Identification of inhibitors for neurodegenerative diseases targeting dual leucine zipper kinase through virtual screening and molecular dynamics simulations.

Neurodegenerative diseases lead to a gradual decline in cognitive and motor functions due to the progressive loss of neurons in the central nervous system. The role of dual leucine zipper kinase (DLK) in regulating stress responses and neuronal death pathways highlights its significance as a target against neurodegenerative diseases. The non-availability of FDA-approved drugs emphasizes a need to identify novel DLK-inhibitors. We screened NPAtlas (Natural products) and MedChemExpress (FDA-approved) libraries to identify potent ATP-competitive DLK inhibitors. ADMET analyses identified four compounds (two natural products and two FDA-approved) with favourable features. Subsequently, we performed molecular dynamics simulations to examine the binding-stability and ligand-induced conformational dynamics. Molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations demonstrated CID139591660, dithranol, and danthron having greater affinity, while CID156581477 showed lower affinity than control sunitinib. PCA and network analysis results indicated structural and network alteration post-ligand binding. Furthermore, we identified an analogue of CID156581477 using the deep learning-based web server DeLA Drug which demonstrated a higher affinity than its parent compound and the control and identified several crucial interacting residues. Overall, our study provides significant theoretical guidance for designing potent novel DLK inhibitors and compounds that could emerge as promising drug candidates against DLK following laboratory validation.

Exploring molecular interactions of potential inhibitors against the spleen tyrosine kinase implicated in autoimmune disorders via virtual screening and molecular dynamics simulations.

The spleen tyrosine kinase (Syk) plays a pivotal role in immune cells' signal transduction mechanism. While fostamatinib, an FDA-approved Syk inhibitor, is currently used to treat immune thrombocytopenia, the search for improved Syk-targeted medications to treat autoimmune diseases is still underway. Herein, we screened 38,493 compounds against Syk and selected eight leads based on the docking score and ADMET properties, and performed 3×200 ns long molecular dynamics simulations of the apo and Syk-ligand complexes. We considered R406, the active component of fostamatinib, as a control. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations demonstrated the lead1 (ΔGbind = -30.35 kcal/mol) exhibited a similar binding free energy as the control (ΔGbind= -29.82 kcal/mol). The Syk stabilizing effect of lead1 was also indicated in its network features, sampling space, and residual correlation motion analysis. We further generated 100 structural analogues of lead1 using deep learning, and one of the analogues displayed a better binding free energy (ΔGbind= -47.58 kcal/mol) compared to the control or lead1, facilitated by more favourable van der Waals interactions and lesser binding-opposing net polar forces. This analogue may be further exploited to develop effective therapeutics against Syk-associated diseases after validation in vitro and in vivo.

Finding inhibitors and deciphering inhibitor-induced conformational plasticity in the Janus kinase via multiscale simulations.

The Janus kinase (JAK) is a master regulator of the JAK/STAT pathway. Dysregulation of this signalling cascade causes neuroinflammation and autoimmune disorders. Therefore, JAKs have been characterized as an attractive target for developing anti-inflammatory drugs. Nowadays, designing efficient, effective, and specific targeted therapeutics without being cytotoxic has gained interest. We performed the virtual screening of natural products in combination with pharmacological analyses. Subsequently, we performed molecular dynamics simulations to study the stability of the ligand-bound complexes and ligand-induced inactive conformations. Notably, inactive kinases display remarkable conformational plasticity; however, ligand-induced molecular mechanisms of these conformations are still poorly understood. Herein, we performed a free energy landscape analysis to explore the conformational plasticity of the JAK1 kinase. Leonurine, STOCK1N-68642, STOCK1N-82656, and STOCK1N-85809 bound JAK1 exhibited a smooth transition from an active (αC-in) to a completely inactive conformation (αC-out). Ligand binding induces disorders in the αC-helix. Molecular mechanics Poisson Boltzmann surface area (MM/PBSA) calculation suggested three phytochemicals, namely STOCK1N-68642, Epicatechin, and STOCK1N-98615, have higher binding affinity compared to other ligand molecules. The ligand-induced conformational plasticity revealed by our simulations differs significantly from the available crystal structures, which might help in designing allosteric drugs.

Discovery of potential competitive inhibitors against With-No-Lysine kinase 1 for treating hypertension by virtual screening, inverse pharmacophore-based lead optimization, and molecular dynamics simulations.

The With-No-Lysine (WNK) has received attention because of its involvement in hypertension. Genetic mutation in the genes of WNK, leading to its overexpression, has been reported in Familial Hyperkalaemic Hypertension, and thus WNK is considered a potential drug target. Herein, we have performed a high-throughput virtual screening of ~11,000 compounds, mainly the natural phytochemical compounds and kinase inhibitory libraries, to find potential competitive inhibitors against WNK1. Initially, candidates with a docking score of ~ -10.0 kcal/mol or less were selected to further screen their good pharmacological properties by applying absorption, distribution, metabolism, excretion, and toxicity (ADMET). Finally, six docked compounds bearing appreciable binding affinities and WNK1 selectivity were complimented with 500 ns long all-atom molecular dynamic simulations. Subsequently, the MMPBSA scheme (Molecular Mechanics Poisson Boltzmann Surface Area) suggested three phytochemical compounds, C00000947, C00020451, and C00005031, with favourable binding affinity against WNK1. Among them, C00000947 acts as the most potent competitive inhibitor of WNK1. Further, inverse pharmacophore-based lead optimization of the C00000947 leads to one potential compound, meciadanol, which shows better binding affinity and specificity than C00000947 towards WNK1, which may be further exploited to develop effective therapeutics against WNK1-associated hypertension after in vitro and in vivo validation.

Metagenomic outlooks of microbial dynamics influenced by organic manure in tea garden soils of North Bengal, India.

Soil microbial diversity consisted of both culturable and non-culturable microbes. The cultivated microbes can be identified by conventional microbiological processes. However, that is not possible for the non-culturable ones. In those cases, next-generation sequencing (NGS)-based metagenomics become useful. In this study, we targeted two very popular tea gardens of Darjeeling hills-Makaibari (Mak) and Castleton (Cas). The main difference between these two study areas is the type of manure they use. Mak is solely an organic tea garden using all organic manure and fertilizers whereas Cas uses inorganic pesticides and fertilizers. The main aim was to compare the effect of organic manure over chemical fertilizers on the soil microbiomes. We have performed the 16 s metagenomics analysis based on the V3-V4 region. Downstream bioinformatics analysis including reverse ecology was performed. We found that the overall microbial diversity is higher in Mak compared to Cas. Moreover, the use of organic manure has reduced the population of pathogenic bacteria in Mak soil when compared to Cas soil. From the observations made through the metagenomics analysis of Mak and Cas soil samples, we may conclude that the application of organic manure supports the population of good bacteria in the soil which may eventually impact the tea garden workers' health.

Investigating potency of TMC-126 against wild-type and mutant variants of HIV-1 protease: a molecular dynamics and free energy study.

A detailed computational study was performed to investigate the conformational changes of flap region and the mechanism underlying the binding of the inhibitor TMC-126 to HIV-1 protease (PR1) and its mutant variants through molecular dynamics simulations in conjunction with the molecular mechanics Poisson-Boltzmann (MM-PBSA) free energy calculation. Further, we have studied the effectiveness of the inhibitor against HIV-2 protease (PR2). The MM-PBSA calculation suggests that TMC-126 loses its potency against mutant variants and PR2 compared to wild-type PR1 mainly due to the loss in intermolecular electrostatic interactions. The potency of the inhibitor decreases in the order: wild type PR1 > M46L > MDR20 > I50V > PR2 > V32I > A28S. Our study reveals that the flap of PR1 adopts a semi-open conformation due to the mutation I50V or MDR20. The dissimilar nature of the movement of the flap tip of both monomers is evident from the dynamic cross-correlation map. The protein structural network analysis displays that mutation causes structural rearrangements and changes the communication path between residues. Overall, we believe our study may help explore and accelerate the development of novel HIV-1/HIV-2 protease inhibitors with better potency.

Prevalence of cirrhotic cardiomyopathy and its relationship with serum pro-brain natriuretic peptide, hepatorenal syndrome, spontaneous bacterial peritonitis, and mortality.

