Structural impact of pathogenic SNPs on ß-tubulin using molecular dynamics study.

Single nucleotide polymorphisms (SNPs) in the TUBB1 (ß-tubulin) gene have been implicated as the primary cause of macro thrombocytopenia. Therefore it is essential to identify the potential SNPs which are harmful to cause diseases such as macro thrombocytopenia. The impact caused by these variants on ß-tubulin is twofold, both structural and functional. Multiple in-silico tools were used to scrutinise the most deleterious nsSNPs (non-synonymous SNPs) via sequence and structure-based approaches. Further, the ß-tubulin protein model incorporating identified mutants was subjected to MD (molecular dynamic) simulations to analyse the impact on protein structure. A total of 2974 SNPs of TUBB1 were retrieved from various sources, and 32 nsSNPs were identified. By screening through sequence-based technique, 13 variants were detected as deleterious and further structure-based filtration was carried out to find thermally destabilising variants. Finally, three variants have been detected as highly destabilising by the mCSM server and chosen for the MD study. All three variants are present in the N-terminal, Intermediate, and C-terminal regions, breaking the spatial arrangement required for microtubule assembly. The spatial arrangement of these variants is in deviation with respect to WT (wild type) ß-tubulin. The protein model was subjected to a simulation period of 100 ns. The FEL analysis revealed multiple clusters with minor populations indicating the unstable conformation adapted by the ß-tubulin. The normal mode vector analysis exhibited high-intensity flexible motions at the C-terminal end, responsible for binding with MAPs (microtubule-associated proteins), an essential region in microtubule assembly. All these results reveal that the SNP's predicted eventually influence the spatial arrangement of ß-tubulin, which would disturb the stacking arrangement of αß tubulin dimer in microtubule assembly. The present study may set a path to cure the diseases like macro thrombocytopenia.Communicated by Ramaswamy H. Sarma.

Two-way association between alopecia areata and sleep disorders: A systematic review of observational studies.

Background: Alopecia Areata (AA) is found to be the most prevalent autoimmune disorder amongst the general population. It was observed that AA patients are at a significantly higher risk of developing obstructive sleep apnea and non-apneic insomnia than patients without AA. On the contrary, patients with identified sleep disorders were found to be more prone to developing AA as compared to the patients without sleep disorders. This study, therefore, validated the hypothesis of a bidirectional association between AA and sleep disorders. Aims: In this systematic review, our primary aim is to assess the prevalence of sleep disorders in Alopecia Areata patients while also assessing the inverse relationship between the two disorders. Methods: A literature search of MEDLINE, Google Scholar and Cochrane CENTRAL was performed from their inception to April 2022. Articles were selected for inclusion if they met the following eligibility criteria: (a) Studies enrolling patients having alopecia areata to assess the sleep quality. (b) Studies assessing the risks of alopecia areata in individuals with sleep disorder (c) Studies evaluating the bidirectional association between alopecia areata and sleep quality. Case reports, commentaries, and editorials were excluded. The outcomes of recruited studies were qualitatively synthesised and study findings are summarized in the results section and tabulated in summary tables. Results: Our search on electronic databases yielded 1562 articles. After abstract screening and full text review, 5 cross sectional and 3 cohort studies are included in this systematic review. Cases with PSQI scores higher than 5 and 6 were found to be in greater numbers amongst the AA patient population when compared to the control population (p < 0.001). Moreover, studies showed that patients with sleep disorders were greatly predisposed to develop subsequent AA as compared to patients without sleep disorders (aHR 4.70; 95% CI 3.99-5.54) (P < 0.0001). Conclusion: The findings from our results display a significant bi-directional cause-effect relation between AA and sleep disorders. However, more large-scale observational studies on this subject are required to further validate our findings.

Effects of SARS-CoV-2 infection and COVID-19 pandemic on menstrual health of women: A systematic review.

