Antenatal depression and children's developmental outcomes: potential mechanisms and treatment options.

During the last decade there has been increased recognition of the prevalence of antenatal depression as well as an expansion in research examining the impact of maternal mood during pregnancy on offspring development. The aim of this review was to summarise the theoretical underpinnings and empirical evidence regarding the impact of antenatal depression on children's developmental outcomes. Biological mechanisms hypothesised to account for an association between antenatal depression and adverse offspring outcomes are first identified including the functioning of the prenatal Hypothalamic Pituitary Adrenal (HPA) axis and epigenetic processes.

Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism.

Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues.

Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains.

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations.

α-Calcitonin gene related peptide (α-CGRP) mediated lipid mobilization in 3T3-L1 adipocytes.

The neuropeptide, α-calcitonin gene-related peptide (α-CGRP), is expressed from sensory nerves that innervate fat. However, how α-CGRP may act in adipose tissue is unclear. Using 3T3-L1 adipocytes we observed that rat α-CGRP (rα-CGRP) evoked either a biphasic or monophasic reduction in intracellular free fatty acid (FFA) content.

Galectin-3 regulates hepatic progenitor cell expansion during liver injury.

Objective: Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.

A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-Ï€ interaction.

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series.

The role of inner and outer face parts in holistic processing: a developmental study.

The effects of inner-outer feature interactions with unfamiliar faces were investigated in 6- and 10-year-old children and adults (20-30 years) to determine their contribution in holistic face vision. Participants completed a two-alternative forced-choice (2AFC) task under two conditions. The congruent condition used whole, inner-only, and outer-only stimuli.

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 2.

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability.

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part 1.

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought.

Fish navigation of large dams emerges from their modulation of flow field experience.

Navigating obstacles is innate to fish in rivers, but fragmentation of the world's rivers by more than 50,000 large dams threatens many of the fish migrations these waterways support. One limitation to mitigating the impacts of dams on fish is that we have a poor understanding of why some fish enter routes engineered for their safe travel around the dam but others pass through more dangerous routes. To understand fish movement through hydropower dam environments, we combine a computational fluid dynamics model of the flow field at a dam and a behavioral model in which simulated fish adjust swim orientation and speed to modulate their experience to water acceleration and pressure (depth).

Differentiation and molecular profiling of human embryonic stem cell-derived corneal epithelial cells.

It has been suggested that the isolation of scalable populations of limbal stem cells may lead to radical changes in ocular therapy. In particular, the derivation and transplantation of corneal stem cells from these populations may result in therapies providing clinical normality of the diseased or damaged cornea. Although feasible in theory, the lack of donor material in sufficient quantity and quality currently limits such a strategy.

Peak hip and knee joint moments during a sit-to-stand movement are invariant to the change of seat height within the range of low to normal seat height.

Background: Previous studies have consistently reported that decreasing seat height increases the peak hip and knee joint moments; however, these findings may not apply to biomechanical changes at very low seat heights. The purpose of this study, therefore, was to examine the effect of a large range of seat heights on peak joint moments of the lower limb during a sit-to-stand (STS) movement.

Methods: Eight healthy young subjects participated in this experiment.

Precursors to aggression are evident by 6 months of age.

We tested the hypothesis that developmental precursors to aggression are apparent in infancy. Up to three informants rated 301 firstborn infants for early signs of anger, hitting and biting; 279 (93%) were assessed again as toddlers. Informants' ratings were validated by direct observation at both ages.

Current status and effectiveness of mentorship programmes in urology: a systematic review.

The objectives of this review were to identify and evaluate the efficacy of mentorship programmes for minimally invasive procedures in urology and give recommendations on how to improve mentorship. A systematic literature search of the PubMed/Medline databases was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In all, 21 articles were included in the review and divided into four categories: fellowships, mini-fellowships, mentored skills courses and novel mentorship programmes.

Generation of functional neurons from feeder-free, keratinocyte-derived equine induced pluripotent stem cells.

Pluripotent stem cells (PSCs) offer unprecedented biomedical potential not only in relation to humans but also companion animals, particularly the horse. Despite this, attempts to generate bona fide equine embryonic stem cells have been unsuccessful. A very limited number of induced PSC lines have so far been generated from equine fibroblasts but their potential for directed differentiation into clinically relevant tissues has not been explored.

Ethical, legal and practical issues of establishing an adipose stem cell bank for research.

Access to human tissue is critical to medical research, however the laws and regulations surrounding gaining ethical and legal access to tissue are often poorly understood. Recently, there has been a huge increase in the interest surrounding the therapeutic application of adipose tissue, and adipose-derived stem cells. To facilitate our own research interests and possibly assist our local colleagues and collaborators, we established a Research Tissue Bank (RTB) to collect, store and distribute human adipose tissue derived cells with all the appropriate ethical approval for subsequent downstream research.

The Concise Guide to PHARMACOLOGY 2013/14: overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database.

Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment.

Gene expression during development and differentiation is regulated in a cell- and stage-specific manner by complex networks of intergenic and intragenic cis-regulatory elements whose numbers and representation in the genome far exceed those of structural genes. Using chromosome conformation capture, it is now possible to analyze in detail the interaction between enhancers, silencers, boundary elements and promoters at individual loci, but these techniques are not readily scalable. Here we present a high-throughput approach (Capture-C) to analyze cis interactions, interrogating hundreds of specific interactions at high resolution in a single experiment.

Accurate prediction of drug-induced liver injury using stem cell-derived populations.

Despite major progress in the knowledge and management of human liver injury, there are millions of people suffering from chronic liver disease. Currently, the only cure for end-stage liver disease is orthotopic liver transplantation; however, this approach is severely limited by organ donation. Alternative approaches to restoring liver function have therefore been pursued, including the use of somatic and stem cell populations.

The worm has turned: unexpected similarities between the transcription of enhancers and promoters in the worm and mammalian genomes.

Our understanding of biological processes in humans is often based on examination of analogous processes in other organisms. The nematode worm Caenorhabditis elegans has been a particularly valuable model, leading to Nobel prize winning discoveries in development and genetics. Until recently, however, the worm has not been widely used as a model to study transcription due to the lack of a comprehensive catalogue of its RNA transcripts.

PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells.

Background And Purpose: A major challenge in the development of new medicines targeting GPCRs is the ability to quantify drug action in physiologically relevant models. Primary cell models that closely resemble the clinically relevant in vivo site of drug action are important translational tools in drug development. However, pharmacological studies in these models are generally very limited due to the methodology used.

Comorbidity profile and healthcare utilization in elderly patients with serious mental illnesses.

Objectives: Patients with serious mental illness are living longer. Yet, there remain few studies that focus on healthcare utilization and its relationship with comorbidities in these elderly mentally ill patients.

Design: Comparative study.

Modeling human liver biology using stem cell-derived hepatocytes.

Stem cell-derived hepatocytes represent promising models to study human liver biology and disease. This concise review discusses the recent progresses in the field, with a focus on human liver disease, drug metabolism and virus infection.

Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor: implications for adrenomedullin and calcitonin gene-related peptide pharmacology.

Background And Purpose: Receptor activity-modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor-like receptor (CLR). The interactions of the different RAMPs with this class B GPCR yield high-affinity calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear.