Comparison of clinical, para-clinical and laboratory findings in survived and deceased patients with COVID-19: diagnostic role of inflammatory indications in determining the severity of illness

Background: Since December 2019, when a cluster of pneumonia cases due to SARS-CoV-2 initially emerged in Wuhan city and then rapidly spread throughout the world, the necessity for data concerning the clinical and para-clinical features of Iranian patients with COVID-19 was highlighted. Therefore, we aimed to compare the clinical, para-clinical and laboratory evidences of deceased patients with survival group. Methods: We extracted data regarding 233 patients with laboratory-confirmed COVID-19 from Buali Hospital in Iran; clinical/para-clinical and inflammatory indexes data were collected and analyzed. The data of laboratory examinations and chest CT findings were compared between deceased and survived patients. Results: The mean age of the patients was 49.8 years and 64 of our patients were male. The acute respiratory distress syndrome occurred in 64 patients, 52 who were admitted to the ICU, which all of them underwent invasive mechanical ventilation, and 28 who died. Lymphopenia (79), neutrophilia (79), and thrombocytopenia (21) were the most frequently observed laboratory findings of the deceased group on admission. Most patients (68) had a high systematic immune-inflammation (SII) index of > 500 and increased C-reactive protein level (88). Levels of inflammatory indexes such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and SII were documented to be significantly elevated in the deceased group when compared with the patients who survived (P < 0.0001, P < 0.001, P < 0.0001, respectively). The most commonly presented symptoms were fever (70) and cough (63) on admission. Headache was uncommon (11). Ground-glass opacity with consolidation (mixed) was the most common radiologic finding on chest CT (51). No radiographic or CT abnormality was found in 15 of 204 patients (7). Conclusion: Small fraction of patients with COVID-19 may present without fever and abnormal radiologic findings. Elevated NLR, PLR and SII can be considered as prognostic and risk stratifying factor of severe form of disease. © 2020, The Author(s)

Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes

Objective: Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. Research design and methods: We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulfonylurea challenge, and in vitro assays to assess variant protein function. Results: A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2-0.8 mg/L), and those tested demonstrated sensitivity to sulfonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. Conclusions: Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.This work was undertaken with funds from the Diabetes Research & Wellness Foundation (through a Sutherland-Earl Fellowship 2013–2016) and the Imperial College Healthcare Charity, and with infrastructure support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC), Imperial Clinical Research Facility, and Clinical Research Network. S.M. is currently supported by a Future Leaders Mentorship Award from the European Association for the Study of Diabetes. A.J. was a Diabetes UK George Alberti Clinical Research Fellow when contributing to this study. S.E. received a Senior Investigator Award from Wellcome Trust. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. Part of this work was funded in Oxford by the Wellcome Trust (grants 095101 and 200837 [both to A.L.G.]). The research was also funded by the NIHR Oxford and BRC (to A.L.G.).Accepted version, submitted versio

IN VITRO AND IN VIVO ANTI-TRYPANOSOMAL ACTIVITIES OF METHANOL EXTRACT OF AZADIRACHTA INDICA STEM-BARK

Background: Current chemotherapeutic agents for the treatment of African trypanosomiasis have become largely ineffective, necessitating the search for alternative compounds. The objective of this study was to evaluate in vitro anti-trypanosomal activities of methanol extracts of parts of Azadirachta indica against Trypanosoma brucei rhodesiense, Trypanosoma brucei brucei and Trypanosoma evansi and establish the in vivo efficacy of the most active extract. Materials and methods: Maceration of powdered leaves, stem bark and root bark of the plant in methanol afforded three extracts. In vitro assays were carried out with the extracts on the three trypanosome strains in 96-well microtitre plates at concentration ranges of 4000 - 1000μg/ml. The most active extract was assayed in vivo using Trypanosoma brucei rhodesiense infected Swiss albino mice at doses of 100, 200 and 400 mg/kg body weight. Melarsoprol and suramin served as positive controls. The infected untreated group served as the negative control. Parasitaemia levels, packed cell volume, body weight changes and mean survival period of all groups were monitored throughout the experimental period. Results: Methanol extract of the stem bark of A.indica was most active in vitro against all the three trypanosome strains (MIC values of 9.93±1.88, 16.25±0.92 and 9.97±0.44μg/ml for T. b. rhodesiense, T. b. brucei and T. evansi, respectively). The extract showed optimum activity at 400 mg/kg and was comparable to the positive control groups. Parasitaemia levels were kept at a significantly low level (p 0.05) in mean survival time of mice treated with the extract at 400 mg/kg and the positive controls. Conclusion: In vitro and in vivo anti-trypanosomal activities of the methanol extract of A. indica stem bark could be attributed to the presence of constituents of moderate polarity

