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Radiative decays of the radially excited charmonium resonance, (Formula presented) into (Formula presented) (Formula presented) and (Formula presented) final states have been measured in a sample of (Formula presented) (Formula presented) events collected by the BES Collaboration. The branching ratios (Formula presented) and (Formula presented) are obtained. When compared to the corresponding radiative (Formula presented) decays, the observed (Formula presented) radiative decay rates into (Formula presented) and (Formula presented) are consistent with the prediction of the “12%” rule. © 2003 The American Physical Society.

Radiative decays of the radially excited charmonium resonance, (Formula presented) into (Formula presented) (Formula presented) and (Formula presented) final states have been measured in a sample of (Formula presented) (Formula presented) events collected by the BES Collaboration. The branching ratios (Formula presented) and (Formula presented) are obtained. When compared to the corresponding radiative (Formula presented) decays, the observed (Formula presented) radiative decay rates into (Formula presented) and (Formula presented) are consistent with the prediction of the “12%” rule. © 2003 The American Physical Society.

The branching fraction of the ψ(2S) decay into τ+τ - has been measured for the first time using the BES detector at the Beijing Electron-Positron Collider. The result is Bττ=(2.710. 43±0.55)× 10-3, where the first error is statistical and the second is systematic. This value, along with those for the branching fractions into e+e- and μ+ μ- of this resonance, satisfy well the relation predicted by the sequential lepton hypothesis. Combining all these values with the leptonic width of the resonance, the total width of the ψ(25) is determined to be (252±37) keV. ©2002 The American Physical Society.

The absolute inclusive semileptonic branching fraction of the [Formula presented] meson has been measured based on [Formula presented] of [Formula presented] collision data collected with the Beijing Spectrometer at [Formula presented] At this energy, the [Formula presented] are produced in pairs: [Formula presented] We reconstructed [Formula presented] [Formula presented] events in five hadronic decay modes. In the recoil system of these events, several [Formula presented] inclusive semileptonic decays were observed and the branching fraction is estimated to be [Formula presented] © 1997 The American Physical Society.

The absolute inclusive semileptonic branching fraction of the [Formula presented] meson has been measured based on [Formula presented] of [Formula presented] collision data collected with the Beijing Spectrometer at [Formula presented] At this energy, the [Formula presented] are produced in pairs: [Formula presented] We reconstructed [Formula presented] [Formula presented] events in five hadronic decay modes. In the recoil system of these events, several [Formula presented] inclusive semileptonic decays were observed and the branching fraction is estimated to be [Formula presented] © 1997 The American Physical Society.

Background: The prevalence of self-injury and suicide is higher than the general population of people living with HIV/AIDS (PLWHA). However, the results reported in existing studies are highly variable in China. The purpose of this systematic review and meta-analysis was to synthesize the currently available high-quality evidence to explore the prevalence and influence factors of self-injury and suicide among PLWHA in China., Method: We retrieve literature written in Chinese and English through databases such as PubMed, Embase, Web of Science, Cochrane Library, SinoMed, CNKI, WanFang Database, and CQVIP from inception to 1 September 2022. Sata 16.0 software was used for analysis., Results: A total of 28 studies were included with a sample size of 1,433,971 and had a satisfactory quality score of ≥ 5. The prevalence among PLWHA in China were 30% for suicidal ideation (SI), 5% for suicide attempt (SA), 8% for suicide plan (SP), 7% for attempted suicide (AS), and 3‰ for completed suicide. High stigma (OR = 2.94, 95%CI: 1.90 - 4.57), depression (OR, 3.17; 95%CI, 2.20 - 4.57), anxiety (OR, 3.06; 95%CI, 2.23 - 4.20), low self-esteem (OR, 3.82, 95%CI, 2.22 - 6.57), high HIV related stress (OR, 2.53; 95%CI, 1.36 - 4.72), and unemployment (OR, 2.50; 95%CI, 1.51 - 4.15) are risk factors for SI; high social support (OR, 0.61; 95%CI, 0.44 - 0.84) and spouse infected with HIV (OR, 0.39; 95%CI, 0.21 - 0.74) are protective factors for SI; depression (OR, 1.62; 95%CI, 1.24 - 2.13), high aggression (OR, 4.66; 95%CI, 2.59 - 8.39), and more negative life events (OR, 2.51; 95%CI, 1.47 - 4.29) are risk factors for AS; high level of education (OR, 1.31; 95%CI, 1.21 - 1.43) is risk factor for CS., Conclusion: Figures indicate that approximately one-third of PLWHA had suicidal ideation, and three out of 1,000 completed suicide in China. Positive events are protective factors for self-injury and suicide among PLWHA, while negative events are risk factors. This suggests that psychosocial support and risk assessment should be integrated into the care of PLWHA., (© 2024. The Author(s).)

Many neurotransmitter receptors activate G proteins through exchange of GDP for GTP. The intermediate nucleotide-free state has eluded characterization, due largely to its inherent instability. Here we characterize a G protein variant associated with a rare neurological disorder in humans. Gα o K46E has a charge reversal that clashes with the phosphate groups of GDP and GTP. As anticipated, the purified protein binds poorly to guanine nucleotides yet retains wild-type affinity for G protein βγ subunits. In cells with physiological concentrations of nucleotide, Gα o K46E forms a stable complex with receptors and Gβγ, impeding effector activation. Further, we demonstrate that the mutant can be easily purified in complex with dopamine-bound D2 receptors, and use cryo-electron microscopy to determine the structure, including both domains of Gα o , without nucleotide or stabilizing nanobodies. These findings reveal the molecular basis for the first committed step of G protein activation, establish a mechanistic basis for a neurological disorder, provide a simplified strategy to determine receptor-G protein structures, and a method to detect high affinity agonist binding in cells., (© 2024. The Author(s).)

Solar-driven interfacial evaporation (SIE) is very promising to solve the issue of fresh water shortage, however, poor salt resistance severely hinders long-term stable SIE and fresh water collection. Here, we report design of superhydrophilic solar evaporators for long-term stable desalination, fresh water collection and salt collection by vertical salt deposition. The evaporators are prepared by sequentially deposition of silicone nanofilaments, polypyrrole and Au nanoparticles on a polyester fabric composed of microfibers. The evaporators feature excellent photothermal effect and ultrafast water transport, due to their unique micro-/nanostructure and superhydrophilicity. As a result, during SIE the salt gradually deposits vertically rather than occupies larger area on the evaporators. Consequently, long-term stable SIE with high evaporation rates of 2.4-2.1 kg m -2  h -1 for 3.5-20 wt % brine in continuous 10 h is achieved under 1 sun illumination. Meanwhile, the loosely deposited salt can be easily collected, realizing zero brine discharge. Moreover, scalable preparation of the evaporator is achieved, which exhibits efficient collection of high quality fresh water (10.08 kg m -2 in 8 h) via SIE desalination under weak natural sunlight (0.46~0.66 sun). This strategy sheds a new light on the design of high-performance solar evaporators and their real-world fresh water collection., (© 2024 Wiley-VCH GmbH.)

Background: The efficacy of Vonoprazan-amoxicillin dual therapy (VAT) in the treatment of Helicobacter pylori ( H. pylori ) is controversial., Aim: To evaluate the efficacy of VAT in the Chinese population., Methods: This prospective, multicenter, randomized, open-label, and two-stage study was conducted at 23 centers in Fujian, China (May 2021-April 2022). H. pylori -infected patients were randomized to bismuth quadruple therapy (BQT), BQT-Vonoprazan (BQT-V), seven-day VAT (VAT-7), ten-day VAT (VAT-10), and fourteen-day VAT (VAT-14) groups. The primary endpoint was the H. pylori eradication rate. The secondary endpoint was the frequency of adverse events. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2100045778., Results: In the first stage, VAT-7 and BQT-V groups were selected for early termination because less than 23 among 28 cases were eradicated. In the second stage, the eradication rates for BQT, VAT-10, and VA-14 were 80.2% [95% confidence interval (95%CI): 71.4%-86.8%], 93.2% (86.6%-96.7%), 92.2% (85.3%-96.0%) in the intention-to-treat (ITT) analysis, and 80.9% (95%CI: 71.7%-87.5%), 94.0% (87.5%-97.2%), and 93.9% (87.4%-97.2%) in the per-protocol analysis. The ITT analysis showed a higher eradication rate in the VAT-10 and VAT-14 groups than in the BQT group ( P = 0.022 and P = 0.046, respectively). The incidence of adverse events in the VAT-10 and VAT-14 groups was lower than in the BQT group (25.27% and 13.73% vs 37.62%, respectively; P < 0.001)., Conclusion: VAT with a duration of 10 or 14 days achieves a higher eradication rate than the BQT, with a more tolerable safety profile in H. pylori -infected patients in Fujian., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Cardiomyocyte injury is closely related to various myocardial diseases, and S-Allyl-L-cysteine (SAC) has been found to have myocardial protective effects, but its mechanism is currently unclear. Meanwhile, copper also has various physiological functions, and this study found that copper inhibited cell viability in a concentration and time-dependent manner, and was associated with multiple modes of death. Elesclomol plus CuCl 2 (ES + Cu) significantly inhibited cell viability, and this effect could only be blocked by copper chelator TTM, indicating that "ES + Cu" induced cuproptosis in cardiomyocytes. SAC reduced the inhibitory effects of high concentration copper and "ES + Cu" on cell viability in a concentration and time-dependent manner, indicating that SAC plays a cardioprotective role under stress. Further mechanism study showed that high concentration of copper significantly induced cardiomyocyte apoptosis and increased the levels of LDH, MDA and ROS, while SAC inhibited the apoptosis and injury of cardiomyocytes induced by copper. "ES + Cu" significantly increased intracellular copper levels and decreased the expression of FDX1, LIAS, Lip-DLST and Lip-DLAT; FDX1 siRNA did not affect the expression of LIAS, but further reduced the expression of Lip-DLST and Lip-DLAT; SAC did not affect the expression of these genes, but enhanced the effect of "ES + Cu" in down-regulating these gene expression and restored intracellular copper levels. In addition, "ES + Cu" reduced ATP production, weakened the activity of mitochondrial complex I and III, inhibited cell viability, and increased the contents of injury markers LDH, MDA, CK-MB and cTnI, while SAC significantly improved mitochondrial function injury and cardiomyocyte injury induced by "ES + Cu". Therefore, SAC can inhibit apoptosis and cuproptosis to play a cardioprotective role., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions., Competing Interests: Declaration of competing interest MLB, ACN, and ZAM are subcontracted by Epicypher® on an unrelated project. ND is an uncompensated board member of Remedy Alliance For The People, a 501(c)3 non-profit organization that distributes naloxone. BRL is on the SAB of several companies: Septerna, Onsero, Epiodyne, Escient; he has stock in Septerna; and he has had many technologies licensed by UNC to pharmaceutical and biotech companies. The remaining authors do not have any disclosures.

