Machine learning and classical MD simulation to identify inhibitors against the P37 envelope protein of monkeypox virus.

Monkeypox virus (MPXV) outbreak is a serious public health concern that requires international attention. P37 of MPXV plays a pivotal role in DNA replication and acts as one of the promising targets for antiviral drug design. In this study, we intent to screen potential analogs of existing FDA approved drugs of MPXV against P37 using state-of-the-art machine learning and computational biophysical techniques. AlphaFold2 guided all-atoms molecular dynamics simulations optimized P37 structure is used for molecular docking and binding free energy calculations. Similar to members of Phospholipase-D family , the predicted P37 structure also adopts a ß-α-ß-α-ß sandwich fold, harbouring strongly conserved HxKxxxxD motif. The binding pocket comprises of Tyr48, Lys86, His115, Lys117, Ser130, Asn132, Trp280, Asn240, His325, Lys327 and Tyr346 forming strong hydrogen bonds and dense hydrophobic contacts with the screened analogs and is surrounded by positively charged patches. Loops connecting the two domains and C-terminal region exhibit high degree of flexibility. In some structural ensembles, the partial disorderness in the C-terminal region is presumed to be due to its low confidence score, acquired during structure prediction. Transition from loop to ß-strands (244-254 aa) in P37-Cidofovir and its analog complexes advocates the need for further investigations. MD simulations support the accuracy of the molecular docking results, indicating the potential of analogs as potent binders of P37. Taken together, our results provide preferable understanding of molecular recognition and dynamics of ligand-bound states of P37, offering opportunities for development of new antivirals against MPXV. However, the need of in vitro and in vivo assays for confirmation of these results still persists.Communicated by Ramaswamy H. Sarma.

An immunoinformatic approach towards development of a potent and effective multi-epitope vaccine against monkeypox virus (MPXV).

Monkeypox is a viral zoonotic disease, often transmitted to humans from animals. While the whole world is haggling with the COVID-19 pandemic, the emergence of the monkeypox virus (MPXV) arose as a new challenge to mankind. Till date, numerous cases related to the MPXV have been reported in several countries across the globe, but, its momentary distribution in the current time has left everyone in fright with increasing mortality and limited clinically approved treatments. Therefore, it is of immense importance to develop a potent and highly effective vaccine capable of inducing desired immunogenic responses against the highly contagious MPXV. Herein, using various immunoinformatic and computational biology tools, we made an attempt to develop a multi-epitope vaccine construct against the MPXV which is antigenic, non-allergen and non-toxic in nature and capable of exhibiting immunogenic behavior. The sequence of vaccine construct was designed using the proposed 4 MHC-I, 3 MHC-II and 4 B-cell epitopes linked with suitable adjuvant and linkers. The modeled structure of the vaccine construct was used to assess its interaction with the Toll-like Receptor 4 (TLR4) using ClusPro and HADDOCK. All-atoms molecular dynamics simulation of the MPXV vaccine construct-TLR4 complex followed by a high level of gene expression of the construct within the bacterial system affirmed its stability along with induction of immunogenic response within the host cell. Altogether, our immunoinformatic approach aid in the development of a stable chimeric vaccine construct against MPXV and needs further experimental validation for its immunological relevance and usefulness as a vaccine candidate.Communicated by Ramaswamy H. Sarma.

Crude Extracts of Bacopa Monnieri Induces Dendrite Formation in Rodent Neural Stem Cell Cultures-A Possible Use in Neuronal Injury.

Background Repair of nervous tissue injury impairs positive functional outcome. Major challenges involved are formation of new neuronal cells at the site of injury, growth and development of existing or stem cell-derived neuronal cells, and proper anatomical alignment of the cells required for the functional organization of the nervous system. Stem cells and various agents have been tried to overcome the above challenges yielding only limited positive results. Bacopa has been in frequent usage for cognitive impairment in Ayurvedic medicine. The assumption that Bacopa monnieri (BM) extracts may lead to certain specific changes at the cellular structural level benefitting the central nervous system repair, prompted us for the present study. Objective This is an in vitro study evaluating the effect of BM extracts (bacopasides and analogues) on the neuronal stem cells (NSC) culture in various concentrations. The study investigates the possibility of BM as an agent for the regeneration and differentiation of nervous tissue injury. This may have clinical and therapeutic implications. Materials and Methods NSC were harvested from the newborn albino rats, Rattus norvegicus, and the BM extracts were obtained from product "brahmi" manufactured by Himalaya Drug Company. Aqueous suspension of 2 µL of alcoholic extract of BM was locally added to the culture plates of NSC in concentrations of 5, 10, and 20 µg/mL after development of NSC in the media. The control NSC (without BM) and BM-rich NSC were simultaneously observed at regular unit intervals after inoculation. The morphological change in the NSC were observed and recorded. Result NSC could be successfully cultured from the newborn rat's brain harvested at 3 and 6 hours of birth. NSCs derived at 3 hours of birth were more primitive (predominantly neurospheres) than derived those at 6 hours of birth. BM had significant positive effect on the neurospheres, that is, dendritic formation was seen in the NSC predominating when 2 µL of suspensions containing 5 and 10 µg/mL concentration of the extracts were used but showed relatively lesser effect at concentration of 20 µg/mL. The positive effect was biologically significant. Conclusion NSC can be cultured from brain of the newborn rodent. BM and its extracts act positively on NSC in terms of dendritic formation when used in proper appropriate concentration. The study opens up a new area of research and explores newer avenues in nervous tissue injury repair. It may have future clinical implication in the treatment of injury of central and peripheral nervous tissue. However, the hypothesis needs to be validated by adequate number of experimental runs as well as in vivo studies to know the reproducibility of the findings in other centers.

Acoustic Bruit Transduction Interface for Non-Invasive Vascular Access Monitoring.

Hemodialysis is a treatment for patients suffering from chronic or acute kidney disease, and is administered via an arteriovenous vascular access. One symptom of a dysfunctional vascular access are blood sounds (bruits) produced by turbulent flow. This paper discusses the design and characterization of a multichannel transducer array to capture blood sounds from multiple sites simultaneously. Recorded sounds can be classified by digital signal analysis to categorize severity of dysfunction based on acoustic features. Using a vascular access phantom with 5-80% degree of stenosis and blood mimicking fluid flowing at a rate of 850-1200 mL/min, we analyzed the acoustic properties of blood sounds recorded from a flexible microphone transducer. The signal bandwidth (2.25 kHz) and the dynamic range (60.2 dB) were determined, allowing optimization of a transimpedance transducer interface amplifier.Clinical Relevance-Vascular access stenosis causing turbulent flow produces bruits with spectral content related to degree of stenosis. A flexible microphone recording array could be used for point-of-care monitoring of vascular access function.

Totally cystic intradural schwannoma in thoracic region.

Spinal schwannomas are benign intradural extramedullary tumors arising from spinal nerve root sheath. They are usually solid or heterogeneously solid. Totally cystic schwannomas are rare entities. Herein, we report a 60-year-old male presenting with backache radiating along the chest wall and weakness of both lower limbs. He had spastic paraparesis. Magnetic resonance imaging revealed a cystic mass in the thoracic region. At operation, the cystic mass was seen to be attached to D4 dorsal rootlets. It was excised in toto and histopathology confirmed it to be a schwannoma. The relevant literature is reviewed.

Moyamoya Disease Associated with Recurrent Right Thalamic Haemorrhage and Hydrocephalus: A Case Report.

Moyamoya disease, a rare chronic, progressive cerebrovascular disease leads to occlusion of intracranial internal carotid arteries and its proximal branches. We report a case of a 51-year-old female who presented with recurrent thalamic bleed and intraventricular haemorrhage nine years apart in the same territory. The first bleed was managed conservatively and second bleed led to development of hydrocephalus. The acute phase of the hydrocephalus was managed by external ventricular drainage and the final CSF diversion was managed by ventriculoperitoneal shunt. The definitive treatment could not be done to denial of consent from the patient. We present the case to highlight the role CSF diversion as a means of palliative treatment for the Moyamoya disease.

