Unraveling the assembloid: Real-time monitoring of dopaminergic neurites in an inter-organoid pathway connecting midbrain and striatal regions.

Modern in vitro technologies for preclinical research, including organ-on-a-chip, organoids- and assembloid-based systems, have rapidly emerged as pivotal tools for elucidating disease mechanisms and assessing the efficacy of putative therapeutics. In this context, advanced in vitro models of Parkinson's Disease (PD) offer the potential to accelerate drug discovery by enabling effective platforms that recapitulate both physiological and pathological attributes of the in vivo environment. Although these systems often aim at replicating the PD-associated loss of dopaminergic (DA) neurons, only a few have modelled the degradation of dopaminergic pathways as a way to mimic the disruption of downstream regulation mechanisms that define the characteristic motor symptoms of the disease. To this end, assembloids have been successfully employed to recapitulate neuronal pathways between distinct brain regions. However, the investigation and characterization of these connections through neural tracing and electrophysiological analysis remain a technically challenging and time-consuming process. Here, we present a novel bioengineered platform consisting of surface-grown midbrain and striatal organoids at opposite sides of a self-assembled DA pathway. In particular, dopaminergic neurons and striatal GABAergic neurons spontaneously form DA connections across a microelectrode array (MEA), specifically integrated for the real-time monitoring of electrophysiological development and stimuli response. Calcium imaging data showed spiking synchronicity of the two organoids forming the inter-organoid pathways (IOPs) demonstrating that they are functionally connected. MEA recordings confirm a more robust response to the DA neurotoxin 6-OHDA compared to midbrain organoids alone, thereby validating the potential of this technology to generate highly tractable, easily extractable real-time functional readouts to investigate the dysfunctional dopaminergic network of PD patients.

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes.

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12, 13-dihydroxy-9Z-octadecenoic acid (12, 13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12, 13-diHOME and 9, 10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro, which implicates this pathway and 9, 10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

Quantum critical dynamics in a 5,000-qubit programmable spin glass.

Experiments on disordered alloys1-3 suggest that spin glasses can be brought into low-energy states faster by annealing quantum fluctuations than by conventional thermal annealing. Owing to the importance of spin glasses as a paradigmatic computational testbed, reproducing this phenomenon in a programmable system has remained a central challenge in quantum optimization4-13. Here we achieve this goal by realizing quantum-critical spin-glass dynamics on thousands of qubits with a superconducting quantum annealer. We first demonstrate quantitative agreement between quantum annealing and time evolution of the Schrödinger equation in small spin glasses. We then measure dynamics in three-dimensional spin glasses on thousands of qubits, for which classical simulation of many-body quantum dynamics is intractable. We extract critical exponents that clearly distinguish quantum annealing from the slower stochastic dynamics of analogous Monte Carlo algorithms, providing both theoretical and experimental support for large-scale quantum simulation and a scaling advantage in energy optimization.

Transplantation of Brown Adipose Tissue with the Ability of Converting Omega-6 to Omega-3 Polyunsaturated Fatty Acids Counteracts High-Fat-Induced Metabolic Abnormalities in Mice.

A balanced omega (ω)-6/ω-3 polyunsaturated fatty acids (PUFAs) ratio has been linked to metabolic health and the prevention of chronic diseases. Brown adipose tissue (BAT) specializes in energy expenditure and secretes signaling molecules that regulate metabolism via inter-organ crosstalk. Recent studies have uncovered that BAT produces different PUFA species and circulating oxylipin levels are correlated with BAT-mediated energy expenditure in mice and humans. However, the impact of BAT ω-6/ω-3 PUFAs on metabolic phenotype has not been fully elucidated. The Fat-1 transgenic mice can convert ω-6 to ω-3 PUFAs. Here, we demonstrated that mice receiving Fat-1 BAT transplants displayed better glucose tolerance and higher energy expenditure. Expression of genes involved in thermogenesis and nutrient utilization was increased in the endogenous BAT of mice receiving Fat-1 BAT, suggesting that the transplants may activate recipients' BAT. Using targeted lipidomic analysis, we found that the levels of several ω-6 oxylipins were significantly reduced in the circulation of mice receiving Fat-1 BAT transplants than in mice with wild-type BAT transplants. The major altered oxylipins between the WT and Fat-1 BAT transplantation were ω-6 arachidonic acid-derived oxylipins via the lipoxygenase pathway. Taken together, these findings suggest an important role of BAT-derived oxylipins in combating obesity-related metabolic disorders.