Objectives: To unravel the heterogeneity and function of microenvironmental neutrophils during intervertebral disc degeneration (IDD)., Methods: Single-cell RNA sequencing (scRNA-seq) was utilized to dissect the cellular landscape of neutrophils in intervertebral disc (IVD) tissues and their crosstalk with nucleus pulposus cells (NPCs). The expression levels of macrophage migration inhibitory factor (MIF) and ACKR3 in IVD tissues were detected. The MIF/ACKR3 axis was identified and its effects on IDD were investigated in vitro and in vivo., Results: We sequenced here 71520 single cells from 5 control and 9 degenerated IVD samples using scRNA-seq. We identified a unique cluster of neutrophils abundant in degenerated IVD tissues that highly expressed MIF and was functionally enriched in extracellular matrix organization (ECMO). Cell-to-cell communication analyses showed that this ECMO-neutrophil subpopulation was closely interacted with an effector NPCs subtype, which displayed high expression of ACKR3. Further analyses revealed that MIF was positively correlated with ACKR3 and functioned via directly binding to ACKR3 on effector NPCs. MIF inhibition attenuated degenerative changes of NPCs and extracellular matrix, which could be partially reversed by ACKR3 overexpression. Clinically, a significant correlation of high MIF/ACKR3 expression with advanced IDD grade was observed. Furthermore, we also found a positive association between MIF + ECMO-neutrophil counts and ACKR3 + effector NPCs density as well as higher expression of the MIF/ACKR3 signaling in areas where these two cell types were neighbors., Conclusions: These data suggest that ECMO-neutrophil promotes IDD progression by their communication with NPCs via the MIF/ACKR3 axis, which may shed light on therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The lipid prostaglandin E 2 (PGE 2 ) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice., (© 2023. The Author(s).)

Objective: To summarize the reliability and validity of ultrasonography in evaluating the stiffness, excursion, stiffness, or strain rate of diaphragm, intercostals and abdominal muscles in healthy or non-hospitalized individuals., Literature Search: PubMed, Embase, SPORTDiscus, CINAHL and Cochrane Library were searched from inception to May 30, 2022., Study Selection Criteria: Case-control, cross-sectional, and longitudinal studies were included if they investigated the reliability or validity of various ultrasonography technologies (e.g., brightness-mode, motion-mode, shear wave elastography) in measuring the thickness, excursion, stiffness, or strain rate of any respiratory muscles., Data Synthesis: Relevant data were summarized based on healthy and different patient populations. The methodological quality by different checklist depending on study design. The quality of evidence of each psychometric property was graded by the Grading of Recommendations, Assessment, Development and Evaluations, respectively., Results: This review included 24 studies with 787 healthy or non-hospitalized individuals (e.g., lower back pain (LBP), adolescent idiopathic scoliosis (AIS), and chronic obstructive pulmonary disease (COPD)). Both inspiratory (diaphragm and intercostal muscles) and expiratory muscles (abdominal muscles) were investigated. Moderate-quality evidence supported sufficient (intra-class correlation coefficient > 0.7) within-day intra-rater reliability of B-mode ultrasonography in measuring right diaphragmatic thickness among people with LBP, sufficient between-day intra-rater reliability of M-mode ultrasonography in measuring right diaphragmatic excursion in non-hospitalized individuals. The quality of evidence for all other measurement properties in various populations was low or very low. High-quality evidence supported sufficient positive correlations between diaphragm excursion and forced expiratory volume in the first second or forced vital capacity (r >  = 0.3) in healthy individuals., Conclusions: Despite the reported sufficient reliability and validity of using ultrasonography to assess the thickness, excursion, stiffness, and strain rate of respiratory muscles in non-hospitalized individuals, further large-scale studies are warranted to improve the quality of evidence regarding using ultrasonography for these measurements in clinical practice. Researchers should establish their own reliability before using various types of ultrasonography to evaluate respiratory muscle functions., Trial Registration: PROSPERO NO. CRD42022322945., (© 2023. The Author(s).)

