An ISG15-Based High-Throughput Screening Assay for Identification and Characterization of SARS-CoV-2 Inhibitors Targeting Papain-like Protease.

Emergence of newer variants of SARS-CoV-2 underscores the need for effective antivirals to complement the vaccination program in managing COVID-19. The multi-functional papain-like protease (PLpro) of SARS-CoV-2 is an essential viral protein that not only regulates the viral replication but also modulates the host immune system, making it a promising therapeutic target. To this end, we developed an in vitro interferon stimulating gene 15 (ISG15)-based Förster resonance energy transfer (FRET) assay and screened the National Cancer Institute (NCI) Diversity Set VI compound library, which comprises 1584 small molecules.

Broad-Spectrum Small-Molecule Inhibitors Targeting the SAM-Binding Site of Flavivirus NS5 Methyltransferase.

Flavivirus infections, such as those caused by dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), and Zika virus (ZIKV), pose a rising threat to global health. There are no FDA-approved drugs for flaviviruses, although a small number of flaviviruses have vaccines. For flaviviruses or unknown viruses that may appear in the future, it is particularly desirable to identify broad-spectrum inhibitors.

A universal fluorescence polarization high throughput screening assay to target the SAM-binding sites of SARS-CoV-2 and other viral methyltransferases.

SARS-CoV-2 has caused a global pandemic with significant humanity and economic loss since 2020. Currently, only limited options are available to treat SARS-CoV-2 infections for vulnerable populations. In this study, we report a universal fluorescence polarization (FP)-based high throughput screening (HTS) assay for SAM-dependent viral methyltransferases (MTases), using a fluorescent SAM-analogue, FL-NAH.

Unusual trifurcation of left main coronary artery in a patient with hypertrophic obstructive cardiomyopathy: Issues in management strategy.

Background: Hypertrophic cardiomyopathy (HCM) and anomalous coronary artery arising from the opposite sinus are independently associated with increased risk of sudden cardiac death (SCD). Their coexistence in a single patient further complicates the issue by affecting management strategy and increasing the risk of sudden death.

Case Report: A 21-year-old woman with hypertrophic obstructive cardiomyopathy (HOCM) having strong family history of SCD presented with exertional fatigue and palpitation.

Allosteric inhibitors of the main protease of SARS-CoV-2.

SARS-CoV-2 has raised the alarm to search for effective therapy for this virus. To date several vaccines have been approved but few available drugs reported recently still need approval from FDA. Remdesivir was approved for emergency use only.

Isolated pneumopericardium; An extremely rare complication following active resuscitation in a term neonate.

Background: Pneumopericardium, presence of air in pericardial cavity, is rare entity with potentially severe complications and mortality. In the neonatal period, it is associated with prematurity, low birth weight, and assisted ventilation, but in full term neonates its occurrence after resuscitation is exceedingly rare.

Case Report: Our patient was a 2-day old full term neonate who developed respiratory distress following active resuscitation which was carried out at the time of birth in lieu of perinatal asphyxia.

Unguided temporary pacing via jugular/subclavian vein in an emergency department of a high-volume tertiary care hospital of India: its safety, efficacy, and practicability.

Background: Temporary pacing is usually performed by cardiologists under fluoroscopic, echocardiographic, or ECG guidance. However, in the developing world, there are inadequate number of cardiologists, and C-arm, catheterization laboratories, or echocardiography are not available at primary or secondary healthcare facilities. In addition, in emergencies option of fluoroscopy and echocardiography is limited.

Assessment of the Left Atrial Reservoir Function and Left Atrial Volume After Percutaneous Balloon Mitral Valvuloplasty Using Peak Atrial Longitudinal Strain.

Objective To evaluate the impact of successful percutaneous balloon mitral valvuloplasty (BMV) on left atrial (LA) reservoir function and LA volume in patients with severe mitral stenosis (MS) using peak atrial longitudinal strain (PALS). Method This was a prospective, non-randomized observational study conducted at the Laxmipat Singhania (LPS) Institute of Cardiology, Kanpur from August 2018 to February 2020 among patients with severe rheumatic MS undergoing BMV to assess LA reservoir function and its volume after BMV using PALS. Inclusion criteria were symptomatic severe rheumatic MS (NYHA ≥II), normal ventricular systolic function, and suitable valve morphology.

Antiviral Agents against Flavivirus Protease: Prospect and Future Direction.

Flaviviruses cause a significant amount of mortality and morbidity, especially in regions where they are endemic. A recent example is the outbreak of Zika virus throughout the world. Development of antiviral drugs against different viral targets is as important as the development of vaccines.

Targeting Crucial Host Factors of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since its first incidence in Wuhan, China, in December 2019. Although the case fatality rate of COVID-19 appears to be lower than that of SARS and Middle East respiratory syndrome (MERS), the higher transmissibility of SARS-CoV-2 has caused the total fatality to surpass other viral diseases, reaching more than 1 million globally as of October 6, 2020. The rate at which the disease is spreading calls for a therapy that is useful for treating a large population.

Methylene blue is a potent and broad-spectrum inhibitor against Zika virus and .

Many flaviviruses including the Dengue virus (DENV), Zika virus (ZIKV), West Nile virus, Yellow Fever virus, and Japanese encephalitis virus are significant human pathogens, unfortunately without any specific therapy. Here, we demonstrate that methylene blue, an FDA-approved drug, is a broad-spectrum and potent antiviral against Zika virus and Dengue virus both and . We found that methylene blue can considerably inhibit the interactions between viral protease NS3 and its NS2B co-factor, inhibit viral protease activity, inhibit viral growth, protect 3D mini-brain organoids from ZIKV infection, and reduce viremia in a mouse model.