Background: The menstrual cycle in women is the main indicator of their reproductive health which is affected by the ongoing coronavirus disease 2019 (COVID-19) pandemic. This review aims to summarize the effects of the COVID-19 infection and the global pandemic on the menstrual health of women. Methods: The literature search was conducted in PubMed, Cochrane library, and Google Scholar using keywords "COVID-19," "Menstrual Cycle," "Menstrual Cycle Irregularities," "Amenorrhea," "Polymenorrhea," and "Dysmenorrhea." The articles were selected according to the following inclusion criteria: (i) cross-sectional studies, (ii) cohort studies, (iii) surveys, and (iv) other observational studies observing the effects of SARS-CoV-2 infection or COVID-19 pandemic on menstrual health of women. Exclusion criteria included: case reports, gray literature, and website articles regarding menstrual health. Results: A total of 30,510 articles were shortlisted after a comprehensive search. Sixteen articles were included out of which 13 studies investigated the effects of the COVID-19 pandemic on the menstrual cycle while 3 evaluated the possible effects of COVID-19 infection on the menstrual health of women. Menstrual disorders or irregularities were a more common finding during the pandemic as compared to before (p = 0.008). Women affected by pandemic-related stress were more prone to changes in the duration of their menses (p = 0.0008), reported heavier bleeding (p = 0.028), and increased incidence of painful periods (p < 0.0001). COVID-19 infected women also reported changes in their menstrual cycle including irregular menstruation, increased symptoms of premenstrual syndrome, and infrequent menstruation. Conclusions: Women suffering from COVID-19 infection or pandemic-associated stress and anxiety were more likely to experience irregular menstruation, dysmenorrhea, amenorrhea, and other menstrual abnormalities compared to those who were less exposed.

Computational investigations of indanedione and indanone derivatives in drug discovery: Indanone derivatives inhibits cereblon, an E3 ubiquitin ligase component.

BACKGROUND: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component. Cereblon is a well-known target of thalidomide and its derivatives. Cereblon is involved in multiple myeloma cell apoptosis. When ligands such as thalidomide and lenalidomide bind to cereblon, it recognizes various neosubstrates based on the ligand shape and properties. We have identified novel CRBN inhibitors, namely DHFO and its analogs, with structural features that are slightly different from thalidomide but stronger cereblon-binding affinity. We selected indanedione and indanone derivatives from the literature to understand and compare their cereblon-mediated substrate recognition potential. METHODS: Computational investigations of possible CRBN inhibitors were investigated by molecular docking with Autodock Vina and DockThor programs. The properties of the compounds' ADME/T and drug-likeness were investigated. A molecular dynamics study was carried out for four selected molecules, and the molecular interactions were analyzed using PCA-based FEL methods. The binding affinity was calculated using the MM/PBSA method. RESULTS: We conducted computational investigations on 68 indanedione and indanone derivatives binding with cereblon. Ten molecules showed better CRBN binding affinity than thalidomide. We studied the drug-likeness properties of the selected ten molecules, and four of the most promising molecules (DHFO, THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor, has the highest binding affinity of - 163.16 kJ/mol with cereblon. CONCLUSION: The selected CRBN inhibitor DHFO has demonstrated the highest binding affinity with cereblon protein compared to other molecules. Thalidomide and its derivatives have a new substitute in the form of DHFO, which produces an interaction hotspot on the surface of the cereblon. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHFO analogs provide an opportunity for exploring clinical alternatives with versatile therapeutic potential for a new category of indanedione molecules as novel modulators of E3 ubiquitin ligases.

Monkeypox virus: A future scourge to the Pakistani Healthcare system.

Monkeypox is a rare viral infection that is mostly concentrated in the regions of Central and West Africa. During the last couple of weeks, reports of confirmed monkeypox cases in non-endemic countries such as the United Kingdom have alerted health authorities in Pakistan as well. Keeping in mind the devastating effects of the recent COVID-19 pandemic on the healthcare system of Pakistan, a subsequent monkeypox outbreak can be catastrophic. During the COVID-19 outbreak, the lack of financial resources and manpower exposed the vulnerability of the country's healthcare system. Therefore, it is imperative that relevant health authorities proactively work towards educating the public regarding effective precautionary measures that can keep them safe in the event of a monkeypox outbreak.

Chronic myeloid leukemia: a type of MPN.

This review article classifies chronic myeloid leukemia (CML) based on cytogenetic analyses and different mutations detected in CML patients. The use of advanced technologies, such as karyotyping, fluorescent in situ hybridization, and comparative genomic hybridization, has allowed us to study CML in detail and observe the different biochemical changes that occur in different CML types. This review also highlights the different types of receptor and signaling pathway mutations that occur in CML.

Assessment of Skeletal Age Using Hand-Wrist Radiographs following Bjork System.

The knowledge of the skeletal maturation and the stage of the growth of the patients seeking orthodontic treatment are of great value in planning efficient orthodontic therapy. However, different craniofacial structures of patient show variation in growth potential. The routine use of hand-wrist radiograph for growth prediction exposes the patient to extra radiation. Cervical vertebrae in the lateral cephalograph have been recommended as an alternative method. The pubertal growth spurt is a vital period in the orthodontic treatment and should be kept in mind when planning orthodontic treatment in growing children. One of the main objectives of taking hand and wrist radiograph is to determine the amount of growth and get used of it in patients with skeletal discrepancy during adolescence. Further, this will help in the selection of the appliances required, the course of the treatment and the retention after active orthodontic therapy.