Neurofeedback training is a common treatment option for attention deficit hyperactivity disorder (ADHD). Given theta/beta-based neurofeedback (T/B NF) training targets at the electrophysiological characteristics of children with ADHD, benefits for attention may be expected. PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science were searched through December 31, 2020. Studies were evaluated with Risk of Bias tools. Within-group effects based on Pre- and Post-treatment comparisons of the Intervention Group, and Between-group effects based on the between-group differences from Pre-treatment to Post-treatment were calculated. Nineteen studies met selection criteria for systematic review, 12 of them were included in meta-analysis. Within-group effects were medium at Post-treatment and large at Follow-up. Between-group analyses revealed that T/B NF was superior to waitlist control and physical activities, but not stimulant medication. Results showed that T/B NF has benefits for attention in children with ADHD, however, cautions should be taken when interpreting the findings., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the relationship between upper airway morphology and the severity of obstructive sleep apnea (OSA) in patients with anatomically small retruded mandibles., Methods: Fifty-two patients with small retruded mandibles underwent polysomnography and airway computed tomography. The airway morphology parameters and sleep assessment were compared between the patients with or without OSA., Results: Twenty-eight patients diagnosed with OSA, according to polysomnography, had a higher distance between the hyoid bone and mandibular plane (HMP), lateral dimension (LAT)/anteroposterior dimension (AP), but lower minimum cross-sectional area (mCSA), AP, surface area, volume, avgCSA, and airway uniformity (U). The apnea-hypopnea index had negative correlations with mCSA, AP, surface area, volume, avgCSA, and U, and had a positive correlation with HMP and LAT/AP., Conclusion: OSA is common among patients with small retruded mandibles and is associated with a more compressed upper airway shape and longer HMP.

Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain reward deficits in rodents during withdrawal, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a generative deep-learning framework for the de novo design of chemotypes with putative KOR antagonistic activity. Molecules generated by models trained with this framework were prioritized for chemical synthesis based on their predicted optimal interactions with the receptor. Our models and proposed training protocol were experimentally validated by binding and functional assays.

Bone defect (BD) caused by trauma, infection, congenital defects, or neoplasia is a major cause of physical limitation. Distraction osteogenesis (DO) is a highly effective procedure for bone regeneration, while the concrete mechanism remains unknown. In this study, canine DO and BD models of the mandible were established. The results of micro-computed tomography and histological staining revealed that DO led to an increased mineralized volume fraction and robust new bone formation; in contrast, BD demonstrated incomplete bone union. Mesenchymal stem cells (MSCs) from DO and BD calluses were isolated and identified. Compared with BD-MSCs, DO-MSCs were found to have a stronger osteogenic capability. Single-cell RNA sequencing analysis was further performed to comprehensively define cell differences between mandibular DO and BD calluses. Twenty-six clusters of cells representing 6 major cell populations were identified, including paired related homeobox 1-expressing MSCs ( PRRX1 + MSCs), endothelial cells (ECs), T cells, B cells, neutrophils, and macrophages. Interestingly, 2 subpopulations in PRRX1 + MSCs in the DO group were found to express the marker of neural crest cells (NCCs) and were associated with the process of epithelial-mesenchymal transition. The immunofluorescence assay was performed to further corroborate these results in vivo and in vitro, experimentally validating that continuous distraction maintained the PRRX1 + MSCs in an embryonic-like state. Finally, we used CRISPR/Cas9 to knock out (KO) PRRX1 in the context of DO, which significantly blunted the capability of jawbone regeneration, resulting in a diminished NCC-like program and reduction of new bone volume. In addition, the ability of osteogenesis, cell migration, and proliferation in cultured PRRX1 KO MSCs was inhibited. Taken together, this study provides a novel, comprehensive atlas of the cell fates in the context of DO regeneration, and PRRX1 + MSCs act essential roles.

The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system., (© 2023. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.)

