A Randomized Trial Comparing Inhaled Insulin Plus Basal Insulin Versus Usual Care in Adults With Type 1 Diabetes.

Objective: To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring.

Research Design And Methods: At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks.

Results: Prestudy, AID was used by 48% and MDI by 45%.

Domoic Acid as a Lead for the Discovery of the First Selective Ligand for Kainate Receptor Subtype 5 (GluK5).

Twenty-one simplified analogues of the natural product domoic acid were designed, synthesized, and then characterized at homomeric kainic acid (KA) receptors (GluK1-3,5). displays a high affinity for homomeric GluK5 receptors (IC = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and ≫100-fold selectivity over native AMPA and -methyl d-aspartate receptors. Functional studies of on heteromeric GluK2/5 receptors show no agonist or antagonist functional response at 10 μM, while a concentration of 100 μM at neuronal slices (rat) shows low agonist activity.

Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538.

Kainate receptors play an important role in the central nervous system by mediating postsynaptic excitatory neurotransmission and modulating the release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. To date, only three structures of the ligand-binding domain (LBD) of the kainate receptor subunit GluK1 in complex with positive allosteric modulators have been determined by X-ray crystallography, all belonging to class II modulators. Here, we report a high-resolution structure of GluK1-LBD in complex with kainate and BPAM538, which belongs to the full-spanning class III.

A Randomized Comparison of Postprandial Glucose Excursion Using Inhaled Insulin Versus Rapid-Acting Analog Insulin in Adults With Type 1 Diabetes Using Multiple Daily Injections of Insulin or Automated Insulin Delivery.

Objective: To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin.

Research Design And Methods: A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61).

Results: The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference -12 mg/dL, 95% CI -22 to -2, P = 0.

The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2.

Kainate receptors belong to the family of ionotropic glutamate receptors and contribute to the majority of fast excitatory neurotransmission. Consequently, they also play a role in brain diseases. Therefore, understanding how these receptors can be modulated is of importance.

Tritium and deuterium labelling of a kainate receptor antagonist and evaluation as a radioligand.

Kainate receptors play a crucial role in mediating synaptic transmission within the central nervous system. However, the lack of selective pharmacological tool compounds for the GluK3 subunit represents a significant challenge in studying these receptors. Recently presented compound 1 stands out as a potent antagonist of GluK3 receptors, exhibiting nanomolar affinity at GluK3 receptors and strongly inhibiting glutamate-induced currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with K values of 65 and 39 nM, respectively.

The use of creative case studies to explore non-verbal and non-ambulant children and young people's well-being.

Background And Purpose: The aim of this paper is to describe and critically analyse creative research methods, exploring how these can offer ways to enable non-verbal and non-ambulant children and young people with cerebral palsy, to express their views about their well-being. The context of this research explored their choices for recreational activities, seeking to understand how their level of participation impacted upon their well-being.

Methods: A qualitative comparative case study design was chosen comprising of two interviews, using photographs and diaries to elicit discussion, supported by observations.

Small-molecule positive allosteric modulation of homomeric kainate receptors GluK1-3: development of screening assays and insight into GluK3 structure.

The kainate receptors GluK1-3 (glutamate receptor ionotropic, kainate receptors 1-3) belong to the family of ionotropic glutamate receptors and are essential for fast excitatory neurotransmission in the brain, and are associated with neurological and psychiatric diseases. How these receptors can be modulated by small-molecule agents is not well understood, especially for GluK3. We show that the positive allosteric modulator BPAM344 can be used to establish robust calcium-sensitive fluorescence-based assays to test agonists, antagonists, and positive allosteric modulators of GluK1-3.

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators.

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344).

Solution structure of the N-terminal extension domain of a asparaginyl-tRNA synthetase.

Several secreted proteins from helminths (parasitic worms) have been shown to have immunomodulatory activities. Asparaginyl-tRNA synthetases are abundantly secreted in the filarial nematode (AsnRS) and the parasitic flatworm (AsnRS), indicating a possible immune function. The suggestion is supported by AsnRS alleviating disease symptoms in a T-cell transfer mouse model of colitis.

Structure-Activity Relationship and Solubility Studies of N1-Substituted Quinoxaline-2,3-diones as Kainate Receptor Antagonists.

Kainate receptors are a class of ionotropic glutamate receptors that respond to the excitatory neurotransmitter glutamate in the central nervous system and play an important role in the development of neurodegenerative disorders and the regulation of synaptic function. In the current study, we investigated the structure- activity relationship of the series of quinoxaline-2,3-diones substituted at N1, 6, and 7 positions, as ligands of kainate homomeric receptors GluK1-3 and GluK5. Pharmacological characterization showed that all derivatives obtained exhibited micromolar affinity at GluK3 receptors with K values in the range 0.

A kaleidoscope of well-being to authentically represent the voices of children and young people with complex cerebral palsy: a case study series.

Purpose: This paper authentically represents the voices of non-verbal children with cerebral palsy using a case study design. Policy suggests that children should have the right to play and leisure opportunities, however non-verbal children with cerebral palsy have fewer choices. Additionally, children with communication, learning and mobility limitations are usually excluded from research.

