Probing PAC1 receptor activation across species with an engineered sensor.

Class-B1 G-protein-coupled receptors (GPCRs) are an important family of clinically relevant drug targets that remain difficult to investigate via high-throughput screening and in animal models. Here, we engineered PAClight1, a novel genetically encoded sensor based on a class-B1 GPCR (the human PAC1 receptor, hmPAC1R) endowed with high dynamic range (Δ/ = 1100%), excellent ligand selectivity, and rapid activation kinetics ( = 1.15 s).

Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.

Background And Objectives: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD).

Methods: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging.

Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD).

Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD.

Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD.

Implementation and evaluation of a multi-level mental health promotion intervention for the workplace (MENTUPP): study protocol for a cluster randomised controlled trial.

Background: Well-organised and managed workplaces can be a source of wellbeing. The construction, healthcare and information and communication technology sectors are characterised by work-related stressors (e.g.

Emotionally congruent music and text increase immersion and appraisal.

Numerous studies indicate that listening to music and reading are processes that interact in multiple ways. However, these interactions have rarely been explored with regard to the role of emotional mood. In this study, we first conducted two pilot experiments to assess the conveyed emotional mood of four classical music pieces and that of four narrative text excerpts.

Crossmodal Correspondence between Music and Ambient Color Is Mediated by Emotion.

The quality of a concert hall primarily depends on its acoustics. But does visual input also have an impact on musical enjoyment? Does the color of ambient lighting modulate the perceived music quality? And are certain colors perceived to fit better than others with a given music piece? To address these questions, we performed three within-subjects experiments. We carried out two pretests to select four music pieces differing in tonality and genre, and 14 lighting conditions of varying hue, brightness, and saturation.

The Association Between the Occurrence of Common Treatment-Emergent Adverse Events and Efficacy Outcomes After Lasmiditan Treatment of a Single Migraine Attack: Secondary Analyses from Four Pooled Randomized Clinical Trials.

Background: In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).

Objective: To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment.

Methods: Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN.

Background: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.

Methods: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN.

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

Purpose: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population.

Methods: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study.

Lasmiditan in patients with common migraine comorbidities: a efficacy and safety analysis of two phase 3 randomized clinical trials.

Objective: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT receptor agonist approved in the United States for the acute treatment of migraine.

Methods: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo.

The Louder, the Longer: Object Length Perception Is Influenced by Loudness, but Not by Pitch.

Sound by itself can be a reliable source of information about an object's size. For instance, we are able to estimate the size of objects merely on the basis of the sound they make when falling on the floor. Moreover, loudness and pitch are crossmodally linked to size.

Having a Drink with Tchaikovsky: The Crossmodal Influence of Background Music on the Taste of Beverages.

Previous research has shown that auditory cues can influence the flavor of food and drink. For instance, wine tastes better when preferred music is played. We have investigated whether a music background can modify judgments of the specific flavor pattern of a beverage, as opposed to mere preference.

Cognate Nonlytic Interactions between CD8 T Cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties.

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8 T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A.

Alveolar capillary dysplasia with left heart obstruction - rare but lethal.

Alveolar capillary dysplasia (ACD) is a rare neonatal lung disease characterized anatomically by a defective and hypoplastic development of pulmonary alveoli leading to persistent pulmonary hypertension (PPHN) and finally lethal respiratory failure. It is often associated with congenital left heart obstruction. Given the fatal prognosis an early diagnosis is important.

Health status, quality of life and medical care in adult women with Turner syndrome.

Background: Previous studies have shown that only a minority of patients with Turner syndrome (TS) have adequate medical care after transfer to adult care.

Aim Of This Study: To assess the status of medical follow-up and quality of life (QoL) in adult women diagnosed with TS and followed up until transfer. To compare the subjective and objective view of the medical care quality and initiate improvements based on patients' experiences and current recommendations.

The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2).

Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized.

Anti-Stigma HIV-Related Social Advertising: No Evidence for Side Effects on Condom Use.

Recent campaigns try to reduce social stigma associated with persons living with HIV. For example, a German campaign raised awareness that infection is unlikely in low-risk day-to-day interactions. Research has yet to show that there are no harmful side effects.

Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function.

Metastasis of cancer cells to distant organ systems is a complex process that is initiated with the programming of cells in the primary tumor. The formation of distant metastatic foci is correlated with poor prognosis and limited effective treatment options. We and others have correlated Mouse double minute 2 (Mdm2) with metastasis; however, the mechanisms involved have not been elucidated.

Partial pharmacologic blockade shows sympathetic connection between blood pressure and cerebral blood flow velocity fluctuations.

Cerebral autoregulation (CA) dampens transfer of blood pressure (BP)-fluctuations onto cerebral blood flow velocity (CBFV). Thus, CBFV-oscillations precede BP-oscillations. The phase angle (PA) between sympathetically mediated low-frequency (LF: 0.

Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase.

Murine double minute-2 protein (Mdm2) is a multifaceted phosphorylated protein that plays a role in regulating numerous proteins including the tumor suppressor protein p53. Mdm2 binds to and is involved in conjugating either ubiquitin or Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8) to p53. Although regulation of the E3 ubiquitin activity of Mdm2 has been investigated, regulation of the neddylating activity of Mdm2 remains to be defined.

Serdemetan antagonizes the Mdm2-HIF1α axis leading to decreased levels of glycolytic enzymes.

Serdemetan (JNJ-26854165), an antagonist to Mdm2, was anticipated to promote the activation of p53. While regulation of p53 by Mdm2 is important, Mdm2 also regulates numerous proteins involved in diverse cellular functions. We investigated if Serdemetan would alter the Mdm2-HIF1α axis and affect cell survival in human glioblastoma cells independently of p53.