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Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions. The development of therapeutics for central nervous system disorders suffers from high failure rates owing to poor blood–brain barrier penetration and lack of targeted delivery. This Review discusses how nanoparticles can help to overcome these challenges to enable precision targeting of the brain for different central nervous system diseases.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.Recent advances in the development of gene therapy tools provide hope that these approaches might modulate the altered gene expression that characterizes many CNS disorders. Gao et al. provide an overview of current gene therapy strategies, highlighting the interdependence of therapeutic modality, delivery vehicle and administration route for translational success.

Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create cross-linked depots (ISCD). The ISCD's solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platform's biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions.

Previous studies have shown that transplanted enteric glia enhance axonal regeneration, reduce tissue damage, and promote functional recovery following spinal cord injury. However, the mechanisms by which enteric glia mediate these beneficial effects are unknown. Neurotrophic factors can promote neuronal differentiation, survival and neurite extension. We hypothesized that enteric glia may exert their protective effects against spinal cord injury partially through the secretion of neurotrophic factors. In the present study, we demonstrated that primary enteric glia cells release nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor over time with their concentrations reaching approximately 250, 100 and 50 pg/mL of culture medium respectively after 48 hours. The biological relevance of this secretion was assessed by incubating dissociated dorsal root ganglion neuronal cultures in enteric glia-conditioned medium with and/or without neutralizing antibodies to each of these proteins and evaluating the differences in neurite growth. We discovered that conditioned medium enhances neurite outgrowth in dorsal root ganglion neurons. Even though there was no detectable amount of neurotrophin-3 secretion using ELISA analysis, the neurite outgrowth effect can be attenuated by the antibody-mediated neutralization of each of the aforementioned neurotrophic factors. Therefore, enteric glia secrete nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neurotrophin-3 into their surrounding environment in concentrations that can cause a biological effect.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.In 2018, the Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened to discuss strategies to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Biological ion channels have remarkable ion selectivity, permeability and rectification properties, but it is challenging to develop artificial analogues. Here, we report a metal–organic framework-based subnanochannel (MOFSNC) with heterogeneous structure and surface chemistry to achieve these properties. The asymmetrically structured MOFSNC can rapidly conduct K + , Na + and Li + in the subnanometre-to-nanometre channel direction, with conductivities up to three orders of magnitude higher than those of Ca 2+ and Mg 2+ , equivalent to a mono/divalent ion selectivity of 10 3 . Moreover, by varying the pH from 3 to 8 the ion selectivity can be tuned further by a factor of 10 2 to 10 4 . Theoretical simulations indicate that ion–carboxyl interactions substantially reduce the energy barrier for monovalent cations to pass through the MOFSNC, and thus lead to ultrahigh ion selectivity. These findings suggest ways to develop ion selective devices for efficient ion separation, energy reservation and power generation. Here, using an interfacial growth strategy, UiO-66 MOF nanocrystals are asymmetrically embedded into conical pores in a polymer membrane. These pores have a mono/divalent cation selectivity of 10 3 , which can be tuned by pH, and act as ionic rectifiers.

Purpose of ReviewIn recent decades, food allergy has become an increasing concern for families, clinicians, and policymakers. This review aims to summarize what is currently known about the epidemiology and population-level burden of IgE-mediated food allergy, including its effects on quality of life.Recent FindingsPrevalence surveys, healthcare utilization data, and findings from longitudinal cohort studies across the globe indicate that food allergy imposes a growing societal burden. Worryingly, recent data indicate that food allergies may be more prevalent among adult populations than previously acknowledged, with many reported cases of adult-onset allergies.SummaryWhile it remains unclear how much of the current population-level burden of disease results from true, IgE-mediated allergy, as much epidemiological data does not incorporate clinical confirmation of disease prevalence—it is clear that affected individuals suffer impairments in their quality of life and incur substantial economic costs—beyond the physical health burden imposed by anaphylaxis.