Peptides derived from hookworm anti-inflammatory proteins suppress inducible colitis in mice and inflammatory cytokine production by human cells.

A decline in the prevalence of parasites such as hookworms appears to be correlated with the rise in non-communicable inflammatory conditions in people from high- and middle-income countries. This correlation has led to studies that have identified proteins produced by hookworms that can suppress inflammatory bowel disease (IBD) and asthma in animal models. Hookworms secrete a family of abundant netrin-domain containing proteins referred to as AIPs (Anti-Inflammatory Proteins), but there is no information on the structure-function relationships.

Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype.

Kainate receptors belong to the family of glutamate receptors ion channels, which are responsible for the majority of rapid excitatory synaptic transmission in the central nervous system. The therapeutic potential of kainate receptors is still poorly understood, which is also due to the lack of potent and subunit-selective pharmacological tools. In search of selective ligands for the GluK3 kainate receptor subtype, a series of quinoxaline-2,3-dione analogues was synthesized and pharmacologically characterized at selected recombinant ionotropic glutamate receptors.

()-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist.

The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of ()-2-hydroxyhistidine () and ()-2-mercaptohistidine () as mediators of glutamatergic neurotransmission. While displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range ( = 6.

Behavior Change Techniques and Delivery Modes in Interventions Targeting Adolescent Gambling: A Systematic Review.

Background: Adolescent gambling can lead to significant harms, yet participation rates continue to rise. Interventions targeting gambling reduction have been implemented in this population. However, it is not clear which behavior change techniques (BCTs) and modes of delivery (MOD) are most effective at reducing gambling.

Na-AIP-1 secreted by human hookworms suppresses collagen-induced arthritis.

Proteins from helminths have been posed as new immunomodulatory agents with exciting potential in the treatment of immune-mediated diseases including rheumatoid arthritis (RA). In this study we assess the effects of a helminthic excretory/secretory (ES) protein Na-AIP-1 as monotherapy and in combination with methotrexate (MTX) in the well-described collagen-induced arthritis (CIA) model of RA. CIA was induced in DBA/1 J mice which were treated after the onset of arthritis with Na-AIP-1 monotherapy, MTX or Na-AIP-1 + MTX.

Online self-exclusion from multiple gambling venues: Stakeholder co-design of a usable and acceptable self-directed website.

Gambling self-exclusion programs are under-utilised and barriers to entry include shame and embarrassment with face-to-face registration, and complex and effortful procedures. The current study aimed to facilitate self-exclusion from gambling venues via an online self-directed website. A co-design approach was used to elicit key stakeholders' perspectives on required website features, functionality, and to identify variables potentially impacting on development and implementation.

Monoclonal Antibodies Targeting an Extracellular Vesicle Tetraspanin Protect Hamsters against Challenge Infection.

causes severe pathology in the bile ducts of infected human hosts, and chronic infection can culminate in bile duct cancer. The prevention of infection by vaccination would decrease opisthorchiasis-induced morbidity and mortality. The tetraspanin protein, -TSP-2, is located on the membrane of secreted extracellular vesicles (EVs), and is a candidate antigen for inclusion in a subunit vaccine.

Frequency, variations, and prognostic implications of chromosome 14q32 deletions in chronic lymphocytic leukemia.

The clinical implications of deletions within chromosome 14q32 in CLL pathogenesis remain unclear. We examined the frequency of 14q32 deletions among CLL cases by karyotype and FISH, categorized the variation using genomic microarray, and assessed the prognostic impact by time-to-first-treatment (TTFT) analysis. A 14q32 abnormality was detected in 35 % (245/698) of cases, with the majority containing a 5' partial telomeric 14q32 deletion.

Structural basis for positive allosteric modulation of AMPA and kainate receptors.

This paper summarizes the present knowledge on how positive allosteric modulators (PAMs) interact with the ligand-binding domain (LBD) of AMPA and kainate receptors, based on structure determinations. AMPA and kainate receptors belong to the family of ionotropic glutamate receptors that are responsible for mediating the majority of fast excitatory neurotransmission. These receptors have been related to brain disorders, e.

A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis.

The symbiotic relationships shared between humans and their gastrointestinal parasites present opportunities to discover novel therapies for inflammatory diseases. A prime example of this phenomenon is the interaction of humans and roundworms such as the hookworm, Necator americanus. Epidemiological observations, animal studies and clinical trials using experimental human hookworm infection show that hookworms can suppress inflammation in a safe and well-tolerated way, and that the key to their immunomodulatory properties lies within their secreted proteome.

Study framing influences crowdsourced rates of problem gambling and alcohol use disorder.

Objective: Crowdsourcing is an increasingly popular source of participants in studies of problem gambling. Studies with crowdsourced samples have reported prevalence rates of problem gambling between 10 and 50 times higher than traditional sources of estimates. These elevated rates may be due to study framing motivating self-selection.

Development and psychometric evaluation of the Recovery Index for Gambling Disorder (RIGD).

Recovery from Gambling Disorder lacks established operational criteria and a dedicated outcome measure. Cross-study comparisons and treatment efficacy determinants are difficult without a valid and widely used tool to assess recovery. The current article describes the development and psychometric evaluation of the Recovery Index for Gambling Disorder (RIGD).