Research

ABSTRACT We demonstrated earlier that post-exposure prophylaxis with 3′-azido-3′-deoxythymidine (AZT, zidovudine) or with AZT + interferon-α (IFN-α) prevented viremia and disease in BALB/c mice inoculated with Rauscher murine leukemia virus (RLV). After the 20-day treatment course, most animals were resistant to rechallenge with live virus. Adoptive transfer of T cells from such resistant but not from normal mice into naive recipients provided full protection against virus challenge. From these experiments, we concluded that post-exposure chemoprophylaxis restricted virus replication and allowed the animals to form protective, long-lasting cellular immune responses. Here, the role for cellular immunity during antiviral chemoprophylaxis was tested by comparing treatment success in normal BALB/c mice and in their nude, athymic counterparts. Both were inoculated with equal doses of RLV (104 plaque-forming units, pfu). Single-agent AZT or combination therapy with AZT + IFN-α, started before or after RLV inoculation, prevented viremia in all normal but not in most nude mice. A significant number of nude mice were completely protected by chemoprevention only when given a 10 times lower virus dose. When normal mice were injected with a 10 times higher virus dose (105 pfu), complete protection by chemoprevention was lost. These results demonstrate that the success of chemoprevention depends critically on the virus inoculum. The differential success of chemoprevention in normal and T-cell-deficient mice implies that effective cellular immunity plays an important role in protecting virus-exposed animals against viremia and disease.

We investigated transmission of rhinovirus colds by examining shedding by infected patients, survival of virus outside the host, and inoculation of susceptible persons. Two of 25 infected persons e...

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ABSTRACT The heptad repeat (HR), a conserved structural motif of class I viral fusion proteins, is responsible for the formation of a six-helix bundle structure during the envelope fusion process. The insect baculovirus F protein is a newly found budded ...

ABSTRACT During viral entry, the paramyxovirus fusion (F) protein fuses the viral envelope to a cellular membrane. Similar to other class I viral fusion glycoproteins, the F protein has two heptad repeat regions (HRA and HRB) that are important in ...

Extensive regions of heptad repeat units consistent with an α-helical coiled coil conformation are located adjacent to hydrophobic, potentially fusion-related regions in the amino acid sequences of paramyxovirus fusion and retrovirus envelope glycoproteins. Similar arrangements of hydrophobic peptides and heptad repeat units exist in coronavirus peplomer proteins and influenza virus haemagglutinins. This suggests that there may be similarities in the structures of these proteins and in the functions of the hydrophobic fusion-related regions during virus entry.

Archives of Virology - A large set of monoclonal antibodies (MAbs) directed against the fusion glycoprotein complex F1F2 of bovine respiratory syncytial virus (BRSV) and several polyclonal sera...

Abstract. The fusion of the SARS-CoV-2 virus with cells, a key event in the pathogenesis of Covid-19, depends on the assembly of a six-helix fusion core (F

Author Summary The HIV-1 envelope glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41 is the prime target for neutralizing antibodies. Receptor binding induces a conformational change in gp41 that transiently exposes the conserved heptad repeat 1 (HR1) region. We have previously isolated the human HR1-specific mAb HK20 and provide now the structural basis for epitope recognition. HK20 employs mainly its CDR H2 and H3 for binding similar to HR1 binding of mAb D5. We demonstrate that HK20 and D5 bind HR1 with similar affinities; however, HK20 has a broader neutralization breadth than D5, which might be due to the differences in their approach angles of epitope recognition. Competition analyses of 33 sera from HIV-1 infected individuals reveal significant titers of HK20-inhibiting antibodies in 20 cases, confirming the immunogenicity of the epitope. We demonstrate further that HK20 IgG have limited neutralization breadth and potency while smaller HK20 Fabs and scFv reveal a broad cross clade neutralization breadth. This suggests that the accessibility of the HR1 epitope limits the value of HR1 mAbs for infection prevention, but highlights the importance of smaller versions such Fabs or scFv to combat infection alone or in synergistic approaches with other antivirals.

Acta Pharmacologica Sinica - Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

Retrocyclin RC-101, a θ-defensin with lectin-like properties, potently inhibits infection by many HIV-1 subtypes by binding to the heptad repeat 2 (HR2) region of glycoprotein 41 (gp41) and preventin...

Crystals of the fusion core of SARS-CoV spike protein have been grown at 291 K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.8 Å resolution at 100 K in-house. The crystals have unit-cell parameters a = 121.2, b = 66.3, c = 70.0 Å, α = γ = 90, β = 107.4° and belong to space group C2.

InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.

In spite of the important regulatory functions of antisense transcripts in gene expression, it remains unknown how antisense transcription is initiated. Recent studies implicated RNA polymerase II in initiation of antisense transcription. However, ...

