Unveiling the occurrence of COVID-19 in a diverse Bangladeshi population during the pandemic.

Introduction: COVID-19 pandemic hit Bangladesh with relatively low intensity, unlike its neighbors India and European countries and USA. Methods: The present report included data of 8,480 individuals tested for COVID-19 RT-PCR of the workers and officials from readymade garments (RMG) industry in Chandra area in Gazipur. The present data looked into the clinic-demographic factors associated with the susceptibility of the condition. Result: The data elucidated the susceptibility of the individuals to SARS-CoV-2 based on age, gender, pre-existing health conditions, and the presence of symptoms. It was observed that individuals aged over 60 had the highest rate of COVID-19 positivity, and men exhibited a higher infection rate compared to women. Regardless of age, fever and cough were the most frequently reported symptoms. Two-thirds of the individuals included in this report appeared to be asymptomatic carriers. The prevalence of comorbidities among individuals who tested positive for COVID-19 was notably higher, and this exhibited a gender-specific pattern. Discussion: Although our study provides important epidemiological insights into the initial year of the pandemic among Bangladeshi populations, it can also add value for future drug and vaccine development. However, it is essential to acknowledge the limitations like - restriction of public movement, unavailability of vehicle yielding a selection bias, due to the lockdown conditions imposed owing to the pandemic and the diverse characteristics of the participants. The report emphasizes the significance of figuring out how age, gender, and underlying health conditions impact susceptibility to and transmission of COVID-19, thereby providing valuable insights for public health strategies and future research initiatives.

Structural comparison of human mammalian ste20-like kinases.

BACKGROUND: The serine/threonine mammalian Ste-20 like kinases (MSTs) are key regulators of apoptosis, cellular proliferation as well as polarization. Deregulation of MSTs has been associated with disease progression in prostate and colorectal cancer. The four human MSTs are regulated differently by C-terminal regions flanking the catalytic domains. PRINCIPAL FINDINGS: We have determined the crystal structure of kinase domain of MST4 in complex with an ATP-mimetic inhibitor. This is the first structure of an inactive conformation of a member of the MST kinase family. Comparison with active structures of MST3 and MST1 revealed a dimeric association of MST4 suggesting an activation loop exchanged mechanism of MST4 auto-activation. Together with a homology model of MST2 we provide a comparative analysis of the kinase domains for all four members of the human MST family. SIGNIFICANCE: The comparative analysis identified new structural features in the MST ATP binding pocket and has also defined the mechanism for autophosphorylation. Both structural features may be further explored for inhibitors design. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.

Kinase domain insertions define distinct roles of CLK kinases in SR protein phosphorylation.

Splicing requires reversible phosphorylation of serine/arginine-rich (SR) proteins, which direct splice site selection in eukaryotic mRNA. These phosphorylation events are dependent on SR protein (SRPK) and cdc2-like kinase (CLK) families. SRPK1 phosphorylation of splicing factors is restricted by a specific docking interaction whereas CLK activity is less constrained. To understand functional differences between splicing factor targeting kinases, we determined crystal structures of CLK1 and CLK3. Intriguingly, in CLKs the SRPK1 docking site is blocked by insertion of a previously unseen helix alphaH. In addition, substrate docking grooves present in related mitogen activating protein kinases (MAPKs) are inaccessible due to a CLK specific beta7/8-hairpin insert. Thus, the unconstrained substrate interaction together with the determined active-site mediated substrate specificity allows CLKs to complete the functionally important hyperphosphorylation of splicing factors like ASF/SF2. In addition, despite high sequence conservation, we identified inhibitors with surprising isoform specificity for CLK1 over CLK3.

Structure and regulation of the human Nek2 centrosomal kinase.

The dimeric Ser/Thr kinase Nek2 regulates centrosome cohesion and separation through phosphorylation of structural components of the centrosome, and aberrant regulation of Nek2 activity can lead to aneuploid defects characteristic of cancer cells. Mutational analysis of autophosphorylation sites within the kinase domain identified by mass spectrometry shows a complex pattern of positive and negative regulatory effects on kinase activity that are correlated with effects on centrosomal splitting efficiency in vivo. The 2.2-A resolution x-ray structure of the Nek2 kinase domain in complex with a pyrrole-indolinone inhibitor reveals an inhibitory helical motif within the activation loop. This helix presents a steric barrier to formation of the active enzyme and generates a surface that may be exploitable in the design of specific inhibitors that selectively target the inactive state. Comparison of this "auto-inhibitory" conformation with similar arrangements in cyclin-dependent kinase 2 and epidermal growth factor receptor kinase suggests a role for dimerization-dependent allosteric regulation that combines with autophosphorylation and protein phosphatase 1c phosphatase activity to generate the precise spatial and temporal control required for Nek2 function in centrosomal maturation.

