healing. The cells treated with MS-NS-NF in vivo demonstrated that wound dressings successfully reduced both acute and chronic inflammations. To improve the healing of diabetic wounds, MS-NS-NF may be regarded as an appropriate candidate for wound dressing.

Pulsatile drug delivery systems have drawn attention in contemporary research for designing chronotherapeutic systems. The current work aims to design pulsatile ketorolac tromethamine tablets using compression coating for delayed delivery with a lag time suitable for the treatment of morning stiffness in arthritis. Rapidly disintegrating core tablets of ketorolac tromethamine were formulated using super-disintegrants, and the optimized formulation was compression using PEO WSR coagulant and Eudragit RLPO for delaying the release. The central composite design and response surface methodology were employed to optimize the formulation and process parameters namely PEO WSR Coagulant (X1), Eudragit RLPO (X2), and Hardness (X3). The dependent variables optimized were lag time and time required for 95% drug release. Analysis using response surface graphs and mathematical modeling of the results allowed identifying and quantifying the formulation variables active on the selected responses. A polynomial equation fitted to the data was used to predict the composition with optimum responses. Compression-coated pulsatile tablets’ optimized composition exhibited a lag time of 9 h and released 95% of the ketorolac tromethamine in 17.42 h. Validation of the mathematical model assured the reliability of QBD in formulation design. In vivo X-ray imaging and pharmacokinetic studies established a strong relationship between the coated polymers maintaining the desired lag time for delayed delivery of the active to coincide with the chronobiology for enhanced bioavailability at the right time when needed.

Abstract The 2020 National Building Code of Canada (NBCC) seismic hazard model (SHM) marks a comprehensive update over its predecessor (NBCC 2015). For different regions in Canada, this will have an impact on the design of new buildings and performance assessment of existing ones. In the present study, a recently developed hybrid building system with reinforced concrete (RC) moment-resisting frames and cross-laminated timber (CLT) infills is assessed for its seismic performance against the latest SHM. The six-story RC-CLT hybrid system, designed using the direct displacement-based method, is located in Vancouver, Canada. Along with very high seismicity, southwestern British Columbia is characterized by complex seismotectonics, consisting of subduction, shallow crustal, and in-slab faulting mechanisms. A hazard-consistent set of 40 ground motion pairs is selected from the PEER and KiK-net databases, and used to estimate the building’s seismic performance. The effects of using steel slit dampers (associated with large hysteresis loops) and flag-shaped energy dissipators (associated with the recentering capability) are investigated. The results indicate that the hybrid system has good seismic performance with a probability of collapse of 2–3% at the 2475-year return period shaking intensity. The hybrid building with steel slit dampers exhibits a collapse margin ratio of 2.8, which increases to 3.5–3.6 when flag-shaped dissipators are used. The flag-shaped dissipators are found to significantly reduce the residual drift of the hybrid building. Additionally, the seismic performance of the hybrid building equipped with flag-shaped dissipators is found to improve marginally when the recentering ratio is increased.

The emerging smart grid technology known as Electric Spring (ES) has been employed previously to maintain voltage and power stability in renewable energy-based grids that are minimally regulated or self-contained. This study thoroughly investigated the foundational theories, modeling approaches, practical uses, and restrictions associated with Electric Springs by analyzing existing Scholarly works in this domain Electric Springs implement a direct power control approach. solution for the next-generation single-phase Systems, addressing the limitations of current ES control methods. This solution aims to improve power management in microgrids, where integrating renewable energy sources (RESs) poses challenges due to the unpredictable power output. The challenge involves managing two aspects: the variable Power consumed by ES and the power fed into the grid. The suggested straightforward and accurate signal manipulation method, namely, ANN-based Electric Spring (ES), is set to be deployed. This technique can adeptly manage these aspects in both stable conditions and during transitions in Renewable Energy Sources (RES).

Now a days the research work is going on to improve the performance of electric springs (ESs) by integrating a current source inverter (CSI) and a neural network controller. A new ES configuration that includes CSIs is introduced to enhance ES functionality. This configuration is accompanied by a control strategy that involves direct current control and mitigation of harmonic distortion, like the methods used in active power filters (APFs). By transitioning from voltage source inverters (VSIs) to CSIs and integrating a neural network controller, a significant reduction in total harmonic distortion (THD) can be achieved. The paper presents two distinct control loops, each equipped with proportional-integral (PI) controllers. One loop is focused on regulating the Critical load voltage (CL voltage), while the other is specifically designed for reactive power compensation.

