Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output.

Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air-liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease

Interacting Spin-2 Fields

We construct consistent theories of multiple interacting spin-2 fields in arbitrary spacetime dimensions using a vielbein formulation. We show that these theories have the additional primary constraints needed to eliminate potential ghosts, to all orders in the fields, and to all orders beyond any decoupling limit. We postulate that the number of spin-2 fields interacting at a single vertex is limited by the number of spacetime dimensions. We then show that, for the case of two spin-2 fields, the vielbein theory is equivalent to the recently proposed theories of ghost-free massive gravity and bi-metric gravity. The vielbein formulation greatly simplifies the proof that these theories have an extra primary constraint which eliminates the Boulware-Deser ghost.Comment: 42 pages, 3 figures. v3 alternative argument using constrained spatial vielbeins has been removed (see footnote 3

Chronic pain among homeless persons: characteristics, treatment, and barriers to management

<p>Abstract</p> <p>Background</p> <p>Little information is available on the problem of chronic pain among homeless individuals. This study aimed to describe the characteristics of and treatments for chronic pain, barriers to pain management, concurrent medical conditions, and substance use among a representative sample of homeless single adult shelter users who experience chronic pain in Toronto, Canada.</p> <p>Methods</p> <p>Participants were randomly selected at shelters for single homeless adults between September 2007 and February 2008 and screened for chronic pain, defined as having pain in the body for ≥ 3 months or receiving treatment for pain that started ≥ 3 months ago. Cross-sectional surveys obtained information on demographic characteristics, characteristics of and treatments for chronic pain, barriers to pain management, concurrent medical conditions, and substance use. Whenever possible, participants' physicians were also interviewed.</p> <p>Results</p> <p>Among 152 homeless participants who experienced chronic pain, 11 (8%) were classified as Chronic Pain Grade I (low disability-low intensity), 47 (32%) as Grade II (low disability-high intensity), 34 (23%) as Grade III (high disability-moderately limiting), and 54 (37%) as Grade IV (high disability-severely limiting). The most common self-reported barriers to pain management were stress of shelter life, inability to afford prescription medications, and poor sleeping conditions. Participants reported using over-the-counter medications (48%), street drugs (46%), prescribed medications (43%), and alcohol (29%) to treat their pain. Of the 61 interviewed physicians, only 51% reported treating the patient's pain. The most common physician-reported difficulties with pain management were reluctance to prescribe narcotics due to the patient's history of substance abuse, psychiatric comorbidities, frequently missed appointments, and difficulty getting the patient to take medications correctly.</p> <p>Conclusions</p> <p>Clinicians who provide healthcare for homeless people should screen for chronic pain and discuss barriers to effective pain management with their patients.</p

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Update on HHV-8-Associated Malignancies

The human herpesvirus 8 (HHV-8) is the oncogenic virus associated with Kaposi’s sarcoma (KS) and lymphoproliferative disorders, namely, primary effusion lymphoma and multicentric Castleman’s disease. KS is among the most common malignancies seen in HIV-infected patients despite the decreased incidence of KS in the era of highly active antiretroviral therapy. Advances in molecular pathology reveal HHV-8 tumorigenesis is mediated through molecular mimicry wherein viral-encoded proteins can activate several cellular signaling cascades while evading immune surveillance. This knowledge has led to the evolution of multiple therapeutic strategies against specific molecular targets. Many such therapeutic modalities have shown activity, but none have proven to be curative. Identifying possible prognostic factors is another active area of research. This review summarizes the recent developments in the fields of virus transmission, molecular biology, and treatment of HHV-8-related neoplasms

The role of off-board EV battery chargers in smart homes and smart grids: operation with renewables and energy storage systems

Concerns about climate changes and environmental air pollution are leading to the adoption of new technologies for transportation, mainly based on vehicle electrification and the interaction with smart grids, and also with the introduction of renewable energy sources (RES) accompanied by energy storage systems (ESS). For these three fundamental pillars, new power electronics technologies are emerging to transform the electrical power grid, targeting a flexible and collaborative operation. As a distinctive factor, the vehicle electrification has stimulated the presence of new technologies in terms of power management, both for smart homes and smart grids. As the title indicates, this book chapter focuses on the role of off-board EV battery chargers in terms of operation modes and contextualization for smart homes and smart grids in terms of opportunities. Based on a review of on-board and off-board EV battery charging systems (EV-BCS), this chapter focus on the off-board EV-BCS framed with RES and ESS as a dominant system in future smart homes. Contextualizing these aspects, three distinct cases are considered: (1) An ac smart home using separate power converters, according to the considered technologies; (2) A hybrid ac and dc smart home with an off-board EV-BCS interfacing RES and ESS, and with the electrical appliances plugged-in to the ac power grid; (3) A dc smart home using a unified 2 off-board EV-BCS with a single interface for the electrical power grid, and with multiple dc interfaces (RES, ESS, and electrical appliances). The results for each case are obtained in terms of efficiency and power quality, demonstrating that the off-board EV-BCS, as a unified structure for smart homes, presents better results. Besides, the off-board EV-BCS can also be used as an important asset for the smart grid, even when the EV is not plugged-in at the smart home.(undefined

Structural and Functional Insights into the Malaria Parasite Moving Junction Complex

Members of the phylum Apicomplexa, which include the malaria parasite Plasmodium, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the host cell is common to these intracellular pathogens. The MJ contains two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, which is targeted to the host cell membrane during invasion. In particular, RON2, a transmembrane component of the RON complex, interacts directly with AMA1. Here, we report the crystal structure of AMA1 from Plasmodium falciparum in complex with a peptide derived from the extracellular region of PfRON2, highlighting clear specificities of the P. falciparum RON2-AMA1 interaction. The receptor-binding site of PfAMA1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible Domain II loop. Mutations of key contact residues of PfRON2 and PfAMA1 abrogate binding between the recombinant proteins. Although PfRON2 contacts some polymorphic residues, binding studies with PfAMA1 from different strains show that these have little effect on affinity. Moreover, we demonstrate that the PfRON2 peptide inhibits erythrocyte invasion by P. falciparum merozoites and that this strong inhibitory potency is not affected by AMA1 polymorphisms. In parallel, we have determined the crystal structure of PfAMA1 in complex with the invasion-inhibitory peptide R1 derived by phage display, revealing an unexpected structural mimicry of the PfRON2 peptide. These results identify the key residues governing the interactions between AMA1 and RON2 in P. falciparum and suggest novel approaches to antimalarial therapeutics

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans