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Abstract Autophagy is a conserved, catabolic process essential for maintaining cellular homeostasis. Malfunctional autophagy contributes to neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we report a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and brain LC3-interactome reveals roles of neuronal autophagy in targeting proteins of multiple cellular organelles/pathways, including endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) for degradation. By combining phosphoproteomics and functional analysis in human and mouse neurons, we uncovered a function of neuronal autophagy in controlling cAMP-PKA and c-FOS-mediated neuronal activity through selective degradation of the protein kinase A - cAMP-binding regulatory (R)-subunit I (PKA-RI) complex. Lack of AKAP11 causes accumulation of the PKA-RI complex in the soma and neurites, demonstrating a constant clearance of PKA-RI complex through AKAP11-mediated degradation in neurons. Our study thus reveals the landscape of autophagy degradation in human neurons and identifies a physiological function of autophagy in controlling homeostasis of PKA-RI complex and specific PKA activity in neurons.

Abstract Objective Protocols to evaluate for myocardial infarction (MI) using high‐sensitivity cardiac troponin (hs‐cTn) have the potential to drive costs upward due to the added sensitivity. We performed an economic evaluation of an accelerated protocol (AP) to evaluate for MI using hs‐cTn to identify changes in costs of treatment and length of stay compared with conventional testing. Methods We performed a planned secondary economic analysis of a large, cluster randomized trial across nine emergency departments (EDs) from July 2020 to April 2021. Patients were included if they were 18 years or older with clinical suspicion for MI. In the AP, patients could be discharged without further testing at 0 h if they had a hs‐cTnI

Introduction: In recent decades, there has been a growing focus on addressing social needs in healthcare settings. California has been at the forefront of making state-level investments to improve care for patients with complex social and medical needs, including patients experiencing homelessness (PEH). Examples include Medicaid 1115 waivers such as the Whole Person Care pilot program and California Advancing and Innovating Medi-Cal (CalAIM). To date, California is also the only state to have passed a legislative mandate to address concerns related to the hospital discharge of PEH who lack sufficient resources to support self-care. To this end, California enacted Senate Bill 1152 (SB 1152), a unique legislative mandate that requires hospitals to standardize comprehensive discharge processes for PEH by providing (and documenting the provision of) social and preventive services. Understanding the implementation and impact of this law will help inform California and other states considering legislative investments in healthcare activities to improve care for PEH. Methods: To understand health system stakeholders’ perceived impact of SB 1152 on hospital discharge processes and key barriers and facilitators to SB 1152’s implementation, we conducted 32 semi-structured interviews with key informants across 16 general acute care hospitals in Humboldt and Los Angeles counties. Study data were coded and analyzed using thematic analysis informed by the Consolidated Framework for Implementation Research. Results: Participants perceived several positive impacts of SB 1152, including streamlined services, increased accountability, and more staff awareness about homelessness. In parallel, participants also underscored concerns about the law’s limited scope and highlighted multiple implementation challenges, including lack of clarity about accountability measures, scarcity of implementation supports, and gaps in community resources. Conclusion: Our findings suggest that SB 1152 was an important step toward the goal of more universal safe discharge of PEH. However, there are also several addressable concerns. Recommendations to improve future legislation include adding targeted funding for social care staff and improving implementation training. Participants’ broader concerns about the parallel need to increase community resources are more challenging to address in the immediate term, but such changes will also be necessary to improve the overall health outcomes of PEH.

Abstract Huntington’s disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. CRISPR-Cas9 nuclease causes double-strand breaks (DSBs) in the targeted DNA that induces toxicity, whereas CRISPR interference (CRISPRi) using dead Cas9 (dCas9) suppresses the target gene expression without DSBs. Delivery of dCas9-sgRNA targeting CAG repeat region does not damage the targeted DNA in HEK293T cells containing CAG repeats. When this study investigates whether CRISPRi can suppress mutant HTT (mHTT), CRISPRi results in reduced expression of mHTT with relative preservation of the wild-type HTT in human HD fibroblasts. Although both dCas9 and Cas9 treatments reduce mHTT by sgRNA targeting the CAG repeat region, CRISPRi delays behavioral deterioration and protects striatal neurons against cell death in HD mice. Collectively, CRISPRi can delay disease progression by suppressing mHtt, suggesting DNA DSB-free CRISPRi is a potential therapy for HD that can compensate for the shortcoming of CRISPR-Cas9 nuclease.

While prime editing is a promising technology, PE2 systems often have low efficiency. Here the authors fuse a Rad51 DNA-binding domain to create hyPE2 with improved editing efficiency.