China has undergone rapid demographic and epidemiological changes in the past few decades, including striking declines in fertility and child mortality and increases in life expectancy at birth. Popular discontent with the health system has led to major reforms. To help inform these reforms, we did a comprehensive assessment of disease burden in China, how it changed between 1990 and 2010, and how China's health burden compares with other nations. We used results of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) for 1990 and 2010 for China and 18 other countries in the G20 to assess rates and trends in mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 231 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to China. We assessed relative performance of China against G20 countries (significantly better, worse, or indistinguishable from the G20 mean) with age-standardised rates and 95% uncertainty intervals. The leading causes of death in China in 2010 were stroke (1·7 million deaths, 95% UI 1·5–1·8 million), ischaemic heart disease (948 700 deaths, 774 500–1 024 600), and chronic obstructive pulmonary disease (934 000 deaths, 846 600–1 032 300). Age-standardised YLLs in China were lower in 2010 than all emerging economies in the G20, and only slightly higher than noted in the USA. China had the lowest age-standardised YLD rate in the G20 in 2010. China also ranked tenth (95% UI eighth to tenth) for HALE and 12th (11th to 13th) for life expectancy. YLLs from neonatal causes, infectious diseases, and injuries in children declined substantially between 1990 and 2010. Mental and behavioural disorders, substance use disorders, and musculoskeletal disorders were responsible for almost half of all YLDs. The fraction of DALYs from YLDs rose from 28·1% (95% UI 24·2–32·5) in 1990 to 39·4% (34·9–43·8) in 2010. Leading causes of DALYs in 2010 were cardiovascular diseases (stroke and ischaemic heart disease), cancers (lung and liver cancer), low back pain, and depression. Dietary risk factors, high blood pressure, and tobacco exposure are the risk factors that constituted the largest number of attributable DALYs in China. Ambient air pollution ranked fourth (third to fifth; the second highest in the G20) and household air pollution ranked fifth (fourth to sixth; the third highest in the G20) in terms of the age-standardised DALY rate in 2010. The rapid rise of non-communicable diseases driven by urbanisation, rising incomes, and ageing poses major challenges for China's health system, as does a shift to chronic disability. Reduction of population exposures from poor diet, high blood pressure, tobacco use, cholesterol, and fasting blood glucose are public policy priorities for China, as are the control of ambient and household air pollution. These changes will require an integrated government response to improve primary care and undertake required multisectoral action to tackle key risks. Analyses of disease burden provide a useful framework to guide policy responses to the changing disease spectrum in China. Bill & Melinda Gates Foundation.

A quantum computer has the potential to efficiently solve problems that are intractable for classical computers. However, constructing a large-scale quantum processor is challenging because of the errors and noise that are inherent in real-world quantum systems. One approach to addressing this challenge is to utilize modularity—a strategy used frequently in nature and engineering to build complex systems robustly. Such an approach manages complexity and uncertainty by assembling small, specialized components into a larger architecture. These considerations have motivated the development of a quantum modular architecture, in which separate quantum systems are connected into a quantum network via communication channels 1 , 2 . In this architecture, an essential tool for universal quantum computation is the teleportation of an entangling quantum gate 3 – 5 , but such teleportation has hitherto not been realized as a deterministic operation. Here we experimentally demonstrate the teleportation of a controlled-NOT (CNOT) gate, which we make deterministic by using real-time adaptive control. In addition, we take a crucial step towards implementing robust, error-correctable modules by enacting the gate between two logical qubits, encoding quantum information redundantly in the states of superconducting cavities 6 . By using such an error-correctable encoding, our teleported gate achieves a process fidelity of 79 per cent. Teleported gates have implications for fault-tolerant quantum computation 3 , and when realized within a network can have broad applications in quantum communication, metrology and simulations 1 , 2 , 7 . Our results illustrate a compelling approach for implementing multi-qubit operations on logical qubits and, if integrated with quantum error-correction protocols, indicate a promising path towards fault-tolerant quantum computation using a modular architecture. A teleported controlled-NOT gate is realized experimentally between two logical qubits implemented as superconducting cavity quantum memories, thus demonstrating an important tool for universal computation in a quantum modular architecture.

Efficient interconversion of both classical and quantum information between microwave and optical frequency is an important engineering challenge. The optomechanical approach with gigahertz-frequency mechanical devices has the potential to be extremely efficient due to the large optomechanical response of common materials, and the ability to localize mechanical energy into a micron-scale volume. However, existing demonstrations suffer from some combination of low optical quality factor, low electrical-to-mechanical transduction efficiency, and low optomechanical interaction rate. Here we demonstrate an on-chip piezo-optomechanical transducer that systematically addresses all these challenges to achieve nearly three orders of magnitude improvement in conversion efficiency over previous work. Our modulator demonstrates acousto-optic modulation with V π = 0.02 V. We show bidirectional conversion efficiency of 1 0 − 5 with 3.3 μW  red-detuned optical pump, and 5.5 % with 323 μW blue-detuned pump. Further study of quantum transduction at millikelvin temperatures is required to understand how the efficiency and added noise are affected by reduced mechanical dissipation, thermal conductivity, and thermal capacity. Current optomechanical implementations of microwave and optical frequency interconversion are lacking in efficiency and interaction strength. The authors design and demonstrate an on-chip piezo-optomechanical solution which overcomes several technical barriers to reach several orders of magnitude improvement in efficiency.