Dental Care Of The Pregnant Patient: An Update Of Guidelines And Recommendations.

Pregnancy is a dynamic state marked by several physiological changes. Oral healthcare in pregnancy is often avoided and misunderstood, with healthcare professionals struggling to interpret the safety and appropriateness of dental treatment during this period. Despite international guidelines and consensus reports indicating that preventive and restorative dental treatment are safe and essential, there is still a widespread belief among healthcare professionals and general population in Pakistan that dental treatment during pregnancy may pose damage to the foetus. Over the past three decades, as human knowledge of the biology behind periodontal diseases broadened, its systemic impact upon various physiological states is better understood and management protocols are accordingly formulated. Lack of knowledge among dentists regarding the timing of routine dental treatment, avoidance of certain medications and poor understanding of the clinical changes in the periodontium of the pregnant patient needs to be addressed so that timely treatment is provided. The current narrative review was planned to highlight the physiological and pathological changes that may occur in the oral cavity of a pregnant patient.

Virtual Screening of Artemisia annua Phytochemicals as Potential Inhibitors of SARS-CoV-2 Main Protease Enzyme.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronaviruses that emerged in China at Wuhan city, Hubei province during December 2019. Subsequently, SARS-CoV-2 has spread worldwide and caused millions of deaths around the globe. Several compounds and vaccines have been proposed to tackle this crisis. Novel recommended in silico approaches have been commonly used to screen for specific SARS-CoV-2 inhibitors of different types. Herein, the phytochemicals of Pakistani medicinal plants (especially Artemisia annua) were virtually screened to identify potential inhibitors of the SARS-CoV-2 main protease enzyme. The X-ray crystal structure of the main protease of SARS-CoV-2 with an N3 inhibitor was obtained from the protein data bank while A. annua phytochemicals were retrieved from different drug databases. The docking technique was carried out to assess the binding efficacy of the retrieved phytochemicals; the docking results revealed that several phytochemicals have potential to inhibit the SARS-CoV-2 main protease enzyme. Among the total docked compounds, the top-10 docked complexes were considered for further study and evaluated for their physiochemical and pharmacokinetic properties. The top-3 docked complexes with the best binding energies were as follows: the top-1 docked complex with a -7 kcal/mol binding energy score, the top-2 docked complex with a -6.9 kcal/mol binding energy score, and the top-3 docked complex with a -6.8 kcal/mol binding energy score. These complexes were subjected to a molecular dynamic simulation analysis for further validation to check the dynamic behavior of the selected top-complexes. During the whole simulation time, no major changes were observed in the docked complexes, which indicated complex stability. Additionally, the free binding energies for the selected docked complexes were also estimated via the MM-GB/PBSA approach, and the results revealed that the total delta energies of MMGBSA were -24.23 kcal/mol, -26.38 kcal/mol, and -25 kcal/mol for top-1, top-2, and top-3, respectively. MMPBSA calculated the delta total energy as -17.23 kcal/mol (top-1 complex), -24.75 kcal/mol (top-2 complex), and -24.86 kcal/mol (top-3 complex). This study explored in silico screened phytochemicals against the main protease of the SARS-CoV-2 virus; however, the findings require an experimentally based study to further validate the obtained results.

In vitro evaluation of antiviral activity of Sisybrium irio (Khaksi) against SARS-COV-2.

SARS-CoV-2 pandemic, drawn attention to the need of virus culture. In vitro SARS-COV-2 culture was performed to carry out therapeutic, environmental and virus genome studies. Isolation of virus from nasopharyngeal swab was performed by inoculating virus positive samples in available cell lines. SARS-CoV-2 topography was observed by using Scanning Electron Microscopy (SEM). Virus specificity was defined by serological confirmation through neutralization assay with COVID 19 convalescent sera. The SARS-COV-2 virus replicated successfully in Vero cell lines (both in E6 and CCL-81). The TCID50 and PFUs of isolated virus were defined as 107 TCID50/mL and 1.4 Х 106 pfu/mL respectively. The virus particles with the SARS-CoV morphology was <150ɳM size. Virus inhibition in presence of convalescent sera of COVID-19 patients was observed. Sisybrium irio (Khaksi) was found cytotoxic on Vero E6 cell line and its antiviral activity could not be established against SARS-COV-2 virus in vitro. Successful isolated and archived native SARS-COV-2 may be utilized further for therapeutic, environmental and virus genome sequencing studies.

