High-enhancement photoluminescence of monolayer MoS2 in hybrid plasmonic systems.

Monolayer molybdenum disulfide (M o S 2) has a weak light-matter interaction due to ultrathin thickness, which limits its potential application in lasing action. In this study, we propose a hybrid structure consisting of a nanocavity and Au nanoparticles to enhance the photon emission efficiency of monolayer M o S 2. Numerical simulations show that photoluminescence (PL) emission is significantly enhanced by introducing localized surface plasmon resonance (LSPR) to the proposed structure. Furthermore, an exciton energy band system is proposed to elucidate the physical mechanism of the PL process. By optimizing the spacer thickness, a high Purcell enhancement factor of 95 can be achieved. The results provided by this work pave the way to improve the PL efficiency of two-dimensional (2D) material, which constitutes a significant step towards the development of nanodevices such as nanolasers and sensors.

Double Perovskite Single Crystals with High Laser Irradiation Stability for Solid-State Laser Lighting and Anti-counterfeiting.

Laser lighting devices, comprising an ultraviolet (UV) laser chip and a phosphor material, have emerged as a highly efficient approach for generating high-brightness light sources. However, the high power density of laser excitation may exacerbate thermal quenching in conventional polycrystalline or amorphous phosphors, leading to luminous saturation and the eventual failure of the device. Here, for the first time, we raise a single-crystal (SCs) material for laser lighting considering the absence of grain boundaries that scatter electrons and phonons, achieving high thermal conductivity (0.81 W m-1 K-1) and heat-resistance (575 °C). The SCs products exhibit a high photoluminescence quantum yield (89%) as well as excellent stability toward high-power lasers (>12.41 kW/cm2), superior to all previously reported amorphous or polycrystalline matrices. Finally, the laser lighting device was fabricated by assembling the SC with a UV laser chip (50 mW), and the device can maintain its performance even after continuous operation for 4 h. Double perovskite single crystals doped with Yb3+/Er3+ demonstrated multimodal luminescence with the irradiation of 355 and 980 nm lasers, respectively. This characteristic holds significant promise for applications in spectrally tunable laser lighting and multimodal anticounterfeiting.

Comparison of early postoperative pulmonary complications between two-lung ventilation with artificial pneumothorax and one-lung ventilation with bronchial blockade in patients undergoing minimally invasive esophagectomy: a retrospective propensity score-matched cohort study.

Background: Two-lung ventilation (TLV) with artificial carbon dioxide (CO2) pneumothorax is used during the thoracoscopic phase of minimally invasive esophagectomy (MIE). However, the impact of TLV with artificial pneumothorax on postoperative pulmonary complications (PPCs) after MIE is unclear. This study aimed to compare the incidence of early PPCs between TLV with CO2 pneumothorax and one-lung ventilation (OLV) with bronchial blockade in patients undergoing MIE. Methods: Five hundred ninety-three patients with esophageal cancer who underwent elective MIE with two-field lymph node dissection were analyzed. Patients in the TLV group were intubated using a single-lumen endotracheal tube and underwent surgery using TLV with artificial CO2 pneumothorax. Patients in the OLV group underwent surgery using OLV with a bronchial blocker. Patient characteristics and intraoperative and PPC data were collected and analyzed. Propensity score matching (PSM) was performed to reduce confounding bias. Results: The TLV and OLV group comprised 513 and 80 patients, respectively. PSM matched 197 TLV group and 73 OLV group patients. Incidence of pneumonia within the first 3 days of surgery was higher in the TLV group (11.7% vs. 4.1%) but the difference was not significant (P=0.06). The incidence of infiltrates on chest radiography was 36.0% in the TLV group and 28.8% in the OLV group (P=0.26). Incidence of other major PPCs requiring treatment and major non-pulmonary postoperative complications did not significantly differ between the groups. Length of hospital stay was significantly longer in the TLV group (13.0 vs. 11.0 days; P=0.03). Conclusions: Compared with OLV with bronchial blockade, TLV with CO2 pneumothorax did not reduce the incidence of early PPCs after MIE.

Chiral Iridium-Based TLD-1433 Analogues: Exploration of Enantiomer-Dependent Behavior in Photodynamic Cancer Therapy.

