ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

Diet-enhanced LRG1 expression promotes insulin hypersecretion and ER stress in pancreatic beta cells.

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes.

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) , the most common embryonal brain tumor in children, and pineoblastoma . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST .

Validation of single reference variable flip angle (SR-VFA) dynamic T mapping with T * correction using a novel rotating phantom.

Purpose: To validate single reference variable flip angle (SR-VFA) dynamic T mapping with and without T * correction against inversion recovery (IR) T measurements.

Methods: A custom cylindrical phantom with three concentric compartments was filled with variably doped agar to produce a smooth spatial gradient of the T relaxation rate as a function of angle across each compartment. IR T , VFA T , and B measurements were made on the phantom before rotation, and multi-echo stack-of-radial dynamic images were acquired during rotation via an MRI-compatible motor.

Bradykinin release following trauma and hemorrhagic shock causes pulmonary alveolar leak in a rodent model.

Background: Hemorrhage accounts for 40% of the preventable death following severe injury. Activation of systemic coagulation produces bradykinin (BK), which may cause leak from the plasma to the extravascular space and to the tissues, which is part of the complex pathophysiology of trauma-induced end-organ injury. We hypothesize that BK, released during activation of coagulation in severe injury, induces pulmonary alveolar leak.

A proposed clinical coagulation score for research in trauma-induced coagulopathy.

Background: Trauma-induced coagulopathy (TIC) has been the subject of intense study for greater than a century, and it is associated with high morbidity and mortality. The Trans-Agency Consortium for Trauma-Induced Coagulopathy, funded by the National Health Heart, Lung and Blood Institute, was tasked with developing a clinical TIC score, distinguishing between injury-induced bleeding from persistent bleeding due to TIC. We hypothesized that the Trans-Agency Consortium for Trauma-Induced Coagulopathy clinical TIC score would correlate with laboratory measures of coagulation, transfusion requirements, and mortality.

Animation supported communication on intensive care; a service improvement initiative.

Objective: COVID-19 has created unique challenges for families of patients admitted to intensive care units. Restricted visiting, language barriers and time constraints have limited communication, resulting in a lack of understanding and anxiety. We introduced digital animations to support communication and assessed the impact on families of patients admitted to intensive care.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

Background: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation.

Objective: To better elucidate the effects of PB on cognition.

Predicting the dissolution rate constant of mineral wool fibers from fiber composition.

Objective: We developed predictive formulae for the dissolution rate constant k of acid-soluble synthetic vitreous fibers (SVF), paralleling our earlier work with glass wools, which are typically more soluble at neutral pH. Developing simple models for predicting the k of a fiber can allow prediction of behavior, aid fiber developers, and potentially reduce testing.

Methods: The k of several acid-soluble SVF were determined using high simulant fluid flow/fiber surface area (F/A) conditions a single-fiber measurement system.

SHOCK INDUCES ENDOTHELIAL PERMEABILITY AFTER TRAUMA THROUGH INCREASED ACTIVATION OF RHOA GTPASE.

Introduction: Severely injured patients develop a dysregulated inflammatory state characterized by vascular endothelial permeability, which contributes to multiple organ failure. To date, however, the mediators of and mechanisms for this permeability are not well established. Endothelial permeability in other inflammatory states such as sepsis is driven primarily by overactivation of the RhoA GTPase.

A pilot study of the metabolic profiles of apheresis platelets modified by donor age and sex and in vitro short-term incubation with sex hormones.

Background: Platelets are part of innate immunity and comprise the cellular portion of hemostasis. Platelets express sex hormone receptors on their plasma membrane and sex hormones can alter their function in vitro. Little is known about how age and sex may affect platelet biology; thus, we hypothesized that platelets from males and females have different metabolomic profiles, which may be altered by age and in vitro treatment with sex hormones.

Association between high-risk extracranial carotid plaque and covert brain infarctions and cerebral microbleeds.

