Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice.

Despite accumulating data on underlying mechanisms, the influence of sex and prevalent cardio-metabolic co-morbidities on the manifestation and severity of immune checkpoint inhibitor (ICI)-induced cardiotoxicity has not been well defined. To elucidate whether sex and prevalent cardio-metabolic co-morbidities affect ICI-induced cardiotoxicity, we randomized 17-month-old male and female mice to receive control diet (CON) or high-fat diet (HFD) + L-NAME-a well-established mouse model of cardio-metabolic co-morbidities-for 17 weeks (n = 5-7), and evaluated markers of T-cell function in the spleen. As expected, HFD + L-NAME significantly increased body- and heart weight, and serum cholesterol levels, and caused no systolic dysfunction, however, led to diastolic dysfunction, cardiomyocyte hypertrophy, and increased fibrosis only in males compared to corresponding CON.

Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.

Background: Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6.

Aim: This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism.

Methods: Forty-two patients received oral doses of 1.

Annealing Behavior of a Mg-Y-Zn-Al Alloy Processed by Rapidly Solidified Ribbon Consolidation.

Mg-Y-Zn-Al alloys processed by the rapidly solidified ribbon consolidation (RSRC) technique are candidate materials for structural applications due to their improved mechanical performance. Their outstanding mechanical strength is attributed to solute-enriched stacking faults (SESFs), which can form cluster-arranged layers (CALs) and cluster-arranged nanoplates (CANaPs) or complete the long-period stacking ordered (LPSO) phase. The thermal stability of these solute arrangements strongly influences mechanical performance at elevated temperatures.

Site-directed allostery perturbation to probe the negative regulation of hypoxia inducible factor-1α.

The interaction between the intrinsically disordered transcription factor HIF-1α and the coactivator proteins p300/CBP is essential in the fast response to low oxygenation. The negative feedback regulator, CITED2, switches off the hypoxic response through a very efficient irreversible mechanism. The negative cooperativity with HIF-1α relies on the formation of a ternary intermediate that leads to allosteric structural changes in p300/CBP, in which the cooperative folding/binding of the CITED2 sequence motifs plays a key role.

Dominant suppressor genes of p53-induced apoptosis in Drosophila melanogaster.

One of the major functions of programmed cell death (apoptosis) is the removal of cells that suffered oncogenic mutations, thereby preventing cancerous transformation. By making use of a Double-Headed-EP (DEP) transposon, a P element derivative made in our laboratory, we made an insertional mutagenesis screen in Drosophila melanogaster to identify genes that, when overexpressed, suppress the p53-activated apoptosis. The DEP element has Gal4-activatable, outward-directed UAS promoters at both ends, which can be deleted separately in vivo.