Number and Grammatical Gender Attraction in Spanish Pronouns: Evidence for a Syntactic Route to Their Features.

When a speaker produces a pronoun, they must choose a form that carries the appropriate features. The current study investigates how speakers identify these features. We consider two possible routes: a conceptual-lexical route, whereby pronouns derive their features from the concept of the referent, and a syntactic route, whereby pronoun form is determined through a feature matching operation with the linguistic antecedent.

The Missing VP Illusion in Spanish: Assessing the Role of Language Statistics and Working Memory.

In English, double center-embedded sentences yield a so-called "missing VP illusion": When they are ungrammatical due to a missing verb, they are judged as equally or even more acceptable than their grammatical counterparts. The illusion is often attributed to working memory limitations. Additionally, it has been suggested that statistical differences across languages-e.

Community-Engaged Participatory Methods to Address Lesbian, Gay, Bisexual, Transgender, Queer, and Questioning Young People's Health Information Needs With a Resource Website: Participatory Design and Development Study.

Background: Lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ+) young people (aged 15 to 25 years) face unique health challenges and often lack resources to adequately address their health information needs related to gender and sexuality. Beyond information access issues, LGBTQ+ young people may need information resources to be designed and organized differently compared with their cisgender and heterosexual peers and, because of identity exploration, may have different information needs related to gender and sexuality than older people.

Objective: The objective of our study was to work with a community partner to develop an inclusive and comprehensive new website to address LGBTQ+ young people's health information needs.

A Community-Developed, Web-Based Mobile App Intervention Addressing Social Work and Legal Needs of Black Sexual Minority Men Living With HIV: Protocol for a Randomized Comparison Trial.

Background: Black sexual minority men (BSMM) are disproportionately affected by HIV. Los Angeles County (LAC) carries a substantial burden of the HIV epidemic in California. Negative effects of both psychosocial and structural barriers highlight the timely need to increase HIV treatment among BSMM.

Synthetic nanocarriers for the delivery of polynucleotides to the eye.

This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers. Attention has been addressed to the capacity of different nanocarriers for the specific delivery of polynucleotides to both, the anterior and posterior segments of the eye, with emphasis on their ability to (i) improve the transport of polynucleotides across the different eye barriers; (ii) promote their intracellular penetration into the target cells; (iii) protect them against degradation and, (iv) deliver them in a long-term fashion way. Overall, the conclusion is that despite the advantages that nanotechnology may offer to the area of ocular polynucleotide-based therapies (especially AS-ODN and siRNA delivery), the knowledge disclosed so far is still limited.

Safety and Efficacy Clinical Trials for SYL1001, a Novel Short Interfering RNA for the Treatment of Dry Eye Disease.

Purpose: To evaluate the efficacy and safety of SYL1001, a short interfering (si) RNA targeting the transient receptor potential cation channel subfamily V member 1 (TRPV1), for the treatment of dry eye disease (DED).

Methods: This study combines a phase I and two phase II clinical trials to test different doses of SYL1001 in a total of 156 healthy subjects and patients with DED. After 10 days of treatment, the primary efficacy endpoints were the effect on (1) the scoring in the Visual Analogue Scale (VAS) and Ocular Surface Disease Index (OSDI) questionnaires, and (2) ocular tolerance evaluated by corneal fluorescein staining and conjunctival hyperemia.

Short-interference RNAs: becoming medicines.

RNA interference is a cellular mechanism by which small molecules of double stranded RNA modulate gene expression acting on the concentration and/or availability of a given messenger RNA. Almost 10 years after Fire and Mello received the Nobel Prize for the discovery of this mechanism in flat worms, RNA interference is on the edge of becoming a new class of therapeutics. With various phase III studies underway, the following years will determine whether RNAi-therapeutics can rise up to the challenge and become mainstream medicines.

Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic receptor 2, for lowering intraocular pressure.

