The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation.

Reports of Batch-Dependent Suspected Adverse Events of the BNT162b2 mRNA COVID-19 Vaccine: Comparison of Results from Denmark and Sweden.

: An unexpected batch-dependent safety signal for the BNT162b2 mRNA COVID-19 vaccine was recently identified in a nationwide study from Denmark, but the generalizability of this finding is unknown. Therefore, we compared batch-dependent rates of suspected adverse events (SAEs) reported to national authorities in Denmark and Sweden. : SAE and vaccine batch data were received from national authorities in Denmark and Sweden, and analyses of heterogeneity in the relationship between numbers of vaccine doses and SAEs per batch were performed, along with comparison of SAE rates and severities for batches that were shared between the two countries.

A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation.

The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging.

ApoE Isoforms Inhibit Amyloid Aggregation of Proinflammatory Protein S100A9.

Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer's disease (AD). The amyloid co-aggregation of S100A9 with amyloid-β (Aβ) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one of the important genetic risk factors of AD.

Genomic evidence for the suitability of Göttingen Minipigs with a rare seizure phenotype as a model for human epilepsy.

Epilepsy is a complex genetic disorder that affects about 2% of the global population. Although the frequency and severity of epileptic seizures can be reduced by a range of pharmacological interventions, there are no disease-modifying treatments for epilepsy. The development of new and more effective drugs is hindered by a lack of suitable animal models.

Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans.

G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C.

Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs.

Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming.

Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

Resistance to chicken amyloid arthropathy is associated with a dysfunctional mutation in serum amyloid A.

Chicken amyloid arthropathy is a debilitating disease with a major impact on animal welfare. Since the disease is triggered by bacterial infection, preventative treatment also contributes to the widespread overuse of antibiotics. Bacterial infection initiates an acute phase response including increased serum amyloid A (SAA) production by the liver.

ATP-independent molecular chaperone activity generated under reducing conditions.

Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and aggregation, are established, those specialized to work in the extracellular environment are less understood. Extracellular proteins reside in a considerably more oxidizing milieu than cytoplasmic proteins and are stabilized by abundant disulfide bonds.

Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS.

Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs).

Erratum: Generation and analysis of innovative genomically humanized knockin , (TDP-43), and mouse models.

[This corrects the article DOI: 10.1016/j.isci.

Generation and analysis of innovative genomically humanized knockin , (TDP-43), and mouse models.

Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation knockin mouse models, by replacing the mouse genomic region of , (TDP-43), and , with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing.

Altered perivascular fibroblast activity precedes ALS disease onset.

Apart from well-defined factors in neuronal cells, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia and blood vessels. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response.

Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice.

Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice.

Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism.

Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation.

Role of pannexin-1 in the cellular uptake, release and hydrolysis of anandamide by T84 colon cancer cells.

The large pore ion channel pannexin-1 (Panx1) has been reported to play a role in the cellular uptake and release of anandamide (AEA) in the hippocampus. It is not known whether this is a general mechanism or limited to the hippocampus. We have investigated this pharmacologically using T84 colon cancer cells.

The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension.

Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied.

Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer.

Background: Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes.

Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study.

Objectives: To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period.

Methods: Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months.

Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis.

Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls.

Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin.

Background: Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against flavivirus infection.

Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects.

Background: Neurotropic flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne flavivirus infection. However, the cells responsible for mounting this protective response are not defined.