Residential energy trading systems (RETS) enable homeowners with distributed energy resources (DERs) to participate in virtualized energy markets that have the potential to reduce the peak demand of residential communities. Blockchains are key enablers of RETS, by virtue of providing a decentralized, self-governed network that mitigates concerns regarding privacy and transparency. However, more real-world case studies are needed to evaluate the techno-economic viability of blockchain-based RETS to improve their positive uptake. Thus, this article develops a permissioned blockchain-based RETS, which enables homeowners to select bidding strategies that consider the individual preferences of their DERs, and further evaluates the impact of the bidding strategies on reducing the peak demand of the community. The proposed system is implemented on the permissioned Hyperledger Fabric platform, where a decentralized ledger is used to store all energy bids, and a smart contract is used to execute a double auction mechanism and dispatch the homeowner DERs. The proposed system is validated by conducting simulations on a 8-home community using real-world data, and also by deploying the system to a Canadian microgrid, where the smart contract execution time is benchmarked. Simulation results demonstrate the efficacy of the proposed system by achieving a peak demand reduction of up to 48 kW (62%), which leads to an average savings of $1.02 M for the distribution system operator by avoiding transformer upgrades. Also, the simulation results show that the execution time of the proposed smart contract is 17.12 seconds across 12 nodes, which is sufficient for RETS.

Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in hIAPP + mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.

X-linked adrenoleukodystrophy (ALD) caused by the ABCD1 mutation, is the most common inherited peroxisomal disease. Previously, we generated an ALD patient-derived SCHi001-A iPSC model. In this study, we have performed the first genome editing of ALD patient-derived SCHi001-A iPSCs using homology-directed repair (HDR). The mutation site, c.1534G > A [GenBank: NM_000033.4], was corrected by introducing ssODN and the CRISPR/Cas9 system. The cell line exhibited normal iPSC plulipotency marker expression following genome editing. Mutation-corrected iPSCs from SCHi001-A iPSC line can be used in research into the pathophysiology of and therapeutics for ALD.

Evidence suggests that physical activity and alcohol use are positively related among young adults. Two studies have examined daily relations, and results have shown conflicting findings. We examined relations between physical activity and alcohol use at both within- and between-individual levels and investigated moderators of the relation at both levels. 269 college students wore accelerometers to collect physical activity data over a 2-week period. At the end of each day, they indicated whether or not they drank alcohol. Multilevel logistic regression indicated neither within- nor between-subject relations were statistically significant. Positive affect, negative affect, and drinking motives moderated these relations at the between-subject level. Contrary to previous research, we did not observe a relation between physical activity and alcohol use at the daily level. Unique features of the current study suggest next steps for future research examining the perplexing PA-alcohol relation in this population., Author(s): Craig E. Henderson [sup.1] , John M. Manning [sup.1] , Cindy M. Davis [sup.1] , David E. Conroy [sup.2] , M. Lee Van Horn [sup.3] , Kim Henry [sup.4] [...]

Here, we found two genomic safe harbor (GSH) candidates from chromosomes 3 and 8, based on large-scale population-based cohort data from 4,694 Koreans by CNV analysis. Furthermore, estimated genotype of these CNVRs was validated by quantitative real-time PCR, and epidemiological data examined no significant genetic association between diseases or traits and two CNVRs. After screening the GSH candidates by in silico approaches, we designed TALEN pairs to integrate EGFP expression cassette into human cell lines in order to confirm the functionality of GSH candidates in an in vitro setting. As a result, transgene insertion into one of the two loci using TALEN showed robust transgene expression comparable to that with an AAVS1 site without significantly perturbing neighboring genes. Changing the promoter or cell type did not noticeably disturb this trend. Thus, we could validate two CNVRs as a site for effective and safe transgene insertion in human cells. Keywords: genome editing, TALEN, safe harbor, copy number variation region

As technology revolutionizes the methods of both production and communication, economists have to respond to new market structures and efficiencies, and the controversial concept of decentralization emerging in recent decades should also be examined in terms of its capacity to induce structural changes in the economy. This paper takes look at one specific market of interest and models the decentralization of a hypothetical emission quota market with the inclusion of households though automated auctions, in order to provide a preliminary analysis of how the redistribution of emission quotas would impact short-run equilibrium in this market and long-run growths. Given the endogenous dynamics, we would also examine the effects of exogenous technological shocks. For the purpose and scope of this paper, a simple mathematical formulation based on the Solow growth model as well as certain strong assumptions derived from economic intuitions is established, aiming to provide a more quantitative illustration of the effects from decentralization on such a system.

Transactive energy systems (TES) are modern mechanisms in electric power systems that allow disparate control agents to utilise distributed generation units to engage in energy transactions and provide ancillary services to the grid. Although voltage regulation is a crucial ancillary grid service within active distribution networks (ADNs), previous work has not adequately explored how this service can be offered in terms of its incentivisation, contract auditability, and enforcement. Blockchain technology shows promise in being a key enabler of TES, allowing agents to engage in trustless, persistent transactions that are both enforceable and auditable. To that end, this study proposes a blockchain based TES that enables agents to receive incentives for providing voltage regulation services by (i) maintaining an auditable reputation rating for each agent that is increased proportionately with each mitigation of a voltage violation, (ii) utilising smart contracts to enforce the validity of each transaction and penalise reputation ratings in case of a mitigation failure, and (iii) automating the negotiation and bidding of agent services by implementing the contract net protocol as a smart contract. Experimental results on both simulated and real-world ADNs are executed to demonstrate the efficacy of the proposed system.