Prospect of SARS-CoV-2 spike protein: Potential role in vaccine and therapeutic development.

The recent outbreak of the betacoronavirus SARS-CoV-2 has become a significant concern to public health care worldwide. As of August 19, 2020, more than 22,140,472 people are infected, and over 781,135 people have died due to this deadly virus. In the USA alone, over 5,482,602 people are currently infected, and more than 171,823 people have died.

3D MHD nonlinear radiative flow of CuO-MgO/methanol hybrid nanofluid beyond an irregular dimension surface with slip effect.

The 3D MHD nonlinear radiative hybrid nanofluid flow across an irregular dimension sheet with slip effect is studied numerically. The hybrid nanofluid consists of copper oxide (CuO) and magnesium oxide (MgO) nanoparticles embedded in methanol or methyl alcohol (MA). The governing PDEs' are altered as ODEs' using similarities and numerical solutions are attained using shooting scheme.

Effect of SUMO-SIM Interaction on the ICP0-Mediated Degradation of PML Isoform II and Its Associated Proteins in Herpes Simplex Virus 1 Infection.

ND10 nuclear bodies, as part of the intrinsic defenses, impose repression on incoming DNA. Infected cell protein 0 (ICP0), an E3 ubiquitin ligase of herpes simplex virus 1 (HSV-1), can derepress viral genes by degrading ND10 organizers to disrupt ND10. These events are part of the initial tug of war between HSV-1 and host, which determines the ultimate outcome of infection.

Temporal Analysis of the Nuclear-to-cytoplasmic Translocation of a Herpes Simplex Virus 1 Protein by Immunofluorescent Confocal Microscopy.

Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an immediate early protein containing a RING-type E3 ubiquitin ligase. It is responsible for the proteasomal degradation of host restrictive factors and the subsequent viral gene activation. ICP0 contains a canonical nuclear localization sequence (NLS).

Characterization of Elements Regulating the Nuclear-to-Cytoplasmic Translocation of ICP0 in Late Herpes Simplex Virus 1 Infection.

Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an immediate early protein containing a RING-type E3 ubiquitin ligase. It targets several host factors for proteasomal degradation and subsequently activates viral expression. ICP0 has a nuclear localization sequence and functions in the nucleus early during infection.

A Tale of Two PMLs: Elements Regulating a Differential Substrate Recognition by the ICP0 E3 Ubiquitin Ligase of Herpes Simplex Virus 1.

Unlabelled: Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an α gene product required for viral replication at low multiplicities of infection. Upon entry, nuclear domain 10 (ND10) converges at the incoming DNA and represses viral gene expression. ICP0 contains a RING-type E3 ubiquitin ligase that degrades the ND10 organizer PML and disperses ND10 to alleviate the repression.

Heterologous Immunity between Adenoviruses and Hepatitis C Virus: A New Paradigm in HCV Immunity and Vaccines.

Adenoviruses (Ad) are commonly used as vectors for gene therapy and/or vaccine delivery. Recombinant Ad vectors are being tested as vaccines for many pathogens. We have made a surprising observation that peptides derived from various hepatitis C virus (HCV) antigens contain extensive regions of homology with multiple adenovirus proteins, and conclusively demonstrate that adenovirus vector can induce robust, heterologous cellular and humoral immune responses against multiple HCV antigens.

Immunization with Recombinant Adenoviral Vectors Expressing HCV Core or F Proteins Leads to T Cells with Reduced Effector Molecules Granzyme B and IFN-γ: A Potential New Strategy for Immune Evasion in HCV Infection.

Multispecific, broad, and potent T cell responses have been correlated with viral clearance in hepatitis C virus (HCV) infection. However, the majority of infected patients develop chronic infection, suggesting that natural infection mostly leads to development of inefficient T cell immunity. Multiple mechanisms of immune modulation and evasion have been shown in HCV infection through various investigations.

Co-incubation with core proteins of HBV and HCV leads to modulation of human dendritic cells.

Hepatitis B and C (HBV and HCV) are hepatotropic viruses in humans with approximately 350 and 170 million chronic carriers respectively. Since both viruses have similar modes of transmission, many people are co-infected. Co-infection is common in intravenous drug users, HIV-positive individuals, and transplant recipients.

Recombinant adenoviral vector expressing HCV NS4 induces protective immune responses in a mouse model of Vaccinia-HCV virus infection: a dose and route conundrum.

Hepatitis C virus (HCV) leads to chronic infection in the majority of infected patients presumably due to failure or inefficiency of the immune responses generated. Both antibody and cellular immune responses have been suggested to be important in viral clearance. Non-replicative adenoviral vectors expressing antigens of interest are considered as attractive vaccine vectors for a number of pathogens.

Alternate reading frame protein (F protein) of hepatitis C virus: paradoxical effects of activation and apoptosis on human dendritic cells lead to stimulation of T cells.

Hepatitis C virus (HCV) leads to chronic infection in the majority of infected individuals due to lack, failure, or inefficiency of generated adaptive immune responses. In a minority of patients, acute infection is followed by viral clearance. The immune correlates of viral clearance are not clear yet but have been extensively investigated, suggesting that multispecific and multifunctional cellular immunity is involved.