Abstract Post-traumatic stress disorder (PTSD), which frequently occurs in the aftermath of a psychologically traumatic event is characterized by heightened inflammation. People with PTSD also suffer from a number of comorbid clinical and behavioral disorders that are related to chronic inflammation. Thus, understanding the mechanisms of enhanced inflammation in PTSD can provide insights into the relationship between PTSD and associated comorbid disorders. In the current study, we investigated the role of large intervening non-coding RNAs (lincRNAs) in the regulation of inflammation in people diagnosed with PTSD. We observed that WNT ligand, WNT10B, was upregulated in the peripheral blood mononuclear cells (PBMCs) of PTSD patients. This observation was associated with higher H3K4me3 signals around WNT10B promotor in PTSD patients compared to those without PTSD. Increased H3K4me3 resulted from LINC00926, which we found to be upregulated in the PTSD sample, bringing in histone methyltransferase, MLL1, onto WNT10B promotor leading to the introduction of H3K4 trimethylation. The addition of recombinant human WNT10B to pre-activated peripheral blood mononuclear cells (PBMCs) led to increased expression of inflammatory genes such as IFNG and IL17A, suggesting that WNT10B is involved in their upregulation. Together, our data suggested that LINC00926 interacts physically with MLL1 and thereby controls the expression of IFNG and IL17A. This is the first time a long non-coding RNA is shown to regulate the expression of WNT10B and consequently inflammation. This observation has high relevance to our understanding of disease mechanisms of PTSD and comorbidities associated with PTSD.

Abstract Background White grubs are highly polyphagous and most destructive soil pests inflicting damage to a groundnut crop that causes economic yield losses in commercial groundnut production in India. In this study, potential of the two entomopathogenic fungi (EPF) viz., Metarhizium anisopliae (Metchnikoff) Sorokin and Beauveria bassiana (Balsamo) Vuillemin enriched with organic amendments like neem cake, castor cake, vermicompost and poultry manure was evaluated to manage buildup of white grub population in groundnut crop. Results Results showed that the plot treated with soil application of vermicompost @ 1 ton/ha + M. anisopliae 1.15 WP (1 × 108 cfu/g) @ 2 kg/ha showed the least amount of plant mortality due to white grub which was at par with castor cake @ 1 ton/ha + M. anisopliae 1.15 WP (1 × 108 cfu/g) @ 2 kg/ha and neem cake @ 1 ton/ha + M. anisopliae 1.15 WP (1 × 108 cfu/g) @ 2 kg/ha which showed only 1.74, 2.00 and 2.24% plant damage, respectively. Plots treated with vermicompost @ 1 ton/ha + M. anisopliae 1.15 WP (1 × 108 cfu/g) @ 2 kg/ha had the fewest (0.19) white grubs per one meter row length. Based on highest pod yield, net realization and net gain, the treatment with soil application of vermicompost @ 1 ton/ha + M. anisopliae 1.15 WP (1 × 108 cfu/g) @ 2 kg/ha was found most effective treatments for the management of white grub in groundnut. Conclusions Results indicated that M. anisopliae supplemented with various organic amendments, such as vermicompost, castor cake, and neem cake can be commercialized as a healthy alternative to minimize the use of synthetic pesticides in groundnut crops for white grub management.

The prevalence, incidence, and severity of a wide variety of diseases and ailments are significantly influenced by the significant disparities that occur between the sexes. The way that men and women react to pharmacological treatment also varies. Therefore, it is crucial to comprehend these reactions in order to conduct risk assessment correctly and to develop safe and efficient therapies. Even from that limited vantage point, the manner and timing of our drug usage might have unintended and unanticipated consequences. There are sex-specific differences in the incidence and mortality of certain malignancies. One of the most important discoveries in cancer epidemiology is the gender inequalities. Cancer incidence differences between the sexes are thought to be regulated at the genetic and molecular levels and by sex hormones like oestrogen. Differences based on sex and gender are among the least investigated factors impacting cancer susceptibility, progression, survival, and therapy response despite their established importance in clinical care. The molecular mechanisms underlying sex differences in particular are poorly known, hence the majority of precision medicine approaches employ mutational or other genetic data to assign therapy without taking into account how the patient's sex may affect therapeutic efficacy. In patients receiving chemotherapy, there are definite gender-dependent disparities in response rates and the likelihood of side effects. This review explores the influence of sex as a biological variable in drug effects or toxicity in oncology.

Summary: While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1−/− recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1−/− in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.

Sabrina Schaly, Merry Ghebretatios, Satya Prakash Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, H3A 2B4, CanadaCorrespondence: Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory Department of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Montreal, Quebec, H3A 2B4, CanadaTel +1 514 398 3676Fax +1 514 398 7461Email satya.prakash@mcgill.caAbstract: This review will outline the role of baculoviruses in gene therapy and future potential in personalized medicine. Baculoviruses are a safe, non-toxic, non-integrative vector with a large cloning capacity. Baculoviruses are also a highly adaptable, low-cost vector with a broad tissue and host tropism due to their ability to infect both quiescent and proliferating cells. Moreover, they only replicate in insect cells, not mammalian cells, improving their biosafety. The beneficial properties of baculoviruses make it an attractive option for gene delivery. The use of baculoviruses in gene therapy has advanced significantly, contributing to vaccine production, anti-cancer therapies and regenerative medicine. Currently, baculoviruses are primarily used for recombinant protein production and vaccines. This review will also discuss methods to optimize baculoviruses protein production and mammalian cell entry, limitations and potential for gene therapy and personalized medicine. Limitations such as transient gene expression, complement activation and virus fragility are discussed in details as they can be overcome through further genetic modifications and other methods. This review concludes that baculoviruses are an excllent candidate for gene therapy, personalized medicine and other biotherapeutic applications.Keywords: baculovirus, gene therapy, personalized medicine

