Circadian disruption dysregulates lung gene expression associated with inflammatory lung injury.

Rationale: Circadian systems drive the expression of multiple genes in nearly all cells and coordinate cellular-, tissue-, and system-level processes that are critical to innate immunity regulation.

Objective: We examined the effects of circadian rhythm disorganization, produced by light shift exposure, on innate immunity-mediated inflammatory lung responses including vascular permeability and gene expression in a C57BL/6J murine model of inflammatory lung injury.

Methods: A total of 32 C57BL/6J mice were assigned to circadian phase shifting (CPS) with intratracheal phosphate-buffered saline (PBS), CPS with intratracheal lipopolysaccharide (LPS), control (normal lighting) condition with intratracheal PBS, and control condition with intratracheal LPS.

Vagal sensory neurons mediate the Bezold-Jarisch reflex and induce syncope.

Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders. The Bezold-Jarisch reflex (BJR), first described in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown.

Loss of In Vivo Replication Fitness of HIV-1 Variants Resistant to the Tat Inhibitor, dCA.

HIV resistance to the Tat inhibitor didehydro-cortistatin A (dCA) in vitro correlates with higher levels of Tat-independent viral transcription and a seeming inability to enter latency, which rendered resistant isolates more susceptible to CTL-mediated immune clearance. Here, we investigated the ability of dCA-resistant viruses to replicate in vivo using a humanized mouse model of HIV infection. Animals were infected with WT or two dCA-resistant HIV-1 isolates in the absence of dCA and followed for 5 weeks.

Quality control ensures fidelity in ribosome assembly and cellular health.

The coordinated integration of ribosomal RNA and protein into two functional ribosomal subunits is safeguarded by quality control checkpoints that ensure ribosomes are correctly assembled and functional before they engage in translation. Quality control is critical in maintaining the integrity of ribosomes and necessary to support healthy cell growth and prevent diseases associated with mistakes in ribosome assembly. Its importance is demonstrated by the finding that bypassing quality control leads to misassembled, malfunctioning ribosomes with altered translation fidelity, which change gene expression and disrupt protein homeostasis.

Unraveling multilayered extracellular vesicles: Speculation on cause.

Extracellular vesicles (EVs) are cell-released, heterogenous nanoparticles that play important roles in (patho)physiological processes through intercellular communication. EVs are often depicted as having a single lipid bilayer, but many studies have demonstrated the existence of multilayered EVs. There has been minimal inquiry into differences between unilamellar and multilamellar EVs in terms of biogenesis mechanisms and functional effects.

Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease.

Background: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's disease (AD). Amyloid-β protein precursor and amyloid-β peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology.

The chaperone protein p32 stabilizes HIV-1 Tat and strengthens the p-TEFb/RNAPII/TAR complex promoting HIV transcription elongation.

HIV gene expression is modulated by the combinatorial activity of the HIV transcriptional activator, Tat, host transcription factors, and chromatin remodeling complexes. To identify host factors regulating HIV transcription, we used specific single-guide RNAs and endonuclease-deficient Cas9 to perform chromatin affinity purification of the integrated HIV promoter followed by mass spectrometry. The scaffold protein, p32, also called ASF/SF2 splicing factor-associated protein, was identified among the top enriched factors present in actively transcribing HIV promoters but absent in silenced ones.

Genetics and Molecular Biology of Memory Suppression.

The brain is designed not only with molecules and cellular processes that help to form memories but also with molecules and cellular processes that suppress the formation and retention of memory. The latter processes are critical for an efficient memory management system, given the vast amount of information that each person experiences in their daily activities and that most of this information becomes irrelevant with time. Thus, efficiency dictates that the brain should have processes for selecting the most critical information for storage and suppressing the irrelevant or forgetting it later should it escape the initial filters.

Design, synthesis, biological evaluation and crystal structure determination of dual modulators of carbonic anhydrases and estrogen receptors.

Multi-target compounds have become increasingly important for the development of safer and more effective drug candidates. In this work, we devised a combined ligand-based and structure-based multi-target repurposing strategy and applied it to a series of hexahydrocyclopenta[c]quinoline compounds synthesized previously. The in silico analyses identified human Carbonic Anhydrases (hCA) and Estrogen Receptors (ER) as top scoring candidates for dual modulation.

Regulation of ribonucleoprotein condensates by RNase L during viral infection.

In response to viral infection, mammalian cells activate several innate immune pathways to antagonize viral gene expression. Upon recognition of viral double-stranded RNA, protein kinase R (PKR) phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α) on serine 51. This inhibits canonical translation initiation, which broadly antagonizes viral protein synthesis.

MIBiG 3.0: a community-driven effort to annotate experimentally validated biosynthetic gene clusters.

With an ever-increasing amount of (meta)genomic data being deposited in sequence databases, (meta)genome mining for natural product biosynthetic pathways occupies a critical role in the discovery of novel pharmaceutical drugs, crop protection agents and biomaterials. The genes that encode these pathways are often organised into biosynthetic gene clusters (BGCs). In 2015, we defined the Minimum Information about a Biosynthetic Gene cluster (MIBiG): a standardised data format that describes the minimally required information to uniquely characterise a BGC.

RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus.

The antiviral endoribonuclease, RNase L, is activated by the mammalian innate immune response to destroy host and viral RNA to ultimately reduce viral gene expression. Herein, we show that RNase L and RNase L-mediated mRNA decay are primarily localized to the cytoplasm. Consequently, RNA-binding proteins (RBPs) translocate from the cytoplasm to the nucleus upon RNase L activation due to the presence of intact nuclear RNA.