Scaling advantage over path-integral Monte Carlo in quantum simulation of geometrically frustrated magnets.

The promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for such simulations, and a scaling advantage of this type was recently shown to be impossible in certain restricted settings. This is therefore an important piece of experimental evidence that PIMC does not simulate QA dynamics even for sign-problem-free Hamiltonians, and that near-term quantum devices can be used to accelerate computational tasks of practical relevance.

Prefrontal mechanisms of comorbidity from a transdiagnostic and ontogenic perspective.

Accumulating behavioral and genetic research suggests that most forms of psychopathology share common genetic and neural vulnerabilities and are manifestations of a relatively few core underlying processes. These findings support the view that comorbidity mostly arises, not from true co-occurrence of distinct disorders, but from the behavioral expression of shared vulnerability processes across the life span. The purpose of this review is to examine the role of the prefrontal cortex (PFC) in the shared vulnerability mechanisms underlying the clinical phenomena of comorbidity from a transdiagnostic and ontogenic perspective. In adopting this perspective, we suggest complex transactions between neurobiologically rooted vulnerabilities inherent in PFC circuitry and environmental factors (e.g., parenting, peers, stress, and substance use) across development converge on three key PFC-mediated processes: executive functioning, emotion regulation, and reward processing. We propose that individual differences and impairments in these PFC-mediated functions provide intermediate mechanisms for transdiagnostic symptoms and underlie behavioral tendencies that evoke and interact with environmental risk factors to further potentiate vulnerability.

Demographic correlates of attenuated positive psychotic symptoms.

It is now well established that the utilization of standardized clinical criteria can enhance prediction of psychosis. These criteria are primarily concerned with the presence and severity of attenuated positive symptoms. Because these symptom criteria are used to derive algorithms for designating clinical high risk (CHR) status and for maximizing prediction of psychosis risk, it is important to know whether the symptom ratings vary as a function of demographic factors that have previously been linked with symptoms in diagnosed psychotic patients. Using a sample of 356 CHR individuals from the NAPLS-II multi-site study, we examined the relation of three sex, age, and educational level, with the severity of attenuated positive symptom scores from the Scale of Prodromal Symptoms (SOPS). Demographic factors accounted for little of the variance in symptom ratings (5-6%). Older CHR individuals manifested more severe suspiciousness, and female CHR participants reported more unusual perceptual experiences than male participants. Contrary to prediction, higher educational level was associated with more severe ratings of unusual thought content, but less severe perceptual abnormalities. Overall, sex, age and education were modestly related to unusual thought content and perceptual abnormalities, only, suggesting minimal implication for designating CHR status and predicting psychosis-risk.

The development of psychotic disorders in adolescence: a potential role for hormones.

This article is part of a Special Issue "Puberty and Adolescence". The notion that adolescence is characterized by dramatic changes in behavior, and often by emotional upheaval, is widespread and longstanding in popular western culture. In recent decades, this notion has gained increasing support from empirical research showing that the peri- and post-pubertal developmental stages are associated with a significant rise in the rate of psychiatric symptoms and syndromes. As a result, interest in adolescent development has burgeoned among researchers focused on the origins of schizophrenia and other psychotic disorders. Two factors have fueled this trend: 1) increasing evidence from longitudinal research that adolescence is the modal period for the emergence of "prodromal" manifestations, or precursors of psychotic symptoms, and 2) the rapidly accumulating scientific findings on brain structural and functional changes occurring during adolescence and young adulthood. Further, gonadal and adrenal hormones are beginning to play a more prominent role in conceptualizations of adolescent brain development, as well as in the origins of psychiatric symptoms during this period (Walker and Bollini, 2002; Walker et al., 2008). In this paper, we begin by providing an overview of the nature and course of psychotic disorders during adolescence/young adulthood. We then turn to the role of hormones in modulating normal brain development, and the potential role they might play in the abnormal brain changes that characterize youth at clinical high-risk (CHR) for psychosis. The activational and organizational effects of hormones are explored, with a focus on how hormone-induced changes might be linked with neuropathological processes in the emergence of psychosis.