Introduction: The primary goal of cholesteatoma surgery is to eradicate it from the middle ear cleft. However, due to linear axis of illumination of the microscope, in some of the recesses or hidden areas in middle ear are not visualised. To overcome this, many studies have been done on the complimentary use of endoscopes in visualising these hidden areas. Aim: To assess the outcome of complimentary use of endoscopes in addition to microscope on improved access to hidden areas in the middle ear and resultant cholesteatoma clearance. Materials and Methods: In this systematic review, literature search was conducted using the keywords both manually and electronically in PubMed, Google scholar and Directory of Open Access Journals for articles published till December 2021 at ESIC Medical College and PGIMSR, Bengaluru, Karnataka, India. The primary inclusion criteria used was all full text original, both prospective and retrospective, articles in which endoscopes were used as an adjunct to microscope for cholesteatoma clearance from middle ear cleft. Retrieved articles were reviewed by two independent authors for their eligibility for inclusion in the study. The selected original papers were analysed. Data was entered in Microsoft Excel 2007 and analysed for descriptive statistics like frequency and proportions. Results: A total of 48 studies were identified initially. After removing duplicates, screening was done for title, abstracts and full text retrieval to check for inclusion criteria being met. Six studies were found using complimentary endoscopes for cholesteatoma surgery and were analysed. Of these, four were prospective and two were retrospective studies. Total 604 patients underwent endoscopic examination after microscopic clearance. Residual cholesteatoma was seen in 105 patients (17%), which were cleared with endoscopic assistance. Conclusion: Complimentary endoscopy detects residual cholesteatoma in significant number of cases during primary cholesteatoma surgery. In cholesteatoma surgery, they are predominantly used as observational tools.

Abstract Background Posttraumatic stress disorder (PTSD) is a psychiatric disorder accompanied by chronic peripheral inflammation. What triggers inflammation in PTSD is currently unclear. In the present study, we identified potential defects in signaling pathways in peripheral blood mononuclear cells (PBMCs) from individuals with PTSD. Methods RNAseq (5 samples each for controls and PTSD), ChIPseq (5 samples each) and miRNA array (6 samples each) were used in combination with bioinformatics tools to identify dysregulated genes in PBMCs. Real time qRT-PCR (24 samples each) and in vitro assays were employed to validate our primary findings and hypothesis. Results By RNA-seq analysis of PBMCs, we found that Wnt signaling pathway was upregulated in PTSD when compared to normal controls. Specifically, we found increased expression of WNT10B in the PTSD group when compared to controls. Our findings were confirmed using NCBI’s GEO database involving a larger sample size. Additionally, in vitro activation studies revealed that activated but not naïve PBMCs from control individuals expressed more IFNγ in the presence of recombinant WNT10B suggesting that Wnt signaling played a crucial role in exacerbating inflammation. Next, we investigated the mechanism of induction of WNT10B and found that increased expression of WNT10B may result from epigenetic modulation involving downregulation of hsa-miR-7113-5p which targeted WNT10B. Furthermore, we also observed that WNT10B overexpression was linked to higher expression of H3K4me3 histone modification around the promotor of WNT10B. Additionally, knockdown of histone demethylase specific to H3K4me3, using siRNA, led to increased expression of WNT10B providing conclusive evidence that H3K4me3 indeed controlled WNT10B expression. Conclusions In summary, our data demonstrate for the first time that Wnt signaling pathway is upregulated in PBMCs of PTSD patients resulting from epigenetic changes involving microRNA dysregulation and histone modifications, which in turn may promote the inflammatory phenotype in such cells.

Background and Aims: The incidence of specific complications and adverse outcomes in dengue patients needing admission to intensive care units (ICU) may be quite variable in different regions of India presumably because of different strains of dengue virus or due to re infection. Methods: Patients admitted with acute febrile illness (AFI) with either positive IgM antibody or NS1 antigen for dengue were enrolled. Data were collected for 3 years (2015-2017). A total of 313 patients with acute febrile illness were admitted in the study period (2252 total ICU admissions). A total of 137 (43.76%) cases were serologically proven as dengue fever. Results: Median age (IQR) of study population was 36.0 (26.0–52.0) years. Liver (65.7%) was the main organ involved followed by acute kidney Injury (AKI) (18.6%). Dengue Shock Syndrome (DSS) was found in 18.6% of cases. Fifty-two patients died and the crude mortality was 38.0%. On multivariate analysis APACHE Score