The aetiological agent of an emergent outbreak of atypical pneumonia, severe acute respiratory syndrome (SARS), is a positive-stranded RNA virus (SARS-CoV) belonging to the Coronaviridae family with a genome that differs substantially from those of other known coronaviruses. Highly conserved heptad-repeat (HR1 and HR2) regions in class I viral fusion proteins, including spike protein from SARS coronavirus, interact with each other to form a six-helix bundle, which is called a fusion core. The crystal structure of the fusion core is expected to greatly facilitate drug design. Crystals of the fusion core of SARS-CoV spike protein have been grown at 291 K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.8 Å resolution at 100 K in-house. The crystals have unit-cell parameters a = 121.2, b = 66.3, c = 70.0 Å, α = γ = 90, β = 107.4° and belong to space group C2. Assuming the presence of six molecules per asymmetric unit, the solvent content is estimated to be about 28%.

Cryptic antisense transcription contributes to tumorigenesis.

Non-coding antisense transcripts arise from the strand opposite the sense strand. Over 70% of the human genome generates non-coding antisense transcripts while less than 2% of the genome codes for proteins. Antisense transcripts and/or the act of antisense transcription regulate gene expression and genome integrity by interfering with sense transcription and modulating histone modifications or DNA methylation. Hence, they have significant pathological and physiological relevance. Indeed, antisense transcripts were found to be associated with various diseases including cancer, diabetes, cardiac and neurodegenerative disorders, and, thus, have promising potentials for prognostic and diagnostic markers and therapeutic development. However, it is not clearly understood how antisense transcription is initiated and epigenetically regulated. Such knowledge would provide new insights into the regulation of antisense transcription, and hence disease pathogenesis with therapeutic development. The recent studies on antisense transcription initiation and its epigenetic regulation, which are limited, are discussed here. Furthermore, we concisely describe how antisense transcription/transcripts regulate gene expression and genome integrity with implications in disease pathogenesis and therapeutic development.

Natural antisense transcripts (NATs) are a group of RNAs encoded within a cell that have transcript complementarity to other RNA transcripts.[1] They have been identified in multiple eukaryotes, including humans, mice, yeast and Arabidopsis thaliana.[2] This class of RNAs includes both protein-coding and non-coding RNAs.[3] Current evidence has suggested a variety of regulatory roles for NATs, such as RNA interference (RNAi), alternative splicing, genomic imprinting, and X-chromosome inactivation.[4] NATs are broadly grouped into two categories based on whether they act in cis or in trans.[5] Trans-NATs are transcribed from a different location than their targets and usually have complementarity to multiple transcripts with some mismatches.[6] MicroRNAs (miRNA) are an example of trans-NATs that can target multiple transcripts with a few mismatches.[6] Cis-natural antisense transcripts (cis-NATs) on the other hand are transcribed from the same genomic locus as their target but from the opposite DNA strand and form perfect pairs.[7]

Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington’s disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies.

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Background Recent studies in budding yeast have shown that antisense transcription occurs at many loci. However, the functional role of antisense transcripts has been demonstrated only in a few cases and it has been suggested that most antisense transcripts may result from promiscuous bi-directional transcription in a dense genome. Results Here, we use strand-specific RNA sequencing to study anti-sense transcription in Saccharomyces cerevisiae. We detect 1,103 putative antisense transcripts expressed in mid-log phase growth, ranging from 39 short transcripts covering only the 3' UTR of sense genes to 145 long transcripts covering the entire sense open reading frame. Many of these antisense transcripts overlap sense genes that are repressed in mid-log phase and are important in stationary phase, stress response, or meiosis. We validate the differential regulation of 67 antisense transcripts and their sense targets in relevant conditions, including nutrient limitation and environmental stresses. Moreover, we show that several antisense transcripts and, in some cases, their differential expression have been conserved across five species of yeast spanning 150 million years of evolution. Divergence in the regulation of antisense transcripts to two respiratory genes coincides with the evolution of respiro-fermentation. Conclusions Our work provides support for a global and conserved role for antisense transcription in yeast gene regulation.

Healthcare has long been marked by the authoritative-physician-passive-patient interaction, with patients seeking help and physicians seeking to restore patients back to health. However, globalisation, social movements, and technological advancements are transforming the nature of this relationship. …

Antisense nucleic acids have been shown to be potent and specific inhibitors of gene expression and viral replication in cells from various species, including mammals. Their potential applicability in vivo has been demonstrated by the use of antisense oligonucleotides and antisense RN A transcribed from recombinant antisense genes, respectively. It is conceivable that both classes of antisense nucleic acids can be used to correct pathogenic cellular or viral gene expression, thereby extending the range of therapeutic options from new techniques developed in the field of molecular biology. Possible improvements in the inhibitory potential of antisense nucleic acids and selected points to consider concerning their design, their function, and their application are discussed.

Adherence to prescribed oral anticancer therapy is an important determinant of patient outcomes, including progression-free and overall survival. While many factors (eg, medication side effects and out-of-pocket costs, problems with insurance authorization, and timely medication refills) can affect …

Given the relatively low cost of the Wellth intervention, our findings provide preliminary evidence of cost savings from implementing Wellth among adults with several common chronic conditions.

Chronic obstructive pulmonary disease (COPD) is a condition that significantly impacts both patients and healthcare systems. The management of COPD involves various pharmacological intervention strategies, and addressing the issue of low adherence to these strategies has become a subject of signific …

Gain-framed incentives are superior to loss-framed ones in improving adherence to pediatric obesity treatments.