The prodrome and clinical risk for psychotic disorders.

The psychosis prodrome offers great promise for identifying neural mechanisms involved in psychotic disorders and offers an opportunity to implement empirical interventions to delay, and ultimately ameliorate, illness onset. This article summarizes the literature on individuals in the putatively prodromal phase of psychosis/deemed at clinical high risk (CHR) for psychosis onset. Standardized measurement and manifestation of the CHR syndromes are discussed, followed by empirical findings that highlight the psychological deficits and biological abnormalities seen in CHR syndromes and psychotic disorders. Current controversies surrounding the diagnosis of CHR syndromes and issues related to the treatment of CHR individuals are also presented.

Characteristics of noise exposure during solitary trumpet playing: immediate impact on distortion-product otoacoustic emissions and long-term implications for hearing.

OBJECTIVES: The objectives of this investigation were to quantify noise exposures generated during a 1 hr trumpet practice session and to determine whether distortion-product otoacoustic emissions (DPOAEs) are affected by such exposure, to describe the distribution of intensity levels and temporal characteristics of noise produced by trumpet practice, and to determine the effect of earplug use on generated noise levels and DPOAEs. DESIGN: In experiment 1, eight college-age trumpeters underwent an otoscopic inspection, tympanometry, and pure-tone threshold testing. Using a Grason-Stadler 60 DPOAE system, DPOAEs were recorded just before a 1 hr practice session, at 2 min after the practice session, 4 min after the session, and at 4 min intervals thereafter for a total period of 1 hr. A Hewlett-Packard 3569A Real-Time Frequency Analyzer was used to integrate noise levels to assess the overall level of exposure averaged over the course of the hour. In experiment 2, seven different trumpeters participated in two data-collection sessions. The main difference between the sessions was that subjects wore E.A.R. earplugs during session 2. All other design parameters were similar to those of experiment 1. RESULTS: Noise levels generated during the practice sessions resulted in average Leqs of 95.96, 96.6, and 96.43 dB SPL. A sound-distribution analysis revealed that noise levels exceeded 85 dB for an average of 43.73 min per session. Mean Leq values did not change when subjects wore earplugs (96.6 dB SPL versus 96.43 dB SPL.) Predictions (ISO 1999) of the increased risk of hearing loss that trumpeters would experience at 40, 50, and 60 years of age were made and indicated that trumpeters are at a significantly increased risk of hearing loss over that contributable to age alone. This increased risk is apparent with as little as 1 hr of exposure per day and suggests that 60-year-old male and female musicians exposed to trumpet noise for 4 hr per day for 40 years would be 85% and 300%, respectively, more likely to have hearing loss than their peers with negative noise exposure histories. Statistically significant decreases in DPOAE amplitudes from the prenoise exposure collection point to the 2 min post exposure point were observed only when subjects were not wearing earplugs during their practice session. Recovery of DPOAEs to baseline level varied in form for four test frequencies. CONCLUSION: During solitary play, trumpeters generate noise levels that temporarily decrease DPOAE amplitudes and that by themselves have the potential to result in permanent noise-induced hearing loss. Trumpeters who practice/perform over a period of years should be concerned about the implications of their craft on their hearing and should be offered personalized hearing conservation programs. The use of earplugs offers a practical and cost-effective means of hearing protection and, for this group of trumpeters, did not lead to an increase in playing level.

School experiences of families of children with brain tumors.

Families and children often report a diverse range of academic achievements and challenges after undergoing treatment for a brain tumor. This study explores the experiences of children, youth, and their families as they seek to reintegrate into mainstream educational systems. Despite the variable experiences, there are many common strategies that could positively influence the child's success in school. Strong communication between parents, school, and health professionals is paramount. Preparing parents to advocate for their children's academic and social needs and developing an awareness of the challenges among school staff has potential to improve outcomes for these children. Equipping the children with the social skills needed to manage social situations will strengthen their ability to overcome the challenges that they face. These study findings shed light on the academic experiences of these children and can lead to the development of strategies to support families facing similar challenges.