Objective: To study the effect of borneol combined with astragaloside IV and Panax notoginseng saponins (BAP) on promoting neurogenesis by regulating microglia polarization after cerebral ischaemia-reperfusion(CI/R) in rats., Methods: A focal CI/R injury model was established. Evaluated the effects of BAP on ischaemic brain injury, on promoting neurogenesis, on inhibiting Inflammatory microenvironment and TLR4/MyD88/NFκB signalling pathway. A microglia oxygen-glucose deprivation reoxygenation (OGD/R) model was established that evaluated the effects of BAP on regulating the polarization of microglia and inflammatory microenvironment., Results: BAP can inhibit the expression of TLR4, MyD88 and NFκB proteins, reduce IL-1β and increase IL-10, reduce M1 type microglia and increase M2 microglia. The proliferation of neural stem cells increased, synaptic gap decreased, synaptic interface curvature increased, expression of SYN and PSD95 proteins increased, which improved the neurological dysfunction and reduced the volume of cerebellar infarction and nerve cell injury., Conclusion: BAP can reduce CI/R injury and promote neurogenesis, the effect is related to inhibition of the activation of TLR4/MyD88/NFκB, regulating the polarization of microglia from M1 type to M2 type and inhibition of inflammatory response., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Odontogenic keratocyst is one of the most common benign odontogenic neoplasms with a high recurrence rate. Its resection has the potential to lead to mandibular segmental defects. In this case report, we describe a patient with odontogenic keratocyst who underwent radical resection using a novel distraction osteogenesis (DO) method to reconstruct mandibular segmental defect., Case Presentation: This case report describes a 19-year-old woman with odontogenic keratocyst of the mandible that recurred after multiple curettages and eventually necessitated radical resection. Mandibular segmental defect after radical resection was reconstructed using a novel DO method that involved directly contacting the segment ends of the defect without the transport disk. However, the distractor broke during the retention period, and a molding titanium plate was used for fixation. This novel distraction method achieved mandibular reconstruction and restored mandibular function and contour., (© 2023. The Author(s).)

The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT 1 R and its downstream signaling proteins G q and β-arrestin. AT 1 R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT 1 R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT 1 R in complex with a balanced agonist, Sar 1 -AngII, and G q protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT 1 R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT 1 R signal transduction from the ligand-binding pocket to both G q and β-arrestin pathways. Specifically, we found that the MHN mutations N111 3.35 A and N294 7.45 A induce biased signaling to G q and β-arrestin, respectively. These insights should facilitate AT 1 R structure-based drug discovery for the treatment of cardiovascular diseases., (© 2023 The Authors.)

Objective: To study the construction of a prognostic model for hepatocellular carcinoma (HCC) based on pyroptosis-related genes (PRGs). Methods: HCC patient datasets were obtained from the Cancer Genome Atlas (TCGA) database, and a prognostic model was constructed by applying univariate Cox and least absolute shrinkages and selection operator (LASSO) regression analysis. According to the median risk score, HCC patients in the TCGA dataset were divided into high-risk and low-risk groups. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, univariate and multivariate Cox analysis, and nomograms were used to evaluate the predictive ability of the prognostic models. Functional enrichment analysis and immune infiltration analysis were performed on differentially expressed genes between the two groups. Finally, two HCC datasets (GSE76427 and GSE54236) from the Gene Expression Omnibus database were used to externally validate the prognostic value of the model. Univariate and multivariate Cox regression analysis or Wilcoxon tests were performed on the data. Results: A total of 366 HCC patients were included after screening the HCC patient dataset obtained from the TCGA database. A prognostic model related to HCC was established using univariate Cox regression analysis, LASSO regression analysis, and seven genes (CASP8, GPX4, GSDME, NLRC4, NLRP6, NOD2, and SCAF11). 366 cases were evenly divided into high-risk and low-risk groups based on the median risk score. Kaplan-Meier survival analysis showed that there were statistically significant differences in the survival time between patients in the high-risk and low-risk groups in the TCGA, GSE76427, and GSE54236 datasets (median overall survival time was 1 149 d vs. 2 131 d, 4.8 years vs. 6.3 years, and 20 months vs. 28 months, with P = 0.000 8, 0.034 0, and 0.0018, respectively). ROC curves showed good survival predictive value in both the TCGA dataset and two externally validated datasets. The areas under the ROC curves of 1, 2, and 3 years were 0.719, 0.65, and 0.657, respectively. Multivariate Cox regression analysis showed that the risk score of the prognostic model was an independent predictor of overall survival time in HCC patients. The risk model score accurately predicted the survival probability of HCC patients according to the established nomogram. Functional enrichment analysis and immune infiltration analysis showed that the immune status of the high-risk group was significantly decreased. Conclusion: The prognostic model constructed in this study based on seven PRGs accurately predicts the prognosis of HCC patients.

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects., Competing Interests: Declaration of interests B.K.S. serves on the SAB of Schrödinger, Umbra Therapeutics, and Deep Apple; with J.J.I., he co-founded Deep Apple Therapeutics and Blue Dolphin; with A.M. and B.L.R., he co-founded Epiodyne Ltd, while A.M. also founded Stipple Bio and consults for Abolone and Septerna. W.C.W. consults for Onsero Therapeutics, company co-founded by B.L.R., who also serves on the SAB of Escient Pharmaceuticals and of Septerna., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bystander activation of T cells is defined as induction of effector responses by innate cytokines in the absence of cognate antigens and independent of T cell receptor (TCR) signaling. Here we show that C-reactive protein (CRP), a soluble pattern-recognition receptor assembled noncovalently by five identical subunits, can instead trigger bystander activation of CD4 + T cells by evoking allosteric activation and spontaneous signaling of TCR in the absence of cognate antigens. The actions of CRP depend on pattern ligand-binding induced conformational changes that result in the generation of monomeric CRP (mCRP). mCRP binds cholesterol in plasma membranes of CD4 + T cells, thereby shifting the conformational equilibrium of TCR to the cholesterol-unbound, primed state. The spontaneous signaling of primed TCR leads to productive effector responses manifested by upregulation of surface activation markers and release of IFN-γ. Our results thus identify a novel mode of bystander T cell activation triggered by allosteric TCR signaling, and reveal an interesting paradigm wherein innate immune recognition of CRP transforms it to a direct activator that evokes immediate adaptive immune responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Primary Epstein-Barr virus (EBV)-associated poorly differentiated nasopharyngeal adenocarcinoma (NAC) is an extremely rare tumor. In this study, we report a case of EBV-associated poorly differentiated NAC in a 35-year-old man who presented with a clogging sensation in the right ear for 1 month. The first biopsy of the nasopharynx was suggestive of nonkeratinizing carcinoma with weak positivity for CK5/6 and p63. Based on magnetic resonance imaging of the nasopharynx and neck, chest computed tomography, abdominal ultrasound, and whole-body bone scan, the patient was diagnosed with T3N2M0 disease. After the patient received neoadjuvant chemotherapy, concurrent chemoradiotherapy, and adjuvant chemotherapy, partial remission was observed. However, reassessment after 7 months of treatment revealed tumor enlargement. Transnasal endoscopic resection was performed to remove the nasopharyngeal tumor. The postoperative immunostaining results were as follows: CK5/6 (-), p63 (-), MOC31 (+), and Ber-EP4 (+). Meanwhile, EBV-encoded RNA in situ hybridization was positive. A final diagnosis of EBV-associated poorly differentiated NAC was made. Then, the patient received chemotherapy and irradiation but died several months later because of disease progression. Our patient presented with highly malignant EBV-associated poorly differentiated NAC insensitive to chemoradiotherapy with a short survival time of 27 months.

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1.

The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1-Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Occupational exposure to diacetyl can lead to bronchiolitis obliterans. In this paper, two patients with severe obstructive ventilation disorder who were exposed to diacetyl at a fragrance and flavours factory were analyzed. The clinical manifestations were cough and shortness of breath. One of them showed Mosaic shadows and uneven perfusion in both lungs on CT, while the other was normal. Field investigation found that 4 of the 8 workers in the factory were found to have obstructive ventilation disorder, and 2 had small airway dysfunction. This paper summarizes the diagnostic process of patients in order to improve the understanding of airway dysfunction caused by occupational exposure to diacetyl and promote the development of relevant standards.

A Gram-negative, non-motile, facultatively anaerobic, rod-shaped bacterium, designated strain RS1-74 T , was isolated from the surface water of Sayram Lake, Xinjiang Uygur Autonomous Region, China. The strain was able to grow optimally at 30 °C and pH 7.0-7.5, and in the presence of 0-0.5 % (v/w) NaCl. Catalase and oxidase activities were present. H 2 S was produced. Chemotaxonomic analysis showed Q-10 was the sole respiratory quinone. The polar lipids were composed of phosphatidylethanolamine, diphosphatidylglycerol, two glycolipids, phosphatidylglycerol, sphingoglycolipid and two unidentified lipids. Summed feature 3 (C 16 : 1  ω 7 c and/or C 16 : 1  ω 6 c ) and summed feature 8 (C 18 : 1  ω 7 c and/or C 18 : 1  ω 6 c ) were the predominant fatty acids. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain RS1-74 T was closely related to ' Sandaracinobacter neustonicus ' JCM 30 734 (98.65 %), ' Sandaracinobacter sibiricus ' RB16-17 (98.42 %) and Sandaracinobacteroides hominis SZY PN-1 T (97.09%). The genomic DNA G+C content was 66.45 mol%. The average nucleotide identity and DNA-DNA hybridization values among the genomes of strain RS1-74 T and ' Sandaracinobacter neustonicus ' JCM 30734 and Sandaracinobacteroides hominis SZY PN-1 T were 78.2 and 77.22 %, and 22.2 and 20.40 %, respectively. Based on the physiological, biochemical, phylogenetic and genomic data, strain RS1-74 T represents a novel species within the genus Sandaracinobacteroides , for which the name Sandaracinobacteroides sayramensis sp. nov. is proposed, with type strain RS1-74 T (=KCTC 82674 T =MCCC 1K06282 T ).