Metallodrug-based photodynamic therapy (PDT) agents have demonstrated significant superiority against cancers, while their different chirality-induced biological activities remain largely unexplored. In this work, we successfully developed a pair of enantiopure mononuclear Ir(III)-based TLD-1433 analogues, Δ-Ir-3T and Λ-Ir-3T, and their enantiomer-dependent anticancer behaviors were investigated. Photophysical measurements revealed that they display high photostability and chemical stability, strong absorption at 400 nm with high molar extinction coefficients (ε = 5.03 × 104 M-1 cm-1), and good 1O2 relative quantum yields (ΦΔ ≈ 47%). Δ- and Λ-Ir-3T showed potent efficacy against MCF-7 cancer cells, with a photocytotoxicity index of ≤44 238. This impressive result, to the best of our knowledge, represents the highest value among reported mononuclear Ir(III)-based PDT agents. Remarkably, Λ-Ir-3T tended to be more potent than Δ-Ir-3T when tested against SK-MEL-28, HepG2, and LO2 cells, with consistent results across multiple test repetitions.

Resveratrol ameliorates ulcerative colitis by upregulating Nrf2/HO­1 pathway activity: Integrating animal experiments and network pharmacology.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory condition affecting the rectum and colon. Inflammation and compromisation of the intestinal mucosal barrier are key in UC pathogenesis. Resveratrol (Res) is a naturally occurring polyphenol that exhibits anti­inflammatory and antioxidant properties. Nuclear factor erythroid­2­related factor 2/heme oxygenase 1 (Nrf2/HO­1) pathway regulates occurrence and development of numerous types of diseases through anti­inflammatory and antioxidant activity. However, it is not clear whether Nrf2/HO­1 pathway is involved in the treatment of Res in UC. Therefore, the present study aimed to investigate whether Res modulates the Nrf2/HO­1 signaling pathway to attenuate UC in mice. Dextran sulfate sodium (DSS) was used to induce experimental UC in male C57BL/6J mice. Disease activity index (DAI) and hematoxylin eosin (H&E) staning was used to assessed the magnitude of colonic lesions in UC mice. ELISA) was utilized to quantify inflammatory cytokines (IL­6, IL­1ß, TNF­α and IL­10) in serum and colon tissues. Immunohistochemistry and Western blot were used to evaluate the expression levels of tight junction (TJ) proteins [zonula occludens (ZO)­1 and Occludin] in colon tissues. Pharmacokinetic (PK) parameters of Res were derived from TCMSP database. Networkpharmacology was employed to identify the biological function and pharmacological mechanism of Res in the process of relieving UC, and the key target was screened. The binding ability of Res and key target was verified by molecular docking. Finally, the effectiveness of key target was substantiated by Western blot. Res decreased DAI, ameliorated histopathological changes such as crypt loss, disappeatance of the mucosal epithelium, and inflammatory infiltration in mice. Additionally, Res decreased expression of pro­inflammatory cytokines IL­6, IL­1ß and TNF­α and increased anti­inflammatory factor IL­10 expression. Res also restored the decreased protein expression of ZO­1 and occludin after DSS treatment, increasing the integrity of the intestinal mucosal barrier. The PK properties of Res suggested that Res possesses the therapeutic potential for oral administration. Network pharmacology revealed that Res alleviated UC through anti­inflammatory and antioxidant pathways, and confirmed that Nrf2 has a high binding affinity with Res and is a key target of Res against UC. Western blotting demonstrated that Res treatment increased the protein levels of Nrf2 and HO­1. In conclusion, Res treatment activated the Nrf2/HO­1 pathway to decrease clinical symptoms, inflammatory responses, and intestinal mucosal barrier damage in experimental UC mice.

Improving the predictive accuracy of efficacy evaluation using tumor orthotopic transplant and resection model.