From Epidemic to Pandemic: Comparing Hospital Staff Emotional Experience Between MERS and COVID-19.

Objective: Both Middle East Respiratory Syndrome (MERS) and Coronavirus Disease 2019 (COVID-19) have an emotional toll on healthcare workers (HCWs), but the difference of the impact between the two diseases remains unknown.Design: A cross sectional descriptive survey.Setting: A tertiary care hospital.Participants: 125 HCWs who worked during the 2014 MERS as well as the 2020 COVID-19 outbreaks in high-risk areas of the hospital including critical care, emergency room and COVID-19 clinics.Methods: The comprehensive survey comprised 5 sections and 68 questions and was administered to HCWs before availability of the COVID-19 vaccine. The survey evaluated hospital staff emotions, perceived stressors, external factors that reduced stress, personal coping strategies, and motivators for future outbreaks. The participants rated each question for MERS and COVID-19 simultaneously on a scale from 0-3. The responses were reported as mean and standard deviation, while Wilcoxon signed-rank test was used to calculate the difference in responses.Results: There were 102 (82%) participants who returned the questionnaire. The ritual of obsessive hand washing, emotional and physical fatigue, ongoing changes in infection control guidelines, fear of community transmission, and limitations on socialization and travel were the major stressors that were significantly worse during COVID-19 compared to MERS (P<0.05) and led to HCWs adoption of additional 'personal' coping strategies during COVID-19. There was no difference between COVID-19 and MERS, however, among preferences for 'external' factors made available to HCWs that could reduce stress or in their preferences for motivators to work in future outbreaks (P>.05).Conclusion: Both the MERS and COVID-19 outbreaks were emotionally draining for HCWs. However, COVID-19 was a relatively more stressful experience than MERS for HCWs and led to greater personal, behavioral, and protective adaptations by the hospital staff.

A new approach to extend the storage of donor corneas after 28 days of corneal culture in an Italian eye bank.

This study aimed to evaluate the possibility to extend the storage of unused organ-cultured donor corneas. After 28 days of corneal culture in TISSUE-C (AL.CHI.MI.A. S.R.L., Italy) and 5-day storage in transport/deswelling medium CARRY-C (AL.CHI.MI.A. S.R.L., Italy), 25 corneas that were deemed suitable for transplantation were transferred in fresh TISSUE-C at 31 °C for additional 7 days and then in fresh CARRY-C at room temperature for 24 h. Tissues were assessed for endothelial cell density (ECD), endothelial mortality and morphology after the standard and the extended corneal storage. In addition, the effect of donor age < 85 years and ≥ 85 years on corneal characteristics was assessed. After the extended storage, 6 out of 25 tested corneas (24%) showed ECD values below the acceptance limit (< 2000 cells/mm2). 19 corneas (76%) were still suitable for transplantation and showed a 5.9% loss in ECD, which was not statistically significant (P = 0.0949) compared to standard storage period. The two donor age groups did not show statistically significant differences in any tested parameter, although a trend for lower ECD and higher mortality in Descemet's folds after standard storage was observed in the ≥ 85 age donor group. Thus, the attempt of the current study to provide new sight-restorative options for unused tissues and increasing the availability of corneas in case of shortage gave encouraging results. Although a higher vulnerability of corneas from very old donors could not be statistically demonstrated in the present study, higher sample size could be required for prolonging the shelf life of these tissues.

High burn out among doctors working in a tertiary care hospital; a wakeup call.

OBJECTIVE: To determine the frequency of burnout and its associated factors among doctors in a tertiary care setting. METHODS: The descriptive study was conducted at Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from October 1, 2016, to January 31, 2017, and comprised doctors working there regardless of age, gender and professional experience. A self-reported questionnaire with demographic data and Maslach Burnout Inventory was used. Levels of each component of and composite burnout score were calculated and associated with each independent variable. Data was analysed using SPSS 21. RESULTS: Of the 365 doctors, 238(65.2%) were females, 200(54.8%) were single, and the overall mean age was 28.68}4.58 years. Besides, 172(58%) subjects were postgraduate residents, 77 (21%) belonged to Obstetrics and Gynaecology, 198(54.2%) had 1-in-4 rota, and 123(33.7%) had job duration of 1-4 years. High burnout was reported by 49(13.5%) and moderate burnout by 227(62.2%) doctors respectively. Severe burnout frequency was the highest in Anaesthesia department 9(36%) followed by 18(23.4%) doctors in Obstetrics and Gynaecology. Overall, 140(38%) doctors reported high degree of emotional exhaustion, 100(27%) had high degree of depersonalization and 208(57%) had severely reduced personal accomplishment. Of the total, 120(33%) doctors wanted to leave their jobs. CONCLUSIONS: Different levels of burnout were found in doctors. Amongst the three components of burnout, severely reduced personal accomplishment was the highest.