Human, rat, and mouse C-reactive protein (CRP) possess distinct expression patterns, but have similar conformations and conserved in vivo functions. We have previously demonstrated that this level-function mismatch is delicately tuned by the hidden activities of unfolded CRP. The cholesterol-binding sequence (CBS; a.a. 35-47) is a major functional motif exposed on monomeric CRP, which is the unfolded and activated conformation of CRP. We replaced the CBS of rat CRP with that of either mouse or human CRP, yielding two grafting mutants with unaffected pentameric assembly. However, these mutants exhibited altered cellular foldability and conformational activation efficiency that matched those of the CRP that provided the grafted CBS. These results indicate that CBS is a critical regulatory motif, whose variation maintains the pentameric assembly of CRP but derives distinct cellular foldabilities and conformational activation efficiencies, therefore helping to ensure that CRPs with various expression patterns exhibit overall conserved functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Although metabolic abnormalities have been deemed one of the essential risk factors for growth and development, the relationship between metabolic abnormalities and microtia is still unclear. In this study, we aimed to establish a cell model of microtia and the changes of serum metabolites in patients with microtia., Methods: After constructing a cell model of microtia with low expression of BMP5, we performed integrative metabolomics analysis. For the altered metabolites, the content of glycerophosphocholine (PC), triacylglycerol (TG), and choline in the serum of 28 patients (15 patients with microtia and 13 controls) with microtia was verified by enzyme-linked immunosorbent assay (ELISA)., Results: Detailed metabolomic evaluation showed distinct clusters of metabolites between BMP5-low expressing cells and normal control (NC) cells. The cell model of microtia had significantly higher levels of TG, PC, glycerophosphoethanolamine (PE), sphingomyelin, sulfatide, glycerophosphoglycerol, diacylglycerol, and glycosphingolipid. The main abnormal metabolites were mainly concentrated in the glycerophospholipid metabolism pathway, and PC and choline were closely related. In the serum of patients with microtia, the contents of PC, TG, and choline were significantly increased., Conclusions: The individual serum samples confirmed the different metabolites between patients with microtia and controls. In particular, we showed that a newly developed metabolic biomarker panel has a high sensitivity and specificity for separating patients with microtia from controls., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5614/coif). All authors report that the study was supported by grants from the National Natural Science Foundation of China (Nos. 82171160, 81801132, and 81971190); the National Natural Science Foundation of Guangdong (No. 2019A1515010902); the Science and Technology Program of Guangzhou (No. 201903010075); the National Key R&D Program of China (No. 2020YFB020003); and GD Frontier & Key Tech Innovation Program (Nos. 2018B030337001 and 2019B020228001). The authors have no other conflicts of interest to declare, (2022 Annals of Translational Medicine. All rights reserved.)

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling 1-4 . The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The G q -coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the G i/o -coupled DREADD (hM4Di) is utilized to inhibit neuronal activity 5 . Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniG q complex and a hM4Di-miniG o complex bound to deschloroclozapine; a hM3Dq-miniG q complex bound to clozapine-N-oxide; and a hM3R-miniG q complex bound to iperoxo. Complemented with mutagenesis, functional and computational simulation data, our structures reveal key details of the recognition of DREADD chemogenetic actuators and the molecular basis for activation. These findings should accelerate the structure-guided discovery of next-generation chemogenetic tools., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: On prostate biopsy, multiparametric magnetic resonance imaging (mpMRI) and the Prostate Health Index (PHI) have allowed prediction of clinically significant prostate cancer (csPCa)., Methods: To predict the likelihood of csPCa, we created a nomogram based on a multivariate model that included PHI and mpMRI. We assessed 315 males who were scheduled for prostate biopsies., Results: We used the Prostate Imaging Reporting and Data System version 2 (PI-RADS V2) to assess mpMRI and optimize PHI testing prior to biopsy. Univariate analysis showed that csPCa may be identified by PHI with a cut-off value of 77.77, PHID with 2.36, and PI-RADS with 3 as the best threshold. Multivariable logistic models for predicting csPCa were developed using PI-RADS, free PSA (fPSA), PHI, and prostate volume. A multivariate model that included PI-RADS, fPSA, PHI, and prostate volume had the best accuracy (AUC: 0.882). Decision curve analysis (DCA), which was carried out to verify the nomogram's clinical applicability, showed an ideal advantage (13.35% higher than the model that include PI-RADS only)., Discussion: In conclusion, the nomogram based on PHI and mpMRI is a valuable tool for predicting csPCa while avoiding unnecessary biopsy as much as possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mo, Zhang, Zheng, Huang, Zheng, Zhou and Wang.)

