Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes.

Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles.

STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.

Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal downstream mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but little is known about the role of STAT1 in regulating homeostatic hematopoietic stem/progenitor cells (HSPCs). Here, we show that loss of STAT1 altered the steady state HSPC landscape, impaired HSC function in transplantation assays, delayed blood cell regeneration following myeloablation, and disrupted molecular programs that protect HSCs, including control of quiescence.

Alpine altitude climate treatment for severe and uncontrolled asthma: An EAACI position paper.

Currently available European Alpine Altitude Climate Treatment (AACT) programs combine the physical characteristics of altitude with the avoidance of environmental triggers in the alpine climate and a personalized multidisciplinary pulmonary rehabilitation approach. The reduced barometric pressure, oxygen pressure, and air density, the relatively low temperature and humidity, and the increased UV radiation at moderate altitude induce several physiological and immunological adaptation responses. The environmental characteristics of the alpine climate include reduced aeroallergens such as house dust mites (HDM), pollen, fungi, and less air pollution.

Overhead throwing biomechanics in cricketers: The effect of a run-up approach.

Overhead throwing by cricketers when fielding with different approaches has been described using two-dimensional analysis. Currently, the three-dimensional kinematic and kinetic characteristics of an overhead throw performed by cricketers following a run-up are unknown. Fifteen South African cricketers performed six overhead throws, from a stationary position and with a run-up over 15-20 m prior to fielding a ball, respectively.

The association between gird and overhead throwing biomechanics in cricket.

The development of GIRD is a well-documented adaptation associated with repetitive overhead throwing in numerous sports. In occurrence with total rotational range of motion deficit, GIRD is considered pathological and increases shoulder injury risk. While cricketers demonstrate these deficits in rotational range; the association between GIRD and overhead throwing has yet to be explored.

Small Airway Reduction and Fibrosis Is an Early Pathologic Feature of Idiopathic Pulmonary Fibrosis.

To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Explanted lungs from patients with IPF ( = 8) and donor control subjects ( = 8) were inflated with air and frozen.

White matter alterations in glaucoma and monocular blindness differ outside the visual system.

The degree to which glaucoma has effects in the brain beyond the eye and the visual pathways is unclear. To clarify this, we investigated white matter microstructure (WMM) in 37 tracts of patients with glaucoma, monocular blindness, and controls. We used brainlife.

The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production.

Frameshift mutations in (calreticulin) are associated with essential thrombocythemia (ET), but the stages at and mechanisms by which mutant CALR drives transformation remain incompletely defined. Here, we use single-cell approaches to examine the hematopoietic stem/progenitor cell landscape in a mouse model of mutant CALR-driven ET. We identify a trajectory linking hematopoietic stem cells (HSCs) with megakaryocytes and prospectively identify a previously unknown intermediate population that is overrepresented in the disease state.

Mutant Calreticulin in the Myeloproliferative Neoplasms.

Mutations in the gene for calreticulin () were identified in the myeloproliferative neoplasms (MPNs) essential thrombocythaemia (ET) and primary myelofibrosis (MF) in 2013; in combination with previously described mutations in and , driver mutations have now been described for the majority of MPN patients. In subsequent years, researchers have begun to unravel the mechanisms by which mutant CALR drives transformation and to understand their clinical implications. Mutant CALR activates the thrombopoietin receptor (MPL), causing constitutive activation of Janus kinase 2 (JAK2) signaling and cytokine independent growth in vitro.

Overhead throwing in cricketers: A biomechanical description and playing level considerations.

This study aimed to describe stationary overhead throwing biomechanics in South African cricketers, considering playing level, and relative to baseball. Kinematics and ground reaction forces were collected during throwing trials. Inverse dynamics was used to calculate joint kinetics.

The relationship between burnout, personality traits, and medical specialty. A national study among Dutch residents.

To examine the associations between residents' personality traits, type of specialty, and symptoms of burnout. A cross-sectional online survey among Dutch residents was conducted (see Supplementary Material ). The 20-item Dutch translation of the Maslach Burnout Inventory was used to ascertain burnout.

Running Economy: Neuromuscular and Joint-Stiffness Contributions in Trained Runners.

Context: It is debated whether running biomechanics make good predictors of running economy, with little known about the neuromuscular and joint-stiffness contributions to economical running gait.

Purpose: To understand the relationship between certain neuromuscular and spatiotemporal biomechanical factors associated with running economy.

Methods: Thirty trained runners performed a 6-min constant-speed running set at 3.

The learning environment and resident burnout: a national study.

