A Discovery with Potential to Revitalize Hammerhead Ribozyme Therapeutics for Treatment of Inherited Retinal Degenerations.

Hammerhead ribozymes (hhRzs), RNA enzymes capable of site-specific cleavage of arbitrary target mRNAs, have faced significant hurdles in development and optimization as gene therapeutics for clinical translation. Chemical and biological barriers must be overcome to realize an effective therapeutic. A new Facilitated ribozyme has been identified with greatly enhanced kinetic properties that lead new insight on the capacity of ribozymes to target mutant genes to treat inherited retinal degenerations.

Baseline characteristics of gay and bisexual men in a HIV pre-exposure prophylaxis demonstration project with equity quotas in Auckland, New Zealand.

Unlabelled: Background In New Zealand, pre-exposure prophylaxis (PrEP) should target gay and bisexual men (GBM), and equity is an important principle. Baseline characteristics of GBM offered PrEP in a demonstration project with an enrolment quota of 50% non-Europeans are described.

Methods: An open-label, single-arm treatment evaluation study design ('NZPrEP') was used.

Gating reaction mechanism of neuronal NMDA receptors.

The activation mechanisms of recombinant N-methyl-d-aspartate receptors (NRs) have been established in sufficient detail to account for their single channel and macroscopic responses; however, the reaction mechanism of native NRs remains uncertain due to indetermination of the isoforms expressed and possible neuron-specific factors. To delineate the activation mechanism of native NRs, we examined the kinetic properties of currents generated by individual channels located at the soma of cultured rat neurons. Cells were dissociated from the embryonic cerebral cortex or hippocampus, and on-cell single channel recordings were done between 4 and 50 days in vitro (DIV).

Ifenprodil effects on GluN2B-containing glutamate receptors.

N-Methyl-d-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that mediate fast excitatory transmission in the central nervous system and are critical to synaptic development, plasticity, and integration. They have a rich complement of modulatory sites, which represent important pharmacological targets. Ifenprodil is a well tolerated NMDA receptor inhibitor; it is selective for GluN2B-containing receptors and has neuroprotective effects.

Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice.

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360.

Factors controlling fibroblast growth factor receptor-1's cytoplasmic trafficking and its regulation as revealed by FRAP analysis.

Biochemical and microscopic studies have indicated that FGFR1 is a transmembrane and soluble protein present in the cytosol and nucleus. How FGFR1 enters the cytosol and subsequently the nucleus to control cell development and associated gene activities has become a compelling question. Analyses of protein synthesis, cytoplasmic subcompartmental distribution and movement of FGFR1-EGFP and FGFR1 mutants showed that FGFR1 exists as three separate populations (a) a newly synthesized, highly mobile, nonglycosylated, cytosolic receptor that is depleted by brefeldin A and resides outside the ER-Golgi lumen, (b) a slowly diffusing membrane receptor population, and (c) an immobile membrane pool increased by brefeldin A.

Integrative nuclear FGFR1 signaling (INFS) as a part of a universal "feed-forward-and-gate" signaling module that controls cell growth and differentiation.

A novel signaling mechanism is described through which extracellular signals and intracellular signaling pathways regulate proliferation, growth, differentiation, and other functions of cells in the nervous system. Upon cell stimulation, fibroblast growth factor receptor-1 (FGFR1), a typically plasma membrane-associated protein, is released from ER membranes into the cytosol and translocates to the cell nucleus by an importin-beta-mediated transport pathway along with its ligand, FGF-2. The nuclear accumulation of FGFR1 is activated by changes in cell contacts and by stimulation of cells with growth factors, neurotransmitters and hormones as well as by a variety of different second messengers and thus was named integrative nuclear FGFR1 signaling (INFS).

Nuclear trafficking of FGFR1: a role for the transmembrane domain.

Several members of the fibroblast growth factor (FGF) family lack signal peptide (SP) sequences and are present only in trace amounts outside the cell. However, these proteins contain nuclear localization signals (NLS) and accumulate in the cell nucleus. Our studies have shown that full length FGF receptor 1 (FGFR1) accumulates within the nuclear interior in parallel with FGF-2.