Overcoming the conversion reaction limitation at three-phase interfaces using mixed conductors towards energy-dense solid-state Li-S batteries.

Lithium-sulfur (Li-S) all-solid-state batteries (ASSBs) hold great promise for next-generation safe, durable and energy-dense battery technology. However, solid-state sulfur conversion reactions are kinetically sluggish and primarily constrained to the restricted three-phase boundary area of sulfur, carbon and solid electrolytes, making it challenging to achieve high sulfur utilization. Here we develop and implement mixed ionic-electronic conductors (MIECs) in sulfur cathodes to replace conventional solid electrolytes and invoke conversion reactions at sulfur-MIEC interfaces in addition to traditional three-phase boundaries.

A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis.

The age-associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy.

Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis.

Not available.

Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans.

Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies.

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine-binding cavity known as the "WIN" site. Multiple pharmacological inhibitors of the WDR5-interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice.

Repair of leukemia-associated single nucleotide variants via interallelic gene conversion.

CRISPR-Cas9 is a useful tool for inserting precise genetic alterations through homology-directed repair (HDR), although current methods rely on provision of an exogenous repair template. Here, we tested the possibility of repairing heterozygous single nucleotide variants (SNVs) using the cell's own wild-type allele rather than an exogenous template. Using high-fidelity Cas9 to perform allele-specific CRISPR across multiple human leukemia cell lines as well as in primary hematopoietic cells from patients with leukemia, we find high levels of reversion to wild-type in the absence of exogenous template.

Clonal hematopoiesis and inflammation in the vasculature: CHIVE, a prospective, longitudinal clonal hematopoiesis cohort and biorepository.

Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated.

Solid Organ Transplant Recipients Exhibit More TET2-Mutant Clonal Hematopoiesis of Indeterminate Potential Not Driven by Increased Transplantation Risk.

Purpose: Solid organ transplant recipients comprise a unique population of immunosuppressed patients with increased risk of malignancy, including hematologic neoplasms. Clonal hematopoiesis of indeterminate potential (CHIP) represents a known risk factor for hematologic malignancy and this study describes the prevalence and patterns of CHIP mutations across several types of solid organ transplants.

Experimental Design: We use two national biobank cohorts comprised of >650,000 participants with linked genomic and longitudinal phenotypic data to describe the features of CHIP across 2,610 individuals who received kidney, liver, heart, or lung allografts.

Multiomic profiling of human clonal hematopoiesis reveals genotype and cell-specific inflammatory pathway activation.

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases the risk of hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood.1 Here, we profile peripheral blood gene expression in 66 968 single cells from a cohort of 17 patients with CH and 7 controls.

Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia.

Unlabelled: Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy.

Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk.

Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p).

Cost-effective and scalable clonal hematopoiesis assay provides insight into clonal dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable.

A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples that are sequenced using approaches that cover the whole genome, the whole exome, or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germ line variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls.

Predicting Individual Treatment Response to rTMS for Motor Recovery After Stroke: A Review and the CanStim Perspective.

Background: Rehabilitation is critical for reducing stroke-related disability and improving quality-of-life post-stroke. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique used as stand-alone or adjunct treatment to physiotherapy, may be of benefit for motor recovery in subgroups of stroke patients. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) seeks to advance the use of these techniques to improve post-stroke recovery through clinical trials and pre-clinical studies using standardized research protocols.

Patient-specific comorbidities as prognostic variables for survival in myelofibrosis.

Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient-specific comorbidities have influence on treatment-related survival and are considered in clinical contexts but have not been routinely incorporated into current prognostic models. We hypothesized that patient-specific comorbidities would inform prognosis and could be incorporated into a quantitative score.

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.

Germline risk of clonal haematopoiesis.

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood.

Chemical and Bio Sensing Using Graphene-Enhanced Raman Spectroscopy.

Graphene is a two-dimensional (2D) material consisting of a single sheet of sp² hybridized carbon atoms laced in a hexagonal lattice, with potentially wide usage as a Raman enhancement substrate, also termed graphene-enhanced Raman scattering (GERS), making it ideal for sensing applications. GERS improves upon traditional surface-enhanced Raman scattering (SERS), combining its single-molecule sensitivity and spectral fingerprinting of molecules, and graphene's simple processing and superior uniformity. This enables fast and highly sensitive detection of a wide variety of analytes.

Clonal hematopoiesis: Pre-cancer PLUS.

Clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. This phenomenon has been observed in populations across the globe and, while virtually non-existent in children is estimated to affect >10% of the 70-and-older age group. The mutations are thought to occur in stem cells, which makes them pre-cancerous, and precursors to cancer stem cells.

-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.

Truncating mutations in the terminal exon of protein phosphatase Mg2/Mn2 1D () have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating mutations confer a chemoresistance phenotype, resulting in the selective expansion of -mutant hematopoietic cells in the presence of chemotherapy in vitro and in vivo. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease mutational profiling of in the presence of chemotherapy selected for the same exon 6 mutations identified in patient samples.

Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms.

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling.

Identification of two novel functional tRNA-derived fragments induced in response to respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children from infancy up to early childhood. Recently, we demonstrated that RSV infection alters cellular small non-coding RNA (sncRNA) expression, most notably the tRNA-derived RNA fragments (tRFs). However, the functions of the tRFs in virus-host interaction are largely unknown.

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.

Methods: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls.