Germline Genetic Variation Modulates Tumor Progression and Metastasis in a Mouse Model of Neuroendocrine Prostate Carcinoma

Neuroendocrine (NE) differentiation has gained increased attention as a prostate cancer (PC) prognostic marker. The aim of this study is to determine whether host germline genetic variation influences tumor progression and metastasis in C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive NEPC. TRAMP mice were crossed to the eight progenitor strains of the Collaborative Cross recombinant inbred panel to address this. Tumor growth and metastasis burden were quantified in heterozygous transgene positive F1 male mice at 30 weeks of age. Compared to wild-type C57BL/6J-Tg(TRAMP)824Ng/J males, TRAMP x CAST/EiJ, TRAMP x NOD/ShiLtJ and TRAMP x NZO/HlLtJ F1 males displayed significant increases in tumor growth. Conversely, TRAMP x WSB/EiJ and TRAMP x PWK/PhJ F1 males displayed significant reductions in tumor growth. Interestingly, despite reduced tumor burden, TRAMP x WSB/EiJ males had an increased nodal metastasis burden. Patterns of distant pulmonary metastasis tended to follow the same patterns as that of local dissemination in each of the strains. All tumors and metastases displayed positive staining for NE markers, synaptophysin, and FOXA2. These experiments conclusively demonstrate that the introduction of germline variation by breeding modulates tumor growth, local metastasis burden, and distant metastasis frequency in this model of NEPC. These strains will be useful as model systems to facilitate the identification of germline modifier genes that promote the development of aggressive forms of PC.     

Peristaltic regimes in esophageal transport

Biomechanics and Modeling in Mechanobiology - A FLIP device gives cross-sectional area along the length of the esophagus and one pressure measurement, both as a function of time. Deducing...     

Effects of nitric oxide synthase inhibition on cutaneous vasodilation during body heating in humans

We sought toexamine further the potential role of nitric oxide (NO) in the neurallymediated cutaneous vasodilation in nonacral skin during body heating inhumans. Six subjects were heated with a water-perfused suit whilecutaneous blood flow was measured by using laser-Doppler flowmetersplaced on both forearms. The NO synthase inhibitorN^G-monomethyl-L-arginine(L-NMMA) was given selectivelyto one forearm via a brachial artery catheter after marked cutaneousvasodilation had been established. During body heating, oraltemperature increased by 1.1 ± 0.1°C while heart rate increasedby 30 ± 6 beats/min. Mean arterial pressure stayed constant at 84 ± 2 mmHg. In the experimental forearm, cutaneous vascularconductance (CVC; laser-Doppler) decreased to 86 ± 5% of the peakresponse to heating (P < 0.05 vs.pre-L-NMMA values) afterL-NMMA infusion. In somesubjects, L-NMMA caused CVC tofall by ~30%; in others, it had little impact on the cutaneouscirculation. CVC in the control arm showed a similar increase withheating, then stayed constant whileL-NMMA was given to thecontralateral side. These results demonstrate that NO contributesmodestly, but not consistently, to cutaneous vasodilation during bodyheating in humans. They also indicate that NO is not the only factorresponsible for the dilation.

     

Effects of heme on the structure of the denatured state and folding kinetics of cytochrome b562

Heme-linked proteins, such as cytochromes, are popular subjects for protein folding studies. There is the underlying question of whether the heme affects the structure of the denatured state by cross-linking it and forming other interactions, which would perturb the folding pathway. We have studied wild-type and mutant cytochrome b562 from Escherichia coli, a 106 residue four-alpha-helical bundle. The holo protein apparently refolds with a half-life of 4 micros in its ferrous state. We have analysed the folding of the apo protein using continuous-flow fluorescence as well as stopped-flow fluorescence and CD. The apo protein folded much more slowly with a half-life of 270 micros that was unaffected by the presence of exogenous heme. We examined the nature of the denatured states of both holo and apo proteins by NMR methods over a range of concentrations of guanidine hydrochloride. The starting point for folding of the holo protein in concentrations of denaturant around the denaturation transition was a highly ordered native-like species with heme bound. Fully denatured holo protein at higher concentrations of denaturant consisted of denatured apo protein and free heme. Our results suggest that the very fast folding species of denatured holo protein is in a compact state, whereas the normal folding pathway from fully denatured holo protein consists of the slower folding of the apo protein followed by the binding of heme. These data should be considered in the analysis of folding of heme proteins.     

Effect of oregano essential oil and carvacrol on Cryptosporidium parvum infectivity in HCT-8 cells

Cryptosporidium parvum is the second leading cause of persistent diarrhea among children in low-resource settings. This study examined the effect of oregano essential oil (OEO) and carvacrol (CV) on inhibition of C. parvum infectivity in vitro. HCT-8 cells were seeded (1 × 10⁶) in 96-well microtiter plates until confluency. Cell viability and infectivity were assessed by seeding HCT-8 cell monolayers with C. parvum oocysts (1 × 10⁴) in two modalities: 1) 4 h co-culture with bioactive (0–250 μg/mL) followed by washing and incubation (48 h, 37 °C, 5% CO₂) in bioactive-free media; and 2) 4 h co-culture of C. parvum oocysts followed by washing and treatment with bioactive (0–250 μg/mL) during 48-h incubation. Cell viability was tested using Live/Dead? assay whereas infectivity was measured using C. parvum-specific antibody staining via immunofluorescence detection. Loss of cell viability was observed starting at 125 μg/mL and 60 μg/mL for OEO and CV, respectively. Neither OEO nor CV modulated the invasion of C. parvum sporozoites in HCT-8 cells. Treatment with bioactive after invasion reduced relative C. parvum infectivity in a dose-dependent manner to 55.6 ± 10.4% and 45.8 ± 4.1% at 60 and 30 μg/mL of OEO and CV, respectively. OEO and CV are potential bioactives to counteract C. parvum infection in children.     

High Power Magnetic Field Energy Harvesting through Amplified Magneto‐Mechanical Vibration

Internet of Things (IoT) is driving the development of new generation of sensors, communication components, and power sources. Ideally, IoT sensors and communication components are expected to be powered by sustainable energy source freely available in the environment. Here, a breakthrough in this direction is provided by demonstrating high output power energy harvesting from very low amplitude stray magnetic fields, which exist everywhere, through magnetoelectric (ME) coupled magneto‐mechano‐electric (MME) energy conversion. ME coupled MME harvester comprised of multiple layers of amorphous magnetostrictive material, piezoelectric macrofiber composite, and magnetic tip mass, interacts with an external magnetic field to generate electrical energy. Comprehensive experimental investigation and a theoretical model reveal that both the magnetic torque generated through magnetic loading and amplification of magneto‐mechanical vibration by ME coupling contributes toward the generation of high electrical power from the stray magnetic field around power cables of common home appliances. The generated electrical power from the harvester is sufficient for operating microsensors (gyro, temperature, and humidity sensing) and wireless data transmission systems. These results will facilitate the deployment of IoT devices in emerging intelligent infrastructures.     

An Immunocompetent Mouse Model of Zika Virus Infection

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