Secretion of functional interferon by the type 3 secretion system of enteropathogenic Escherichia coli.

Background: Type I interferons (IFN-I)-a group of cytokines with immunomodulatory, antiproliferative, and antiviral properties-are widely used as therapeutics for various cancers and viral diseases. Since IFNs are proteins, they are highly susceptible to degradation by proteases and by hydrolysis in the strong acid environment of the stomach, and they are therefore administered parenterally. In this study, we examined whether the intestinal bacterium, enteropathogenic Escherichia coli (EPEC), can be exploited for oral delivery of IFN-Is.

Direct and indirect effects of CYTOR lncRNA regulate HIV gene expression.

The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a stable pool of infected cell reservoir that is resistant to therapy and thus a main barrier towards complete elimination of viral infection. While the mechanisms by which host proteins govern viral gene expression and latency are well-studied, the emerging regulatory functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and viral latency have not yet been thoroughly explored.

Role of long noncoding RNA in regulating HIV infection-a comprehensive review.

A complete cure against human immunodeficiency virus (HIV) infection remains out of reach, as the virus persists in stable cell reservoirs that are resistant to antiretroviral therapy. The key to eliminating these reservoirs lies in deciphering the processes that govern viral gene expression and latency. However, while we comprehensively understand how host proteins influence HIV gene expression and viral latency, the emerging role of long noncoding RNAs (lncRNAs) in the context of T cell activation, HIV gene expression, and viral latency remain unexplored.

Differential platelet activation through an interaction with spike proteins of different SARS-CoV-2 variants.

COVID-19 disease is associated with an increased risk of thrombotic complications, which contribute to high short-term mortality. Patients with COVID-19 demonstrate enhanced platelet turnover and reactivity, which may have a role in the development of thrombotic events and disease severity. Evidence has suggested direct interaction between SARS-CoV-2 and platelets, resulting in platelets activation.

Correlates of protection for booster doses of the SARS-CoV-2 vaccine BNT162b2.

Vaccination, especially with multiple doses, provides substantial population-level protection against COVID-19, but emerging variants of concern (VOC) and waning immunity represent significant risks at the individual level. Here we identify correlates of protection (COP) in a multicenter prospective study following 607 healthy individuals who received three doses of the Pfizer-BNT162b2 vaccine approximately six months prior to enrollment. We compared 242 individuals who received a fourth dose to 365 who did not.

Functional Analysis of Spike from SARS-CoV-2 Variants Reveals the Role of Distinct Mutations in Neutralization Potential and Viral Infectivity.

Enhanced viral transmission and escape from vaccine-elicited neutralizing antibodies drive worldwide spread of SARS-CoV-2 variants and promote disease progression. However, the impact of specific spike mutations that are carried by different viral variants on viral infectivity and neutralization sensitivity has not been completely defined. Here, we use pseudoviruses to assess the contribution of spike mutations within the Receptor Binding Domain (RBD) and the Furin Cleavage Site (FCS), and appear in circulating viral variants, on viral infectivity and neutralization potential against sera that was drawn from fully vaccinated individuals.

Bcl-2-Homology-Only Proapoptotic Peptides Modulate β-Amyloid Aggregation and Toxicity.

Aggregation of the β-Amyloid (Aβ) peptide in brain tissues is the hallmark of Alzheimer's disease (AD). While Aβ is presumed to be insidiously involved in the disease's pathophysiology, concrete mechanisms accounting for the role of Aβ in AD are yet to be deciphered. While Aβ has been primarily identified in the extracellular space, the peptide also accumulates in cellular compartments such as mitochondria and lysosomes and impairs cellular functions.

Amyloid β structural polymorphism, associated toxicity and therapeutic strategies.

A review of the multidisciplinary scientific literature reveals a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and morphology. These species, which may assemble via either on- or off-aggregation pathways, exhibit differences in stability, function and neurotoxicity, according to different experimental settings. The conformations of the different Aβ species are stabilized by intra- and inter-molecular hydrogen bonds and by electrostatic and hydrophobic interactions, all depending on the chemical and physical environment (e.

SARS-CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera.

Toward eradicating the COVID-19 pandemic, vaccines that induce high humoral and cellular immune responses are essential. However, SARS-CoV-2 variants have begun to emerge and raise concerns, as they may potentially compromise vaccine efficiency. Here, we monitored neutralization potency of convalescent or Pfizer-BTN162b2 post-vaccination sera against pseudoviruses displaying spike proteins derived from wild-type SARS-CoV-2, or its UK-B.

CRISPRi-mediated depletion of Spt4 and Spt5 reveals a role for DSIF in the control of HIV latency.

Pivotal studies on the control of HIV transcription has laid the foundations for our understanding of how metazoan transcription is executed, and what are the factors that control this step. Part of this work established a role for DRB Sensitivity Inducing Factor (DSIF), consisting of Spt4 and Spt5, in promoting pause-release of RNA Polymerase II (Pol II) for optimal elongation. However, while there has been substantial progress in understanding the role of DSIF in mediating HIV gene transcription, its involvement in establishing viral latency has not been explored.

Genome-wide CRISPR knockout screen identifies ZNF304 as a silencer of HIV transcription that promotes viral latency.

Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a whole-genome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency.

The pro-apoptotic domain of BIM protein forms toxic amyloid fibrils.

BIM is a key apoptotic protein, participating in diverse cellular processes. Interestingly, recent studies have hypothesized that BIM is associated with the extensive neuronal cell death encountered in protein misfolding diseases, such as Alzheimer's disease. Here, we report that the core pro-apoptotic domain of BIM, the BIM-BH3 motif, forms ubiquitous amyloid fibrils.

Aβ42 Double Mutant Inhibits Aβ42-Induced Plasma and Mitochondrial Membrane Disruption in Artificial Membranes, Isolated Organs, and Intact Cells.

Destabilization of plasma and inner mitochondrial membranes by extra- and intracellular amyloid β peptide (Aβ42) aggregates may lead to dysregulated calcium flux through the plasma membrane, mitochondrial-mediated apoptosis, and neuronal cell death in patients with Alzheimer's disease. In the current study, experiments performed with artificial membranes, isolated mitochondria, and neuronal cells allowed us to understand the mechanism by which a nonaggregating Aβ42 double mutant (designated Aβ42) exerts its neuroprotective effects. Specifically, we showed that Aβ42 protected neuronal cells from Aβ42-induced accumulation of toxic intracellular levels of calcium and from apoptosis.

Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation.

Background: The human immunodeficiency virus (HIV) cell reservoir is currently a main obstacle towards complete eradication of the virus. This infected pool is refractory to anti-viral therapy and harbors integrated proviruses that are transcriptionally repressed but replication competent. As transcription silencing is key for establishing the HIV reservoir, significant efforts have been made to understand the mechanism that regulate HIV gene transcription, and the role of the elongation machinery in promoting this step.

A hyperthermophilic protein G variant engineered via directed evolution prevents the formation of toxic SOD1 oligomers.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective death of motor neurons in the brainstem, motor cortex, and spinal cord, leading to muscle atrophy and eventually to death. It is currently held that various oligomerization-inducing mutations in superoxide dismutase 1 (SOD1), an amyloid-forming protein, may be implicated in the familial form of this fast-progressing highly lethal neurodegenerative disease. A possible therapeutic approach could therefore lie in developing inhibitors to SOD1 mutants.

An Engineered Variant of the B1 Domain of Protein G Suppresses the Aggregation and Toxicity of Intra- and Extracellular Aβ42.

Intra- and extraneuronal deposition of amyloid β (Aβ) peptides have been linked to Alzheimer's disease (AD). While both intra- and extraneuronal Aβ deposits affect neuronal cell viability, the molecular mechanism by which these Aβ structures, especially when intraneuronal, do so is still not entirely understood. This makes the development of inhibitors challenging.

An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability.

Aggregation and accumulation of the 42-residue amyloid β peptide (Aβ42) in the extracellular matrix and within neuronal cells is considered a major cause of neuronal cell cytotoxicity and death in Alzheimer's disease (AD) patients. Therefore, molecules that bind to Aβ42 and prevent its aggregation are therapeutically promising as AD treatment. Here, we show that a non-self-aggregating Aβ42 variant carrying two surface mutations, F19S and L34P (Aβ42), inhibits wild-type Aβ42 aggregation and significantly reduces Aβ42-mediated cell cytotoxicity.

Measles Virus Persistent Infection of Human Induced Pluripotent Stem Cells.

In this study, we found that the measles virus (MV) can infect human-induced pluripotent stem cells (hiPSCs). Wild-type MV strains generally use human signaling lymphocyte activation molecule (SLAM; CD150) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both CD150 and CD46 as receptors. It is not yet known how early in the embryonal differentiation stages these receptors are expressed.

A computational combinatorial approach identifies a protein inhibitor of superoxide dismutase 1 misfolding, aggregation, and cytotoxicity.

Molecular agents that specifically bind and neutralize misfolded and toxic superoxide dismutase 1 (SOD1) mutant proteins may find application in attenuating the disease progression of familial amyotrophic lateral sclerosis. However, high structural similarities between the wild-type and mutant SOD1 proteins limit the utility of this approach. Here we addressed this challenge by converting a promiscuous natural human IgG-binding domain, the hyperthermophilic variant of protein G (HTB1), into a highly specific aggregation inhibitor (designated HTB1) of two familial amyotrophic lateral sclerosis-linked SOD1 mutants, SOD1 and SOD1 We utilized a computational algorithm for mapping protein surfaces predisposed to HTB1 intermolecular interactions to construct a focused HTB1 library, complemented with an experimental platform based on yeast surface display for affinity and specificity screening.

Super elongation complex promotes early HIV transcription and its function is modulated by P-TEFb.

Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear.

Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes.

Chemokine G protein coupled receptors, principally CCR5 or CXCR4, function as co-receptors for HIV-1 entry into CD4+ T cells. Initial binding of the viral envelope glycoprotein (Env) gp120 subunit to the host CD4 receptor induces a cascade of structural conformational changes that lead to the formation of a high-affinity co-receptor-binding site on gp120. Interaction between gp120 and the co-receptor leads to the exposure of epitopes on the viral gp41 that mediates fusion between viral and cell membranes.

A single point mutation in cyclin T1 eliminates binding to Hexim1, Cdk9 and RNA but not to AFF4 and enforces repression of HIV transcription.

Background: Human immunodeficiency virus (HIV) gene expression is primarily regulated at the step of transcription elongation. The viral Tat protein recruits the Positive Transcription Elongation Factor b (P-TEFb) and the Super Elongation Complex (SEC) to the HIV promoter and enhances transcription by host RNA polymerase II.

Results: To map residues in the cyclin box of cyclin T1 that mediate the binding of P-TEFb to its interacting host partners and support HIV transcription, a pool of N-terminal cyclin T1 mutants was generated.