Convergent Adaptation of True Crabs (Decapoda: Brachyura) to a Gradient of Terrestrial Environments.

For much of terrestrial biodiversity, the evolutionary pathways of adaptation from marine ancestors are poorly understood and have usually been viewed as a binary trait. True crabs, the decapod crustacean infraorder Brachyura, comprise over 7600 species representing a striking diversity of morphology and ecology, including repeated adaptation to non-marine habitats. Here, we reconstruct the evolutionary history of Brachyura using new and published sequences of 10 genes for 344 tips spanning 88 of 109 brachyuran families.

Regulation of HCN2 Current by PI3K/Akt Signaling.

It has long been known that heart rate is regulated by the autonomic nervous system. Recently, we demonstrated that the pacemaker current, I , is regulated by phosphoinositide 3-kinase (PI3K) signaling independently of the autonomic nervous system. Inhibition of PI3K in sinus node (SN) myocytes shifts the activation of I by almost 16 mV in the negative direction.

Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling.

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization.

Tumor-intrinsic PIK3CA represses tumor immunogenecity in a model of pancreatic cancer.

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice.

Acquired long QT syndrome and phosphoinositide 3-kinase.

While it is well known that mutation of several different ion channels can cause congenital long QT syndrome, block of I is widely thought to be responsible for most cases of drug-induced acquired long QT syndrome (aLQTS). In this article, we review evidence supporting another cause of aLQTS due to inhibition of phosphoinositide 3-kinase (PI3K) signaling. Inhibition of PI3K affects multiple plateau currents, reducing I, I, and I while increasing the persistent sodium current (I).

Activation of Gαq in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy.

Receptors that activate the heterotrimeric G protein Gαq are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gαq is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gαq activation (termed GαqQ209L) to address this question.

Energy balancing by fat Pik3ca.

Obesity is often associated with systemic insulin resistance, and the decline of insulin sensitivity marks the progression of obesity into a disease state. We recently generated a mouse with adipose-specific ablation of the p110α phosphoinositide 3-kinase (PI3K) catalytic subunit to model insulin resistance in this organ. The phenotypes of this animal revealed novel roles of adipose PI3K signaling in regulating body weight and systemic glucose and lipid homeostasis.

Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels.

Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity.

Adipose tissue insulin resistance due to loss of PI3K p110α leads to decreased energy expenditure and obesity.

Adipose tissue is a highly insulin-responsive organ that contributes to metabolic regulation. Insulin resistance in the adipose tissue affects systemic lipid and glucose homeostasis. Phosphoinositide 3-kinase (PI3K) mediates downstream insulin signaling in adipose tissue, but its physiological role in vivo remains unclear.

Increased persistent sodium current due to decreased PI3K signaling contributes to QT prolongation in the diabetic heart.

Diabetes is an independent risk factor for sudden cardiac death and ventricular arrhythmia complications of acute coronary syndrome. Prolongation of the QT interval on the electrocardiogram is also a risk factor for arrhythmias and sudden death, and the increased prevalence of QT prolongation is an independent risk factor for cardiovascular death in diabetic patients. The pathophysiological mechanisms responsible for this lethal complication are poorly understood.

Class IA PI3K p110β subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation.

Autophagy is an evolutionarily conserved membrane trafficking process. Induction of autophagy in response to nutrient limitation or cellular stress occurs by similar mechanisms in organisms from yeast to mammals. Unlike yeast, metazoan cells rely more on growth factor signaling for a wide variety of cellular activities including nutrient uptake.

Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.

Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling.

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function.

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34.

PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes.

Background: Phosphoinositide 3-kinases (PI3Ks) regulate numerous physiological processes including some aspects of cardiac function. Although regulation of cardiac contraction by individual PI3K isoforms has been studied, little is known about the cardiac consequences of downregulating multiple PI3Ks concurrently.

Methods And Results: Genetic ablation of both p110α and p110β in cardiac myocytes throughout development or in adult mice caused heart failure and death.

Restoration of defective L-type Ca2+ current in cardiac myocytes of type 2 diabetic db/db mice by Akt and PKC-ι.

Diabetes is associated with an increased risk of heart failure and the development of a cardiomyopathy whose etiology is only partially understood. Ca entry through the voltage-dependent L-type Ca channel CaV1.2 initiates the contractile cycle in cardiac myocytes.

Ablation of PI3K p110-α prevents high-fat diet-induced liver steatosis.

Objective: To determine whether the phosphoinositide 3-kinase (PI3K) catalytic subunits p110-α and p110-β play a role in liver steatosis induced by a high-fat diet (HFD).

Research Design And Methods: Liver-specific p110-α and p110-β knockout mice and control animals for each group were fed an HFD or normal chow for 8 weeks. Biochemical assays and quantitative real-time PCR were used to measure triglyceride, expression of lipogenic and gluconeogenic genes, and activity of protein kinases downstream of PI3K in liver lysates.

The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy.

Autophagy is an evolutionarily conserved cell renewal process that depends on phosphatidylinositol 3-phosphate (PtdIns(3)P). In metazoans, autophagy is inhibited by PtdIns(3,4,5)P(3), the product of class IA PI3Ks, which mediates the activation of the Akt-TOR kinase cascade. However, the precise function of class IA PI3Ks in autophagy remains undetermined.

Loss of cardiac phosphoinositide 3-kinase p110 alpha results in contractile dysfunction.

Background: Phosphoinositide 3-kinase (PI3K) p110alpha plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca(2+) current (I(Ca,L)) through the voltage-dependent L-type Ca(2+) channel (LTCC). The aim of this study was to evaluate whether p110alpha also controls cardiac contractility by regulating the LTCC.

Rapamycin and mTOR kinase inhibitors.

Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions.

Acetaminophen: antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant.

Acetaminophen (AC) reduces the core temperatures (T(c)) of febrile and non-febrile mice alike. Evidence has been adduced that the selectively AC-sensitive PGHS isoform, PGHS-1b (COX-3), mediates these effects. PGHS-1b, however, has no catalytic potency in mice.

Cyclic equibiaxial tensile strain induces both anabolic and catabolic responses in articular chondrocytes.

Mechanical disturbance is directly implicated in the development of osteoarthritis (OA) but the precise mode for degenerative changes is still largely unknown because of the complexity of the biomechanical and biochemical milieu in the articular joint. To investigate the effects of tensile strain on articular cartilage, cyclic equibiaxial tensile strain (CTS, 0.5 Hz, 10% strain) was applied to monolayer cultures of porcine articular chondrocytes by using a Flexercell strain unit.

Decreased L-type Ca2+ current in cardiac myocytes of type 1 diabetic Akita mice due to reduced phosphatidylinositol 3-kinase signaling.

Objective: Contraction of cardiac myocytes is initiated by Ca(2+) entry through the voltage-dependent L-type Ca(2+) channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling.

Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one.

Signaling through the mammalian target of rapamycin (mTOR) is hyperactivated in many human tumors, including hamartomas associated with tuberous sclerosis complex (TSC). Several small molecules such as LY294002 inhibit mTOR kinase activity, but they also inhibit phosphatidylinositol 3-kinase (PI3K) at similar concentrations. Compound 401 is a synthetic inhibitor of DNA-dependent protein kinase (DNA-PK) that also targets mTOR but not PI3K in vitro (Griffin, R.