Preclinical efficacy evaluation and tumor drug sensitivity analysis are two main applications of efficacy evaluation. Preclinical efficacy evaluation is to predict whether candidate drugs or therapies may improve patient outcomes in clinical trials. Tumor drug sensitivity analysis is an approach for the personalized evaluation and optimization of approved anti-cancer drugs and treatment regimens. Overall survival (OS) is the gold standard to evaluate the outcome of drugs or therapies in both clinical trials and clinical treatment. Many efficacy evaluation models, such as cell model, tumor cell-line transplant model, patient-derived tumor xenograft model, tumor organoid model, have been developed to assess the inhibitory effect of tested drugs or therapies on tumor growth. In fact, many treatments may also lead to malignant progression of tumors, such as chemotherapy, which can lead to metastasis. Therefore, tumor growth inhibition does not necessarily predict OS benefit. Whether it can prevent or inhibit tumor recurrence and metastasis is the key to whether drugs and therapies can improve patient outcomes. In this perspective, we summarize the current understanding of the pathological progression of tumor recurrence and metastasis, point out the shortcomings of existing tumor transplant models for simulating the clinical scenario of malignant progression of tumors, and propose five improved indicators for comprehensive efficacy evaluation to predict OS benefit using tumor orthotopic transplant and resection model. Improvement in the accuracy of efficacy evaluation will accelerate the development process of anti-cancer drugs or therapies, optimize treatment regimens to improve OS benefit, and reduce drug development and cancer treatment costs.

Resveratrol attenuates intestinal epithelial barrier dysfunction via Nrf2/HO-1 pathway in dextran sulfate sodium-induced Caco-2 cells.

INTRODUCTION: The intestinal tract serves as an innate barrier, safeguarding the internal milieu from microorganisms and toxins. Various intestinal inflammatory diseases have a strong association with intestinal barrier dysfunction. The primary functional cells within the intestinal tract, intestinal epithelial cells (IECs) and their tight junctions (TJs), are crucial in preserving the integrity of this mechanical barrier. Resveratrol (Res), a plant-derived phenolic compound, exhibits a range of health-promoting benefits attributed to its anti-inflammatory properties. This study aims to examine Res's efficacy in bolstering IECs barrier function. METHODS: Dextran sulfate sodium (DSS) was employed to induce barrier dysfunction in IECs. Inflammatory cytokines in supernatants (interleukin [IL]-6, IL-1ß, tumor necrotic factor [TNF]-α, and IL-10) were quantified via enzyme-linked immunosorbent assay (ELISA). Then we assessed monolayer integrity using transepithelial electrical resistance (TEER). TJ protein expression (zonula occludens [ZO]-1 and Occludin) in IECs was evaluated through immunofluorescence and Western blot analysis. Network pharmacology helped identify the biological processes, signaling pathways, and key targets involved in Res's mitigation of DSS-induced IECs barrier dysfunction. The efficacy of the primary target was further corroborated using Western blot. RESULTS: Res was shown to increase cell viability and IL-10 expression while reducing TNF-α, IL-6, and IL-1ß levels, thus mitigating the inflammatory response. It enhanced TEER values and upregulated TJ protein expression (ZO-1 and Occludin). Network pharmacology revealed that Res potentially targets the NFE2L2 (nuclear factor erythroid-2-related factor 2, Nrf2), a vital antioxidant factor. Significantly, Res augmented Nrf2 and heme oxygenase 1 (HO-1) protein levels, counteracting oxidative stress in the IECs barrier dysfunction model. CONCLUSION: Overall, our findings suggested that Res ameliorated DSS-induced IECs barrier dysfunction by activating Nrf2/HO-1 pathway, showcasing significant therapeutic potential in the early stages of colitis.

Preparation, stability and controlled release properties of starch-based micelles for oral delivery of hydrophobic bioactive molecules.

Amphiphilic starches incorporating fatty acid ester chains of varying lengths and degrees of substitution (DS) were synthesized to fabricate starch-based micelles for oral delivery of hydrophobic bioactive molecules. The assembly of the amphiphilic starches is influenced by the concentration, temperature, and the chain length and DS of their fatty acid ester chain. Highly acidic environment can hydrolyze the amphiphilic starches, resulting in the formation of small-sized micelles. Conversely, high ionic concentration hinders the self-assembly of amphiphilic starches and the digestive fluids can dilute the amphiphilic starches concentration, leading to the micelle dissociation. However, amphiphilic starches with longer chain length and/or higher DS of the fatty acid ester chain possess greater hydrophobicity, enhancing the stability of starch-based micelles under varying conditions and favouring the protection of Trp-2 peptides during storage. The micelles demonstrate high cell bioaccessibility for Trp-2 peptides, with 59.25 % of Trp-2 peptides being transferred by the intestinal epithelium. These findings suggest a potential starch-based micelle system can be adjusted for the oral delivery of hydrophobic bioactive molecules.

