Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

A second wave of topological phenomena in photonics and acoustics.

Light and sound are the most ubiquitous forms of waves, associated with a variety of phenomena and physical effects such as rainbows and echoes. Light and sound, both categorized as classical waves, have lately been brought into unexpected connections with exotic topological phases of matter. We are currently witnessing the onset of a second wave of active research into this topic. The past decade has been marked by fundamental advances comprising two-dimensional quantum Hall insulators and quantum spin and valley Hall insulators, whose topological properties are characterized using linear band topology. Here, going beyond these conventional topological systems, we focus on the latest frontiers, including non-Hermitian, nonlinear and non-Abelian topology as well as topological defects, for which the characterization of the topological features goes beyond the standard band-topology language. In addition to an overview of the current state of the art, we also survey future research directions for valuable applications.

Ultralow contact resistance between semimetal and monolayer semiconductors.

Advanced beyond-silicon electronic technology requires both channel materials and also ultralow-resistance contacts to be discovered1,2. Atomically thin two-dimensional semiconductors have great potential for realizing high-performance electronic devices1,3. However, owing to metal-induced gap states (MIGS)4-7, energy barriers at the metal-semiconductor interface-which fundamentally lead to high contact resistance and poor current-delivery capability-have constrained the improvement of two-dimensional semiconductor transistors so far2,8,9. Here we report ohmic contact between semimetallic bismuth and semiconducting monolayer transition metal dichalcogenides (TMDs) where the MIGS are sufficiently suppressed and degenerate states in the TMD are spontaneously formed in contact with bismuth. Through this approach, we achieve zero Schottky barrier height, a contact resistance of 123 ohm micrometres and an on-state current density of 1,135 microamps per micrometre on monolayer MoS2; these two values are, to the best of our knowledge, the lowest and highest yet recorded, respectively. We also demonstrate that excellent ohmic contacts can be formed on various monolayer semiconductors, including MoS2, WS2 and WSe2. Our reported contact resistances are a substantial improvement for two-dimensional semiconductors, and approach the quantum limit. This technology unveils the potential of high-performance monolayer transistors that are on par with state-of-the-art three-dimensional semiconductors, enabling further device downscaling and extending Moore's law.

Strain engineering and epitaxial stabilization of halide perovskites.

Strain engineering is a powerful tool with which to enhance semiconductor device performance1,2. Halide perovskites have shown great promise in device applications owing to their remarkable electronic and optoelectronic properties3-5. Although applying strain to halide perovskites has been frequently attempted, including using hydrostatic pressurization6-8, electrostriction9, annealing10-12, van der Waals force13, thermal expansion mismatch14, and heat-induced substrate phase transition15, the controllable and device-compatible strain engineering of halide perovskites by chemical epitaxy remains a challenge, owing to the absence of suitable lattice-mismatched epitaxial substrates. Here we report the strained epitaxial growth of halide perovskite single-crystal thin films on lattice-mismatched halide perovskite substrates. We investigated strain engineering of α-formamidinium lead iodide (α-FAPbI3) using both experimental techniques and theoretical calculations. By tailoring the substrate composition-and therefore its lattice parameter-a compressive strain as high as 2.4 per cent is applied to the epitaxial α-FAPbI3 thin film. We demonstrate that this strain effectively changes the crystal structure, reduces the bandgap and increases the hole mobility of α-FAPbI3. Strained epitaxy is also shown to have a substantial stabilization effect on the α-FAPbI3 phase owing to the synergistic effects of epitaxial stabilization and strain neutralization. As an example, strain engineering is applied to enhance the performance of an α-FAPbI3-based photodetector.

ß-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.

ß-hydroxybutyrate (ß-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether ß-HB alters the senescence pathway in vascular cells remains unknown. Here we report that ß-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of ß-HB. ß-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of ß-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that ß-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

Efficient and stable acidic CO2 electrolysis to formic acid by a reservoir structure design.

Electrochemical synthesis of valuable chemicals and feedstocks through carbon dioxide (CO2) reduction in acidic electrolytes can surmount the considerable CO2 loss in alkaline and neutral conditions. However, achieving high productivity, while operating steadily in acidic electrolytes, remains a big challenge owing to the severe competing hydrogen evolution reaction. Here, we show that vertically grown bismuth nanosheets on a gas-diffusion layer can create numerous cavities as electrolyte reservoirs, which confine in situ-generated hydroxide and potassium ions and limit inward proton diffusion, producing locally alkaline environments. Based on this design, we achieve formic acid Faradaic efficiency of 96.3% and partial current density of 471 mA cm-2 at pH 2. When operated in a slim continuous-flow electrolyzer, the system exhibits a full-cell formic acid energy efficiency of 40% and a single pass carbon efficiency of 79% and performs steadily over 50 h. We further demonstrate the production of pure formic acid aqueous solution with a concentration of 4.2 weight %.

Influence of glycan structure on the colonization of Streptococcus pneumoniae on human respiratory epithelial cells.

Virtually all living cells are encased in glycans. They perform key cellular functions such as immunomodulation and cell-cell recognition. Yet, how their composition and configuration affect their functions remains enigmatic. Here, we constructed isogenic capsule-switch mutants harboring 84 types of capsular polysaccharides (CPSs) in Streptococcus pneumoniae. This collection enables us to systematically measure the affinity of structurally related CPSs to primary human nasal and bronchial epithelial cells. Contrary to the paradigm, the surface charge does not appreciably affect epithelial cell binding. Factors that affect adhesion to respiratory cells include the number of rhamnose residues and the presence of human-like glycomotifs in CPS. Besides, pneumococcal colonization stimulated the production of interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractantprotein-1 (MCP-1) in nasal epithelial cells, which also appears to be dependent on the serotype. Together, our results reveal glycomotifs of surface polysaccharides that are likely to be important for colonization and survival in the human airway.

A social theory-enhanced graph representation learning framework for multitask prediction of drug-drug interactions.

Current machine learning-based methods have achieved inspiring predictions in the scenarios of mono-type and multi-type drug-drug interactions (DDIs), but they all ignore enhancive and depressive pharmacological changes triggered by DDIs. In addition, these pharmacological changes are asymmetric since the roles of two drugs in an interaction are different. More importantly, these pharmacological changes imply significant topological patterns among DDIs. To address the above issues, we first leverage Balance theory and Status theory in social networks to reveal the topological patterns among directed pharmacological DDIs, which are modeled as a signed and directed network. Then, we design a novel graph representation learning model named SGRL-DDI (social theory-enhanced graph representation learning for DDI) to realize the multitask prediction of DDIs. SGRL-DDI model can capture the task-joint information by integrating relation graph convolutional networks with Balance and Status patterns. Moreover, we utilize task-specific deep neural networks to perform two tasks, including the prediction of enhancive/depressive DDIs and the prediction of directed DDIs. Based on DDI entries collected from DrugBank, the superiority of our model is demonstrated by the comparison with other state-of-the-art methods. Furthermore, the ablation study verifies that Balance and Status patterns help characterize directed pharmacological DDIs, and that the joint of two tasks provides better DDI representations than individual tasks. Last, we demonstrate the practical effectiveness of our model by a version-dependent test, where 88.47 and 81.38% DDI out of newly added entries provided by the latest release of DrugBank are validated in two predicting tasks respectively.

Palladium/Platinum/Ruthenium Trimetallic Dendritic Nanozymes Exhibiting Enhanced Peroxidase-like Activity for Signal Amplification of Lateral Flow Immunoassays.

Developing ultrasensitive lateral flow immunoassays (LFIAs) has garnered significant attention in the field of point-of-care testing. In this study, a trimetallic dendritic nanozyme (Pd@Pt-Ru) was synthesized through Ru deposition on a Pd@Pt core and utilized to enhancing the sensitivity of LFIAs. Pd@Pt-Ru exhibited a Km value of 5.23 mM for detecting H2O2, which indicates an H2O2 affinity comparable with that of horseradish peroxidase. The Ru surface layer reduces the activation energy barrier, which increases the maximum reaction rate. As a proof of concept, the proposed Pd@Pt-Ru nanozyme was incorporated into LFIAs (A-Pd@Pt-Ru-LFIAs) for detecting human chorionic gonadotropin (hCG). Compared with conventional gold nanoparticle (AuNP)-LFIAs, A-Pd@Pt-Ru-LFIAs demonstrated 250-fold increased sensitivity, thereby enabling a visible detection limit as low as 0.1 IU/L. True positive and negative rates both reached 100%, which renders the proposed Pd@Pt-Ru nanozyme suitable for detecting hCG in clinical samples.