Cloning, purification and preliminary crystallographic analysis of a putative pyridoxal kinase from Bacillus subtilis.

Pyridoxal kinases (PdxK) are able to catalyse the phosphorylation of three vitamin B(6) precursors, pyridoxal, pyridoxine and pyridoxamine, to their 5'-phosphates and play an important role in the vitamin B(6) salvage pathway. Recently, the thiD gene of Bacillus subtilis was found to encode an enzyme which has the activity expected of a pyridoxal kinase despite its previous assignment as an HMPP kinase owing to higher sequence similarity. As such, this enzyme would appear to represent a new class of ;HMPP kinase-like' pyridoxal kinases. B. subtilis thiD has been cloned and the protein has been overexpressed in Escherichia coli, purified and subsequently crystallized in a binary complex with ADP and Mg(2+). X-ray diffraction data have been collected from crystals to 2.8 A resolution at 100 K. The crystals belong to a primitive tetragonal system, point group 422, and analysis of the systematic absences suggest that they belong to one of the enantiomorphic pair of space groups P4(1)2(1)2 or P4(3)2(1)2. Consideration of the space-group symmetry and unit-cell parameters (a = b = 102.9, c = 252.6 A, alpha = beta = gamma = 90 degrees ) suggest that the crystals contain between three and six molecules in the asymmetric unit. A full structure determination is under way to provide insights into aspects of the enzyme mechanism and substrate specificity.

The crystal structure of an ADP complex of Bacillus subtilis pyridoxal kinase provides evidence for the parallel emergence of enzyme activity during evolution.

Pyridoxal kinase catalyses the phosphorylation of pyridoxal, pyridoxine and pyridoxamine to their 5' phosphates and plays an important role in the pyridoxal 5' phosphate salvage pathway. The crystal structure of a dimeric pyridoxal kinase from Bacillus subtilis has been solved in complex with ADP to 2.8 A resolution. Analysis of the structure suggests that binding of the nucleotide induces the ordering of two loops, which operate independently to close a flap on the active site. Comparisons with other ribokinase superfamily members reveal that B. subtilis pyridoxal kinase is more closely related in both sequence and structure to the family of HMPP kinases than to other pyridoxal kinases, suggesting that this structure represents the first for a novel family of "HMPP kinase-like" pyridoxal kinases. Moreover this further suggests that this enzyme activity has evolved independently on multiple occasions from within the ribokinase superfamily.

Analysis of the open and closed conformations of the GTP-binding protein YsxC from Bacillus subtilis.

Genetic analysis has suggested that the product of the Bacillus subtilis ysxC gene is essential for survival of the microorganism and hence may represent a target for the development of a novel anti-infective agent. B.subtilis YsxC is a member of the translation factor related class of GTPases and its crystal structure has been determined in an apo form and in complex with GDP and GMPPNP/Mg2+. Analysis of these structures has allowed us to examine the conformational changes that occur during the process of nucleotide binding and GTP hydrolysis. These structural changes particularly affect parts of the switch I and switch II region of YsxC, which become ordered and disordered, respectively in the "closed" or "on" GTP-bound state and disordered and ordered, respectively, in the "open" or "off" GDP-bound conformation. Finally, the binding of the magnesium cation results in subtle shifts of residues in the G3 region, at the start of switch II, which serve to optimize the interaction with a key aspartic acid residue. The structural flexibility observed in YsxC is likely to contribute to the role of the protein, possibly allowing transduction of an essential intracellular signal, which may be mediated via interactions with a conserved patch of surface-exposed, basic residues that lies adjacent to the GTP-binding site.

Expression, purification, crystallization and preliminary crystallographic analysis of a putative GTP-binding protein, YsxC, from Bacillus subtilis.

Bacillus subtilis YsxC has been putatively identified as a member of the GTP-binding protein family. Gene-knockout/deletion analysis has suggested that this protein is essential for survival of the microorganism and hence may represent a target for the development of a novel anti-infective agent. The B. subtilis ysxC gene was cloned and the protein was overexpressed in Escherichia coli and subsequently purified. Using hanging-drop vapour-diffusion crystallization techniques, two different crystal forms of YsxC were obtained in the presence and absence of GDP and which have one and two copies of YsxC in the asymmetric unit, respectively. Both crystal forms diffract to beyond 2.0 A resolution and are suitable for structure determination.