Post-traumatic stress disorder (PTSD) is a psychiatric disorder and patients diagnosed with PTSD often express other comorbid health issues, particularly autoimmune and inflammatory disorders. Our previous reports investigating peripheral blood mononuclear cells (PBMCs) from PTSD patients showed that these patients exhibit an increased inflammatory T helper (Th) cell phenotype and widespread downregulation of microRNAs (miRNAs), key molecules involved in post-transcriptional gene regulation. A combination of analyzing prior datasets on gene and miRNA expression of PBMCs from PTSD and Control samples, as well as experiments using primary PBMCs collected from human PTSD and Controls blood, was used to evaluate TP53 expression, DNA methylation, and miRNA modulation on Th17 development. In the current report, we note several downregulated miRNAs were linked to tumor protein 53 (TP53), also known as p53. Expression data from PBMCs revealed that compared to Controls, PTSD patients exhibited decreased TP53 which correlated with an increased inflammatory Th17 phenotype. Decreased expression of TP53 in the PTSD population was shown to be associated with an increase in DNA methylation in the TP53 promotor region. Lastly, the most significantly downregulated TP53-associated miRNA, let-7a, was shown to negatively regulate Th17 T cells. Let-7a modulation in activated CD4+ T cells was shown to influence Th17 development and function, via alterations in IL-6 and IL-17 production, respectively. Collectively, these studies reveal that PTSD patients could be susceptible to inflammation by epigenetic dysregulation of TP53, which alters the miRNA profile to favor a proinflammatory Th17 phenotype.

Bread is one of the highest-selling food products throughout the world. Lots of demand arose from the bread producers by the consumers to convert the traditional bread into functional food. In this study, normal bread was converted to functional herbal bread by infusing it with extracts of Glycyrrhiza glabra. The functional components of the Glycyrrhiza glabra were analyzed by liquid chromatography-mass spectroscopy (LCMS). The antioxidant study revealed that the extract has high antioxidant potency. The present study also investigated the antidiabetic potency of the extract. Bread is fortified with various percentages of Glycyrrhiza glabra, such as 2, 4, and 6. The fortified bread was analyzed for various sensory and taste parameters. Biochemical assays such as the in vitro digestibility test and glycaemic index suggest that fortified bread reduces the glycaemic index. From the study, it was inferred that 6% of infused bread was found to have high potency as a functional food when compared to 2 and 4%. From the above study, it was suggested that fortified bread reduces the glycaemic index and is best suited for diabetic people and diet watchers.

More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, viz., viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection. The vastly accumulated scientific knowledge on all aspects of COVID-19 has currently changed the scenario from great despair to hope. Even though spectacular progress has been made in all of these aspects, multiple knowledge gaps are remaining that need to be addressed in future studies. Moreover, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged across the globe since the onset of the first COVID-19 wave, with seemingly greater transmissibility/virulence and immune escape capabilities than the wild-type strain. In this review, we narrate the progress made since the commencement of the pandemic regarding the knowledge on COVID-19 mechanisms in the human body, including virus–host interactions, pulmonary and other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, and long-term health consequences in the survivors. Additionally, we provide a brief review of the current evidence explaining molecular mechanisms imparting greater transmissibility and virulence and immune escape capabilities to the emerging SARS-CoV-2 variants.

The use of complementary and alternative medical therapies is increasing worldwide. Many of these products have biological activity that can lead to severe toxicity or interact with prescribed medications. We present here a case of 68-year-old female, a known diabetic and hypertensive on treatment, who presented with symptoms of liver failure. This was associated with the consumption of mahogany seeds (sky fruit). She was investigated for other causes of liver failure, which turned out negative. It is important to recognize such possible complications during these therapies and promptly withdraw the offending agent.

Introduction: Tests detecting SARS-CoV-2-specific antigen have recently been developed, and many of them are now commercially available. However, the real-world performance of these assays is uncertain; therefore, their validation is important. In this study, we have evaluated the performance of STANDARD F COVID-19 antigen fluorescence immunoassay (FIA) kit. Methods: Nasopharyngeal samples collected from patients were subjected to the test as per manufacturer's instructions. The performance of the kit was compared with the gold standard real-time polymerase chain reaction. Results: A total of 354 patients were tested with STANDARD F COVID-19 antigen FIA test kit. The overall sensitivity, specificity, positive predictive value, and negative predictive value of this test were found to be 38%, 99%, 96.2%, and 72%, respectively, with a diagnostic accuracy of 75.7%. Conclusion: STANDARD F COVID-19 antigen FIA showed high specificity and positive predictive value but low sensitivity and negative predictive value.

A brand-new nano-crystal (NC) version of the hydrophobic drug Paclitaxel (PT) were formulated for cancer treatment. A stable NC formulation for the administration of PT was created using the triblock co-polymer Pluronic F127. To achieve maximum entrapment effectiveness and minimal particle size, the formulation was improved using the central composite design by considering agitation speed and vacuum pressure at five levels (coded as +1.414, +1, 0, −1, and −1.414). According to the Design Expert software’s predictions, 13 runs were created and evaluated for the chosen responses. The formulation prepared with an agitation speed of 1260 RPM and a vacuum pressure of 77.53 mbar can meet the requirements of the ideal formulation in order to achieve 142.56 nm of PS and 75.18% EE, according to the level of desirability (D = 0.959). Folic acid was conjugated to Pluronic F127 to create folate receptor-targeted NC. The drug release profile of the nano-crystals in vitro demonstrated sustained release over an extended period. Folate receptor (FR)-targeted NC (O-PT-NC-Folate) has also been prepared by conjugating folic acid to Pluronic F127. MTT test is used to validate the targeting efficacy on the FR-positive human oral cancer cell line (KB). At pharmacologically relevant concentrations, the PT nano-crystal formulation did not cause hemolysis. Compared to non-targeted NC of PT, the O-PT-NC-Folate showed a comparable but more sustained anti-cancer effect, according to an in vivo anti-tumor investigation in NCI/ADR-RES cell lines. The remarkable anti-tumor effectiveness, minimal toxicity, and simplicity of scale-up manufacturing of the NC formulations indicate their potential for clinical development. Other hydrophobic medications that are formulated into nano-systems for improved therapy may benefit from the formulation approach.

As a stewardship for watershed services, an incentivizing mechanism of payment for ecosystem services (PES) has been increasingly discussed in global policy arena. In this context, various models of incentivizing mechanisms have been implemented as a pilot program. This study assesses the existing financing mechanisms for watershed services at the national level and examines the pilot PES programs that have been implemented in four different sites of Nepal. Using various participatory and qualitative research methods; this study analyses institutional arrangement, operational procedures and implementation practices from the study sites. Our findings reveal that the pilot PES programs have shown fairly satisfactory outcomes in watershed management. Based on our findings, we argue that the PES mechanism can be a promising approach in financing sustainable watershed management in Nepal. Nevertheless, PES mechanism should be flexible and contextual in terms of institutional arrangement and needs to be strengthened with a strong linkage between service providers and service users, through a regulatory mechanism. An intermediary role of the local government is found to be utmost important to institutionalize the PES mechanism as a sustainable financing mechanism for ensuring watershed services in Nepal.

Currently, gastro-retentive dosage forms achieved a remarkable position among the oral drug delivery systems. This is a broadly used technique to hold the drug delivery systems for a long duration in the gastro intestine (GI) region, slow drug delivery, and overcome other challenges related to typical oral delivery such as low bioavailability. The current work aimed to formulate and characterize a new expandable gastro-retentive system through Itopride Hydrochloride (IH)’s unfolding process for controlled release. The IH-loaded unfolding film formulation was optimized using the Box-Behnken design for folding endurance and length of tested layer (LTL). Initially, the formulation was made using several anti-adhesive additives to promote the unfolding mechanism. Citric acid and sodium bicarbonate were selected as anti-adhesives based on these results. The enfolded film in a capsule shell was shown to unroll in the stomach fluids and render drug delivery up to 12 h in acidic conditions. A fabricated system should have dimensions more than the size of the relaxed pyloric sphincter, and as required, >20 mm LTL was identified. This further confirms that the residence period in the stomach is irrelevant to the fed or fasted condition. Based on desirability criteria, the formulation containing 143.83, 0.7982, and 14.6096 Eudragit L100, PEG, and sodium bicarbonate are selected as optimized formulations (O-IH-UF). The optimized formulation was further analyzed for various parameters such as tensile strength, mechanical strength, unfolding nature, degradability, and in vitro release studies. The pharmacokinetic study revealed greater AUC (area under the curve) and long half-life with the designed O-IH-UF formulation, confirming that the unfolding film type can be a favorable drug system for enhancing the bioavailability of low soluble drugs. The results showed that unfolding types of gastro retentive systems could potentiate the drugs with stability issues in an alkaline medium or those with absorption in acidic conditions.

Biometric security applications have been employed for providing a higher security in several access control systems during the past few years. The handwritten signature is the most widely accepted behavioral biometric trait for authenticating the documents like letters, contracts, wills, MOU’s, etc. for validation in day to day life. In this paper, a novel algorithm to detect gender of individuals based on the image of their handwritten signatures is proposed. The proposed work is based on the fusion of textural and statistical features extracted from the signature images. The LBP and HOG features represent the texture. The writer’s gender classification is carried out using machine learning techniques. The proposed technique is evaluated on own dataset of 4,790 signatures and realized an encouraging accuracy of 96.17, 98.72 and 100% for k-NN, decision tree and Support Vector Machine classifiers, respectively. The proposed method is expected to be useful in design of efficient computer vision tools for authentication and forensic investigation of documents with handwritten signatures.

Maintenance of intestinal homeostasis requires the integration of immunological and molecular processes together with environmental, diet, metabolic and microbial cues. Key to this homeostasis is the proper functioning of epithelial cells originating from intestinal stem cells (ISCs). While local factors and numerous molecular pathways govern the ISC niche, the conduit through which these processes work in concordance is the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, whose role in immunoregulation is critical at barrier surfaces. In this review, we discuss how AhR signaling is emerging as one of the critical regulators of molecular pathways involved in epithelial cell renewal. In addition, we examine the putative contribution of specific AhR ligands to ISC stemness and epithelial cell fate.

BackgroundVitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency.Methods and findingsThis is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 μg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development.ConclusionsIn this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries.Trial registrationClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

The present work aimed to develop a chronotherapeutic system of valsartan (VS) using nanocrystal formulation to improve dissolution. VS nanocrystals (VS-NC) were fabricated using modified anti-solvent precipitation by employing a Box–Behnken design to optimize various process variables. Based on the desirability approach, a formulation containing 2.5% poloxamer, a freezing temperature of −25 °C, and 24 h of freeze-drying time can fulfill the optimized formulation’s requirements to result in a particle size of 219.68 nm, 0.201 polydispersity index, and zeta potential of −38.26 mV. Optimized VS-NC formulation was compressed (VNM) and coated subsequently with ethyl cellulose and HPMC E 5. At the same time, fast dissolving tablets of VS were designed, and the best formulation was loaded with VNM into a capsule size 1 (average fill weight—400–500 mg, lock length—19.30 mm, external diameter: Cap—6.91 mm; Body—6.63 mm). The final tab in cap (tablet-in-capsule) system was studied for in vitro dissolution profile to confirm the chronotherapeutic release of VS. As required, a bi-pulse release of VS was identified with a lag time of 5 h. The accelerated stability studies confirmed no significant changes in the dissolution profiles of the tab in cap system (f2 similarity profile: >90). To conclude, the tab in cap system was successfully developed to induce a dual pulsatile release, which will ensure bedtime dosing with release after a lag-time to match with early morning circadian spikes.

Significant information extraction from the images that are geometrically distorted or transformed is mainstream procedure in image processing. It becomes difficult to retrieve the relevant region when the images get distorted by some geometric deformation. Hu's moments are helpful in extracting information from such distorted images due to their unique invariance property. This work focuses on early detection and gradation of Knee Osteoarthritis utilizing Hu's invariant moments to understand the geometric transformation of the cartilage region in Knee X-ray images. The seven invariant moments are computed for the rotated version of the test image. The results demonstrated are found to be more competitive and promising, which are validated by ortho surgeons and rheumatologists.

Summary: Intestinal disequilibrium leads to inflammatory bowel disease (IBD), and chronic inflammation predisposes to oncogenesis. Antigen-presenting dendritic cells (DCs) and macrophages can tip the equilibrium toward tolerance or pathology. Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40. Working through cannabinoid receptor 2 (CB2), THC increases CD103 expression on DCs and macrophages and upregulates TGF-β1 to increase T regulatory cells (Tregs). THC-induced Tregs are necessary to remedy systemic IFNγ and TNFα caused by anti-CD40, but CB2-mediated suppression of APCs by THC quenches pathogenic release of IL-22 and IL-17A in the colon. By examining tissues from multiple sites, we confirmed that THC affects DCs, especially in mucosal barrier sites in the colon and lungs, to reduce DC CD86. Using models of colitis and systemic inflammation we show that THC, through CB2, is a potent suppressor of aberrant immune responses by provoking coordination between APCs and Tregs.

Abstract Background Long chain polyunsaturated fatty acids (LCPUFA) especially docosahexaenoic acid (DHA) and arachidonic acid (AA) are crucial for normal brain development in utero and in early infancy. Data on fatty acid status and cognitive development in infants and children from low-income countries are scarce. Methods We examined the association between the DHA and AA status in infancy (n = 320) and developmental status and cognitive functioning five years later. At five years of age, we measured development by the Ages and Stages Questionnaire 3rd. ed. (ASQ-3) and cognitive functioning by subtests from the neuropsychological test battery NEPSY II. In addition, infant fatty acid composition in red blood cells (RBC) was analyzed. In multiple linear and logistic regression models, we estimated the associations between DHA and AA status in infancy and scores on the ASQ-3 and the NEPSY II subtests. Results There were no notable associations between infant AA and DHA status, and the scores on the ASQ-3 and the NEPSY II subtests five years later. It should be noted that we found better than expected concentrations of erythrocyte DHA and AA among the infants, and the ASQ scores were left-skewed, which limited the ability to identify associations. Conclusion DHA and AA status in infancy is seemingly not related to neurodevelopment measured 5 years later in this peri-urban population from Nepal.

Abstract eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC.