Perioperative Risk Factors for Postoperative Pulmonary Complications After Minimally Invasive Esophagectomy.

Background: Postoperative pulmonary complications (PPCs) are the most prevalent complication after esophagectomy and are associated with a worse prognosis. This study aimed to investigate the perioperative risk factors for PPCs after minimally invasive esophagectomy (MIE). Methods: Seven hundred and sixty-seven consecutive patients who underwent McKeown MIE via thoracoscopy and laparoscopy were retrospectively studied. Patient characteristics, perioperative data, and postoperative complications were analyzed. Results: The incidence of PPCs after MIE was 25.2% (193/767). Univariate analysis identified age (odds ratio [OR] 1.022, P = 0.044), male sex (OR 2.955, P < 0.001), pulmonary comorbidities (OR 1.746, P = 0.032), chronic obstructive pulmonary disease (COPD) (OR 2.821, P = 0.003), former smoking status (OR 1.880, P = 0.001), postoperative albumin concentration (OR 0.941, P = 0.007), postoperative creatinine concentration (OR 1.011, P = 0.019), and perioperative transfusion (OR 2.250, P = 0.001) as risk factors for PPCs. In multivariate analysis, the independent risk factors for PPCs were male sex (OR 3.135, P < 0.001), body mass index (BMI) (OR 1.088, P = 0.002), COPD (OR 2.480, P = 0.012), neoadjuvant chemoradiotherapy (OR 2.057, P = 0.035), postoperative albumin concentration (OR 0.929, P = 0.002), and perioperative transfusion (OR 1.939, P = 0.013). The area under the receiver operating characteristic curve for the predictive model generated by multivariate logistic regression analysis was 0.671 (95% confidence interval 0.628-0.713). Conclusions: Male sex, BMI, COPD, neoadjuvant chemoradiotherapy, postoperative albumin concentration, and perioperative transfusion were independent predictors of PPCs after MIE.

High-performance MoS2phototransistors with Hf1-xAlxO back-gate dielectric layer grown by plasma enhanced atomic layer deposition.

Molybdenum sulfide (MoS2) as an emerging optoelectronic material, shows great potential for phototransistors owing to its atomic thickness, adjustable band gap, and low cost. However, the phototransistors based on MoS2have been shown to have some issues such as large gate leakage current, and interfacial scattering, resulting in suboptimal optoelectronic performance. Thus, Al-doped hafnium oxide (Hf1-xAlx) is proposed to be a dielectric layer of the MoS2-based phototransistor to solve this problem because of the relatively higher crystallization temperature and dielectric constant. Here, a high-performance MoS2phototransistor with Hf1-xAlxO gate dielectric layer grown by plasma-enhanced atomic layer deposition has been fabricated and studied. The results show that the phototransistor exhibits a high responsivity of 2.2 × 104A W-1, a large detectivity of 1.7 × 1017Jones, a great photo-to-dark current ratio of 2.2 × 106%, and a high external quantum efficiency of 4.4 × 106%. The energy band alignment and operating mechanism were further used to clarify the reason for the enhanced MoS2phototransistor. The suggested MoS2phototransistors could provide promising strategies in further optoelectronic applications.

For the penile length-how shall we choose the straightening procedures in hypospadias repair?

OBJECTIVE: To define the appropriate penile straightening procedures corresponding to the specific penile curvature by comparing the penile length resulting from various straightening procedures in hypospadias repair. METHODS: We retrospectively analyzed hypospadias patients between 2017 and 2019. Patients were divided into three groups based on the penile curvature after degloving: <30°, 30°-45°, and >45°. The penile straightening procedures include dorsal plication (DP), simple urethral plate (UP) transection, and UP transection with ventral lengthening (VL). The paired t-test was conducted for the penile length after fully straightening in each group, simultaneously calculating the length changes (∆T). In addition, the penile length changes among these procedures were compared using Spearman analysis to show the correlation between the penile curvature and the length. RESULTS: The penile length changed significantly after fully straightening in all groups. The length decreased mildly after DP, while increased in the other procedures. The penile curvature after degloving was positively correlated with the absolute change in the penile length (P < 0.001, r = 0.424) and the ratio of ∆T in the original length (P < 0.001, r = 0.433). CONCLUSION: For hypospadias, the 30° after degloving may serve as the cut-off for the selection of the straightening method from the perspective of the penile length. For those with < 30°, methods such as DP or UP transection can either be selected. In patients with > 30°, DP should be used with caution because of the potential risk to shorten the penis. In contrast, UP transection effectively corrects the penile curvature and increases the penile length concurrently, which should be primarily recommended in those patients.

Understanding synchronous regulating effects of starch-protein interactions on starch digestion and retrogradation under thermal shear processing.

Although starch-protein interactions have been widely used to regulate starch digestibility and retrogradation during food processings, their synchronous regulating effects on both properties still remain largely unexplored. The effects of interactions with pea protein (PP) under thermal shear processing on the digestion and retrogradation properties of modified chestnut starch were investigated. Results show that thermal shear processing broke starch multi-scale structure, leading to the reduction in molar mass, short-range ordered structure, crystallinity, and starch compactness, in turn increasing starch digestibility and accelerating starch retrogradation. However, PP molecules would interact with chestnut starch through hydrogen bonding to form the starch-protein complexes during thermal shear processing, which caused an increased resistant starch. These starch-protein interactions also inhibited the formation of short-range, long-range ordered structure, aggregate structure during storage, causing a reduced degree of retrogradation. The results provided new insights into the synchronously regulating effects of starch-protein interactions under thermal shear processing on starch digestion and retrogradation, which would facilitate the development of starch-based foods with high nutrition and quality.

Structural changes of layer-by-layer self-assembled starch-based nanocapsules in the gastrointestinal tract: Implications for their M cell-targeting delivery and transport efficiency.

Characterizing the structural changes of cell-targeting delivery carriers in gastrointestinal tract (GIT) is crucial for understanding their effectiveness in cell targeting and transport. Herein, RGD peptide-grafted carboxymethyl starch (CMS) and cationic quaternary ammonium starch (QAS) were utilized to fabricate quintet-layered nanocapsules loaded with ovalbumin (OVA). The aim was to improve delivery and transportation efficiency, specifically targeting M cells. The research analyzed the impact of pH and enzyme variations in GIT on the structure of nanocapsules, interactions between carriers and the release behavior of OVA. Results showed that the size of nanocapsules increased from 229.2 to 479.8 nm and the zeta potential decreased from -1.08 to -33.33 mV during oral delivery. This was evident in TEM images, showing a more relaxed core-shell structure. Isothermal titration calorimetry and molecular dynamic simulation indicated that pH changes primarily affected the electrostatic interaction between carriers. Increasing pH led to reduced affinity constants, and around 84.42 % of OVA was successfully delivered to M cells. Moreover, the transport efficiency of nanocapsules to M cells was five times greater than that of Caco-2 cells. This suggests the feasibility of developing a nanocapsules delivery system capable of adapting to pH changes in GIT by regulating electrostatic interactions between carriers.

Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results.

Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the ß-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4-15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 1013 vector genome copies kg-1 (Cohort 1, n = 3) or 7.41 × 1013 vector gene copies kg-1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259 .

Cross-Sectional and Longitudinal Associations of Comorbidities with Knee Symptoms and Radiographic Abnormalities of Osteoarthritis.

INTRODUCTION: This study aimed to investigate the associations of comorbidities with knee symptoms and radiographic abnormalities of osteoarthritis (OA). METHODS: Participants were from the Osteoarthritis Initiative. Comorbidities were identified at baseline using the modified Charlson Comorbidity Index. For both knees, symptoms were assessed annually from baseline to 48 months using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores (rescaled range 0-100), and radiographic abnormalities using the Kellgren-Lawrence (KL, 0-4) grades. The presence of significant pain and functional disability was defined as a WOMAC score of ≥ 25 and ≥ 22, respectively, and radiographic OA (ROA) as KL ≥ 2. An increase of ≥ 9 in WOMAC scores and ≥ 1 in KL grades were defined as symptomatic and radiographic progression, respectively. RESULTS: Of 3337 participants, 28% and 9% had one and ≥ 2 comorbidities, respectively. The number of comorbidities was associated with the presence of significant functional disability (odds ratios [ORs] 1.15; 1.46) and predicted the progression of both knee pain and functional disability (ORs 1.11; 1.51). For the type of comorbidities, non-OA musculoskeletal diseases were associated with the presence of ROA and significant functional disability (ORs 1.63; 1.82) and showed a trend to predict incident ROA (OR 1.84, 95% confidence interval 1.00-3.38 p = 0.051). Diabetes and kidney diseases were associated with symptomatic progression of OA (ORs 1.38; 2.72). CONCLUSIONS: Having more comorbidities, especially diabetes and kidney diseases, is associated with symptomatic progression of knee OA. Moreover, non-OA musculoskeletal diseases may be associated with the presence and onset of ROA.

