Search

Multidisciplinary research efforts on potential COVID-19 vaccine and therapeutic candidates have increased since the pandemic outbreak of SARS-CoV-2 in 2019. This search has become imperative due to the increasing emergences and limited widely available medicines. The presence of bioactive anti-SARS-CoV-2 molecules was examined from various plant sources. Among them is a group of proteins called lectins that can bind carbohydrate moieties. In this article, we present ten novel, chitin-specific Hevein-like lectins that were derived from Selaginella moellendorffii v1.0’s genome. The capacity of these lectin homologs to bind with the spike protein of SARS-CoV-2 was examined. Using the HDOCK server, 3D-modeled Hevein-domains were docked to the spike protein’s receptor binding domain (RBD). The Smo446851, Smo125663, and Smo99732 interacted with Asn343-located complex N-glycan and RBD residues, respectively, with binding free energies of −17.5, −13.0, and −26.5 Kcal/mol. The molecular dynamics simulation using Desmond and the normal-state analyses via torsional coordinate association for the Smo99732-RBD complex using iMODS is characterized by overall higher stability and minimum deformity than the other lectin complexes. The three lectins interacting with carbohydrates were docked against five individual mutations that frequently occur in major SARS-CoV-2 variants. These were in the spike protein’s receptor-binding motif (RBM), while Smo125663 and Smo99732 only interacted with the spike glycoprotein in a protein–protein manner. The precursors for the Hevein-like homologs underwent additional characterization, and their expressional profile in different tissues was studied. These in silico findings offered potential lectin candidates targeting key N-glycan sites crucial to the virus’s virulence and infection.

The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall–Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense‐mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6–10 and escape NMD and result in the production of dominant‐negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS‐associated NFIX exon 7 mutations, we used CRISPR‐Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in‐frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix+/Del2, Nfix+/Del24, Nfix+/Del140, NfixDel24/Del24, and NfixDel140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but NfixDel2/Del2 mice had significantly reduced viability (p

Abstract Background Sorghum bicolor is one of the most important crops worldwide with the potential to provide resilience when other economic staples might fail against the continuous environmental changes. Many physiological, developmental and tolerance traits in plants are either controlled or influenced by lectins; carbohydrate binding proteins. Hence, we aimed at providing a comprehensive in silico account on sorghum’s lectins and study their possible implication on various desired agronomical traits. Results We have searched sorghum’s genome from grain and sweet types for lectins putative genes that encode proteins with domains capable of differentially binding carbohydrate moieties and trigger various physiological responses. Of the 12 known plant lectin families, 8 were identified regarding their domain architectures, evolutionary relationships, physiochemical characteristics, and gene expansion mechanisms, and they were thoroughly addressed. Variations between grain and sweet sorghum lectin homologs in term of the presence/absence of certain other joint domains like dirigent and nucleotide-binding adaptor shared by APAF-1, R-proteins, and CED-4 (NB-ARC) indicate a possible neofunctionalization. Lectin sequences were found to be preferentially overrepresented in certain quantitative trait loci (QTLs) related to various traits under several subcategories such as cold, drought, salinity, panicle/grain composition, and leaf morphology. The co-localization and distribution of lectins among multiple QTLs provide insights into the pleiotropic effects that could be played by one lectin gene in numerous traits. Conclusion Our study offers a first-time inclusive details on sorghum lectins and their possible role in conferring tolerance against abiotic stresses and other economically important traits that can be informative for future functional analysis and breeding studies.

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca.sup.2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders.sup.1. CaSR is a family C G-protein-coupled receptor.sup.2 that functions as an obligate homodimer, with each protomer composed of a Ca.sup.2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca.sup.2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor. Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling., Author(s): Yang Gao [sup.1] [sup.2] , Michael J. Robertson [sup.1] [sup.2] , Sabrina N. Rahman [sup.4] , Alpay B. Seven [sup.1] [sup.2] , Chensong Zhang [sup.1] [sup.2] , Justin G. [...]

ObjectivesCOVID-19 is a transmissible illness triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its onset in late 2019 in Wuhan city of China, it continues to spread universally, leading to an ongoing pandemic that shattered all efforts to restrain it. On the other hand, in Africa, the COVID-19 infection may be influenced by malaria coinfection. Hence, in this review article, we aimed to give a comprehensive account of the similarities between COVID-19 and malaria in terms of symptoms, clinical, immunological, and molecular perspectives.MethodologyIn this article, we reviewed over 50 research papers to highlight the multilayered similarities between COVID-19 and malaria infections that might influence the ontology of COVID-19.ResultsDespite the poor health and fragile medical system of many sub-Saharan African countries, they persisted with a statistically significantly low number of COVID-19 cases. This was attributed to many factors such as the young population age, the warm weather, the lack of proper diagnosis, previous infection with malaria, the use of antimalarial drugs, etc. Additionally, population genetics appears to play a significant role in shaping the COVID-19 dynamics. This is evident as recent genomic screening analyses of the angiotensin-converting enzyme 2 (ACE2) and malaria-associated-variants identified 6 candidate genes that might play a role in malaria and COVID-19 incidence and severity. Moreover, the clinical and pathological resemblances between the two diseases have made considerable confusion in the diagnosis and thereafter curb the disease in Africa. Therefore, possible similarities between the diseases in regards to the clinical, pathological, immunological, and genetical ascription were discussed.ConclusionUnderstanding the dynamics of COVID-19 infection in Sub-Saharan Africa and how it is shaped by another endemic disease like malaria can provide insights into how to tailor a successful diagnostic, intervention, and control plans that lower both disease morbidity and mortality.

Introduction Lactation is a hormonally controlled process that promotes infant growth and neurodevelopment and reduces the long-term maternal risk of diabetes, cardiovascular disease and breast cancer. Hormones, such as prolactin and progesterone, mediate mammary development during pregnancy and are critical for initiating copious milk secretion within 24–72 hours post partum. However, the hormone concentrations mediating lactation onset are ill defined.Methods and analysis The primary objective of the investigating hormones triggering the onset of sustained lactation study is to establish reference intervals for the circulating hormone concentrations initiating postpartum milk secretion. The study will also assess how maternal factors such as parity, pregnancy comorbidities and complications during labour and delivery, which are known to delay lactation, may affect hormone concentrations. This single-centre observational study will recruit up to 1068 pregnant women over a 3-year period. A baseline blood sample will be obtained at 36 weeks’ gestation. Participants will be monitored during postpartum days 1–4. Lactation onset will be reported using a validated breast fullness scale. Blood samples will be collected before and after a breastfeed on up to two occasions per day during postpartum days 1–4. Colostrum, milk and spot urine samples will be obtained on a single occasion. Serum hormone reference intervals will be calculated as mean±1.96 SD, with 90% CIs determined for the upper and lower reference limits. Differences in hormone values between healthy breastfeeding women and those at risk of delayed onset of lactation will be assessed by repeated measures two-way analysis of variance or a mixed linear model. Correlations between serum hormone concentrations and milk composition and volume will provide insights into the endocrine regulation of milk synthesis.Ethics and dissemination Approval for this study had been granted by the East of England—Cambridgeshire and Hertfordshire Research Ethics Committee (REC No. 20/EE/0172), by the Health Research Authority (HRA), and by the Oxford University Hospitals National Health Service Foundation Trust. The findings will be published in high-ranking journals and presented at national and international conferences.Trial registration number ISRCTN12667795.

In the presence of ethanol solvent and glacial acetic acids, triazole reacted with different aromatic aldehydes such as 4-methoxybenzaldehyde, 4-hydroxybenzaldehyde, and benzaldehyde to form the imines group known as Schiff bases. Triazole Schiff bases are triazole hydrazone and their derivatives, VA, VB, and VC. The structures of these synthetic triazole hydrazone derivatives were characterized by means of FT-IR and mass spectrometry. The purities and quality of the compounds were evaluated using TLC. It was established, that the active ingredient in the synthesised triazole hydrazone was more effective against the infections than cefuroxime. [ABSTRACT FROM AUTHOR]

This study aims at investigating the potential of Acacia gerrardii pod for the removal of Cr(VI) in batch system. Effect of solution pH, biosorbent dosage, initial concentration of Cr(VI), contact time on the removal process was examined. Complete removal of hexavalent chromium was achieved at pH values 1.0 and 2.0 whereas maximum removal of total chromium was obtained at pH of 3.0. The study showed that the biosorption and bioreduction mechanisms were involved in the removal process. The time required for complete removal of Cr(VI) using the pod of Acacia gerrardii was shortened with an increase in biomaterial dosage and decrease in Cr(VI) concentration. Kinetic data was well described using Park kinetic model. Freundlich isotherm model adequately fitted the equilibrium data indication multilayer adsorption of total chromium on the surface of biomaterial. The pod of Acacia gerrardii could be used efficiently for the removal of hexavalent chromium from aqueous solutions.

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.

ABSTRACT Calcilytics are calcium‐sensing receptor (CaSR) antagonists that reduce the sensitivity of the CaSR to extracellular calcium. Calcilytics have the potential to treat autosomal dominant hypocalcemia type 1 (ADH1), which is caused by germline gain‐of‐function CaSR mutations and leads to symptomatic hypocalcemia, inappropriately low PTH concentrations, and hypercalciuria. To date, only one calcilytic compound, NPSP795, has been evaluated in patients with ADH1: Doses of up to 30 mg per patient have been shown to increase PTH concentrations, but did not significantly alter ionized blood calcium concentrations. The aim of this study was to further investigate NPSP795 for the treatment of ADH1 by undertaking in vitro and in vivo studies involving Nuf mice, which have hypocalcemia in association with a gain‐of‐function CaSR mutation, Leu723Gln. Treatment of HEK293 cells stably expressing the mutant Nuf (Gln723) CaSR with 20nM NPSP795 decreased extracellular Ca2+‐mediated intracellular calcium and phosphorylated ERK responses. An in vivo dose‐ranging study was undertaken by administering a s.c. bolus of NPSP795 at doses ranging from 0 to 30 mg/kg to heterozygous (Casr+/Nuf) and to homozygous (CasrNuf/Nuf) mice, and measuring plasma PTH responses at 30 min postdose. NPSP795 significantly increased plasma PTH concentrations in a dose‐dependent manner with the 30 mg/kg dose causing a maximal (≥10‐fold) rise in PTH. To determine whether NPSP795 can rectify the hypocalcemia of Casr+/Nuf and CasrNuf/Nuf mice, a submaximal dose (25 mg/kg) was administered, and plasma adjusted‐calcium concentrations measured over a 6‐hour period. NPSP795 significantly increased plasma adjusted‐calcium in Casr+/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L, and in CasrNuf/Nuf mice from 1.70 ± 0.03 mmol/L to 1.89 ± 0.05 mmol/L. Our findings show that NPSP795 elicits dose‐dependent increases in PTH and ameliorates the hypocalcemia in an ADH1 mouse model. Thus, calcilytics such as NPSP795 represent a potential targeted therapy for ADH1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.