Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs.

Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function.

Influence of conduction heterogeneities on transient spatiotemporal chaos in cardiac excitable media.

Life-threatening cardiac arrhythmias such as ventricular fibrillation are often based on chaotic spiral or scroll wave dynamics which can be self-terminating. In this work, we investigate the influence of conduction heterogeneities on the duration of such chaotic transients in generic models of excitable cardiac media. We observe that low and medium densities of heterogeneities extend the average transient lifetime, while at high densities very long transients, potentially persistent chaos, and periodic attractors occur.

Unusual metallic state in superconducting A15-type LaH.

Hydride superconductors continue to fascinate the communities of condensed matter physics and material scientists because they host the promising near room-temperature superconductivity. Current research has concentrated on the new hydride superconductors with the enhancement of the superconducting transition temperature ( ). The multiple extreme conditions (high pressure/temperature and magnetic field) will introduce new insights into hydride superconductors.

Targeting mitochondrial metabolism with CPI-613 in chemoresistant ovarian tumors.

Background: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.

Heterogeneity in 10-year course trajectories of moderate to severe major depressive disorder among veterans.

Aims: Epidemiological studies show that despite the episodic nature, the long-term trajectory of depression can be variable. This study evaluated the heterogeneity of 10-year trajectory of major depressive disorder (MDD) related service utilization and associated clinical characteristics among US Veterans with a first diagnosis after 9/11.

Methods: Using a cohort design, electronic health record data for 293,265 Operation Enduring Freedom and Iraqi Freedom (OEF/OIF) Veterans were extracted to identify those with MDD between 2001 and 2021 with a full preceding year of clinical data and 10 years following the diagnosis.

Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.

Purpose: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC.

Chaos control in cardiac dynamics: terminating chaotic states with local minima pacing.

Current treatments of cardiac arrhythmias like ventricular fibrillation involve the application of a high-energy electric shock, that induces significant electrical currents in the myocardium and therefore involves severe side effects like possible tissue damage and post-traumatic stress. Using numerical simulations on four different models of 2D excitable media, this study demonstrates that low energy pulses applied shortly after local minima in the mean value of the transmembrane potential provide high success rates. We evaluate the performance of this approach for ten initial conditions of each model, ten spatially different stimuli, and different shock amplitudes.

Unique and redundant roles of mouse BCMA, TACI, BAFF, APRIL, and IL-6 in supporting antibody-producing cells in different tissues.

Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival.

Predictive modeling of initiation and delayed mental health contact for depression.

Background: Depression is prevalent among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, yet rates of Veteran mental health care utilization remain modest. The current study examined: factors in electronic health records (EHR) associated with lack of treatment initiation and treatment delay; the accuracy of regression and machine learning models to predict initiation of treatment.

Methods: We obtained data from the VA Corporate Data Warehouse (CDW).

Efficient termination of cardiac arrhythmias using optogenetic resonant feedback pacing.

Malignant cardiac tachyarrhythmias are associated with complex spatiotemporal excitation of the heart. The termination of these life-threatening arrhythmias requires high-energy electrical shocks that have significant side effects, including tissue damage, excruciating pain, and worsening prognosis. This significant medical need has motivated the search for alternative approaches that mitigate the side effects, based on a comprehensive understanding of the nonlinear dynamics of the heart.

Mental health treatment utilization patterns among 108,457 Afghanistan and Iraq veterans with depression.

People with depression often underutilize mental health care. This study was conceived as a first step toward a clinical decision support tool that helps identify patients who are at higher risk of underutilizing care. The primary goals were to (a) describe treatment utilization patterns, early termination, and return to care; (b) identify factors associated with early termination of treatment; and (c) evaluate the accuracy of regression models to predict early termination.

In silico optical modulation of spiral wave trajectories in cardiac tissue.

Life-threatening cardiac arrhythmias such as ventricular tachycardia and fibrillation are common precursors to sudden cardiac death. They are associated with the occurrence of abnormal electrical spiral waves in the heart that rotate at a high frequency. In severe cases, arrhythmias are combated with a clinical method called defibrillation, which involves administering a single global high-voltage shock to the heart to reset all its activity and restore sinus rhythm.

Dissolution of spiral wave's core using cardiac optogenetics.

Rotating spiral waves in the heart are associated with life-threatening cardiac arrhythmias such as ventricular tachycardia and fibrillation. These arrhythmias are treated by a process called defibrillation, which forces electrical resynchronization of the heart tissue by delivering a single global high-voltage shock directly to the heart. This method leads to immediate termination of spiral waves.

How Do Survivor and Mandatory Reporter Status Correlate with Program Outcomes for an Adult-Focused Child Sexual Abuse Prevention Program?

This exploratory study investigated group differences and pre-post changes in knowledge, beliefs, and behavior by mandatory reporters and Child Sexual Abuse (CSA) survivor status for a CSA prevention training designed for the general public. Of the 8,114 study participants, 32% identified as having experienced CSA, and 77% indicated they were mandatory reporters for child abuse and neglect. Mandatory reporters had higher baseline knowledge about CSA than those who were not mandatory reporters and reported more CSA preventative behaviors.

Machine learning to develop a predictive model of pressure injury in persons with spinal cord injury.

Study Design: A 5-year longitudinal, retrospective, cohort study.

Objectives: Develop a prediction model based on electronic health record (EHR) data to identify veterans with spinal cord injury/diseases (SCI/D) at highest risk for new pressure injuries (PIs).

Setting: Structured (coded) and text EHR data, for veterans with SCI/D treated in a VHA SCI/D Center between October 1, 2008, and September 30, 2013.

Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8 T cells.

To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8 tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions.

Complementary and Integrative Health Approaches and Pain Care Quality in the Veterans Health Administration Primary Care Setting: A Quasi-Experimental Analysis.

Complementary and integrative health (CIH) approaches have been recommended in national and international clinical guidelines for chronic pain management. We set out to determine whether exposure to CIH approaches is associated with pain care quality (PCQ) in the Veterans Health Administration (VHA) primary care setting. We followed a cohort of 62,721 Veterans with newly diagnosed musculoskeletal disorders between October 2016 and September 2017 over 1-year.

The role of pulse timing in cardiac defibrillation.

Life-threatening cardiac arrhythmias require immediate defibrillation. For state-of-the-art shock treatments, a high field strength is required to achieve a sufficient success rate for terminating the complex spiral wave (rotor) dynamics underlying cardiac fibrillation. However, such high energy shocks have many adverse side effects due to the large electric currents applied.

Optical mapping of contracting hearts.

Optical mapping is a widely used tool to record and visualize the electrophysiological properties in a variety of myocardial preparations such as Langendorff-perfused isolated hearts, coronary-perfused wedge preparations, and cell culture monolayers. Motion artifact originating from the mechanical contraction of the myocardium creates a significant challenge to performing optical mapping of contracting hearts. Hence, to minimize the motion artifact, cardiac optical mapping studies are mostly performed on non-contracting hearts, where the mechanical contraction is removed using pharmacological excitation-contraction uncouplers.

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1 CD8 T cells in chronic viral infection.

T cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 T cells (CD8SL) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8SL as well as for virus control.