Rhodium(I)-Catalyzed Asymmetric Hydroarylative Cyclization of 1,6-Diynes to Access Atropisomerically Labile Chiral Dienes.

Axially chiral open-chained olefins are an underexplored class of atropisomers, whose enantioselective synthesis represents a daunting challenge due to their relatively low racemization barrier. We herein report rhodium(I)-catalyzed hydroarylative cyclization of 1,6-diynes with three distinct classes of arenes, enabling highly enantioselective synthesis of a broad range of axially chiral 1,3-dienes that are conformationally labile (ΔG≠ (rac)=26.6-28.0 kcal/mol). The coupling reactions in each category proceeded with excellent enantioselectivity, regioselectivity, and Z/E selectivity under mild reaction conditions. Computational studies of the coupling of quinoline N-oxide system reveal that the reaction proceeds via initial oxidative cyclization of the 1,6-diyne to give a rhodacyclic intermediate, followed by σ-bond metathesis between the arene C-H bond and the Rh-C(vinyl) bond, with subsequent C-C reductive elimination being enantio-determining and turnover-limiting. The DFT-established mechanism is consistent with the experimental studies. The coupled products of quinoline N-oxides undergo facile visible light-induced intramolecular oxygen-atom transfer, affording chiral epoxides with complete axial-to-central chirality transfer.

Rhodium-Catalyzed Enantioselective Formal [4+1] Cyclization of Benzyl Alcohols and Benzaldimines: Facile Access to Silicon-Stereogenic Heterocycles.

The carbon-to-silicon switch in formation of bioactive sila-heterocycles with a silicon-stereogenic center has garnered significant interest in drug discovery. However, metal-catalyzed synthesis of such scaffolds is still in its infancy. Herein, a rhodium-catalyzed enantioselective formal [4+1] cyclization of benzyl alcohols and benzaldimines has been realized by enantioselective difunctionalization of a secondary silane reagent, affording chiral-at-silicon cyclic silyl ethers and sila-isoindolines, respectively. Mechanistic studies reveal a dual role of the rhodium-hydride catalyst. The coupling system proceeds via rhodium-catalyzed enantio-determining dehydrogenative OH silylation of the benzyl alcohol or hydrosilylation of the imine to give an enantioenriched silyl ether or silazane intermediate, respectively. The same rhodium catalyst also enables subsequent intramolecular cyclative C-H silylation directed by the pendent Si-H group. Experimental and DFT studies have been conducted to explore the mechanism of the OH bond silylation of benzyl alcohol, where the Si-O reductive elimination from a Rh(III) hydride intermediate has been established as the enantiodetermining step.

Piperine improves levodopa availability in the 6-OHDA-lesioned rat model of Parkinson's disease by suppressing gut bacterial tyrosine decarboxylase.

AIM: Tyrosine decarboxylase (TDC) presented in the gut-associated strain Enterococcus faecalis can convert levodopa (L-dopa) into dopamine (DA), and its increased abundance would potentially minimize the availability and efficacy of L-dopa. However, the known human decarboxylase inhibitors are ineffective in this bacteria-mediated conversion. This study aims to investigate the inhibition of piperine (PIP) on L-dopa bacterial metabolism and evaluates the synergistic effect of PIP combined with L-dopa on Parkinson's disease (PD). METHODS: Metagenomics sequencing was adopted to determine the regulation of PIP on rat intestinal microbiota structure, especially on the relative abundance of E. faecalis. Then, the inhibitory effects of PIP on L-dopa conversion and TDC expression of E. faecalis were tested in vitro. We examined the synergetic effect of the combination of L-dopa and PIP on 6-hydroxydopamine (6-OHDA)-lesioned rats and tested the regulations of L-dopa bioavailability and brain DA level by pharmacokinetics study and MALDI-MS imaging. Finally, we evaluated the microbiota-dependent improvement effect of PIP on L-dopa availability using pseudo-germ-free and E. faecalis-transplanted rats. RESULTS: We found that PIP combined with L-dopa could better ameliorate the move disorders of 6-OHDA-lesioned rats by remarkably improving L-dopa availability and brain DA level than L-dopa alone, which was associated with the effect of PIP on suppressing the bacterial decarboxylation of L-dopa via effectively downregulating the abnormal high abundances of E. faecalis and TDC in 6-OHDA-lesioned rats. CONCLUSION: Oral administration of L-dopa combined with PIP can improve L-dopa availability and brain DA level in 6-OHDA-lesioned rats by suppressing intestinal bacterial TDC.

Electronic Structure and Reactivity of Mononuclear Nonheme Iron-Peroxo Complexes as a Biomimetic Model of Rieske Oxygenases: Ring Size Effects of Macrocyclic Ligands.

We report the macrocyclic ring size-electronic structure-electrophilic reactivity correlation of mononuclear nonheme iron(III)-peroxo complexes bearing N-tetramethylated cyclam analogues (n-TMC), [FeIII(O2)(12-TMC)]+ (1), [FeIII(O2)(13-TMC)]+ (2), and [FeIII(O2)(14-TMC)]+ (3), as a model study of Rieske oxygenases. The Fe(III)-peroxo complexes show the same δ and pseudo-σ bonds between iron and the peroxo ligand. However, the strength of these interactions varies depending on the ring size of the n-TMC ligands; the overall Fe-O bond strength and the strength of the Fe-O2 δ bond increase gradually as the ring size of the n-TMC ligands becomes smaller, such as from 14-TMC to 13-TMC to 12-TMC. MCD spectroscopy plays a key role in assigning the characteristic low-energy δ → δ* LMCT band, which provides direct insight into the strength of the Fe-O2 δ bond and which, in turn, is correlated with the superoxo character of the iron-peroxo group. In oxidation reactions, reactivities of 1-3 toward hydrocarbon C-H bond activation are compared, revealing the reactivity order of 1 > 2 > 3; the [FeIII(O2)(n-TMC)]+ complex with a smaller n-TMC ring size, 12-TMC, is much more reactive than that with a larger n-TMC ring size, 14-TMC. DFT analysis shows that the Fe(III)-peroxo complex is not reactive toward C-H bonds, but it is the end-on Fe(II)-superoxo valence tautomer that is responsible for the observed reactivity. The hydrogen atom abstraction (HAA) reactivity of these intermediates is correlated with the overall donicity of the n-TMC ligand, which modulates the energy of the singly occupied π* superoxo frontier orbital that serves as the electron acceptor in the HAA reaction. The implications of these results for the mechanism of Rieske oxygenases are further discussed.

EFNB1 levels determine distinct drug response patterns guiding precision therapy for B-cell neoplasms.

The multi-omics data has greatly improved the molecular diagnosis of B-cell neoplasms, but there is still a lack of predictive biomarkers to guide precision therapy. Here, we analyzed publicly available data and found that B-cell neoplasm cell lines with different levels of EFNB1 had distinctive drug response patterns of inhibitors targeting SRC/PI3K/AKT. Overexpression of EFNB1 promoted phosphorylation of key proteins in drug response, such as SRC and STMN1, conferring sensitivity to SRC inhibitor and cytotoxic drugs. EFNB1 phosphorylation signaling network was significantly associated with the prognosis of GCB-DLBCL patients. Moreover, EFNB1 levels were correlated with cell of origin (COO) scores, suggesting that EFNB1 is a quantitative indicator of cell differentiation. Ultimately, we proposed a model for the stratification of human B-cell malignancies and the implementation of targeted therapies based on EFNB1 levels. Our findings highlight that EFNB1 level is a promising biomarker for predicting drug response, COO and prognosis.