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Persistent radicals facilitate numerous selective radical coupling reactions. Here, we have identified acyl triazole as a new and versatile moiety for generating persistent radical intermediates through single-electron transfer processes. The efficient generation of these persistent radicals is facilitated by the formation of substrate-coordinated cobalt complexes, which subsequently engage in radical cross-coupling reactions. Remarkably, triazole-coordinated cobalt complexes exhibit metal-hydride hydrogen atom transfer (MHAT) capabilities with alkenes, enabling the efficient synthesis of diverse ketone products without the need for external ligands. By leveraging the persistent radical effect, this catalytic approach also allows for the development of other radical cross-coupling reactions with two representative radical precursors. The discovery of acyl triazoles as effective substrates for generating persistent radicals and as ligands for cobalt catalysis, combined with the bifunctional nature of the cobalt catalytic system, opens up new avenues for the design and development of efficient and sustainable organic transformations. Persistent radical-mediated cross-coupling has emerged as a powerful tool in organic synthesis for forging new C–C bonds. Here, the authors identify acyl triazoles as a versatile moiety for generating persistent radical intermediates through single-electron transfer processes, in the context of cobalt-catalysed carbon-carbon couplings under photoirradiation.

The ryanodine receptors (RyRs) are high-conductance intracellular Ca 2+ channels that play a pivotal role in the excitation–contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 Å, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities. Using electron cryomicroscopy, the structure of the closed-state rabbit ryanodine receptor RyR1 in complex with its modulator FKBP12 is solved at 3.8 Å; in addition to determining structural details of the ion-conducting channel domain, three previously uncharacterized domains help to reveal a molecular scaffold that allows long-range allosteric regulation of channel activities. Ryanodine receptor structure Muscle contraction is regulated by the concentration of calcium ions in the cytoplasm of muscle cells. Ryanodine receptors (RyR) release Ca 2+ from the sarcoplasmic reticulum to induce muscle contraction. Dysfunction of these channels contributes to the pathophysiology of important human diseases including muscular dystrophy. Three papers in this issue of Nature report high-resolution electron cryomicroscopy structures of the 2.2 MDa ryanodine receptor RyR1. Efremov et al . report the structure of rabbit RyR1 at 8.5 Å resolution the presence of Ca 2+ in a 'partly open' state, and at 6.1 Å resolution in the absence of Ca 2+ in a closed state. Zalk et al . report the rabbit RyR1 structure at 4.8 Å in the absence of Ca 2+ in a closed state. And third, Yan et al . report the structure of rabbit RyR1 bound to its modulator FKBP12 at a near-atomic resolution of 3.8 Å. These papers reveal how calcium binding to the EF-hand domain of RyR1 regulates channel opening and facilitates calcium-induced calcium release. The authors also note that disease-causing mutations are clustered in regions of the channel that appear to be critical for normal channel function.

This paper proposes a decoupling tracking controller for quadrotors using dynamic surface control (DSC) and second-order sliding mode disturbance observer (SMDO). The DSC used in this paper is improved with the sliding mode differentiators that replace the original low-pass filter, and the SMDO is utilized to restrain the influence of system uncertainties and external disturbances. In addition, instead of the roll attitude angle ( φ ) and pitch attitude angle ( θ ), applying sin φ and sin θ as control variables simplifies the analysis of stability. Moreover, a fuzzy logic-based method is utilized to compensate the influence of battery voltage changing during the procedure of thrust generation. The asymptotic tracking property of the closed-loop system is proven via the Lyapunov-based stability theory. Finally, the real-time experiment results, which contain a hovering case and rectangular path tracking case, are given to validate the practicability of the proposed method.

The air pollution caused by vehicular emissions is associated with cognitive decline. However, the associations between the levels of nitrogen dioxide (NO2) and carbon monoxide (CO) exposure and dementia remain poorly defined and have been addressed in only a few previous studies. In this study, we obtained data on 29547 people from the National Health Insurance Research Database (NHIRD) of Taiwan, including data on 1720 patients diagnosed with dementia between 2000 and 2010, and we evaluated the risk of dementia among four levels of air pollutant. Detailed data on daily air pollution were available from January 1, 1998 to December 31, 2010. Yearly average concentrations of pollutants were calculated from the baseline to the date of dementia occurrence, withdrawal of patients, or the end of the study, and these data were categorized into quartiles, with Q1 being the lowest level and Q4 being the highest. In the case of NO2, the adjusted hazard ratios (HRs) of dementia for all participants in Q2, Q3, and Q4 compared to Q1 were 1.10 (95% confidence interval (CI), 0.96-1.26), 1.01 (95% CI, 0.87-1.17), and 1.54 (95% CI, 1.34-1.77), and in the case of CO, the adjusted HRs were 1.07 (95% CI, 0.92-1.25), 1.37 (95% CI, 1.19-1.58), and 1.61 (95% CI, 1.39-1.85). The results of this large retrospective, population-based study indicate that exposure to NO2 and CO is associated with an increased risk of dementia in the Taiwanese population.

Salinity stress severely inhibits the growth of plant via ionic toxicity and osmotic constraint. Exogenous silicon (Si) can alleviate salinity stress, but the mechanisms behind remain unclear. To investigate the role of Si in alleviating ionic and osmotic components of salinity, rice ( L.) seedlings were grown hydroponically in iso-osmotic stress conditions developed from NaCl or polyethylene glycol (PEG). The effects of Si on the growth of shoot and root of rice under salinity and PEG-derived osmotic stress were evaluated and further compared using principal coordinate analysis (PCoA). We also analyzed the concentrations of Na, K, and compatible osmolytes, tissue sap osmotic potential, antioxidant enzymes activities, and the expression of aquaporin genes. Generally, Si significantly promoted shoot and root growth in rice exposed to both NaCl and PEG. PCoA shows that the Si-induced distance change under NaCl treatment was larger than that under PEG treatment in the shoot, while the Si-induced distance changes under NaCl and PEG treatments were at an equal level in the root. Under salinity, Si decreased Na concentration and Na/K ratio in the shoot but not in the root. However, Si decreased net Na uptake and increased root Na accumulation content. Osmotic potential was increased in the shoot but decreased in the root by Si addition. Si decreased soluble sugar and proline concentrations in the shoot but increased soluble sugar and soluble protein concentrations in the root. Besides, Si promoted shoot transpiration rate and root morphological traits. Although both NaCl and PEG treatments upregulated aquaporin gene expression, Si addition maintained the expression of s under NaCl and PEG treatments at same levels as control treatment. Furthermore, Si alleviated oxidative damages under both NaCl and PEG by regulating antioxidant enzyme activities. In summary, our results show that Si improves salt stress tolerance in rice by alleviating ionic toxicity and osmotic constraint in an organ-specific pattern. Si ameliorates ionic toxicity by decreasing Na uptake and increasing root Na reservation. Si alleviates osmotic constraint by regulating root morphological traits and root osmotic potential but not aquaporin gene expression for water uptake, and promoting transpiration force but not osmotic force in shoot for root-to-shoot water transport.

Kirigami, with facile and automated fashion of three-dimensional (3D) transformations, offers an unconventional approach for realizing cutting-edge optical nano-electromechanical systems. Here, we demonstrate an on-chip and electromechanically reconfigurable nano-kirigami with optical functionalities. The nano-electromechanical system is built on an Au/SiO 2 /Si substrate and operated via attractive electrostatic forces between the top gold nanostructure and bottom silicon substrate. Large-range nano-kirigami like 3D deformations are clearly observed and reversibly engineered, with scalable pitch size down to 0.975 μm. Broadband nonresonant and narrowband resonant optical reconfigurations are achieved at visible and near-infrared wavelengths, respectively, with a high modulation contrast up to 494%. On-chip modulation of optical helicity is further demonstrated in submicron nano-kirigami at near-infrared wavelengths. Such small-size and high-contrast reconfigurable optical nano-kirigami provides advanced methodologies and platforms for versatile on-chip manipulation of light at nanoscale. The authors present on-chip and electromechanically reconfigurable nanokirigami with optical functionalities. 3D deformations are achieved via attractive electrostatic forces between a gold nanostructure layer and silicon substrate, resulting in optical reconfigurations with high modulation contrast and small unit size.

