Abstract: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: The disclosure provides methods, treatments and materials for treating diseases or disorders mediated by cyclic nucleotides and/or sodium glucose cotransporter 2. In particular, the present disclosure provides for methods of treating such diseases and disorders with a PDE1 inhibitor in combination with additional therapeutic agents.

Abstract: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: The disclosure is directed to methods for inhibiting toxic protein accumulation in cells by modulating the phosphorylation of carboxy terminus of heat shock cognate 70 interacting protein (CHIP), as well as a method for treating a disease caused by proteotoxicity in cells by increasing or inducing the activity of CHIP in a subject.

Abstract: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: The invention provides methods related to improving heart function.

Abstract: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: 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.

Abstract: The invention provides methods related to improving heart function.

Abstract: Provided herein are engineered tuberous sclerosis complex 2 (TSC2) polypeptides in which the ability of a residue corresponding to a serine residue in a wild type TSC2 polypeptide to be phosphorylated is altered. In some cases, an engineered TSC2 polypeptide cannot be phosphorylated (e.g., by substituting a serine residue with an alanine residue). In some cases, an engineered TSC2 polypeptide can act as if it is constitutively phosphorylated (e.g., by substituting a serine residue with a glutamic acid residue). Also provided herein are engineered immune cells including altered TSC2 polypeptides or including nucleic acid sequences encoding altered TSC2 polypeptides, and methods of making and using such engineered immune cells.

Abstract: Studies in female mice lacking ovaries (and thus estrogen), and placed on a high fat diet (60% fat) to induce severe obesity, and then stimulated with a low level of high pressure stress on the heart to induce mild hypertrophy and activate natriuretic peptide signaling. Unlike females on the same diet and heart stress but with their ovaries, those without ovaries demonstrated marked weight loss from phosphodiesterase E-9 (PDE9) inhibition, in combination with improvement in their metabolic signature (reduced fasting glucose, cholesterol, and triglycerides), without any change in food intake, nor change in activity. Thus, in one aspect, the invention provides methods for decreasing body fat and increasing lean muscle mass in estrogen deficient obese female subjects comprising administering to the subjects, at least one PDE9 inhibitor.

Abstract: Please add the following heading and paragraph on a separate sheet, after the claims: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Abstract: 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.

Abstract: 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.

Abstract: The invention provides methods related to improving heart function.

Abstract: The invention provides methods related to improving heart function.

Abstract: 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.

Abstract: 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.

Abstract: The invention provides methods related to improving heart function.