Johns Hopkins University

University of California

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Louisiana State University and Agricultural & Mechanical College

Boston Scientific Scimed, Inc.

David A Kass

David A Wink

Gordon Tomaselli

Nazareno Paolocci

Katrina M Miranda

Martin Feelisch

Jon M Fukuto

Jonathan Kirk

Tatsuo Katori

Andrew D Bicek

Umang Anand

Soumyadipta Acharya

Jonathan David Powell

Chao-Wei Hwang

Nichaluk Leartprapun

Peter V Johnston

Viachaslau Barodka

Akira Sawa

Qian Liu

Hunter Clay Champion

Chen-Huan Chen

Elki Takimoto

Neelam Shahani

Toshiaki Saito

Jackline Wanjala

Majd Alghatrif

Eiki Takimoto

B Westbrook Bernier

Pasquale Pagliaro

Hideaki Senzaki

Trent Langston

Mark J Ranek

Kristen Kokkonen

Chirag Patel

Brittany Dunkerly-Eyring

Jonathan D Powell

Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.

Engineered TSC2

The invention provides methods related to improving heart function.

Methods for improving heart function

The present application relates to systems and methods for non-invasively determining at least one of left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) in a subject's heart, comprising: receiving, by a computer, a plurality of signals from a plurality of non-invasive sensors that measure a plurality of physiological effects that are correlated with functioning of said subject's heart, said plurality of physiological effects including at least one signal correlated with left ventricular blood pressure and at least one signal correlated with timing of heartbeat cycles of said subject's heart; training a machine learning model on said computer using said plurality of signals for periods of time in which said plurality of signals were being generated during a heart failure event of said subject's heart; determining said LVEDP or PCWP using said machine learning model at a time subsequent to said training and subsequent to said heart failure event.

Device and method for non-invasive left ventricular end diastolic pressure (LVEDP) measurement

In DN-DISC1 mice, a mouse model for major mental illnesses, the model that expresses pathological phenotypes relevant to schizophrenia, mood disorders, and addiction simultaneously, the inventors of the present invention found pronounced levels of oxidative stress in the prefrontal cortex, but not in the striatum. These mice also displayed greater amounts of GAPDH-Siah1 binding, a protein-protein interaction that is activated under exposure to oxidative stress. The present inventors investigated the role of oxidative stress in other organ systems. As detailed herein, the inventors found that GAPDH-Siah1 binding was increased in mouse models of cardiac failure. It was also found, that certain novel analogs of deprenyl, significantly inhibited GAPDH-Siah1 binding in cardiac tissue. Thus, with experimental data provided herein, it is clear that this GAPDH-Siah1 binding cascade is a crucial mechanism involved in major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs where GAPDH is expressed. The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siah1 binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.

GAPDH cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness

The invention features methods and compositions featuring a PDE5 inhibitor for treating or preventing a cardiac indication in a subject.

PDE5 inhibitor compositions and methods for treating cardiac indications

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Method of treating ischemia/reperfusion injury with nitroxyl donors

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO(Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Nitroxyl progenitors in the treatment of heart failure

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO (Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy

A novel method for estimating the end-systolic pressure-volume relationship (ESPVR) is presented. The method provides for accurate estimation of the ESPVR from a single beat of the cardiac cycle. The method is based on normalized human time varying elastance curves [E.sub.N (t.sub.N)]. The ESPVR is estimated from one beat using PV data measured at normalized time t.sub.N and end-systole (t.sub.max) to predict intercept: ##EQU1## and slope: E.sub.max(SB) =P(t.sub.max)/[V(t.sub.max)-V.sub.0(SB) ]. The present invention provides a method for ESPVR estimation which is non-invasive and particularly applicable for bedside applications.

Assessing cardiac contractility and cardiovascular interaction

Growing community of inventors

Columbia, MD, United States of America

David A Kass