A computational quest for identifying potential vaccine candidates against Moraxella lacunata: a multi-pronged approach.

Moraxella lacunata is an emerging gram-negative bacterium that is responsible for multiple nosocomial infections. The bacterium is evolving resistance to several antibiotics, and currently, no effective licensed vaccines are available, which warrants the search for new therapeutics. A multi-epitope-based vaccine has been designed for M. lacunata. The complete proteome of M. lacunata contains 10,110 core proteins. Subcellular localization analysis revealed the presence of five proteins in the extracellular matrix, while 19 proteins were predicted to be located in the outer membrane, and 21 proteins were predicted to be located in the periplasmic region. Only two proteins, the type VI secretion system tube protein (Hcp) and the transporter substrate-binding domain-containing protein, were selected for epitope prediction as they fulfilled all the criteria for being potential vaccine candidates. Shortlisted epitopes from the selected proteins were fused together using "GPGPG" linkers to overcome the limitations of single-epitope vaccines. Next, the cholera toxin-B adjuvant was attached to the peptide epitope using an EAAAK linker. Docking analysis was performed to examine the interaction between the vaccine and immune cell receptors, revealing robust intermolecular interactions and a stable binding conformation. Molecular dynamics simulation findings revealed no drastic changes in the binding conformation of complexes during the simulation period. The net binding free energy of vaccine-receptor complexes was estimated using the molecular mechanics energies combined with the Poisson-Boltzmann and surface area continuum solvation (MM-PBSA) method. The reported values were -586.38 kcal/mol, -283.74 kcal/mol, and -296.88 kcal/mol for the TLR-4-vaccine complex, MHC-I-vaccine complex, and MHC-II-vaccine complex, respectively. Furthermore, the molecular mechanics energies combined with the generalized Born and surface area continuum solvation (MM-GBSA) analysis predicted binding free energies of -596.69 kcal/mol, -287.39 kcal/mol, and -298.28 kcal/mol for the TLR-4-vaccine complex, MHC-I-vaccine complex, and MHC-II-vaccine complex, respectively. The theoretical vaccine design proposed in the study could potentially serve as a powerful therapeutic against targeted pathogens, subject to validation through experimental studies.Communicated by Ramaswamy H. Sarma.

A new three way decision making technique for supplier selection in logistics service value Cocreation under intuitionistic double hierarchy linguistic term set.

In today's business world, choosing a logistics supplier is a critical factor for companies to improve operational efficiency and reduce business costs. With the development of market economy, it is very difficult for companies to choose a suitable logistics provider according to specific rules. Therefore, this study proposes a new three-way decision making (TWD) technique for supplier selection in logistics service value creation. For this, we first develop a new concept called intuitionistic double hierarchy linguistic term set (IDHLTSs) that can describe uncertainty and ambiguity in a more flexible way. Some Hamacher aggregation operators for collecting IDHLTSs information and its basic aspect are proposed. The unknown weight vector for decision experts and criteria is determined by using entropy measures. In addition, the conditional probability is determined using TOPSIS which makes the decision making process more rational. And the decision result is conducted according to minimum loss principle. Finally, an example of 3 PL supplier selection in the logistics service value co-creation environment and comparison is given to validate and demonstrate the effectiveness of the developed method.

Design and validation of a novel multi-epitopes vaccine against hantavirus.

Hantavirus is a member of the order Bunyavirales and an emerging global pathogen. Hantavirus infections have affected millions of people globally based on available epidemiological data and research studies. Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are the two main human diseases associated with hantavirus infections. Hence, efforts are required to develop a potent vaccine against the pathogen. The only vaccine that is in use for hantavirus is an inactivated virus vaccine, "Hantavax", but it failed to produce neutralizing antibodies. Vaccine development is of much importance in dealing with the surge of hantavirus globally. In this study, hantavirus five proteins (N protein, G1 and G2, L protein, and non-structural proteins) were used in NetCTL 1.2 program to predict T-cell epitopes. To predict major histocompatibility complex (MHC) binding alleles, an immune epitope database (IEDB) was used. All predicted epitopes were then investigated for different immunoinformatics analyses such as antigenicity and toxicity analyses. The good water-soluble, non-toxic, probable antigenic, and DRB*0101 binder was selected. A multi-epitopes-based vaccine designing was then done where linkers were used to connect the shortlisted epitopes. In addition, an adjuvant molecule was supplementary to the multi-epitopes peptide to improve the vaccine's immunogenic potential. The final vaccine construct's three-dimensional structure was modeled by ab initio method. The vaccine molecule was then evaluated for its binding potential with TLR-3 immune receptor, which is key for its recognition and processing by the host immune system. Docking studies were performed using HADDOCK software. The best-docked complex was selected and visualized for intermolecular binding and interactions using UCSF Chimera 1.16 software. The findings revealed that the designed vaccine might be a potential vaccine against hantavirus and can be used in experimental animal model testings.Communicated by Ramaswamy H. Sarma.

Cellular senescence in brain aging and cognitive decline.

Cellular senescence is a biological aging hallmark that plays a key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate the effectiveness of senotherapies for these diseases. However, the impact of senescence on brain aging and cognitive decline in the absence of neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic brain injury survivors, obese individuals, obstructive sleep apnea patients, and chronic kidney disease patients can suffer age-related brain changes like cognitive decline prematurely, suggesting that they may suffer accelerated senescence in the brain. Understanding the role of senescence in neurocognitive deficits linked to these conditions is crucial, especially considering the rapidly evolving field of senotherapeutics. Such treatments could help alleviate early brain aging in these patients, significantly reducing patient morbidity and healthcare costs. This review provides a translational perspective on how cellular senescence plays a role in brain aging and age-related cognitive decline. We also discuss important caveats surrounding mainstream senotherapies like senolytics and senomorphics, and present emerging evidence of hyperbaric oxygen therapy and immune-directed therapies as viable modalities for reducing senescent cell burden.

Proteome-Wide Screening of Potential Vaccine Targets against Brucella melitensis.

The ongoing antibiotic-resistance crisis is becoming a global problem affecting public health. Urgent efforts are required to design novel therapeutics against pathogenic bacterial species. Brucella melitensis is an etiological agent of brucellosis, which mostly affects sheep and goats but several cases have also been reported in cattle, water buffalo, yaks and dogs. Infected animals also represent the major source of infection for humans. Development of safer and effective vaccines for brucellosis remains a priority to support disease control and eradication in animals and to prevent infection to humans. In this research study, we designed an in-silico multi-epitopes vaccine for B. melitensis using computational approaches. The pathogen core proteome was screened for good vaccine candidates using subtractive proteomics, reverse vaccinology and immunoinformatic tools. In total, 10 proteins: catalase; siderophore ABC transporter substrate-binding protein; pyridoxamine 5'-phosphate oxidase; superoxide dismutase; peptidylprolyl isomerase; superoxide dismutase family protein; septation protein A; hypothetical protein; binding-protein-dependent transport systems inner membrane component; and 4-hydroxy-2-oxoheptanedioate aldolase were selected for epitopes prediction. To induce cellular and antibody base immune responses, the vaccine must comprise both B and T-cells epitopes. The epitopes were next screened for antigenicity, allergic nature and water solubility and the probable antigenic, non-allergic, water-soluble and non-toxic nine epitopes were shortlisted for multi-epitopes vaccine construction. The designed vaccine construct comprises 274 amino acid long sequences having a molecular weight of 28.14 kDa and instability index of 27.62. The vaccine construct was further assessed for binding efficacy with immune cell receptors. Docking results revealed that the designed vaccine had good binding potency with selected immune cell receptors. Furthermore, vaccine-MHC-I, vaccine-MHC-II and vaccine-TLR-4 complexes were opted based on a least-binding energy score of -5.48 kcal/mol, 0.64 kcal/mol and -2.69 kcal/mol. Those selected were then energy refined and subjected to simulation studies to understand dynamic movements of the docked complexes. The docking results were further validated through MMPBSA and MMGBSA analyses. The MMPBSA calculated -235.18 kcal/mol, -206.79 kcal/mol, and -215.73 kcal/mol net binding free energy, while MMGBSA estimated -259.48 kcal/mol, -206.79 kcal/mol and -215.73 kcal/mol for TLR-4, MHC-I and MHC-II complexes, respectively. These findings were validated by water-swap and entropy calculations. Overall, the designed vaccine construct can evoke proper immune responses and the construct could be helpful for experimental researchers in formulation of a protective vaccine against the targeted pathogen for both animal and human use.

