Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABA Receptors.

GABA receptors (GABARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability.

Lesotho's progress towards UNAIDS 95-95-95 targets from 2016 to 2020: comparison of Population-based HIV Impact Assessments.

Background: Lesotho has made substantial efforts to control its HIV epidemic. We aimed to assess progress towards UNAIDS 95-95-95 targets in Lesotho by comparing data from the Lesotho Population-based HIV Impact Assessments conducted in 2016-17 (LePHIA 2016) and 2019-20 (LePHIA 2020).

Methods: The LePHIA surveys used a cross-sectional, two-stage, stratified cluster sampling design to obtain a nationally representative sample of adults aged 15-59 years (LePHIA 2016) or aged 15 years and older (LePHIA 2020) from all ten districts of Lesotho.

Image metric-based multi-observation single-step deep deterministic policy gradient for sensorless adaptive optics.

Sensorless adaptive optics (SAO) has been widely used across diverse fields such as astronomy, microscopy, and ophthalmology. Recent advances have proved the feasibility of using the deep deterministic policy gradient (DDPG) for image metric-based SAO, achieving fast correction speeds compared to the coordinate search Zernike mode hill climbing (ZMHC) method. In this work, we present a multi-observation single-step DDPG (MOSS-DDPG) optimization framework for SAO on a confocal scanning laser ophthalmoscope (SLO) system with particular consideration for applications in preclinical retinal imaging.

GABA receptors and neuroligin 2 synergize to promote synaptic adhesion and inhibitory synaptogenesis.

GABA receptors (γ-aminobutyric acid-gated receptors type A; GABARs), the major structural and functional postsynaptic components of inhibitory synapses in the mammalian brain, belong to a family of GABA-gated Cl/HCO ion channels. They are assembled as heteropentamers from a family of subunits including: α (1-6), β(1-3), γ(1-3), δ, ε, π, θ and ρ(1-3). GABARs together with the postsynaptic adhesion protein Neuroligin 2 (NL2) and many other pre- and post-synaptic proteins guide the initiation and functional maturation of inhibitory GABAergic synapses.

Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.

GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits.

Screening for psychosis risk in primary mental health care services - Implementation, prevalence and recovery trajectories.

Objectives: Early interventions improve outcomes for people at high risk of psychosis and are likely to be cost saving. This group tends to seek help for emotional problems - depression and anxiety - via primary care services, where early detection methods are poor. We sought to determine prevalence rates of high risk for psychosis in UK primary care mental health services and clinical outcomes following routinely delivered psychological therapies.

Forty Years Searching for Neurosteroid Binding Sites on GABA Receptors.

Brain inhibition is a vital process for controlling and sculpting the excitability of the central nervous system in healthy individuals. This level of control is provided over several timescales and involves the neurotransmitter GABA acting at inhibitory synapses to: rapidly inhibit neurons by activating the GABA receptor; over a slower timescale, to tonically activate extrasynaptic GABA receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABA receptors to control transmitter release by inhibiting presynaptic Ca channels whilst providing postsynaptic inhibition via K channel activation. From this plethora of roles for GABA and its receptors, the GABA receptor isoform is of major interest due to its dynamic functional plasticity, which in part, is due to being targeted by modulatory brain neurosteroids derived from sex and stress hormones.

Mid-Infrared, Optically Active Black Phosphorus Thin Films on Centimeter Scale.

Black phosphorus (BP) is a narrow bandgap (∼0.3 eV) semiconductor with a great potential for optoelectronic devices in the mid-infrared wavelength. However, it has been challenging to achieve a high-quality scalable BP thin film.

Imaging the Meissner effect in hydride superconductors using quantum sensors.

By directly altering microscopic interactions, pressure provides a powerful tuning knob for the exploration of condensed phases and geophysical phenomena. The megabar regime represents an interesting frontier, in which recent discoveries include high-temperature superconductors, as well as structural and valence phase transitions. However, at such high pressures, many conventional measurement techniques fail.

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.

Reproductive Carrier Screening Results With Maternal Health Implications During Pregnancy.

Objective: To identify conditions on a reproductive carrier screening panel with the potential for carrier manifestations during pregnancy and review the implications for obstetric care.

Methods: This was a retrospective cross-sectional study of consecutive samples from female patients aged 18-55 years submitted to a commercial laboratory for a 274-gene carrier screening panel (January 2020 to September 2022). A literature review was performed to identify genes on the panel with potential for pregnancy complications in carriers.

A systematic review of the impact of postoperative aerobic exercise training in patients undergoing surgery for intra-abdominal cancers.

Introduction: Enhanced recovery after surgery (ERAS) programmes which advocate early mobility after surgery have improved immediate clinical outcomes for patients undergoing abdominal cancer resections with curative intent. However, the impact of continued physical activity on patient-related outcomes and functional recovery is not well defined. The aim of this review was to assess the impact of postoperative aerobic exercise training, either alone or in conjunction with another exercise modality, on patients who have had surgery for intra-abdominal cancer.

Genomic Data Heterogeneity across Molecular Diagnostic Laboratories: A Real-World Connect Myeloid Disease Registry Perspective on Variabilities in Genomic Assay Methodology and Reporting.

