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Graphical abstract Highlights • The present study highlights the formation of Nur77-LKB1 complex and the TMPA induced dissociation of Nur77-LKB1 complex using all atom simulation approach. • Nur77-LKB1 complex is highly stabilized by several H-bonds formed between the Nur77 residues (Thr567, Gln571, Phe598, and Asp594) and the LKB1 residues (Leu344, Leu344, Glu70, and Arg39), respectively. • The strong binding affinity of Nur77 with LKB1 (estimated as –23.58 ± 39.5 kcal/mol) is decreased (to a relatively high energy state having –2.83 ± 20.5 kcal/mol) by the presence of TMPA. • TMPA induces an open-closure motion between Nur77 and LKB1 domains which exposes the interfacial regions to the solvent and destabilizes the Nur77-LKB1 complex. Abstract LKB1 protein is involved in the regulation of cell polarity by phosphorylating the AMPK under energetic stress conditions. LKB1 protein is expressed in both cytoplasm and nucleus. In the nucleus, LKB1 interacts with orphan nuclear receptor protein Nur77. It is reported that the interaction of LKB1 with Nur77 is disrupted by the small molecular ligand TMPA (ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate), such that the LKB1 is enabled to play its role in cytoplasm and further to regulate/reduce the blood glucose level. In the present study, atomistic molecular dynamics simulations are performed to understand the dissociation mechanism of Nur77-LKB1 complex. The present study reveals that TMPAs induce an open-close motion of Nur77 which further decrease the stability of Nur77-LKB1 complex. As a consequence, the interface region in LKB1-Nur77 complex is more exposed for solvation and further releases the interactions existing between Nur77 and LKB1. Altogether, this study explains the TMPAs mediated Nur77-LKB1 complex dissociation. [ABSTRACT FROM AUTHOR]

• Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) remains on the World Health Organization priority pathogens list. • The World Health Organization reports that 2184 of a total of 2591 human MERS cases are from Saudi Arabia. • Three MERS-CoV clades were identified: clade B (n = 462), clade A (n = 10), and clade C (n = 5). • New MERS-CoV variants and co-infections continue to circulate in camels. • Proactive virus surveillance and genomic analyses in camels and humans is required. The World Health Organization priority zoonotic pathogen Middle East respiratory syndrome (MERS) coronavirus (CoV) has a high case fatality rate in humans and circulates in camels worldwide. We performed a global analysis of human and camel MERS-CoV infections, epidemiology, genomic sequences, clades, lineages, and geographical origins for the period January 1, 2012 to August 3, 2022. MERS-CoV Surface gene sequences (4061 bp) were extracted from GenBank, and a phylogenetic maximum likelihood tree was constructed. As of August 2022, 2591 human MERS cases from 26 countries were reported to the World Health Organization (Saudi Arabia, 2184 cases, including 813 deaths [case fatality rate: 37.2%]) Although declining in numbers, MERS cases continue to be reported from the Middle East. A total of 728 MERS-CoV genomes were identified (the largest numbers were from Saudi Arabia [222: human = 146, camels = 76] and the United Arab Emirates [176: human = 21, camels = 155]). A total of 501 'S'-gene sequences were used for phylogenetic tree construction (camels [n = 264], humans [n = 226], bats [n = 8], other [n=3]). Three MERS-CoV clades were identified: clade B, which is the largest, followed by clade A and clade C. Of the 462 clade B lineages, lineage 5 was predominant (n = 177). MERS-CoV remains a threat to global health security. MERS-CoV variants continue circulating in humans and camels. The recombination rates indicate co-infections with different MERS-CoV lineages. Proactive surveillance of MERS-CoV infections and variants of concern in camels and humans worldwide, and development of a MERS vaccine, are essential for epidemic preparedness. [ABSTRACT FROM AUTHOR]

Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families. Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings. Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty. This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation. [ABSTRACT FROM AUTHOR]