Rapamycin Ameliorates Age-Dependent Obesity Associated with Increased mTOR Signaling in Hypothalamic POMC Neurons

The prevalence of obesity in older people is the leading cause of metabolic syndromes. Central neurons serving as homeostatic sensors for body-weight control include hypothalamic neurons that express pro-opiomelanocortin (POMC) or neuropeptide-Y (NPY) and agouti-related protein (AgRP). Here, we report an age-dependent increase of mammalian target of rapamycin (mTOR) signaling in POMC neurons that elevates the ATP-sensitive potassium (K(ATP)) channel activity cell-autonomously to silence POMC neurons. Systemic or intracerebral administration of the mTOR inhibitor rapamycin causes weight loss in old mice. Intracerebral rapamycin infusion into old mice enhances the excitability and neurite projection of POMC neurons, thereby causing?a reduction of food intake and body weight. Conversely, young mice lacking the mTOR-negative regulator TSC1 in POMC neurons, but not those lacking TSC1 in NPY/AgRP neurons, were obese. Our study reveals that an increase in mTOR signaling in hypothalamic POMC neurons contributes to age-dependent obesity. VIDEO ABSTRACT:     

Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein

How transmitter receptors modulate neuronal signaling by regulating voltage-gated ion channel expression remains an open question. Here we report dendritic localization of mRNA of Kv4.2 voltage-gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by fragile X mental retardation protein (FMRP) linked to fragile X syndrome (FXS), the most common heritable mental retardation. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice and in neurons expressing Kv4.2-3'UTR that binds FMRP. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation induced by moderate stimuli. Surprisingly, recovery of Kv4.2 after N-methyl-D-aspartate receptor (NMDAR)-induced degradation also requires FMRP, likely due to NMDAR-induced FMRP dephosphorylation, which turns off FMRP suppression of Kv4.2. Our study of FMRP regulation of Kv4.2 deepens our knowledge of NMDAR signaling and reveals a FMRP target of potential relevance to FXS.     

Elucidation of the protein composition of mouse seminal vesicle fluid

The seminal vesicles are male accessory sex glands that contribute the major portion of the seminal plasma in which mammalian spermatozoa are bathed during ejaculation. In addition to conveying sperm through the ejaculatory duct, seminal vesicle secretions support sperm survival after ejaculation, and influence the female reproductive tract to promote receptivity to pregnancy. Analysis of seminal vesicle fluid (SVF) composition by proteomics has proven challenging, due to its highly biased protein signature with a small subset of dominant proteins and the difficulty of solubilizing this viscous fluid. As such, publicly available proteomic datasets identify only 85 SVF proteins in total. To address this limitation, we report a new preparative methodology involving sequential solubilization of mouse SVF in guanidine hydrochloride, acetone precipitation, and analysis by label-free mass spectrometry. Using this strategy, we identified 126 SVF proteins, including 83 previously undetected in SVF. Members of the seminal vesicle secretory protein family were the most abundant, accounting for 79% of all peptide spectrum matches. Functional analysis identified inflammation and formation of the vaginal plug as the two most prominent biological processes. Other notable processes included modulation of sperm function and regulation of the female reproductive tract immune environment. Together, these findings provide a robust methodological framework for future SVF studies and identify novel proteins with potential to influence both male and female reproductive physiology.     

An Adenovirus–Epstein-Barr Virus Hybrid Vector That Stably Transforms Cultured Cells with High Efficiency

EBV episomes are nuclear plasmids that are stably maintained through multiple cell divisions in primate and canine cells (J. L. Yates, N. Warren, and B. Sugden, Nature 313:812-815, 1985). In this report, we describe the construction and characterization of an E1-deleted recombinant adenovirus vector system that delivers an EBV episome to infected cells. This adenovirus-EBV hybrid vector system utilizes Cre-mediated, site-specific recombination to excise an EBV episome from a target recombinant adenovirus genome. We demonstrate that this vector system efficiently delivers the EBV episome and stably transforms a large fraction of infected canine D-17 cells. Using a colony-forming assay, we demonstrate stable transformation of 37% of cells that survive the infection. However, maximal transformation efficiency is achieved at doses of the E1-deleted recombinant adenoviruses that are toxic to the infected cells. Consequently, E1-deleted vector toxicity imposes a limitation on our current vector system.     

The determination of sense organs in Drosophila: interaction of scute with daughterless

Summary Several genetic loci have been implicated in the formation of the peripheral nervous system during Drosophila embryogenesis. As a first step towards understanding the functional interrelationships between these genes, we have searched for dominant interactions between deficiencies for the achaete-scute complex (AS-C), daughterless (da) and six other regions necessary for peripheral neurogenesis in the embryo. We have found that adult flies doubly heterozygous for deletions of AS-C and of da, or of AS-C and a small region on the fourth chromosome, exhibit characteristic bristle defects, suggesting that these genes cooperate to form sense organs both in the embryo and in the adult.     

Liquid Exfoliated Co(OH)2 Nanosheets as Low‐Cost,Yet High‐Performance,Catalysts for the Oxygen Evolution Reaction

Identifying cheap, yet effective, oxygen evolution catalysts is critical to the advancement of water splitting. Using liquid exfoliated Co(OH)₂ nanosheets as a model system, a simple procedure is developed to maximize the activity of any oxygen evolution reaction nanocatalyst. First the nanosheet edges are confirmed as the active areas by analyzing the catalytic activity as a function of nanosheet size. This allows the authors to select the smallest nanosheets (length ≈50 nm) as the best performing catalysts. While the number of active sites per unit electrode area can be increased via the electrode thickness, this is found to be impossible beyond ≈10 µm due to mechanical instabilities. However, adding carbon nanotubes increases both toughness and conductivity significantly. These enhancements mean that composite electrodes consisting of small Co(OH)₂ nanosheets and 10 wt% nanotubes can be made into freestanding films with thickness of up to 120 µm with no apparent electrical limitations. The presence of diffusion limitations results in an optimum electrode thickness of 70 µm, yielding a current density of 50 mA cm^?2 at an overpotential of 235 mV, close to the state of the art in the field. Applying this procedure to a high‐performance catalyst such as NiFeO_x should significantly surpass the state of the art.     

Forest edges enhance mate‐finding in the invasive European gypsy moth,Lymantria dispar

Habitat type, fragmentation, and edge effects can play important roles in the mate‐finding abilities of many species. These effects can be particularly pronounced in low‐density populations, which are often found at the margins of species' ranges or at the leading edge of an invasion. The European gypsy moth, Lymantria dispar (L.) (Lepidoptera: Erebidae), is a non‐native insect defoliator in the USA and Canada, where flightless females attract male moths through pheromone production and local extirpation of low‐density populations can be due to mate‐finding failure. To assess the effects of habitat edges on the ability of gypsy moths to find mates, we conducted a release experiment with male gypsy moths using female‐baited trap arrays in fields, at forest edges, and in the forest interior. Reduced mate‐finding was expected in fields and near forest edges based on geographic variation in invasion rates, male flight behavior, and pheromone plume dynamics. However, we found that mate‐finding was highest at forest edges, reduced in fields, and lowest within the forest interior. Within an array, traps closest to the forest edge also had the highest mate‐finding, suggesting that habitat characteristics can influence male flight direction in addition to pheromone cues. These results suggest that a moderate level of forest fragmentation enhances mate‐finding ability in the gypsy moth. Understanding the relationship between habitat heterogeneity and mate‐finding success in invasive species can inform predictions of future spread and assist with management plans that target mating disruption.