OBJECTIVES: This study aims at estimating the prevalence of cirrhotic cardiomyopathy in a cohort of cirrhosis patients in northern India using the World Congress of Gastroenterology 2005 criteria and its relationship with grades of cirrhosis, its complications, and all-cause mortality. METHODS: This was a prospective study in which 53 cirrhosis patients underwent the 2D color Doppler, and tissue Doppler echocardiography. Echocardiography findings were compared with thirty age- and sex-matched healthy controls. Additionally, serum pro-brain natriuretic peptide (pro-BNP) and troponin-T levels were measured. Patients were followed up for 6 months to look for complications and mortality. RESULT: 2D echocardiography findings revealed that diastolic cardiomyopathy with no gross systolic dysfunction was significantly prevalent in cirrhosis patients. Using the Montreal criteria, we found the incidence of diastolic cardiomyopathy to be 56.6%. Tissue Doppler echocardiography findings were also correlated. Diastolic dysfunction correlated with the severity of cirrhosis, and patients with higher Child score had more diastolic dysfunction. Serum pro-BNP levels and QTc interval were also higher in patients with diastolic dysfunction. On survival analysis, patients with cirrhotic cardiomyopathy had shorter survival and greater frequency of encephalopathy and hepatorenal syndrome (HRS) episodes as compared with cirrhotic patients without cardiomyopathy, though the differences were not statistically significant. CONCLUSION: The study showed that diastolic dysfunction was highly prevalent (56.6% of the study population) in cirrhosis patients. QTc interval and pro-BNP were also significantly raised. Also, complications of cirrhosis like HRS, spontaneous bacterial peritonitis, and hepatic encephalopathy were more common in the cirrhotic cardiomyopathy group.

A Review of the Diagnosis and Management of Hepatitis E.

Purpose of review: We aim to provide the readers an up-to-date knowledge of the structure, epidemiology, and transmission followed by a detailed discussion on testing, diagnostics and management of hepatitis E virus infection. We have also included a comprehensive review of hepatitis E in pregnancy. Recent findings: European Association for the Study of the Liver established clinical practice guidelines for testing and treatment of suspected hepatitis E virus infections in 2018. Evidence suggests chronic hepatitis E may follow a course similar to hepatitis B/C with progression to cirrhosis and possibly hepatocellular carcinoma in immunocompromised patients. Summary: Hepatitis E virus is the most common cause of acute viral hepatitis worldwide. A combination of serology and nucleic acid amplification testing is the recommended strategy for suspected patients. Ribavirin therapy for a period of 3 months is the drug of choice for severe acute hepatitis, acute-on chronic liver failure, and chronic infections from hepatitis E virus in immunocompromised patients who are unresponsive to decreased immunosuppression. PEGylated interferon α can be used for ribavirin-resistant liver transplant patients with chronic hepatitis E. Further research in therapeutic options is essential considering the stormy course of hepatitis E infection during pregnancy and teratogenicity of all available options.

Guidelines for the management of diabetes services and patients during the COVID-19 pandemic.

The UK National Diabetes Inpatient COVID Response Group was formed at the end of March 2020 to support the provision of diabetes inpatient care during the COVID pandemic. It was formed in response to two emerging needs. First to ensure that basic diabetes services are secured and maintained at a time when there was a call for re-deployment to support the need for general medical expertise across secondary care services. The second was to provide simple safe diabetes guidelines for use by specialists and non-specialists treating inpatients with or suspected of COVID-19 infection. To date the group, comprising UK-based specialists in diabetes, pharmacy and psychology, have produced two sets of guidelines which will be continually revised as new evidence emerges. It is supported by Diabetes UK, the Association of British Clinical Diabetologists and NHS England.

Guidelines for the management of diabetes in care homes during the Covid-19 pandemic.

The National Diabetes Stakeholders Covid-19 Response Group was formed in early April 2020 as a rapid action by the Joint British Diabetes Societies for Inpatient Care, Diabetes UK, the Association of British Clinical Diabetologists, and Diabetes Frail to address and support the special needs of residents with diabetes in UK care homes during Covid-19. It was obvious that the care home sector was becoming a second wave of Covid-19 infection and that those with diabetes residing in care homes were at increased risk not only of susceptibility to infection but also to poorer outcomes. Its key purposes included minimising the morbidity and mortality associated with Covid-19 and assisting care staff to identify those residents with diabetes at highest risk of Covid-19 infection. The guidance was particularly created for care home managers, other care home staff, and specialist and non-specialist community nursing teams. The guidance covers the management of hyperglycaemia by discussion of various clinical scenarios that could arise, the management of hypoglycaemia, foot care and end of life care. In addition, it outlines the conditions where hospital admission is required. The guidance should be regarded as interim and will be updated as further medical and scientific evidence becomes available.

A Type 1 diabetes technology pathway: consensus statement for the use of technology in Type 1 diabetes.