A chemoinformatic-biophysics based approach to identify novel anti-virulent compounds against Pseudomonas aeruginosa disulfide-bond protein A1.

The conventional course of drug discovery is a lengthy, expensive and complex process and often experiences a high failure rate. This in-silico based study screened novel drug molecules against Pseudomonas aeruginosa disulfide-bond protein A1 (PaDsbA1; PDB ID of 4ZL7) using a variety of chemoinformatic and biophysics approaches. The structure-based virtual screening identified three antipseudomonal compounds (BDC_30129064, BDC_20699588 and BDC_25329008) that targeted PaDsbA1 enzyme with a binding energy score of -7.8 kcal/mol, -7.7 kcal/mol and -7.7 kcal/mol, respectively. The compounds revealed deep binding at the enzyme active pocket with close distance hydrogen bond interactions with Thr46, Pro55, Val58, Arg62, His88, and Asp180. The co-crystalized hexaethylene glycol revealed a binding energy of -6.02 kcal/mol. The docked compounds were further subjected to molecular dynamics simulation analysis in order to check the dynamic movements of docked complexes. The complexes reported no drastic changes during simulation time. In the simulation, stable compounds binding and docked conformation were accomplished. The docking and simulation results were validated using free binding energies calculation through molecular mechanics with generalized born surface area solvation and molecular mechanics Poisson Boltzmann surface area (MMGBSA/MMPBSA) approaches. The net binding energy estimated by MMGBSA for BDC_30129064, BDC_20699588 and BDC_25329008 was -75.07 kcal/mol, -77.87 kcal/mol and -59.1 kcal/mol, respectively while that of MMPBSA for the compounds was -72.47 kcal/mol, -78.99 kcal/mol and -60.991 kcal/mol, respectively. The physiochemical properties of the selected compounds indicated them to be physiochemically stable with good absorption, distribution, metabolism and elimination properties. From the above observations and predictions, the compounds can be recommended for further experimental validation in order to decipher their anti-virulence capacity in blocking disulfide bond formation in P. aeruginosa.Communicated by Ramaswamy H. Sarma.

Vaccinomics to design a multi-epitope-based vaccine against monkeypox virus using surface-associated proteins.

In 2022, the ongoing multi-country outbreak of monkeypox virus-now occurring outside Africa, too is a global health concern. Monkeypox is a zoonotic virus, which causes disease mainly in animals, and then it is transferred to humans. Recently, in the monkeypox epidemic, a large number of human cases emerged while the global health community worked to tackle the outbreak and save lives. Herein, a multi-epitope-based vaccine is designed against monkeypox virus using two surface-associated proteins: MPXVgp002 accession number > YP_010377003.1 and MPXVgp008 accession number > YP_010377007.1 proteins. These proteins were utilized for B- and T-cell epitopes prediction. The epitopes were further screened, and the screen filtered KCKDNEYRSR, RSCNTTHNR, and RTRRETGAS with the antigenicity scores of 0.5279, 0.5604, and 0.7628, respectively. Overall, the epitopes can induce immunity in 99.74% population of the world. Further, GPGPG linkers were used for joining the epitopes and EAAAK linker was used for adjuvant attachment. It has a three-dimensional structure modelled for retaining the structural stability. Three pairs of amino acid residues that were able to make disulfide bonds were chosen: Gly1-Ser82, Cys7-Tyr10, and Phe51-Ile55. Molecular docking of vaccine was done with toll-like receptors, viz., 2, 3, 4, and 8 immune cell receptors. The docking results revealed that the vaccine as potential molecule due to its better binding affinity with toll-like receptors 2, 3, 4 and 8. Top complex in docking in with each receptor was selected based on lowest energy scores- -888.7 kcal/mol (TLR-2), -976.3 kcal/mol (TLR-3), -801.9 kcal/mol (TLR-4), and -955.4 kcal/mol (TLR-4)-were subjected to simulation. The docked complexes were evaluated in 500 ns of MD simulation. Throughout the simulation time, no significant deviation occurred. This confirmed that the vaccine as potential vaccine candidate to interact with immune cell receptors. This interaction is important for the immune system activation. In conclusion, the proposed vaccine construct against monkeypox could induce an effective immune response and speed up the vaccine development process. However, the study is completely based on the computational approach, hence, the experimental validation is required.Communicated by Ramaswamy H. Sarma.