Contralateral approach to unruptured superior hypophyseal artery aneurysms.

OBJECTIVE: To evaluate the feasibility and limitations of the contralateral approach to unruptured superior hypophyseal artery (SHA) aneurysms. METHODS: Data regarding eight cases of superior hypophyseal artery aneurysms operated on by a contralateral pterional approach at our center from January 2008 to September 2010 were collected and evaluated retrospectively. Of these eight cases, six were male and two were female. The mean age was 57.1 years (range 28 years to 77 years). All the aneurysms were unruptured; five were on right side and three were on left side. The surgical technique and outcome of patients were reviewed. RESULTS: All aneurysms were successfully clipped without complication and patency of all superior hypophyseal arteries was preserved. Postoperative three-dimensional computed tomography angiography revealed residual aneurysm in only one case. None of the patients had deterioration of visual acuity or field after surgery. The contralateral pterional approach was found to be appropriate for fully exposing the aneurysmal dome and neck without retraction of the optic nerve or the carotid artery in five cases. Slight retraction of the optic nerve was required in two cases, and significant manipulation of the optic nerve was required in one case. CONCLUSIONS: The contralateral pterional approach for clipping of unruptured superior hypophyseal artery aneurysms is technically feasible and safe in a select group of patients where optimal results can be achieved without significant retraction of near by neurovascular structures.

Carotid agenesis with intercavernous anastomosis.

Agenesis of internal carotid artery (ICA) is rare. Association of agenesis with abnormal arterial communication between the cavernous segment of the carotid arteries is extremely rare. We present a case of a middle-aged woman who presented with sudden onset severe holocranial headache. She was investigated and diagnosed to have sub-arachnoid hemorrhage on CT scan. Digital Subtraction Angiogram revealed absent right internal carotid artery. The right middle cerebral artery received blood supply from an incidentally detected intercavernous anastomosis from the left internal carotid artery. No aneurysm, arteriovenous malformation or any other vascular abnormality was detected. The patient was managed conservatively. She has been asymptomatic for five years on follow up.

Primary intraosseus cavernous hemangioma of the skull base.

Primary intraosseous cavernous hemangioma (PICH) of the skull is rare. We present a case of 11-year-old boy with PICH of the sphenoid bone. The Computed Tomogram showed a classical sunburst appearance. Safe excision as much as possible was attempted after embolization. The child however, succumbed to postoperative infection. The preferred treatment is complete tumor removal with normal bony margins. However, this may not be possible in extensive skull base involvement. Preoperative embolisation can reduce intraoperative blood loss. Radiotherapy may be added where complete excision is not possible.

An objective assessment of demography of gallbladder cancer.

BACKGROUND AND OBJECTIVES: Gallbladder cancer (GBC) is a lethal disease with a wide geographical, ethnic, and cultural variation suggesting major environmental influences such as diet and life style factors in the development of disease. An objective assessment of demographic profile and full implication of these features to recognize the population at risk is needed. This study was therefore undertaken to study the demography of GBC in Varanasi. METHODS: A retrospective study as a case-control model comprised 328 cases of GBC and 328 controls with gallstone disease (GSD). The relevant demographic data were collected and analyzed for identification of independent significant features and for the risk of GBC based on these features by calculating odds ratio. RESULTS AND CONCLUSIONS: GBC predominantly a disease of females belonged to fourth and fifth decade of life. Among 328 cases of GBC only 75 were male and 253 female (M:F = 1:3.37). Majority of GBC patients were above 40 years and multiparous females. Family history of GBC was higher in GBC patients. Majority of GBC patients were of low socioeconomic status and hailed from rural background. This group tends to consume open mustard oil and water from hand pump. This study emphasizes the usefulness of demographic evaluation in diagnosis of GBC and a systematic approach to assessment of demographic features of GBC is recommended.