The objective of this study was to evaluate ocular tolerance, safety, and effect on intraocular pressure (IOP) of a topically administered small interfering RNA; SYL040012, on healthy volunteers. The study was an open-label, controlled, single-center study comprised of two intervals that enrolled 30 healthy subjects having IOP below 21 mmHg. SYL040012 was administered to one eye as a single dose to six subjects during interval 1.

In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma.

Glaucoma is a progressive ocular syndrome characterized by degeneration of the optic nerve and irreversible visual field loss. Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Increased IOP is the result of an imbalance between synthesis and outflow of aqueous humor (AH).

Differential expression and localization of transient receptor potential vanilloid 1 in rabbit and human eyes.

Introduction: The superfamily of transient receptor potential (TRP) cation channels is involved in nociception. Members of this family, such as the vanilloid receptor type 1 (TRPV1) channel, are activated by a wide range of stimuli including heat (⟩43°C), low pH (⟨6.5), hypoxia, and hypertonicity.

Silencing human genetic diseases with oligonucleotide-based therapies.

RNA interference is an endogenous mechanism present in most eukaryotic cells that enables degradation of specific mRNAs. Pharmacological exploitation of this mechanism for therapeutic purposes attracted a whole amount of attention in its initial years, but was later hampered due to difficulties in delivery of the pharmacological agents to the appropriate organ or tissue. Advances in recent years have to a certain level started to address this specific issue.

Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice.

Neuropeptide S (NPS) is a recently discovered neuropeptide that increases arousal and wakefulness while decreasing anxiety-like behavior. Here, we used a self-administration paradigm to demonstrate that intracerebroventricular infusion of NPS reinstates extinguished cocaine-seeking behavior in a dose-dependent manner in mice. The highest dose of NPS (0.

Activation of the intrinsic cell death pathway, increased apoptosis and modulation of astrocytes in the cerebellum of diabetic rats.

Poorly controlled diabetes mellitus results in structural and functional changes in many brain regions. We demonstrate that in streptozotocin-induced diabetic rats cell death is increased and proliferation decreased in the cerebellum, indicating overall cell loss. Levels of both the proform and cleaved forms of caspases 3, 6 and 9 are increased, with no change in caspases 7, 8 or 12.

Growth hormone-releasing peptide-6 increases insulin-like growth factor-I mRNA levels and activates Akt in RCA-6 cells as a model of neuropeptide Y neurones.

Chronic systemic administration of growth hormone (GH)-releasing peptide-6 (GHRP-6), an agonist for the ghrelin receptor, to normal adult rats increases insulin-like growth factor (IGF)-I mRNA and phosphorylated Akt (pAkt) levels in various brain regions, including the hypothalamus. Because neuropeptide Y (NPY) neurones of the arcuate nucleus express receptors for ghrelin, we investigated whether these neurones increase their IGF-I and p-Akt levels in response to this agonist. In control rats, immunoreactive pAkt was practically undetectable; however, GHRP-6 increased p-Akt immunoreactivity in the arcuate nucleus, with a subset of neurones also being immunoreactive for NPY.

The corticotropin-releasing factor-hypocretin connection: implications in stress response and addiction.

The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. Recent data have raised the hypothesis that hypocretin neurons are also part of the circuitries that mediate the hypothalamic stress response. In particular, we have recently demonstrated that corticotrophin-releasing factor (CRF)-immunoreactive terminals make direct synaptic contacts with hypocretin-expressing neurons and that numerous hypocretinergic neurons express the CRF-R1/2 receptors.

Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity.

Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2).

Phosphorylation of glycosyl-phosphatidylinositol by phosphatidylinositol 3-kinase changes its properties as a substrate for phospholipases.

Phosphatidylinositol 3-kinases (PI3K) phosphorylate the 3-position of the inositol ring of phosphatidylinositol-4,5-bisphosphate to produce phosphatidylinositol-3,4,5-trisphosphate. It is not clear whether PI3K can phosphorylate the inositol group in other biomolecules. We sought to determine whether PI3K was able to use glycosyl-phosphatidylinositol (GPI) as a substrate.

Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.

S-adenosyl-L-methionine (SAM) is synthesized by methionine adenosyltransferases (MATs). Ablation of the liver-specific MAT1A gene results in liver neoplasia and sensitivity to oxidant injury. Here we show that acidic sphingomyelinase (ASMase) mediates the downregulation of MAT1A by TNF-alpha.

Growth hormone-releasing peptide-6 inhibits cerebellar cell death in aged rats.

Insulin-like growth factor (IGF)-I is essential for cerebellar granule neuron survival and a decline in IGF-I is implicated in various age-dependent processes. Here we show that IGF-I mRNA levels are decreased in the cerebellum of old rats compared with young rats and this was associated with increased cell death and activation of caspases 3 and 9. Growth hormone-releasing peptide (GHRP)-6, a synthetic ligand for the ghrelin receptor, increased IGF-I mRNA levels, decreased cell death and inhibited caspase 3 and 9 activation in the cerebellum of aged rats.

The number of lactotrophs is reduced in the anterior pituitary of streptozotocin-induced diabetic rats.

Aims/hypothesis: Prolactin secretion is often reduced in insulin dependent diabetes mellitus, but little is known about the mechanism involved. Since changes in the hormonal environment modulate cell proliferation, death and cellular makeup of the anterior pituitary, we have analysed whether the number of lactotrophs is reduced in diabetic rats.

Methods: Streptozotocin induced diabetic rats were maintained hyperglycaemic for 2 months.

Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection.

Beneficial effects of GH on memory, mental alertness, and motivation have been documented. Many actions of GH are mediated through IGF-I; hence, we investigated whether systemic administration of GH or GH-releasing peptide (GHRP)-6 modulates the brain IGF system. Treatment of adult male rats with GHRP-6 or GH for 1 wk significantly increased IGF-I mRNA levels in the hypothalamus, cerebellum, and hippocampus, with no effect in cerebral cortex.

Liver cell proliferation requires methionine adenosyltransferase 2A mRNA up-regulation.

Regulation of liver cell proliferation is a key event to control organ size during development and liver regeneration. Methionine adenosyltransferase (MAT) 2A is expressed in proliferating liver, whereas MAT1A is the form expressed in adult quiescent hepatocytes. Here we show that, in H35 hepatoma cells, growth factors such as hepatocyte growth factor (HGF) and insulin up-regulated MAT2A expression.

Purification and characterization of insulin-mimetic inositol phosphoglycan-like molecules from grass pea (Lathyrus sativus) seeds.

Background: Signal transduction through the hydrolysis of glycosyl-phosphatidylinositol (GPI) leading to the release of the water-soluble inositol phosphoglycan (IPG) molecules has been demonstrated to be important for mediating some of the actions of insulin and insulin-like growth factor-I (IGF-I).

Materials And Methods: In the present study, GPI from grass pea (Lathyrus sativus) seeds has been purified and partially characterized on the basis of its chromatographic properties and its compositional analysis.

Results: The results indicate that it shows similarities to GPI previously isolated from other sources such as rat liver.

Short-chain ceramide regulates hepatic methionine adenosyltransferase expression.

Background: The metabolism of methionine plays an important role in regulating hepatic cellular function. Methionine adenosyltransferase (MAT) is the enzyme that catalyses the biosynthesis of S-adenosylmethionine (AdoMet) from ATP and methionine. Liver-specific MAT I/III levels are down-regulated in the regenerating rat liver after partial hepatectomy.

Role of diffusible and transcription factors in inner ear development: implications in regeneration.

Organogenesis involves a dynamic balance of the mechanisms regulating cell division, differentiation and death. The development of the chicken embryo inner ear offers a well-characterised model at the morphological level to study which signals are implicated in the modulation of cellular activation and commitment. The early developmental decisions that control the origin of the inner ear elements are just beginning to be identified by complementary in vivo and in vitro studies.