In both adults and children with diabetes, technologies such as continuous subcutaneous insulin infusion using insulin pumps and continuous glucose monitoring can help improve diabetes control, reduce hypoglycaemia and improve quality of life. Access to these technologies in the UK is very variable. Some technologies are recommended by the National Institute for Health and Care Excellence, while others have not been appraised, and new technologies are emerging all the time. Additionally, different guidelines for adults and children further complicate access to diabetes technology in the transition from paediatric to adult care. Against this background, Diabetes UK and NHS England have brought together a multidisciplinary group of experts, including clinicians and people with diabetes, to develop this consensus guideline, combining the different technologies into a common pathway to aid clinical and policy decision-making. We created a pathway that supports the incremental addition of technology as monotherapy and then dual therapy in the same way that we incrementally add in therapeutic agents to support people with Type 2 diabetes to achieve their personalized glycaemic targets. The pathway emphasizes the importance of structured education, specialist support and appropriate access to psychological therapies, as essential pillars for optimized use of diabetes-related technology, and recommends the re-evaluation of its use when the individual is unable either to use the technology appropriately or to achieve the intended outcomes. This pathway is endorsed by UK-wide clinical and patient associations and we recommend that providers and commissioners use it to ensure the right individual with diabetes has access to the right technology in a timely way to help achieve better outcomes.

Hepatitis B virus precore G1896A mutation in chronic liver disease patients with HBeAg negative serology from North India.

Hepatitis B with precore stop codon mutation is related with severe liver damage in HBeAg negative patients. It is of utmost importance to screen the G1896A precore mutation. The study was designed to assess the impact of G1986A mutations in patients with different clinical spectra of the liver disease by PCR-LCR. 210 HBV positive patients with HBeAg negative serology of different kind of liver diseases (AVH = 72, FH = 21, CH = 79, Cirrhosis = 20 and HCC = 18) were screened. Patients were screened for the presence or absence of precore G1896A mutation by PCR-LCR. Direct nucleotide sequencing was done to confirm the results of LCR. Precore mutant in HCC was 94.4% (17/18), 85.7% (18/21) in FH, 60% (12/20) in liver cirrhosis, 48.1% (38/79) in chronic hepatitis and 27.7% (20/72) in AVH cases. The serum ALT level was statistically significant between HBeAg negative WT and G1896A mutants in chronic hepatitis cases. ALT level and HBV DNA level was slightly raised in the pre core mutant but and was not significant. Genotype D had a higher prevalence (79.5%) as compared to genotype A (20.5%). The mutations detected by PCR-LCR were in 100% concordance with direct sequencing. The exceptionally high prevalence of G1896A in FH and HCC demonstrates that the precore mutants are strongly associated with the progression of liver diseases in patients with HBeAg negative serology. The findings are also suggestive of screening HBV precore G1896A mutation particularly in HBeAg negative cases. The precore G1896A mutation increases proportionately in severe form of liver diseases. LCR can be a suitable tool for screening of G1896A mutations.

Language matters: a UK perspective.

AIM: To review the existing evidence regarding the use of language in clinical encounters. BACKGROUND: Awareness of the importance of language in clinical encounters is mostly lacking or located within broader discussions on communication. METHODS: A scoping study was conducted to review existing research that could increase our understanding of the role language plays as well as identify gaps in knowledge and inform the development of a position statement on language in diabetes care. RESULTS: Evidence shows that, although carefully chosen language can have a positive effect, there is a potential negative impact of language on people's experiences of diabetes care. The use of stigmatizing and discriminatory words during communication between healthcare practitioners and people with diabetes can lead to disengagement with health services as well as sub-optimal diabetes self-management. Clinical encounters can be compromised where language barriers exist or where there is limited understanding of cultural differences that may have an impact on diabetes self-management. What little empirical evidence there is shows that training can improve language and communication skills. CONCLUSION: This review raises a number of questions that are being addressed by the NHS England Language Matters Group, which has developed a set of recommendations to support the use of appropriate language in clinical encounters.

Language matters. Addressing the use of language in the care of people with diabetes: position statement of the English Advisory Group.

The language used by healthcare professionals can have a profound impact on how people living with diabetes, and those who care for them, experience their condition and feel about living with it day-to-day. At its best, good use of language, both verbal and written, can lower anxiety, build confidence, educate and help to improve self-care. Conversely, poor communication can be stigmatizing, hurtful and undermining of self-care and can have a detrimental effect on clinical outcomes. The language used in the care of those with diabetes has the power to reinforce negative stereotypes, but it also has the power to promote positive ones. The use of language is controversial and has many perspectives. The development of this position statement aimed to take account of these as well as the current evidence base. A working group, representing people with diabetes and key organizations with an interest in the care of people with diabetes, was established to review the use of language. The work of this group has culminated in this position statement for England. It follows the contribution of Australia and the USA to this important international debate. The group has set out practical examples of language that will encourage positive interactions with those living with diabetes and subsequently promote positive outcomes. These examples are based on a review of the evidence and are supported by a simple set of principles.