Knowledge, attitude, and perceptions about cancer genetic testing in clinical practice in Karachi, Pakistan.

Healthcare professionals (HCP) play an important role in the practical application of genetic screening tests but often feel inadequately prepared for cancer genetic testing (CGT) in clinical care. As the complexity of gene-related malignancies increases, it demands HCPs' preparedness to cater to patients' needs. Therefore, the aim of our study is to assess the knowledge, attitude, and practices of HCPs in Pakistan regarding the application of cancer genetics. Our cross-sectional survey was conducted from April 2022 to June 2022 amongst HCPs at a private and a governmental institution in Karachi, Pakistan. Non-probability random convenience sampling was used to select the population; however. non-clinical HCPs, as well as Interns, were excluded from our study. A total of 210 HCPs, 56.7% (119) bearing an experience of over 5 years of clinical experience, were included in this study. Most respondents from both hospitals deemed their knowledge inadequate, with only 2% (2) and 1.8% (2) being extremely knowledgeable, respectively. 68.6% (144) HCPs displayed a positive attitude towards CGT, with 55.2% (116) participants perceiving CGT in a positive light. As compared to the private sector, significantly more HCPs in the public sector dedicated ≥ 5 h/week for CME (P = 0.006), and were better prepared to counsel patients (P = 0.021) and interpret results concerning CGT (P = 0.020). Additionally, screening tests for specific cancer types were popularly considered a worthwhile avenue of investment to improve the current state of CGT in our healthcare system [47.6% (N = 100)]. Demonstrating a lack of knowledge among Pakistani doctors, our results call upon the need for additional training concerning CGT in both the public and private sectors alike. Understanding specific gaps in knowledge may further help enhance post-graduate training programs and eventually lead to effective incorporation of CGT into our healthcare setting.

An In Silico Multi-epitopes Vaccine Ensemble and Characterization Against Nosocomial Proteus penneri.

Proteus penneri (P. penneri) is a bacillus-shaped, gram-negative, facultative anaerobe bacterium that is primarily an invasive pathogen and the etiological agent of several hospital-associated infections. P. penneri strains are naturally resistant to macrolides, amoxicillin, oxacillin, penicillin G, and cephalosporins; in addition, no vaccines are available against these strains. This warrants efforts to propose a theoretical based multi-epitope vaccine construct to prevent pathogen infections. In this research, reverse vaccinology bioinformatics and immunoinformatics approaches were adopted for vaccine target identification and construction of a multi-epitope vaccine. In the first phase, a core proteome dataset of the targeted pathogen was obtained using the NCBI database and subjected to bacterial pan-genome analysis using bacterial pan-genome analysis (BPGA) to predict core protein sequences which were then used to find good vaccine target candidates. This identified two proteins, Hcp family type VI secretion system effector and superoxide dismutase family protein, as promising vaccine targets. Afterward using the IEDB database, different B-cell and T-cell epitopes were predicted. A set of four epitopes "KGSVNVQDRE, NTGKLTGTR, IIHSDSWNER, and KDGKPVPALK" were chosen for the development of a multi-epitope vaccine construct. A 183 amino acid long vaccine design was built along with "EAAAK" and "GPGPG" linkers and a cholera toxin B-subunit adjuvant. The designed vaccine model comprised immunodominant, non-toxic, non-allergenic, and physicochemical stable epitopes. The model vaccine was docked with MHC-I, MHC-II, and TLR-4 immune cell receptors using the Cluspro2.0 web server. The binding energy score of the vaccine was - 654.7 kcal/mol for MHC-I, - 738.4 kcal/mol for MHC-II, and - 695.0 kcal/mol for TLR-4. A molecular dynamic simulation was done using AMBER v20 package for dynamic behavior in nanoseconds. Additionally, MM-PBSA binding free energy analysis was done to test intermolecular binding interactions between docked molecules. The MM-GBSA net binding energy score was - 148.00 kcal/mol, - 118.00 kcal/mol, and - 127.00 kcal/mol for vaccine with TLR-4, MHC-I, and MHC-II, respectively. Overall, these in silico-based predictions indicated that the vaccine is highly promising in terms of developing protective immunity against P. penneri. However, additional experimental validation is required to unveil the real immune response to the designed vaccine.

Identification of potential drug molecules against fibroblast growth factor receptor 3 (FGFR3) by multi-stage computational-biophysics correlate.

The fibroblast growth factor receptor 3 (FGFR3) is warranted as a promising therapeutic target in bladder cancer as it is described in 75% of papillary bladder tumors. Considering this, the present study was conducted to use different approaches of computer-aided drug discovery (CADD) to identify the best binding compounds against the active pocket of FGFR3. Compared to control pyrimidine derivative, the study identified three promising lead structures; BDC_24037121, BDC_21200852, and BDC_21206757 with binding energy value of -14.80 kcal/mol, -12.22 kcal/mol, and -11.67 kcal/mol, respectively. The control molecule binding energy score was -9.85 kcal/mol. The compounds achieved deep pocket binding and produced balanced interactions of hydrogen bonds and van der Waals. The FGFR3 enzyme residues such as Leu478, Lys508, Glu556, Asn562, Asn622, and Asp635. The molecular dynamic (MD) simulation studies additionally validated the docked conformation stability with respect to FGFR3 with a mean root mean square deviation (RMSD) value of < 3 Å. The root mean square fluctuation (RMSF) complements the complexes structural stability and the residues showed less fluctuation in the presence of compounds. The Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods revalidated compounds better binding and highlighted van der Waals energy to dominate the overall net energy. The docked stability was additionally confirmed by WaterSwap and AMBER normal mode entropy energy analyses. In a nutshell, the compounds shortlisted in this study are promising in term of theoretical binding affinity for FGFR3 but experimental validation is needed.Communicated by Ramaswamy H. Sarma.

Multi-attribute group decision making based on sine trigonometric spherical fuzzy aggregation operators.

Spherical fuzzy set (SFS) is also one of the fundamental concepts for address more uncertainties in decision problems than the existing structures of fuzzy sets, and thus its implementation was more substantial. The well-known sine trigonometric function maintains the periodicity and symmetry of the origin in nature and thus satisfies the expectations of the experts over the multi parameters. Taking this feature and the significance of the SFSs into the consideration, the main objective of the article is to describe some reliable sine trigonometric laws for SFSs. Associated with these laws, we develop new average and geometric aggregation operators to aggregate the Spherical fuzzy numbers. Then, we presented a group decision-making strategy to address the multi-attribute group decision-making problem using the developed aggregation operators. To verify the value of the defined operators, a MAGDM strategy is provided along with an application for the selection of an authentic COVID-19 laboratory. Moreover, a comparative study is also performed to present the effectiveness of the developed approach.

T-wave Inversions in Cerebellar and Occipital Lobe Infarcts in the Setting of Deep Vein Thrombosis and Pulmonary Embolism Suggestive of Paradoxical Emboli: A Case Report.

Cardiological causes account for the majority of acute electrocardiographic (ECG) changes. The reason for this fear is the irreversibility of myocardial necrosis. Generally, various changes can be observed in the ECG, including ST-T changes, QTc prolongation, arrhythmias, and T-wave inversions. Even though T-wave inversions can be seen in myocardial ischemia/infarction, they are rarely seen in acute cerebrovascular accidents (CVAs). We present the case of a 66-year-old woman who initially presented at our facility with dizziness in the context of orthostatic hypotension. An initial cardiac evaluation revealed no cardiac involvement. She was treated with intravenous fluids (IVF), which improved her symptoms. The patient's mental status was markedly altered approximately four days after admission. In this instance, she was found to have abnormal ECG findings (not previously observed on the ECG that was obtained on the day of admission), elevated troponin T levels, as well as elevated pro-B-type natriuretic peptide (pro-BNP). The patient was given aspirin and clopidogrel immediately and was placed on a heparin drip for a suspected non-ST elevation myocardial infarction (NSTEMI). A non-contrast computed tomography of the head revealed an acute cerebrovascular accident (CVA), following which the heparin drip was stopped. The patient was then transferred to another acute care facility capable of performing neurosurgical interventions. Additionally, a computed tomography angiography (CTA) of the chest and lower extremities venous duplex showed bilateral pulmonary emboli and deep venous thrombosis (DVT), respectively.