Genomic data variability from laboratory reports can impact clinical decisions and population-level analyses; however, the extent of this variability and the impact on the data's value are not well characterized. This pilot study used anonymized genetic and genomic test reports from the Connect Myeloid Disease Registry (NCT01688011), a multicenter, prospective, observational cohort study of patients with newly diagnosed myelodysplastic syndromes, acute myeloid leukemia, or idiopathic cytopenia of undetermined significance, to analyze laboratory test variabilities and limitations. Results for 56 randomly selected patients enrolled in the Registry were independently extracted and evaluated (data cutoff, January 2020).

CGP7930 - An allosteric modulator of GABARs, GABARs and inwardly-rectifying potassium channels.

Type-A and -B GABA receptors (GABARs/GABARs) control brain function and behaviour by fine tuning neurotransmission. Over-time these receptors have become important therapeutic targets for treating neurodevelopmental and neuropsychiatric disorders. Several positive allosteric modulators (PAMs) of GABARs have reached the clinic and selective targeting of receptor subtypes is crucial.

Low recruitment drives the decline of red porgy (Pagrus pagrus) along the southeast USA Atlantic coast: Inferences from fishery-independent trap and video monitoring.

Red porgy (Pagrus pagrus) is a reef-associated, economically-important, winter-spawning, protogynous Sparidae species that appears to have declined in abundance in recent years along the southeast United States Atlantic coast. We used spatially-explicit generalized additive models built with fishery-independent chevron trap (1990-2021) and video data (2011-2021) to quantify the ways in which red porgy relative abundance and mean size varied across temporal, spatial, environmental, and habitat variables. Mean red porgy relative abundance from traps declined by 77% between 1992 and 2021, and declines were similarly large (69%) on video between 2011 and 2021.

Pregnenolone sulfate analogues differentially modulate GABA receptor closed/desensitised states.

Background And Purpose: GABA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.

Electrical Impedance Dermography Differentiates Squamous Cell Carcinoma In Situ from Inflamed Seborrheic Keratoses.

There are no currently available low-cost, noninvasive methods for discerning the depth of squamous cell carcinoma (SCC) invasion or distinguishing SCC from its benign mimics, such as inflamed seborrheic keratosis (SK). We studied 35 subjects with subsequently confirmed SCC or SK. Subjects underwent electrical impedance dermography measurements at six frequencies to assess the electrical properties of the lesion.

Pre- and postsynaptic modulation of hippocampal inhibitory synaptic transmission by pregnenolone sulphate.

Neurosteroids are important endogenous modulators of GABA receptor-mediated neurotransmission within the CNS and play a vital role in maintaining normal healthy brain function. Research has mainly focussed on neurosteroids such as allopregnanolone and tetrahydro-deoxycorticosterone (THDOC) which are allosteric potentiators of GABA receptors, whilst the sulphated steroids, including pregnenolone sulphate (PS), which inhibit GABA receptor function, have been relatively neglected. Importantly, a full description of PS effects on inhibitory synaptic transmission, at concentrations that are expected to inhibit postsynaptic GABA receptors, is lacking.

Prevalence of and factors associated with late diagnosis of HIV in Malawi, Zambia, and Zimbabwe: Results from population-based nationally representative surveys.

Introduction: Late diagnosis of HIV (LD) increases the risk of morbidity, mortality, and HIV transmission. We used nationally representative data from population-based HIV impact assessment (PHIA) surveys in Malawi, Zambia, and Zimbabwe (2015-2016) to characterize adults at risk of LD and to examine associations between LD and presumed HIV transmission to cohabiting sexual partners.

Methods: We estimated the prevalence of LD, defined as CD4 count <350 cells/μL, among adults newly diagnosed with HIV during the surveys and odds ratios for associated factors.

Assessing the effect of interpretation design traits on zoo visitor engagement.

In the past few decades, zoos have undergone a transformation from places of entertainment to centers for conservation, with education becoming a particular focus. Interpretation in zoos is a near-universal method for delivering education in zoos and has been shown to prompt learning and pro-conservation behavior change. However, there is limited understanding on how interpretation design itself can influence visitor engagement.

Photocarrier-induced persistent structural polarization in soft-lattice lead halide perovskites.

The success of the lead halide perovskites in diverse optoelectronics has motivated considerable interest in their fundamental photocarrier dynamics. Here we report the discovery of photocarrier-induced persistent structural polarization and local ferroelectricity in lead halide perovskites. Photoconductance studies of thin-film single-crystal CsPbBr at 10 K reveal long-lasting persistent photoconductance with an ultralong photocarrier lifetime beyond 10 s.

The impacts of dopants on the small polaron mobility and conductivity in hematite - the role of disorder.

Hematite (α-FeO) is a promising transition metal oxide for various energy conversion and storage applications due to its advantages of low cost, high abundance, and good chemical stability. However, its low carrier mobility and electrical conductivity have hindered the wide application of hematite-based devices. Fundamentally, this is mainly caused by the formation of small polarons, which show conduction through thermally activated hopping.

Assessment of an automated approach for variant interpretation in screening for monogenic disorders: A single-center study.

Background: Automation has been introduced into variant interpretation, but it is not known how automated variant interpretation performs on a stand-alone basis. The purpose of this study was to evaluate a fully automated computerized approach.

Method: We reviewed all variants encountered in a set of carrier screening panels over a 1-year interval.