C-reactive protein (CRP) is a circulating marker of inflammation yet with ill-defined biological functions. This is partly due to the uncharacterized activities of endogenous CRP in mice, the major animal model used to define protein function. The hurdles for purification and characterization of mouse CRP are its low circulating levels and the lack of specific antibodies. To clear these hurdles, here we developed an efficient expression system by constructing recombinant Pichia pastoris cells for secretion of native conformation mouse CRP. The recombinant expression of mouse CRP in Escherichia coli failed to yield sufficient amount of native protein, reflecting the importance of post-translational modification of glycosylation in aiding proper folding. By contrast, sufficient amount of native mouse CRP was successfully purified from P. pastoris. Preliminary purification was performed by Nickel Chelating Sepharose Fast-Flow affinity chromatography with 6 × His tags attached to the protein. Subsequently, p-Aminophenyl Phosphoryl Choline Agarose resin affinity chromatography was used for tandem purification. The purified mouse CRP showed native pentamer and capabilities of PC binding. Moreover, the 6 × His tag provides a convenient tool for detecting the interactions of mouse CRP with ligands., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The protein encoded by dynein axonemal heavy chain 1 ( DNAH1 ) is a part of dynein, which regulates the function of cilia and sperm flagella. The mutant of DNAH1 causes the deletion of inner dynein arm 3 in the flagellum, leading to multiple morphological abnormalities of the sperm flagella (MMAF) and severe asthenozoospermia. However, instead of asthenozoospermia and MMAF, the result caused by the mutation of DNAH1 remains unknown. Here we report a male infertility patient with severe asthenozoospermia and teratozoospermia. We found two heterozygous mutations in DNAH1 (c.6912C>A and c.7076G>T) and which were reported to be associated with MMAF for the first time. We next collected and analyzed 65 cases of DNAH1 mutation and found that the proportion of short flagella is the largest, while the bent flagella account for the smallest, and the incidence of head deformity is not high in the sperm of these patients. Finally, we also analyzed 31 DNAH1 mutation patients who were treated with intracytoplasmic sperm injection (ICSI) and achieved beneficial outcomes. We hope our research will be helpful in the diagnosis and treatment of male infertility caused by DNAH1 mutation., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally 1-4 . Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization 5-7 . Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT 2A receptor (5-HT 2A R) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT 2A or the 5-HT 2B receptors. Structure-based optimization led to the 5-HT 2A R agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT 2A R agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT 2A R. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT 2A R agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α 2A -adrenergic receptor (α 2A AR), seeking new α 2A AR agonists chemotypes that lack the sedation conferred by known α 2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G i and G o signaling. Experimental structures of α 2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC 50 ) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

Background: Continuous contrast-enhanced ultrasound (CEUS) video is a challenging direction for radiomics research. We aimed to evaluate machine learning (ML) approaches with radiomics combined with the XGBoost model and a convolutional neural network (CNN) for discriminating between benign and malignant lesions in CEUS videos with a duration of more than 1 min., Methods: We gathered breast CEUS videos of 109 benign and 81 malignant tumors from two centers. Radiomics combined with the XGBoost model and a CNN was used to classify the breast lesions on the CEUS videos. The lesions were manually segmented by one radiologist. Radiomics combined with the XGBoost model was conducted with a variety of data sampling methods. The CNN used pretrained 3D residual network (ResNet) models with 18, 34, 50, and 101 layers. The machine interpretations were compared with prospective interpretations by two radiologists. Breast biopsies or pathological examinations were used as the reference standard. Areas under the receiver operating curves (AUCs) were used to compare the diagnostic performance of the models., Results: The CNN model achieved the best AUC of 0.84 on the test cohort with the 3D-ResNet-50 model. The radiomics model obtained AUCs between 0.65 and 0.75. Radiologists 1 and 2 had AUCs of 0.75 and 0.70, respectively., Conclusions: The 3D-ResNet-50 model was superior to the radiomics combined with the XGBoost model in classifying enhanced lesions as benign or malignant on CEUS videos. The CNN model was superior to the radiologists, and the radiomics model performance was close to the performance of the radiologists., Competing Interests: Author J-QZ was employed by XENIRO. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, He, Lin, Zhao, Jiang, Liang, Huang, Bao, Huang and Chen.)