Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors

Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition

Developing a Dynamic Web-GIS Based Landslide Early Warning System for the Chittagong Metropolitan Area, Bangladesh

This article aims to develop a Web-GIS based landslide early warning system (EWS) for the Chittagong Metropolitan Area (CMA), Bangladesh, where, in recent years, rainfall-induced landslides have caused great losses of lives and property. A method for combining static landslide susceptibility maps and rainfall thresholds is proposed by introducing a purposely-build hazard matrix. To begin with, eleven factor maps: soil permeability; surface geology; landcover; altitude; slope; aspect; distance to stream; fault line; hill cut; road cut; and drainage network along with a detailed landslide inventory map were produced. These maps were used, and four methods were applied: artificial neural network (ANN); multiple regressions; principal component analysis; and support vector machine to produce landslide susceptibility maps. After model validation, the ANN map was found best fitting and was classified into never warning, low, medium, and high susceptibility zones. Rainfall threshold analysis (1960–2017) revealed consecutive 5-day periods of rainfall of 71–282 mm could initiate landslides in CMA. Later, the threshold was classified into three rainfall rates: low rainfall (70–160 mm), medium rainfall (161–250 mm), and high rainfall (>250 mm). Each landslide was associated with a hazard class (no warning vs. warning state) based on the assumption that the higher the susceptibility, the lower the rainfall. Finally, the EWS was developed using various libraries and frameworks that is connected with a reliable online-based weather application programming interface. The system is publicly available, dynamic, and replicable to similar contexts and is able to disseminate alerts five days in advance via email notifications. The proposed EWS is novel and the first of its kind in Bangladesh, and can be applied to mitigate landslide disaster risks

Shonjibon cash and counselling: a community-based cluster randomised controlled trial to measure the effectiveness of unconditional cash transfers and mobile behaviour change communications to reduce child undernutrition in rural Bangladesh.

BackgroundUndernutrition is strongly associated with poverty - levels of undernutrition are higher in poor countries than in better-off countries. Social protection especially cash transfer is increasingly recognized as an important strategy to accelerate progress in improving maternal and child nutrition. A critical method to improve nutrition knowledge and influence feeding practices is through behaviour change communication intervention. The Shonjibon Cash and Counselling study aims to assess the effectiveness of unconditional cash transfers combined with a mobile application on nutrition counselling and direct counselling through mobile phone in reducing the prevalence of stunting in children at 18 months.MethodThe study is a longitudinal cluster randomised controlled trial, with two parallel groups, and cluster assignment by groups of villages. The cohort of mother-child dyads will be followed-up over the intervention period of approximately 24 months, starting from recruitment to 18 months of the child's age. The study will take place in north-central Bangladesh. The primary trial outcome will be the percentage of stunted children at 18 m as measured in follow up assessments starting from birth. The secondary trial outcomes will include differences between treatment arms in (1) Mean birthweight, percentage with low birthweight and small for gestational age (2) Mean child length-for age, weight for age and weight-for-length Z scores (3) Prevalence of child wasting (4) Percentage of women exclusively breastfeeding and mean duration of exclusive breastfeeding (5) Percentage of children consuming > 4 food groups (6) Mean child intake of energy, protein, carbohydrate, fat and micronutrients (7) Percentage of women at risk of inadequate nutrient intakes in all three trimesters (8) Maternal weight gain (9) Household food security (10) Number of events for child suffering from diarrhoea, acute respiratory illness and fever (11) Average costs of mobile phone BCC and cash transfer, and benefit-cost ratio for primary and secondary outcomes.DiscussionThe proposed trial will provide high-level evidence of the efficacy and cost-effectiveness of mobile phone nutrition behavior change communication, combined with unconditional cash transfers in reducing child undernutrition in rural Bangladesh.Trial registrationThe study has been registered in the Australian New Zealand Clinical Trials Registry ( ACTRN12618001975280 )

Increased Oxidative Burden Associated with Traffic Component of Ambient Particulate Matter at Roadside and Urban Background Schools Sites in London