In recent years, biomarkers have been integrated into the diagnostic process and have become increasingly indispensable for obtaining knowledge of the neurodegenerative processes in Alzheimer’s disease (AD). Peripheral blood mononuclear cells (PBMCs) in human blood have been reported to participate in a variety of neurodegenerative activities. Here, a single-cell RNA sequencing analysis of PBMCs from 4 AD patients (2 in the early stage, 2 in the late stage) and 2 normal controls was performed to explore the differential cell subpopulations in PBMCs of AD patients. A significant decrease in B cells was detected in the blood of AD patients. Furthermore, we further examined PBMCs from 43 AD patients and 41 normal subjects by fluorescence activated cell sorting (FACS), and combined with correlation analysis, we found that the reduction in B cells was closely correlated with the patients’ Clinical Dementia Rating (CDR) scores. To confirm the role of B cells in AD progression, functional experiments were performed in early-stage AD mice in which fibrous plaques were beginning to appear; the results demonstrated that B cell depletion in the early stage of AD markedly accelerated and aggravated cognitive dysfunction and augmented the Aβ burden in AD mice. Importantly, the experiments revealed 18 genes that were specifically upregulated and 7 genes that were specifically downregulated in B cells as the disease progressed, and several of these genes exhibited close correlation with AD. These findings identified possible B cell-based AD severity, which are anticipated to be conducive to the clinical identification of AD progression. Alzheimer’s disease: A new biomarker for disease progression? Molecular tests built around analyzing B cells, a specialized type of immune cell, could aid in the diagnosis of Alzheimer’s disease. Liu-Lin Xiong from the Affiliated Hospital of Zunyi Medical University, China, and coworkers used single-cell RNA sequencing to profile gene activity in individual peripheral blood mononuclear cells from people with and without Alzheimer’s disease. They discovered that people with Alzheimer’s, especially those with more advanced disease, had lower levels of circulating B cells than healthy subjects. Twenty-five specific genes in the B cells were expressed at significantly higher or lower levels as the disease progressed. The researchers found similar results regarding B cells and Alzheimer’s progression in mouse models, and showed that massive depletion of B cells in the early onset was associated with accelerated cognitive decline and increased accumulation of sticky brain plaques.

CRISPR/Cas genome editing is a simple, cost effective, and highly specific technique for introducing genetic variations. In mammalian cells, CRISPR/Cas can facilitate non-homologous end joining, homology- directed repair, and single-base exchanges. Cas9/Cas12a nuclease, dCas9 transcriptional regulators, base editors, PRIME editors and RNA editing tools are widely used in basic research. Currently, a variety of CRISPR/Cas-based therapeutics are being investigated in clinical trials. Among many new findings that have advanced the field, we highlight a few recent advances that are relevant to CRISPR/Cas-based gene therapies for monogenic human genetic diseases.

Abstract Study Objectives This study employed longitudinal data collected repeatedly from individuals over the course of several years to examine the trajectories of social jetlag from ages 11 to 22 years and their associations with subsequent body mass index (BMI). Potential sex differences were also investigated. Methods Data were obtained from two longitudinal studies conducted in Taiwan (N = 4287). Social jetlag was defined as ≥ 2 hours of absolute difference in sleep midpoint between weekdays and weekends. BMI was calculated using weight (kg)/height(m)2 and categorized as underweight (<18 kg/m2), normal weight (18 kg/m2 ≤ BMI < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 27 kg/m2), and obese (≥27 kg/m2). Group-based trajectory modeling and multinomial logistic regression were applied to investigate study objectives. Results Four distinct trajectories of social jetlag throughout the adolescent years were identified, with corresponding proportions as follows: low-stable (42%), moderate-decreasing (19%), low-increasing (22%), and chronic (17%) trajectories. Among males, the risk of being underweight (aOR, 1.96; 95% CI: 1.35 to 2.84) or obese (aOR, 1.40; 95% CI: 1.02 to 1.92) was higher in individuals with a low-increasing trajectory than in those with a low-stable trajectory. Among females, those with a low-increasing (aOR, 1.61; 95% CI: 1.02 to 2.54) or chronic (aOR, 2.04; 95% CI: 1.27 to 3.25) trajectory were at a higher risk of being obese relative to those with a low-stable trajectory. Conclusions Addressing the development of increasing or chronic social jetlag during adolescence can help prevent abnormal BMI in young adulthood. Practitioners should consider sex differences in treatment or consultation. Graphical Abstract Graphical Abstract