Background: Allergic rhinitis is one of the very common conditions observed in clinical practice with an increasing incidence and prevalence. It results in decreased productivity and absenteeism. Due to the complications and co-morbidities associated with allergic rhinitis, it is a major health concern. Patients develop complications because of lack of awareness about the disease and inappropriate or incomplete treatment. In view of this, the present study was conducted to study the clinical characteristics of the disease in patients with allergic rhinitis attending Ear, Nose and Throat (ENT) department in a tertiary care centre as well as to evaluate the level of awareness about the disease and its complications among these patients. Materials & Methods: All allergic rhinitis patients attending the ENT Department were included in the study. Patients were verbally administered the questions from a well structured questionnaires and the responses were documented. The questions were structured to elicit information regarding the clinical characteristics of the disease, patient’s awareness about the disease and its complications. Results were tabulated and evaluated. A comparison of the study data to the historical data from published literature was also undertaken. Results: Of the hundred patients administered with the questionnaire, patients of the age group of 31 to 40 years of age (28%) were the most commonly affected. The most common symptoms observed were sneezing, watery discharge from the nose and itching in the nose seen in 97% of the patients followed by nose block, seen in 91% of the patients. 83% of the patients reported worsening of the symptoms on exposure to dust; 69% had bouts of sneezing early in the morning on waking up and 62% of the patients had seasonal variation of symptoms. 32% of the patients also had the symptoms of allergic conjunctivitis and 29% of the patients bronchial asthma. 38% of the patients were aware of the common allergens and 20% said they were aware of possible complications like sinusitis, nasal polyps. 25% understood the need for regular treatment to avoid complications of allergic rhinitis. Only 5% said they may develop bronchial asthma. Conclusion: Though allergic rhinitis is a common disease causing morbidity and complications, patient awareness about the disease is inadequate. Considering the high prevalence of the disease, health education about the disease including etiology, avoidance and management to the population and allergic rhinitis patients is necessary.

Aluminium based metal matrix composites are widely used in automobile components such as cardan shaft of Chevrolet corvette, disc brake and engine push rod. In this experiment a Hybrid Metal Matrix Composites (HMMC) are fabricated and drilled. Drilling is the process of making slots in disc brake and thread in the engine parts. The surface quality of the drilled specimen depends on the speed, feed, drill type and the thrust force. Thrust force plays the major role in drilling the specimen. In this experiment HMMCs are fabricated using two processes-called, sonication and casting. Sonication is the process of coating the carbon nanotubes over the silicon carbide particles (SiCp). Semisolid stir casting is used to reinforce the coated SiCp in the LM 25 alloy. A drilling process is performed on HMMC to analyse the extent to which the input parameters influence the thrust force and Ovality. The tools used for drilling are solid carbide tools of three different diameters. Taguchi’s experimental design is adopted for the drilling operation. A mathematical model is used to determine the influence of input parameters on the outputs thrust force and ovality. This paper proves the combination of N3, f1 and d1 of the carbide tool results in the lowest value of thrust force and ovality while drilling HMMCs. In this work the HMMC is prepared by coating the abrasive nature, silicon carbide particle and there is a good interfacial bonding between the reinforced particle and matrix and the drilling process becomes smoother. The new being of this article is the treated ceramics, SiCp with carbon nanotubes. This HMMC shows the improved mechanical properties compared to other metal matrix composites surveyed in the literatures.

Sanjay Prakash,1 Payal Patel2 1Department of Neurology, Smt. B. K. Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth University, Vadodara, Gujarat, India; 2Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH, USA Abstract: Hemicrania continua (HC) is an indomethacin-responsive primary headache disorder which is currently classified under the heading of trigeminal autonomic cephalalgias (TACs). It is a highly misdiagnosed and underreported primary headache. The pooled mean delay of diagnosis of HC is 8.0 ± 7.2 years. It is not rare. We noted more than 1000 cases in the literature. It represents 1.7% of total headache patients attending headache or neurology clinic. Just like other TACs, it is characterized by strictly unilateral pain in the trigeminal distribution, cranial autonomic features in the same area and agitation during exacerbations/attacks. It is different from other TACs in one aspect. While all other TACs are episodic, HC patients have continuous headaches with superimposed severe exacerbations. The central feature of HC is continuous background headache. However, the patients may be worried only for superimposed exacerbations. Focusing only on exacerbations and ignoring continuous background headache are the most important factors for the misdiagnosis of HC. A large number of patients may have migrainous features during exacerbation phase. Up to 70% patients may fulfill the diagnostic criteria for migraine during exacerbations. Besides migraine, its exacerbations can mimic a large number of other primary and secondary headaches. The other specific feature of HC is a remarkable response to indomethacin. However, a large number of patients develop side effects because of the long-term use of indomethacin. A few other medications may also be effective in a subset of patients with HC. Various surgical interventions have been suggested for patients who are intolerant to indomethacin. Several aspects of HC are still not defined. There is a great heterogeneity in types of patients or articles on the HC in the literature. Diagnostic criteria have been modified several times over the years. The current diagnostic criteria are too restrictive in some aspects. We suggest a more accommodating type of criteria for the appendix of International Classification of Headache Disorder (ICHD). Keywords: side-locked headache, indomethacin, indomethacin-responsive headache, trigeminal autonomic cephalalgias

Abstract Background Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal. Methods/design We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6–11 months old (length for age less than −1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study. Discussion If vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide. Trial registrations ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.

