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This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Posiphen tartrate (Posiphen) is an orally available small molecule that targets a conserved regulatory element in the mRNAs of amyloid precursor protein (APP) and α-synuclein (αSYN) and inhibits their translation. APP and αSYN can cause neurodegeneration when their aggregates induce neurotoxicity. Therefore, Posiphen is a promising drug candidate for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Posiphen's safety has been demonstrated in three independent phase I clinical trials. Moreover, in a proof of concept study, Posiphen lowered neurotoxic proteins and inflammatory markers in cerebrospinal fluid of mild cognitive impaired patients. Herein we investigated whether Posiphen reduced the expression of other proteins, as assessed by stable isotope labeling with amino acids in cell culture (SILAC) followed by mass spectrometry (MS)-based proteomics. Neuroblastoma SH-SY5Y cells, an in vitro model of neuronal function, were used for the SILAC protein profiling response. Proteins whose expression was altered by Posiphen treatment were characterized for biological functions, pathways and networks analysis. The most significantly affected pathway was the Huntington's disease signaling pathway, which, along with huntingtin (HTT) protein, was down-regulated by Posiphen in the SH-SY5Y cells. The downregulation of HTT protein by Posiphen was confirmed by quantitative Western blotting and immunofluorescence. Unchanged mRNA levels of HTT and a comparable decay rate of HTT proteins after Posiphen treatment supported the coclusion that Posiphen reduced HTT via downregulation of the translation of HTT mRNA. Meanwhile, the downregulation of APP and αSYN proteins by Posiphen was also confirmed. The mRNAs encoding HTT, APP and αSYN contain an atypical iron response element (IRE) in their 5'-untranslated regions (5'-UTRs) that bind iron regulatory protein 1 (IRP1), and Posiphen specifically bound this complex. Conversely, Posiphen did not bind the IRP1/IRE complex of mRNAs with canonical IREs, and the translation of these mRNAs was not affected by Posiphen. Taken together, Posiphen shows high affinity binding to the IRE/IRP1 complex of mRNAs with an atypical IRE stem loop, inducing their translation suppression, including the mRNAs of neurotoxic proteins APP, αSYN and HTT.

A set of common-acting iron-responsive 5'untranslated region (5'UTR) motifs can fold into RNA stem loops that appear significant to the biology of cognitive declines of Parkinson's disease dementia (PDD), Lewy body dementia (LDD), and Alzheimer's disease (AD). Neurodegenerative diseases exhibit perturbations of iron homeostasis in defined brain subregions over characteristic time intervals of progression. While misfolding of Aß from the amyloid-precursor-protein (APP), alpha-synuclein, prion protein (PrP) each cause neuropathic protein inclusions in the brain subregions, iron-responsive-like element (IRE-like) RNA stem-loops reside in their transcripts. APP and asyn have a role in iron transport while gene duplications elevate the expression of their products to cause rare familial cases of AD and PDD. Of note, IRE-like sequences are responsive to excesses of brain iron in a potential feedback loop to accelerate neuronal ferroptosis and cognitive declines as well as amyloidosis. This pathogenic feedback is consistent with the translational control of the iron storage protein ferritin. We discuss how the IRE-like RNA motifs in the 5'UTRs of APP, alpha-synuclein and PrP mRNAs represent uniquely folded drug targets for therapies to prevent perturbed iron homeostasis that accelerates AD, PD, PD dementia (PDD) and Lewy body dementia, thus preventing cognitive deficits. Inhibition of alpha-synuclein translation is an option to block manganese toxicity associated with early childhood cognitive problems and manganism while Pb toxicity is epigenetically associated with attention deficit and later-stage AD. Pathologies of heavy metal toxicity centered on an embargo of iron export may be treated with activators of APP and ferritin and inhibitors of alpha-synuclein translation.

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. Although alternative slow-wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (Vm) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256 × 256 pixel cameras. Motion artifact was corrected using a marker-based motion-tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and Vm morphology against alternative nonoptical technologies. Nonantegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and nonantegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored. NEW & NOTEWORTHY: This article introduces a novel method for imaging gastric electrophysiology and mechanical function simultaneously in anesthetized, open-abdomen pigs. We demonstrate it by observing propagating slow-wave depolarization and repolarization along with the strength, spatial distribution, and direction of contractions. In addition, we observe that in this animal preparation, slow waves often do not propagate from the proximal to distal stomach and are frequently asymmetric between the anterior and posterior sides of the stomach. [ABSTRACT FROM AUTHOR]

Key Points: Question: Are differing trajectories of low-grade inflammation throughout childhood and adolescence associated with an increased risk of developing certain mental and related cardiometabolic health conditions in early adulthood? Findings: This longitudinal cohort study found that having persistently raised levels of inflammation as measured by C-reactive protein throughout childhood and adolescence, peaking at age 9 years, was associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance. Meaning: Increased inflammation in childhood may be an important predisposing risk factor to the development of both mental and cardiometabolic disorders in early adulthood. Importance: Research suggests that low-grade, nonresolving inflammation may predate adult mental and physical illness. However, evidence to date is largely cross-sectional or focuses on single disorder outcomes. Objectives: To examine trajectories of inflammation as measured by C-reactive protein (CRP) levels in a large sample of children and adolescents, and to explore associations between different identified trajectories and mental and related cardiometabolic health outcomes in early adulthood. Design, Setting, and Participants: In a longitudinal cohort study using data from the large UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), latent class growth analysis (LCGA) was used to explore different trajectories of inflammation, with logistic regression exploring association with mental and physical health outcomes. Participants with measurable CRP data and associated mental and cardiometabolic health outcomes recorded were included in the analysis. Data analysis was performed from May 1, 2023, to March 30, 2024. Exposures: Inflammation was assessed via CRP levels at ages 9, 15, and 17 years. LCGA was used to identify different trajectories of inflammation. Main Outcomes and Measures: Outcomes assessed at age 24 years included psychotic disorders, depressive disorders, anxiety disorders, hypomania, and, as a measure of insulin resistance, Homeostasis Model Assessment (HOMA2) score. Results: A total of 6556 participants (3303 [50.4%] female) were included. Three classes of inflammation were identified: persistently low CRP levels (reference class, n = 6109); persistently raised CRP levels, peaking at age 9 years (early peak, n = 197); and persistently raised CRP levels, peaking at age 17 years (late peak, n = 250). Participants in the early peak group were associated with a higher risk of psychotic disorder (odds ratio [OR], 4.60; 95% CI, 1.81-11.70; P =.008), a higher risk of severe depression (OR, 4.37; 95% CI, 1.64-11.63; P =.02), and higher HOMA2 scores (β = 0.05; 95% CI, 0.01-0.62, P =.04) compared with participants with persistently low CRP. The late peak group was not associated with any outcomes at age 24 years. Conclusions and Relevance: Low-grade systemic inflammation peaking in midchildhood was associated with specific mental and cardiometabolic disorders in young adulthood. These findings suggest that low-grade persistent inflammation in early life may be an important shared common factor for mental-physical comorbidity and so could be relevant to future efforts of patient stratification and risk profiling. This longitudinal cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) examines trajectories of inflammation in childhood and their associations with mental and related cardiometabolic health outcomes in early adulthood. [ABSTRACT FROM AUTHOR]