Purpose: Covert brain infarctions (CBIs) and cerebral microbleeds (CMBs) represent subclinical sequelae of ischemic and hemorrhagic cerebral small vessel disease, respectively. In addition to thromboembolic stroke, carotid atherosclerosis has been associated with downstream vascular brain injury, including inflammation and small vessel disease. The specific plaque features responsible for this are unknown.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins. However, the anatomical and cellular complexity of developing human tissues-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice.

Hormones, age, and sex affect platelet responsiveness in vitro.

Background: Female sex confers a survival advantage following severe injury in the setting of trauma-induced coagulopathy, with female platelets having heightened responsiveness likely due to estrogen. The effects of testosterone on platelet biology are unknown, and platelets express both estradiol and androgen receptors on the plasma membrane. We hypothesize testosterone decreases platelet responses in vitro, and there are baseline differences in platelet function and metabolism stratified by sex/age.

The Current Accuracy, Cost-Effectiveness, and Uses of Musculoskeletal Telehealth and Telerehabilitation Services.

Musculoskeletal conditions are a major contributor to global morbidity. During the COVID-19 pandemic, clinicians needed to rapidly meet the evolving requirements of their patients, which resulted in an increased adoption of telehealth services. This area needs more research, as there is currently a paucity of studies, and telehealth practices are continuing to advance and evolve.

Astrocytes and pericytes attenuate severely injured patient plasma mediated expression of tight junction proteins in endothelial cells.

Blood Brain Barrier (BBB) breakdown is a secondary form of brain injury which has yet to be fully elucidated mechanistically. Existing research suggests that breakdown of tight junction proteins between endothelial cells is a primary driver of increased BBB permeability following injury, and intercellular signaling between primary cells of the neurovascular unit: endothelial cells, astrocytes, and pericytes; contribute to tight junction restoration. To expound upon this body of research, we analyzed the effects of severely injured patient plasma on each of the cell types in monoculture and together in a triculture model for the transcriptional and translational expression of the tight junction proteins Claudins 3 and 5, (CLDN3, CLDN5) and Zona Occludens 1 (ZO-1).

Receptor Interacting Protein Kinase Pathways Regulate Innate B Cell Developmental Checkpoints But Not Effector Function in Mice.

Mutations in the scaffolding domain of Receptor Interacting Protein kinases (RIP) underlie the recently described human autoimmune syndrome, CRIA, characterized by lymphadenopathy, splenomegaly, and autoantibody production. While disease mechanisms for CRIA remain undescribed, RIP kinases work together with caspase-8 to regulate cell death, which is critical for normal differentiation of many cell types. Here, we describe a key role for RIP1 in facilitating innate B cell differentiation and subsequent activation.

Vorinostat and isotretinoin with chemotherapy in young children with embryonal brain tumors: A report from the Pediatric Brain Tumor Consortium (PBTC-026).

Background: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.

Methods: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS.

Quasistatic Solutions versus Full-Wave Solutions of Single-Channel Circular RF Receive Coils on Phantoms of Varying Conductivities at 3 Tesla.

Purpose: Although full-wave simulations could be used to aid in RF coil design, the algorithms may be too slow for an iterative optimization algorithm. If quasistatic simulations are accurate within the design tolerance, then their use could reduce simulation time by orders of magnitude compared to full-wave simulations. This paper examines the accuracy of quasistatic and full-wave simulations at 3 Tesla.

An Interlaboratory Comparison on the Characterization of a Sub-micrometer Polydisperse Particle Dispersion.

The measurement of polydisperse protein aggregates and particles in biotherapeutics remains a challenge, especially for particles with diameters of ≈ 1 µm and below (sub-micrometer). This paper describes an interlaboratory comparison with the goal of assessing the measurement variability for the characterization of a sub-micrometer polydisperse particle dispersion composed of five sub-populations of poly(methyl methacrylate) (PMMA) and silica beads. The study included 20 participating laboratories from industry, academia, and government, and a variety of state-of-the-art particle-counting instruments.