As the incidence of respiratory and allergic symptoms has been reported to be increased in children attending schools in close proximity to busy roads, it was hypothesised that PM from roadside schools would display enhanced oxidative potential (OP). Two consecutive one-week air quality monitoring campaigns were conducted at seven school sampling sites, reflecting roadside and urban background in London. Chemical characteristics of size fractionated particulate matter (PM) samples were related to the capacity to drive biological oxidation reactions in a synthetic respiratory tract lining fluid. Contrary to hypothesised contrasts in particulate OP between school site types, no robust size-fractionated differences in OP were identified due high temporal variability in concentrations of PM components over the one-week sampling campaigns. For OP assessed both by ascorbate (OPAA m−3) and glutathione (OPGSH m−3) depletion, the highest OP per cubic metre of air was in the largest size fraction, PM1.9–10.2. However, when expressed per unit mass of particles OPAA µg−1 showed no significant dependence upon particle size, while OPGSH µg−1 had a tendency to increase with increasing particle size, paralleling increased concentrations of Fe, Ba and Cu. The two OP metrics were not significantly correlated with one another, suggesting that the glutathione and ascorbate depletion assays respond to different components of the particles. Ascorbate depletion per unit mass did not show the same dependence as for GSH and it is possible that other trace metals (Zn, Ni, V) or organic components which are enriched in the finer particle fractions, or the greater surface area of smaller particles, counter-balance the redox activity of Fe, Ba and Cu in the coarse particles. Further work with longer-term sampling and a larger suite of analytes is advised in order to better elucidate the determinants of oxidative potential, and to fuller explore the contrasts between site types.\ud \u

Co-existence of a giant splenic hemangioma and multiple hepatic hemangiomas and the potential association with the use of oral contraceptives: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatic and splenic hemangiomas are common benign tumors that mainly affect female patients. Giant splenic hemangiomas are extremely rare, especially when correlated with multiple hepatic hemangiomas. Pathogenetic mechanisms between hemangiomas and oral contraceptives, as well as therapeutic approaches, are analyzed in this case report, in particular for the management of synchronous splenic and hepatic hemangiomas.</p> <p>Case presentation</p> <p>We report here a 42-year-old woman with a giant splenic hemangioma, multiple hepatic hemangiomas and a history of oral estrogen intake for many years. At first it was difficult to determine the organ from which the giant hemangioma originated. Angiography proved extremely helpful in tracing its origin in the spleen. Hematomas in the giant hemangioma posed a significant threat of rupture and catastrophic hemorrhage. We left the small hepatic hemangiomas in place, and removed the spleen along with the giant splenic hemangioma.</p> <p>Conclusion</p> <p>Diagnostic pitfalls in the determination of the origin of this giant hemangioma, attribution of its origin to the spleen angiographically, the unusual co-existence of the giant splenic hemangioma with multiple hepatic ones, and the potential threat of rupture of the giant hemangioma are some of the highlights of this case report. Estrogen administration represents a pathogenic factor that has been associated with hemangiomas in solid organs of the abdominal cavity. The therapeutic dilemma between resection and embolization of giant hemangiomas is another point of discussion in this case report. Splenectomy for the giant splenic hemangioma eliminates the risk of rupture and malignant degeneration, whereas observation for the small hepatic ones (<4 cm) was the preferable therapeutic strategy in our patient.</p

Antimicrobial Resistance, Virulence Factors and Genetic Diversity of Escherichia coli Isolates from Household Water Supply in Dhaka, Bangladesh

Background: Unsafe water supplies continue to raise public health concerns, especially in urban areas in low resource countries. To understand the extent of public health risk attributed to supply water in Dhaka city, Bangladesh, Escherichia coli isolated from tap water samples collected from different locations of the city were characterized for their antibiotic resistance, pathogenic properties and genetic diversity. Methodology/Principal Findings: A total of 233 E. coli isolates obtained from 175 tap water samples were analysed for susceptibility to 16 different antibiotics and for the presence of genes associated with virulence and antibiotic resistance. Nearly 36% (n = 84) of the isolates were multi-drug(≥3 classes of antibiotics) resistant (MDR) and 26% (n = 22) of these were positive for extended spectrum β-lactamase (ESBL). Of the 22 ESBL-producers, 20 were positive for blaCTX-M-15, 7 for blaOXA-1-group(all had blaOXA-47) and 2 for blaCMY-2. Quinolone resistance genes, qnrS and qnrB were detected in 6 and 2 isolates, respectively. Around 7% (n = 16) of the isolates carried virulence gene(s) characteristic of pathogenic E. coli; 11 of these contained lt and/or st and thus belonged to enterotoxigenic E. coli and 5 contained bfp and eae and thus belonged to enteropathogenic E. coli. All MDR isolates carried multiple plasmids (2 to 8) of varying sizes ranging from 1.2 to >120 MDa. Ampicillin and ceftriaxone resistance were co-transferred in conjugative plasmids of 70 to 100 MDa in size, while ampicillin, trimethoprim-sulfamethoxazole and tetracycline resistance were co-transferred in conjugative plasmids of 50 to 90 MDa. Pulsed-field gel electrophoresis analysis revealed diverse genetic fingerprints of pathogenic isolates. Significance: Multi-drug resistant E. coli are wide spread in public water supply in Dhaka city, Bangladesh. Transmission of resistant bacteria and plasmids through supply water pose serious threats to public health in urban areas

Physicochemical attack against solid tumors based on the reversal of direction of entropy flow: an attempt to introduce thermodynamics in anticancer therapy

BACKGROUND: There are many differences between healthy tissue and growing tumor tissue, including metabolic, structural and thermodynamic differences. Both structural and thermodynamic differences can be used to follow the entropy differences in cancerous and normal tissue. Entropy production is a bilinear form of the rates of irreversible processes and the corresponding "generalized forces". Entropy production due to various dissipation mechanisms based on temperature differences, chemical potential gradient, chemical affinity, viscous stress and exerted force is a promising tool for calculations relating to potential targets for tumor isolation and demarcation. METHODS: The relative importance of five forms of entropy production was assessed through mathematical estimation. Using our mathematical model we demonstrated that the rate of entropy production by a cancerous cell is always higher than that of a healthy cell apart from the case of the application of external energy. Different rates of entropy production by two kinds of cells influence the direction of entropy flow between the cells. Entropy flow from a cancerous cell to a healthy cell transfers information regarding the cancerous cell and propagates its invasive action to the healthy tissues. To change the direction of entropy flow, in addition to designing certain biochemical pathways to reduce the rate of entropy production by cancerous cells, we suggest supplying external energy to the tumor area, changing the relative rate of entropy production by the two kinds of cells and leading to a higher entropy accumulation in the surrounding normal cells than in the tumorous cells. CONCLUSION: Through the use of mathematical models it was quantitatively demonstrated that when no external force field is applied, the rate of entropy production of cancerous cells is always higher than that of healthy cells. However, when the external energy of square wave electric pulses is applied to tissues, the rate of entropy production of normal cells may exceed that of cancerous cells. Consequently, the application of external energy to the body can reverse the direction of the entropy current. The harmful effect brought about by the entropy flow from cancerous to healthy tissue can be blocked by the reversed direction of entropy current from the irradiated normal tissue around the tumor

An experimental investigation into the dimensional error of powder-binder three-dimensional printing

This paper is an experimental investigation into the dimensional error of the rapid prototyping additive process of powder-binder three-dimensional printing. Ten replicates of a purpose-designed part were produced using a three-dimensional printer, and measurements of the internal and external features of all surfaces were made using a general purpose coordinate measuring machine. The results reveal that the bases of all replicates (nominally flat) have a concave curvature, producing a flatness error of the primary datum. This is in contrast to findings regarding other three-dimensional printing processes, widely reported in the literature, where a convex curvature was observed. All external surfaces investigated in this study showed positive deviation from nominal values, especially in the z-axis. The z-axis error consisted of a consistent positive cumulative error and a different constant error in different replicates. By compensating for datum surface error, the average total height error of the test parts can be reduced by 25.52 %. All the dimensional errors are hypothesised to be explained by expansion and the subsequent distortion caused by layer interaction during and after the printing process

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Comparative Genotyping of Campylobacter jejuni Strains from Patients with Guillain-Barré Syndrome in Bangladesh

Background: Campylobacter jejuni is a common cause of acute gastroenteritis and is associated with post-infectious neuropathies such as the Guillain-Barré syndrome (GBS) and the Miller Fisher syndrome (MFS). We here present comparative genotyping of 49 C. jejuni strains from Bangladesh that were recovered from patients with enteritis or GBS. All strains were serotyped and analyzed by lipo-oligosaccharide (LOS) genotyping, amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Methodology/Principal Findings: C. jejuni HS:23 was a predominant serotype among GBS patients (50%), and no specific serotype was significantly associated with GBS compared to enteritis. PCR screening showed that 38/49 (78%) of strains could be assigned to LOS classes A, B, C, or E. The class A locus (4/7 vs 3/39; p<0.01) was significantly associated in the GBS-related strains as compared to enteritis strains. All GBS/oculomotor related strains contained the class B locus; which was also detected in 46% of control strains. Overlapping clonal groups were defined by MLST, AFLP and PFGE for strains from patients with gastroenteritis and GBS. MLST defined 22 sequence types (STs) and 7 clonal complexes including 7 STs not previously identified (ST-3742, ST-3741, ST-3743, ST-3748, ST-3968, ST-3969 and ST-3970). C. jejuni HS:23 strains from patients with GBS or enteritis were clonal and all strains belonged to ST-403 complex. Concordance between LOS class B and ST-403 complex was revealed. AFLP defined 25 different types at 90% similarity. The predominant AFLP type AF-20 coincided with the C. jejuni HS:23 and ST-403 complex. Conclusion/Significance: LOS genotyping, MLST, AFLP and PFGE helped to identify the HS:23 strains from GBS or enteritis patients as clonal. Overall, genotypes exclusive for enteritis or for GBS-related strains were not obtained although LOS class A was significantly associated with GBS str