Computational Design of a Chimeric Vaccine against Plesiomonas shigelloides Using Pan-Genome and Reverse Vaccinology.

The swift emergence of antibiotic resistance (AR) in bacterial pathogens to make themselves adaptable to changing environments has become an alarming health issue. To prevent AR infection, many ways can be accomplished such as by decreasing the misuse of antibiotics in human and animal medicine. Among these AR bacterial species, Plesiomonas shigelloides is one of the etiological agents of intestinal infection in humans. It is a gram-negative rod-shaped bacterium that is highly resistant to several classes of antibiotics, and no licensed vaccine against the aforementioned pathogen is available. Hence, substantial efforts are required to screen protective antigens from the pathogen whole genome that can be subjected easily to experimental evaluations. Here, we employed a reverse vaccinology (RV) approach to design a multi-antigenic epitopes based vaccine against P. shigelloides. The complete genomes of P. shigelloides were retrieved from the National Center for Biotechnological Information (NCBI) that on average consist of 5226 proteins. The complete proteomes were subjected to different subtractive proteomics filters, and in the results of that analysis, out of total proteins, 2399 were revealed as non-redundant and 2827 as redundant proteins. The non-redundant proteins were further checked for subcellular localization analysis, in which three were localized in the extracellular matrix, eight were outer membrane, and 13 were found in the periplasmic membrane. All surface localized proteins were found to be virulent. Out of a total of 24 virulent proteins, three proteins (flagellar hook protein (FlgE), hypothetical protein, and TonB-dependent hemoglobin/transferrin/lactoferrin family receptor protein) were considered as potential vaccine targets and subjected to epitopes prediction. The predicted epitopes were further examined for antigenicity, toxicity, and solubility. A total of 10 epitopes were selected (GFKESRAEF, VQVPTEAGQ, KINENGVVV, ENKALSQET, QGYASANDE, RLNPTDSRW, TLDYRLNPT, RVTKKQSDK, GEREGKNRP, RDKKTNQPL). The selected epitopes were linked with each other via specific GPGPG linkers in order to design a multi-epitopes vaccine construct, and linked with cholera toxin B subunit adjuvant to make the designed vaccine construct more efficient in terms of antigenicity. The 3D structure of the vaccine construct was modeled ab initio as no appropriate template was available. Furthermore, molecular docking was carried out to check the interaction affinity of the designed vaccine with major histocompatibility complex (MHC-)I (PDB ID: 1L1Y), MHC-II (1KG0), and toll-like receptor 4 ((TLR-4) (PDB: 4G8A). Molecular dynamic simulation was applied to evaluate the dynamic behavior of vaccine-receptor complexes. Lastly, the binding free energies of the vaccine with receptors were estimated by using MMPB/GBSA methods. All of the aforementioned analyses concluded that the designed vaccine molecule as a good candidate to be used in experimental studies to disclose its immune protective efficacy in animal models.

Virtual screening and drug repositioning of FDA-approved drugs from the ZINC database to identify the potential hTERT inhibitors.

The length of the telomeres is maintained with the help of the enzyme telomerase constituting of two components, namely, a core reverse transcriptase protein (hTERT) and RNA (hTR). It serves as a significant and universal cancer target. In silico approaches play a crucial role in accelerating drug development processes, especially cancer drug repurposing is an attractive approach. The current study is aimed at the repurposing of FDA-approved drugs for their potential role as hTERT inhibitors. Accordingly, a library of 2,915 sets of FDA-approved drugs was generated from the ZINC database in order to screen for novel hTERT inhibitors; later on, these were subjected to molecular docking analysis. The top two hits, ZINC03784182 and ZINC01530694, were shortlisted for molecular dynamic simulation studies at 100 ns based on their binding scores. The RMSD, RMSF, Rg, SASA, and interaction energies were calculated for a 100-ns simulation period. The hit compounds were also analyzed for antitumor activity, and the results revealed promising cytotoxic activities of these compounds. The study has revealed the potential application of these drugs as antitumor agents that can be useful in treating cancer and can serve as lead compounds for further in vivo, in vitro, and clinical studies.