A three-dimensional valve-on-chip microphysiological system implicates cell cycle progression, cholesterol metabolism and protein homeostasis in early calcific aortic valve disease progression.

Background: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms.

Boosting the toolbox for live imaging of translation.

Live imaging of translation based on tag recognition by a single-chain antibody is a powerful technique to assess translation regulation in living cells. However, this approach is challenging and requires optimization in terms of expression level and detection sensitivity of the system, especially in a multicellular organism. Here, we improved existing fluorescent tools and developed new ones to image and quantify nascent translation in the living embryo and in mammalian cells.

Pseudomolecule-scale genome assemblies of Drepanocaryum sewerzowii and Marmoritis complanata.

The Nepetoideae, a subfamily of Lamiaceae (mint family), is rich in aromatic plants, many of which are sought after for their use as flavors and fragrances or for their medicinal properties. Here, we present genome assemblies for two species in Nepetiodeae: Drepanocaruym sewerzowii and Marmoritis complanata. Both assemblies were generated using Oxford Nanopore Q20 + reads with contigs anchored to nine pseudomolecules that resulted in 335 Mb and 305 Mb assemblies, respectively, and BUSCO scores above 95% for both the assembly and annotation.

The A53T Mutation in α-Synuclein Enhances Proinflammatory Activation in Human Microglia Upon Inflammatory Stimulus.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, following Alzheimer's. It is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD; however, the exact role of microglia remains unclear and has been understudied.

The guide-RNA sequence dictates the slicing kinetics and conformational dynamics of the Argonaute silencing complex.

The RNA-induced silencing complex (RISC), which powers RNA interference (RNAi), consists of a guide RNA and an Argonaute protein that slices target RNAs complementary to the guide. We find that, for different guide-RNA sequences, slicing rates of perfectly complementary bound targets can be surprisingly different (>250-fold range), and that faster slicing confers better knockdown in cells. Nucleotide sequence identities at guide-RNA positions 7, 10, and 17 underlie much of this variation in slicing rates.

BACH2 regulates diversification of regulatory and proinflammatory chromatin states in T17 cells.

Interleukin-17 (IL-17)-producing helper T (T17) cells are heterogenous and consist of nonpathogenic T17 (npT17) cells that contribute to tissue homeostasis and pathogenic T17 (pT17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T17 heterogeneity and discover substantial differences in the chromatin landscape of npT17 and pT17 cells both in vitro and in vivo. Compared to other CD4 T cell subsets, npT17 cells share accessible chromatin configurations with regulatory T cells, whereas pT17 cells exhibit features of both npT17 cells and type 1 helper T (T1) cells.

Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.

Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1.

Transcriptome-wide characterization of genetic perturbations.

Single cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are often noisy due to cost and technical constraints, limiting power to detect true effects with conventional differential expression analyses. Here, we introduce TRanscriptome-wide Analysis of Differential Expression (TRADE), a statistical framework which estimates the transcriptome-wide distribution of true differential expression effects from noisy gene-level measurements.

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses.

Background: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease.

Objective: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features.

Chronic activation of a negative engram induces behavioral and cellular abnormalities.

Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it is unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice.

An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress.

Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis.

Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation.

Microglia play key roles in shaping synaptic connectivity during neural circuits development. Whether microglia display human-specific features of structural and functional maturation is currently unknown. We show that the ancestral gene and its human-specific (HS) paralogs / are not only expressed in cortical neurons but are the only HS gene duplications expressed in human microglia.

Direct observation of translational activation by a ribonucleoprotein granule.

Biomolecular condensates organize biochemical processes at the subcellular level and can provide spatiotemporal regulation within a cell. Among these, ribonucleoprotein (RNP) granules are storage hubs for translationally repressed mRNA. Whether RNP granules can also activate translation and how this could be achieved remains unclear.

Parental dialectic: Epigenetic conversations in endosperm.

Endosperm is a major evolutionary innovation of flowering plants, and its proper development critically impacts seed growth and viability. Epigenetic regulators have a key function in parental control of endosperm development. Notably, epigenetic regulation of parental genome dosage is a major determinant of seed development success, and disruption of this balance can produce inviable seed, as observed in some interploidy and interspecific crosses.

PTPRD gene variant rs10739150: A potential game-changer in hypertension diagnosis.

Background: High blood pressure, also known as hypertension (HTN), is a complicated disorder that is controlled by a complex network of physiological processes. Untreated hypertension is associated with increased death incidence, rise the need for understanding the genetic basis affecting hypertension susceptibility and development. The current study sought to identify the genetic association between twelve single nucleotide polymorphisms (SNPs) within seven candidate genes (NOS3, NOS1AP, REN, PLA2G4A, TCF7L, ADRB1, and PTPRD).

Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing.

The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here we studied the full-length human MORC2 protein biochemically.

How germ granules promote germ cell fate.

Germ cells are the only cells in the body capable of giving rise to a new organism, and this totipotency hinges on their ability to assemble membraneless germ granules. These specialized RNA and protein complexes are hallmarks of germ cells throughout their life cycle: as embryonic germ granules in late oocytes and zygotes, Balbiani bodies in immature oocytes, and nuage in maturing gametes. Decades of developmental, genetic and biochemical studies have identified protein and RNA constituents unique to germ granules and have implicated these in germ cell identity, genome integrity and gamete differentiation.

Co-transcriptional splicing facilitates transcription of gigantic genes.

Although introns are typically tens to thousands of nucleotides, there are notable exceptions. In flies as well as humans, a small number of genes contain introns that are more than 1000 times larger than typical introns, exceeding hundreds of kilobases (kb) to megabases (Mb). It remains unknown why gigantic introns exist and how cells overcome the challenges associated with their transcription and RNA processing.