Atomic Defects Engineering Boosts Urea Synthesis toward Carbon Dioxide and Nitrate Coelectroreduction.

The atomic defect engineering could feasibly decorate the chemical behaviors of reaction intermediates to regulate catalytic performance. Herein, we created oxygen vacancies on the surface of In(OH)3 nanobelts for efficient urea electrosynthesis. When the oxygen vacancies were constructed on the surface of the In(OH)3 nanobelts, the faradaic efficiency for urea reached 80.1%, which is 2.9 times higher than that (20.7%) of the pristine In(OH)3 nanobelts. At -0.8 V versus reversible hydrogen electrode, In(OH)3 nanobelts with abundant oxygen vacancies exhibited partial current density for urea of -18.8 mA cm-2. Such a value represents the highest activity for urea electrosynthesis among recent reports. Density functional theory calculations suggested that the unsaturated In sites adjacent to oxygen defects helped to optimize the adsorbed configurations of key intermediates, promoting both the C-N coupling and the activation of the adsorbed CO2NH2 intermediate. In-situ spectroscopy measurements further validated the promotional effect of the oxygen vacancies on urea electrosynthesis.

Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial.

BACKGROUND: Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. METHODS: PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. FINDINGS: Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. INTERPRETATION: Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. FUNDING: National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Excitatory Projections from the Prefrontal Cortex to Nucleus Accumbens Core D1-MSNs and κ Opioid Receptor Modulate Itch-Related Scratching Behaviors.

Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.

Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec-/-), in monocrotaline-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats in vivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH.

Nitrogen-Mediated Promotion of Cobalt-Based Oxygen Evolution Catalyst for Practical Anion-Exchange Membrane Electrolysis.

Scarce and expensive iridium oxide is still the cornerstone catalyst of polymer-electrolyte membrane electrolyzers for green hydrogen production because of its exceptional stability under industrially relevant oxygen evolution reaction (OER) conditions. Earth-abundant transition metal oxides used for this task, however, show poor long-term stability. We demonstrate here the use of nitrogen-doped cobalt oxide as an effective iridium substitute. The catalyst exhibits a low overpotential of 240 mV at 10 mA cm-2 and negligible activity decay after 1000 h of operation in an alkaline electrolyte. Incorporation of nitrogen dopants not only triggers the OER mechanism switched from the traditional adsorbate evolution route to the lattice oxygen oxidation route but also achieves oxygen nonbonding (ONB) states as electron donors, thereby preventing structural destabilization. In a practical anion-exchange membrane water electrolyzer, this catalyst at anode delivers a current density of 1000 mA cm-2 at 1.78 V and an electrical efficiency of 47.8 kW-hours per kilogram hydrogen.

Low Levels of IgM Recognizing 4-Hydroxy-2-Nonenal-Modified Apolipoprotein A-I Peptide and Its Association with the Severity of Coronary Artery Disease in Taiwanese Patients.

Autoantibodies against apolipoprotein A-I (ApoA-I) are associated with cardiovascular disease risks. We aimed to examine the 4-hydroxy-2-nonenal (HNE) modification of ApoA-I in coronary artery disease (CAD) and evaluate the potential risk of autoantibodies against their unmodified and HNE-modified peptides. We assessed plasma levels of ApoA-I, HNE-protein adducts, and autoantibodies against unmodified and HNE-peptide adducts, and significant correlations and odds ratios (ORs) were examined. Two novel CAD-specific HNE-peptide adducts, ApoA-I251-262 and ApoA-I70-83, were identified. Notably, immunoglobulin G (IgG) anti-ApoA-I251-262 HNE, IgM anti-ApoA-I70-83 HNE, IgG anti-ApoA-I251-262, IgG anti-ApoA-I70-83, and HNE-protein adducts were significantly correlated with triglycerides, creatinine, or high-density lipoprotein in CAD with various degrees of stenosis (<30% or >70%). The HNE-protein adduct (OR = 2.208-fold, p = 0.020) and IgM anti-ApoA-I251-262 HNE (2.046-fold, p = 0.035) showed an increased risk of progression from >30% stenosis in CAD. HNE-protein adducts and IgM anti-ApoA-I251-262 HNE may increase the severity of CAD at high and low levels, respectively.