Introduction: Concerns exist about the negative impact of burnout on the professional and personal lives of residents. It is suggested that the origins of burnout among residents are rooted in the learning environment. We aimed to evaluate the association between the learning environment and burnout in a national sample of Dutch residents.

Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.

Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion.

Extraskeletal Chondroma with Concomitant Arthrosis of the Foot at the First Metatarsophalangeal Joint .

Extraskeletal chondroma is a benign tumor that is found most often in the fingers but can be found in the feet as well. A symptom of this lesion is pressure from the slow-growing mass. We present the case of a 58-year-old woman who presented with an extraskeletal chondroma in the plantar aspect of the left first metatarsophalangeal joint with concomitant symptomatic arthrosis at the joint.

Rationale and design of ASPIRE-ICU: a prospective cohort study on the incidence and predictors of Staphylococcus aureus and Pseudomonas aeruginosa pneumonia in the ICU.

Background: The epidemiology of ICU pneumonia caused by Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) is not fully described, but is urgently needed to support the development of effective interventions.

Biomechanical analysis of gait waveform data: exploring differences between shod and barefoot running in habitually shod runners.

The aim of this study was to utilise one-dimensional statistical parametric mapping to compare differences between biomechanical and electromyographical waveforms in runners when running in barefoot or shod conditions. Fifty habitually shod runners were assessed during overground running at their current 10-km race running speed. Electromyography, kinematics and ground reaction forces were collected during these running trials.

Loss of Binocular Vision in Monocularly Blind Patients Causes Selective Degeneration of the Superior Lateral Occipital Cortices.

Purpose: Chronic ocular pathology, such as glaucoma and macular degeneration, is associated with neuroanatomic changes in the visual pathways. It is a challenge to determine the mechanism responsible for these changes. This could be functional deprivation or transsynaptic degeneration.

Surface-Based Analyses of Anatomical Properties of the Visual Cortex in Macular Degeneration.

Introduction: Macular degeneration (MD) can cause a central visual field defect. In a previous study, we found volumetric reductions along the entire visual pathways of MD patients, possibly indicating degeneration of inactive neuronal tissue. This may have important implications.

STIM1 is cleaved by calpain.

Store-operated calcium entry (SOCE) is a pathway that moves Ca(2+) across the plasma membrane and is mediated by two major proteins, STIM1 and Orai1. Here, we discovered that the cytoplasmic domain of STIM1 is a target for calpains, a family of Ca(2+)-activated proteases. We found that calpain cleavage of STIM1 serves to control its cellular abundance and was noticeably increased under conditions of cellular stress and apoptosis.

Structural brain MRI studies in eye diseases: are they clinically relevant? A review of current findings.

Many eye diseases reduce visual acuity or are associated with visual field defects. Because of the well-defined retinotopic organization of the connections of the visual pathways, this may affect specific parts of the visual pathways and cortex, as a result of either deprivation or transsynaptic degeneration. For this reason, over the past several years, numerous structural magnetic resonance imaging (MRI) studies have examined the association of eye diseases with pathway and brain changes.

UBC9-dependent association between calnexin and protein tyrosine phosphatase 1B (PTP1B) at the endoplasmic reticulum.

Calnexin is a type I integral endoplasmic reticulum (ER) membrane protein, molecular chaperone, and a component of the translocon. We discovered a novel interaction between the calnexin cytoplasmic domain and UBC9, a SUMOylation E2 ligase, which modified the calnexin cytoplasmic domain by the addition of SUMO. We demonstrated that calnexin interaction with the SUMOylation machinery modulates an interaction with protein tyrosine phosphatase 1B (PTP1B), an ER-associated protein tyrosine phosphatase involved in the negative regulation of insulin and leptin signaling.

Calmodulin-dependent binding to the NHE1 cytosolic tail mediates activation of the Na+/H+ exchanger by Ca2+ and endothelin.

The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitous plasma membrane protein that regulates intracellular pH by removing a single proton (H(+)) in exchange for one extracellular Na(+). The human protein contains a ∼500-amino acid membrane domain and a regulatory, ∼315-amino acid cytosolic domain. NHE1 is activated by a number of hormones including endothelin (ET) and by Ca(2+).

Effectiveness of a locking plate in preserving midcalcaneal length and positional outcome after Evans calcaneal osteotomy: a retrospective pilot study.

When using the Evans calcaneal osteotomy for repair of a calcaneovalgus deformity, lengthening of the lateral column of the foot is the method by which the procedure acts to correct the deformity. Therefore, maintaining the length is a priority. In our experience, substantial length is lost soon after surgery using the traditional nonfixated procedure.