Identification and targeting of a unique Na1.7 domain driving chronic pain.

Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na1.

Implementing use of sucrose analgesia (non-pharmacological management of neonatal pain) in a standalone private facility level 3 neonatal care unit using point of care quality improvement methodology.

Background: Neonatal pain not only has negative impact on the acute physiological parameters of the neonate but also has got the potential to cause long-term neurodevelopmental disabilities. However, neonatal pain especially related to procedures is not well recognised and often poorly managed in neonatal intensive care unit (NICU).

Local Problem: Oral sucrose solution became available commercially in late 2017 and this provided us the opportunity to alleviate some of the procedural pain in neonates admitted in our NICU.

Stereospecific Effects of Benzimidazolonepiperidine Compounds on T-Type Ca Channels and Pain.

T-type calcium channels activate in response to subthreshold membrane depolarizations and represent an important source of Ca influx near the resting membrane potential. These channels regulate neuronal excitability and have been linked to pain. For this reason, T-type calcium channels are suitable molecular targets for the development of new non-opioid analgesics.

Stimulatory responses in α- and β-cells by near-infrared (810 nm) photobiomodulation.

Significant efforts have been committed to better understand and regulate insulin secretion as it has direct implications on diabetes. The first phase of biphasic insulin secretion in response to glucose lasts about 10 minutes, followed by a more sustained release persisting several hours. Attenuated insulin release in the first phase is typically associated with abnormal β-cells.

Neonatal Multisystem Inflammatory Syndrome (MIS-N) Associated with Prenatal Maternal SARS-CoV-2: A Case Series.

Multisystem inflammatory syndrome in children (MIS-C) is a post-infectious immune-mediated condition, seen 3-5 weeks after COVID-19. Maternal SARS-CoV-2 may potentially cause a similar hyperinflammatory syndrome in neonates due to transplacental transfer of antibodies. We reviewed the perinatal history, clinical features, and outcomes of 20 neonates with features consistent with MIS-C related to maternal SARS-CoV-2 in Kolhapur, India, from 1 September 2020 to 30 April 2021.

Enhancing the bystander killing effect of an oncolytic HSV by arming it with a secretable apoptosis activator.

Although oncolytic viruses have shown great promise as cancer therapeutics, results from a recent phase III clinical trial indicate that their potency may need further improvement for a clear clinical benefit. Here, we report a novel strategy to increase the bystander effect of virotherapy by arming an oncolytic virus with a secreted form of a Her2 single chain antibody linked to a self-multimerizing Fas ligand extracellular domain (Her2-COL-sFasL). The rationale is that, due to its much smaller size, this apoptosis activator can overcome obstacles such as the dense collagen in the tumor tissues to spread more freely than the viral particles.

A proposed clinical decision support architecture capable of supporting whole genome sequence information.

Whole genome sequence (WGS) information may soon be widely available to help clinicians personalize the care and treatment of patients. However, considerable barriers exist, which may hinder the effective utilization of WGS information in a routine clinical care setting. Clinical decision support (CDS) offers a potential solution to overcome such barriers and to facilitate the effective use of WGS information in the clinic.

Service oriented architecture for clinical decision support: a systematic review and future directions.

The use of a service-oriented architecture (SOA) has been identified as a promising approach for improving health care by facilitating reliable clinical decision support (CDS). A review of the literature through October 2013 identified 44 articles on this topic. The review suggests that SOA related technologies such as Business Process Model and Notation (BPMN) and Service Component Architecture (SCA) have not been generally adopted to impact health IT systems' performance for better care solutions.

Correlation between shiftide activity and HIV-1 integrase inhibition by a peptide selected from a combinatorial library.

The human immunodeficiency virus type 1 (HIV-1) integrase (IN) protein is an emerging target for the development of anti-HIV drugs. We recently described a new approach for inhibiting IN by "shiftides"--peptides that inhibit the protein by shifting its oligomerization equilibrium from the active dimer to the inactive tetramer. In this study, we used the yeast two-hybrid system with the HIV-1 IN as a bait and a combinatorial peptide aptamer library as a prey to select peptides of 20 amino acids that specifically bind IN.

Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium.

Proteins are involved in various equilibria that play a major role in their activity or regulation. The design of molecules that shift such equilibria is of great therapeutic potential. This fact was demonstrated in the cases of allosteric inhibitors, which shift the equilibrium between active and inactive (R and T) states, and chemical chaperones, which shift folding equilibrium of proteins.

Interaction between HIV-1 Rev and integrase proteins: a basis for the development of anti-HIV peptides.

Human immunodeficiency virus 1 (HIV-1) Rev and integrase (IN) proteins are required within the nuclei of infected cells in the late and early phases of the viral replication cycle, respectively. Here we show using various biochemical methods, that these two proteins interact with each other in vitro and in vivo. Peptide mapping and fluorescence anisotropy showed that IN binds residues 1-30 and 49-74 of Rev.

Expression and characterization of a recombinant novel reverse transcriptase of a porcine endogenous retrovirus.

The study of porcine endogenous retroviruses (PERVs) becomes increasingly important due to the potential use of pig cells, tissues, and organs as a source for xenogenic cell therapy and xenotransplantation into humans. Consequently, we have constructed a plasmid that induces in bacteria the synthesis of a soluble and highly active reverse transcriptase (RT) of PERV-B. The purified PERV RT was studied biochemically in comparison with the RT of murine leukemia virus (MLV), because of the high-sequence homology between these two RTs.

Mutagenesis of cysteine 280 of the reverse transcriptase of human immunodeficiency virus type-1: the effects on the ribonuclease H activity.

Retroviral reverse transcriptases (RTs) have both DNA polymerase and ribonuclease H (RNase H) activities. The RT of human immunodeficiency virus type-1 (HIV-1) is composed of two subunits. The p51, which is the smaller subunit, shares with the larger p66 subunit the same amino-terminal part (which encompasses the DNA polymerase domain) and lacks the carboxyl-terminal segment of the p66 (which is the RNase H domain).

The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is modulated by residue 294 of the small subunit.

Reverse transcriptases (RTs) exhibit DNA polymerase and ribonuclease H (RNase H) activities. The RTs of human immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2) are composed of two subunits, both sharing the same N-terminus (which encompasses the DNA polymerase domain). The smaller subunit lacks the C-terminal segment of the larger one, which contains the RNase H domain.

Mode of inhibition of HIV-1 reverse transcriptase by polyacetylenetriol, a novel inhibitor of RNA- and DNA-directed DNA polymerases.

Polyacetylenetriol (PAT), a natural marine product from the Mediterranean sea sponge Petrosia sp., was found to be a novel general potent inhibitor of DNA polymerases. It inhibits equally well the RNA- and DNA-dependent DNA polymerase activities of retroviral reverse transcriptases (RTs) (i.

Clathsterol, a novel anti-HIV-1 RT sulfated sterol from the sponge Clathria species.

As part of a search for novel inhibitors of humandeficiency virus type 1 (HIV-1) reverse transcriptase (RT), the MeOH-EtOAc extract of a Red Sea sponge, Clathria sp., was shown to be active. Bioassay-guided fractionation of the extract yielded a novel sterol sulfate, clathsterol (1), which is responsible for the activity and is active at a concentration of 10 microM.

The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is affected by the thumb subdomain of the small protein subunits.

Retroviral reverse transcriptases (RTs) have both DNA polymerase and ribonuclease H (RNase H) activities. The RTs of HIV-1 and HIV-2 are heterodimers of p66/p51 and p68/p54 subunits, respectively. The smaller subunit lacks the C-terminal segment of the larger subunit (which is the RNase H domain).

New co-metabolites of the streptazolin pathway.

Variation of the culture conditions of Streptomyces sp. strain A1, which produces streptazolin (1), resulted in the isolation of four new co-metabolites: 5-O-(beta-D-xylopyranosyl)streptazolin (3), 9-hydroxystreptazolin (4), 13-hydroxystreptazolin (5), and streptenol E (6). Their structures were established by spectroscopic and chemical methods.

Polycitone A, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular DNA polymerases.

Polycitone A, an aromatic alkaloid isolated from the ascidian Polycitor sp. exhibits potent inhibitory capacity of both RNA- and DNA-directed DNA polymerases. The drug inhibits retroviral reverse transcriptase (RT) [i.

The inhibition of the reverse transcriptase of HIV-1 by the natural sulfoglycolipids from cyanobacteria: contribution of different moieties to their high potency.

The potent in vitro inhibition of the enzymatic activity of the human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT) by the lipophilic extracts of cyanobacteria8 was primarily attributed to the sulfoquinovosylpranosyl lipids, compounds 1-4. These sulfolipids inhibit efficiently and selectively only the DNA polymerase activity of HIV-1 RT (and not the ribonuclease H function) with 50% inhibitory concentration value (IC50) as low as 24 nM exhibited by compound 1. The novel natural compound 4, in which two hydroxy groups on the sugar moiety are substituted by palmitoyl residues, exhibits a significant decrease in the maximal inhibition capacity.

Reverse transcriptase of mouse mammary tumour virus: expression in bacteria, purification and biochemical characterization.

We have constructed a plasmid that induces in bacteria the synthesis of an enzymically active reverse transcriptase (RT) of mouse mammary tumour virus (MMTV), a retrovirus with a typical B-type morphology. The highest catalytic activity was detected only when 27 residues from the C-terminus of the protease were included in the N-terminus of the recombinant RT, after an extra deoxyadenosine was added between the pro and pol genes to overcome the -1 frameshift event (which occurs naturally in virus-infected cells). The recombinant protein with a six-histidine tag was purified to homogeneity by a two-column purification procedure, Ni2+ nitriloacetic acid/agarose followed by carboxymethyl-Sepharose chromatography.

New acylated sulfoglycolipids and digalactolipids and related known glycolipids from cyanobacteria with a potential to inhibit the reverse transcriptase of HIV-1.

Five novel diacylated sulfoglycolipids (1-5) were isolated from the cyanobacterium Scytonema sp. (TAU strain SL-30-1-4) and four novel acylated diglycolipids (6-9) were isolated from the cyanobacterium Oscillatoria raoi (TAU strain IL-76-1-2). These two groups of glycolipids and related known glycolipids isolated from these two and three other strains of cyanobacteria, Phormidium tenue (TAU strain IL-144-1), O.

Subunit-specific mutagenesis of the cysteine 280 residue of the reverse transcriptase of human immunodeficiency virus type 1: effects on sensitivity to a specific inhibitor of the RNase H activity.

Treatment of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) with N-ethylmaleimide (NEM) selectively inhibits the RNase H activity. The cysteine residue at position 280 (C280) is the target for NEM; HIV-1 RT carrying the mutation C280S is resistant to NEM. Since HIV-1 RT is composed of two related subunits (p66 and p51) that play distinct roles, we asked whether the C280 in p51 or the C280 in p66 is responsible for the sensitivity of the enzyme to NEM.

Mode of inhibition of HIV reverse transcriptase by 2-hexaprenylhydroquinone, a novel general inhibitor of RNA-and DNA-directed DNA polymerases.

A natural compound from the Red Sea sponge Ircinia sp., 2-hexaprenylhydroquinone (HPH), has been shown to be a general inhibitor of retroviral reverse transcriptases (from HIV-1, HIV-2 and murine leukaemia virus) as well as of cellular DNA polymerases (Escherichia coli DNA polymerase I, and DNA polymerases alpha and beta). The pattern of inhibition was found to be similar for all DNA polymerases tested.