Type 2 diabetes mellitus in older people: a brief statement of key principles of modern day management including the assessment of frailty. A national collaborative stakeholder initiative.

Rates of population ageing are unprecedented and this, combined with the progressive urbanization of lifestyles, has led to a dramatic shift in the epidemiology of diabetes towards old age, particularly to those aged 60-79 years. Both ageing and diabetes are recognized as important risk factors for the development of functional decline and disability. In addition, diabetes is associated with a high economic, social and health burden. Traditional macrovascular and microvascular complications of diabetes appear to account for less than half of the diabetes-related disability observed in older people. Despite this, older adults are under-represented in clinical trials. Guidelines from organizations such as the National Institute for Health and Care Excellence (NICE), the European Association for the Study of Diabetes, and the American Diabetes Association acknowledge the need for individualized care, but the glycaemic targets that are suggested to constitute good control [HbA1c 53-59 mmol/mol (7-7.5%)] are too tight for frail older individuals. We present a framework for the assessment of older adults and guidelines for the management of this population according to their frailty status, with the intention of reducing complications and improving quality of life for these people.

Risk factors for vertical transmission of hepatitis E virus infection.

Hepatitis E virus (HEV) infection can be vertically transmitted, but the factors that transmit the disease to foetuses are still unclear. We studied a total of 144 pregnant women with HEV infection. Cord blood and newborn samples were taken for analysis. Nutritional factors were evaluated on the basis of anthropometric parameters and biochemical factors, and HEV viral load was quantified by real-time PCR. Sequencing of HEV-positive samples was performed. Approximately 14.63% (6/41) of pregnant patients with acute liver failure (ALF) died before delivery. Vertical transmission was observed in 46.09% (59/128) of HEV-IgM-positive mothers. Approximately 23.80% (10/42) of newborns in the acute viral hepatitis group and 29.41% (5/17) in the ALF group were positive for HEV-RNA. No significant difference was observed in the occurrence of vertical transmission in HEV groups. Viral load was found to be a significant predictor for vertical transmission of HEV infection adjusted with haemoglobin and folate in derivation cohort group. Incorporating these variables, a new score predicting vertical transmission of HEV was derived. Using these significant predictors, the probability for vertical transmission of HEV was well stratified in the validation group (P>.05). In conclusion, viral load was associated with vertical transmission of HEV infection. A valid prediction score model was generated that was verified in a validation cohort group.

100-fold improvement in carrier drift mobilities in alkanephosphonate-passivated monocrystalline TiO2 nanowire arrays.

Single crystal rutile titania nanowires grown by solvothermal synthesis are actively being researched for use as electron transporting scaffolds in perovskite solar cells, in low detection limit ultraviolet photodetectors, in photoelectrochemical water-splitting, and in chemiresistive and electrochemical sensing. The electron drift mobility (µ n ) in solution-grown TiO2 nanowires is very low due to a high density of deep traps, and reduces performance in optoelectronic devices. In this study, the effects of molecular passivation of the nanowire surface by octadecylphosphonic acid (ODPA), on carrier transport in TiO2 nanowire ensembles, were investigated using transient space charge limited current measurements. Infrared spectroscopy indicated the formation of a highly ordered phosphonate monolayer with a high likelihood of bidentate binding of ODPA to the rutile surface. We report the hole drift mobility (µ p ) for the first time in unpassivated solvothermal rutile nanowires to be 8.2 × 10-5 cm2 V-1 s-1 and the use of ODPA passivation resulted in µ p improving by nearly two orders of magnitude to 7.1 × 10-3 cm2 V-1 s-1. Likewise, ODPA passivation produced between a 2 and 3 order of magnitude improvement in µ n from ∼10-5-10-6 cm2 V-1 s-1 to ∼10-3 cm2 V-1 s-1. The bias dependence of the post-transit photocurrent decays in ODPA-passivated nanowires indicated that minority carriers were lost to trapping and/or monomolecular recombination for small values of bias (<5 V). Bimolecular recombination was indicated to be the dominant recombination mechanism at higher bias values.