The Aryl Hydrocarbon Receptor (AhR) is a transcription factor that, when activated by ligand-binding, has been shown to regulate the immune response. Pertussis Toxin (PTX) is a virulence factor found in Bordetella pertussis, a human respiratory pathogen that causes whooping cough. PTX promotes colonization and disease promotion by triggering a heightened inflammatory response. The role of AhR in the regulation of PTX-mediated inflammation has not previously been studied. In the current study, we investigate if AhR activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a well characterized ligand, can attenuate PTX-mediated systemic inflammation. To that end, C57BL/6 mice were injected intraperitoneally (IP) with PTX twice and treated with TCDD or vehicle (VEH). The PTX+VEH group showed elevated levels of pro-inflammatory cytokines (IL-17A, IL-6, and IFNγ) in serum and increased proportions of CD4+ Th1 and Th17 cells in their spleens. In contrast, the PTX+TCDD group showed significantly lower levels of these inflammatory cytokines and decreased proportions of Th1 and Th17 cells, but increased proportions of Th2 and FoxP3+Tregs when compared to the PTX+VEH group. PTX+TCDD treated mice also showed elevated levels of IL-10, and TFG-b, potent anti-inflammatory cytokines. MicroRNAs (miRs) analysis of CD4+ T cells from the spleens of the PTX+TCDD treated mice revealed significant alterations in their expression and several of these miRs targeted cytokines and signaling molecules involved in inflammation. Specifically, the PTX+TCDD group had a significantly enhanced expression of miR-3082-5p that targeted IL-17, and a decreased expression of miR-1224-5p, which targeted FoxP3. Transfection studies with these miR mimics and inhibitors confirmed the specificity of the target genes. The current study suggests that AhR activation by TCDD suppresses PTX-induced inflammation through miR regulation that triggers reciprocal polarization of Tregs and Th17 cells and also suggests that AhR activation may serve as a treatment modality to suppress heightened inflammation induced during B. pertussis infection.

Multiple sclerosis (MS) is a chronic and disabling disorder of the central nervous system (CNS) characterized by neuroinflammation leading to demyelination. Recently a combination of Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) extracted from Cannabis has been approved in many parts of the world to treat MS-related spasticity. THC+CBD combination was also shown to suppresses neuroinflammation, although the mechanisms remain to be further elucidated. In the current study, we demonstrate that THC+CBD combination therapy (10 mg/kg each) but not THC or CBD alone, attenuates murine experimental autoimmune encephalomyelitis (EAE) by reducing neuroinflammation and suppression of Th17 and Th1 cells. These effects were mediated through CB1 and CB2 receptors inasmuch as, THC+CBD failed to ameliorate EAE in mice deficient in CB1 and CB2. THC+CBD treatment also caused a decrease in the levels of brain infiltrating CD4+ T cells and pro-inflammatory molecules (IL-17, INF-γ, TNF-α, IL-1β, IL-6, and TBX21), while increasing anti-inflammatory phenotype such as FoxP3, STAT5b, IL-4, IL-10, and TGF-β. Also, the brain-derived cells showed increased apoptosis along with decreased percentage in G0/G1 phase with increased percentage in G2/M phase of cell cycle. miRNA microarray analysis of brain-derived CD4+ T cells revealed that THC+CBD treatment significantly down-regulated miR-21a-5p, miR-31-5p, miR-122-5p, miR-146a-5p, miR-150-5p, miR-155-5p, and miR-27b-5p while upregulating miR-706-5p and miR-7116. Pathway analysis showed that majority of the down-regulated miRs targeted molecules involved in cycle arrest and apoptosis such as CDKN2A, BCL2L11, and CCNG1, as well as anti-inflammatory molecules such as SOCS1 and FoxP3. Additionally, transfection studies involving miR-21 and use of Mir21−/− mice suggested that while this miR plays a critical role in EAE, additional miRs may also be involved in THC+CBD-mediated attenuation of EAE. Collectively, this study suggests that combination of THC+CBD suppresses neuroinflammation and attenuates clinical EAE development and that this effect is associated with changes in miRNA profile in brain-infiltrating cells.

Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.

MicroRNAs (miRNAs) are highly conserved, noncoding small RNAs that regulate gene expression, and consequently several important functions including early embryo development, cell cycle, programmed cell death, cell differentiation, and metabolism. While there are no effective treatments available against hepatocellular carcinoma (HCC), some Chinese herbal medicines have been shown to regulate growth, differentiation, invasion, and metastasis of HCC. Many studies have shown that Chinese herbal medicines regulate the expression of miRNAs and this may be associated with their ability to control the development of HCC. In this article, the effects of Chinese herbal medicines on the expression of miRNAs and their functions in the regulation of HCC have been reviewed and discussed. miRNAs such as miRNA-221 and miRNA-222 mediated by Chinese herbal medicines may be good biomarkers and therapeutic targets for HCC.