Secondary analysis of late major gastrointestinal and genitourinary toxicities in unfavorable-risk prostate cancer patients receiving docetaxel: Insights from a randomized trial.

BACKGROUND: This study sought to evaluate the late toxicity associated with neoadjuvant and concurrent docetaxel and radiation therapy in patients with prostate cancer. METHODS: A secondary analysis was performed of the phase 3 multicenter randomized trial (Dana-Farber Cancer Institute 05-043) including 350 patients with nonmetastatic unfavorable-risk prostate cancer. Patients were randomized 1:1 to receive androgen deprivation therapy, radiation therapy, and docetaxel versus androgen deprivation therapy and radiation therapy. The study assessed the cumulative incidence rates of grade 2 and grade 3 or higher gastrointestinal, genitourinary, and sexual toxicity. A multivariable Fine and Gray's competing risks regression model adjusted for age at randomization and pelvic lymph node radiation therapy was used to evaluate the treatment effect of docetaxel on time to late genitourinary and gastrointestinal toxicities. RESULTS: The study included 338 patients who primarily had minimal or no comorbidity (74.9%) and median age 66 years (interquartile range: 61,71). At a median follow-up of 10.2 years, docetaxel was not associated with increased risk of any grade 3 or higher (adjusted hazard ratio [AHR], 0.98; 95% confidence interval [CI], 0.36-2.67; p = .96) or grade 2 gastrointestinal (p = .75), genitourinary (p = .44), and sexual (p = .29) toxicity. Age was associated with increased grade 3 or higher (AHR, 1.08; 95% CI, 1.01-1.16; p = .03) and grade 2 gastrointestinal toxicity (AHR, 1.11; 95% CI, 1.03-1.20; p = .005). A nonsignificant trend (p = .09) toward increased late grade 3 or higher toxicity was observed for pelvic radiation therapy use. CONCLUSIONS: Docetaxel combined with radiotherapy has an acceptable long-term toxicity profile.

The anti-mCRP199-206 antibodies aggravate tubulointerstitial lesions in lupus nephritis.

Tubulointerstitial lesions could also be prominent in lupus nephritis, and the pathogenesis of tubulointerstitial lesions may be different from glomerular lesions. Previous studies have showed that plasma antibodies against modified /monomeric C-reactive protein (mCRP) are associated with renal tubulointerstitial lesions in patients with lupus nephritis, and amino acid (aa) 199-206 was one of the major epitopes of mCRP. However, the role of anti-mCRP199-206 antibodies in the pathogenesis of tubulointerstitial lesions in lupus nephritis is unknown. A total of 95 patients with renal biopsy-proven lupus nephritis were enrolled in this study. Plasma levels of anti-mCRP199-206 antibodies were screened by enzyme-linked immunosorbent assay (ELISA). A lupus prone mouse model was immunized using peptides mCRP199-206 to explore the potential role of anti-mCRP199-206 antibodies in tubulointerstitial lesions. The mechanism of anti-mCRP199-206 antibodies damage to renal tubular epithelial cells was investigated in vitro. Plasma antibodies against mCRP199-206 were associated with renal tubulointerstitial lesions and prognosis in patients with lupus nephritis. Immunization with peptides mCRP199-206 in lupus prone mice could aggravate tubulointerstitial lesions and drive tubulointerstitial inflammation and fibrosis. Anti-mCRP 199-206 antibodies could activate the TGF-ß1/Smad3 signal pathway and induce tubular damage by binding with CRP. Circulating antibodies against mCRP199-206 could be a biomarker to reveal tubulointerstitial lesion, and participate in the pathogenesis of tubulointerstitial lesions, which might provide a potential therapeutic target for lupus nephritis.

Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

Involvement of IL-17 A/IL-17 Receptor A with Neutrophil Recruitment and the Severity of Coronary Arteritis in Kawasaki Disease.

PURPOSE: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA). METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected. RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots. CONCLUSION: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.