Computationally Designed Bispecific Antibodies using Negative State Repertoires

A challenge in the structure-based design of specificity is modeling the negative states, i.e., the complexes that you do not want to form. This is a difficult problem because mutations predicted to destabilize the negative state might be accommodated by small conformational rearrangements. To overcome this challenge, we employ an iterative strategy that cycles between sequence design and protein docking in order to build up an ensemble of alternative negative state conformations for use in specificity prediction. We have applied our technique to the design of heterodimeric CH3 interfaces in the Fc region of antibodies. Combining computationally and rationally designed mutations produced unique designs with heterodimer purities greater than 90%. Asymmetric Fc crystallization was able to resolve the interface mutations; the heterodimer structures confirmed that the interfaces formed as designed. With these CH3 mutations, and those made at the heavy-/light-chain interface, we demonstrate one-step synthesis of four fully IgG-bispecific antibodies

Constituents of the Essential Oil of Suregada zanzibariensis Leaves are Repellent to the Mosquito, Anopheles gambiae s.s.

In traditional African communities, repellent volatiles from certain plants generated by direct burning or by thermal expulsion have played an important role in protecting households against vectors of malaria and other diseases. Previous research on volatile constituents of plants has shown that some are good sources of potent mosquito repellents. In this bioprospecting initiative, the essential oil of leaves of the tree, Suregada zanzibariensis Verdc. (Angiospermae: Euphobiaceae) was tested against the mosquito, Anopheles gambiae s.s. Giles (Diptera: Culicidae) and found to be repellent. Gas chromatography (GC), GC-linked mass spectrometry (GC-MS) and, where possible, GC-co-injections with authentic compounds, led to the identification of about 34 compounds in the essential oil. About 56% of the constituents were terpenoid ketones, mostly methyl ketones. Phenylacetaldehyde (14.4%), artemisia ketone (10.1%), (1S)-(-)-verbenone (12.1%) and geranyl acetone (9.4%) were the main constituents. Apart from phenylacetaldehyde, repellent activities of the other main constituents were higher than that of the essential oil. The blends of the main constituents in proportions found in the essential oil were more repellent to An. gambiae s.s. than was the parent oil (p < 0.05), and the presence of artemisia ketone in the blend caused a significant increase in the repellency of the resulting blend. These results suggested that blends of some terpenoid ketones can serve as effective An. gambiae s.s. mosquito repellents

Repellent Properties of δ-Octalactone Against the Tsetse Fly, Glossina morsitans Morsitans

δ-octalactone, produced by several Bovidae, has been suggested as a potential repellant of tsetse fly attack. Racemic δ-octalactone was synthesized via an abbreviated route. The product was assayed against 3-day old starved teneral female tsetse flies, Glossina morsitans morsitans Wiedemann (Diptera: Glossinidae), in a choice wind tunnel and found to be a potent tsetse repellent at doses ≥0.05 mg in 200 µl of paraffin oil (0.05 >p >0.01)

Structure and dynamics of nanoconfined water and aqueous solutions

This review is devoted to discussing recent progress on the structure, thermodynamic, reactivity, and dynamics of water and aqueous systems confined within different types of nanopores, synthetic and biological. Currently, this is a branch of water science that has attracted enormous attention of researchers from different fields interested to extend the understanding of the anomalous properties of bulk water to the nanoscopic domain. From a fundamental perspective, the interactions of water and solutes with a confining surface dramatically modify the liquid's structure and, consequently, both its thermodynamical and dynamical behaviors, breaking the validity of the classical thermodynamic and phenomenological description of the transport properties of aqueous systems. Additionally, man-made nanopores and porous materials have emerged as promising solutions to challenging problems such as water purification, biosensing, nanofluidic logic and gating, and energy storage and conversion, while aquaporin, ion channels, and nuclear pore complex nanopores regulate many biological functions such as the conduction of water, the generation of action potentials, and the storage of genetic material. In this work, the more recent experimental and molecular simulations advances in this exciting and rapidly evolving field will be reported and critically discussed

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes