Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types.

We evaluated the impact of class I and class II human leukocyte antigen (HLA) genotypes, heterozygosity, and diversity on the efficacy of pembrolizumab. Seventeen pembrolizumab clinical trials across eight tumor types and one basket trial in patients with advanced solid tumors were included (n > 3,500 analyzed). Germline DNA was genotyped using a custom genotyping array. HLA diversity (measured by heterozygosity and evolutionary divergence) across class I loci was not associated with improved response to pembrolizumab, either within each tumor type evaluated or across all patients. Similarly, HLA heterozygosity at each class I and class II gene was not associated with response to pembrolizumab after accounting for the number of tests conducted. No conclusive association between HLA genotype and response to pembrolizumab was identified in this dataset. Germline HLA genotype or diversity alone is not an important independent determinant of response to pembrolizumab and should not be used for clinical decision-making in patients treated with pembrolizumab.

Natriuretic Peptides and Prognosis in Patients With Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: The prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well-known. METHODS AND RESULTS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years of follow-up for hospitalizations for HF, cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. The incidence rate per 1000 patient-years for hospitalizations for HF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4, and 40.1; P < .001) and without (1.8, 3.1, 6.0, and 19.1; P < .001) HF, with a significantly higher risk in patients with HF compared with those without (with HF, quartile 3 HR 9.28 [interquartile range (IQR) 1.15-75.05]; P = .04; without HF, quartile 4 HR 4.86 [95% CI, 2.08-11.35]; P < .001). A similar higher risk for kidney events was seen in HF patients (with HF, quartile 4 HR 6.94 [95% CI, 2.66-18.08]; P = .001; without HF, quartile 4 HR 4.85 [95% CI, 3.02-7.80]; P = .001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general, regardless of history of HF; however, the presence of a clinical diagnosis of HF at baseline was associated with an incrementally higher risk, particularly in higher NT-proBNP quartiles.

Monomer-Recyclable Polyester from CO2 and 1,3-Butadiene.

Synthesis of monomer-recyclable polyesters solely from CO2 and bulk olefins holds great potential in significantly reducing CO2 emissions and addressing the issue of plastic pollution. Due to the kinetic disadvantage of direct copolymerization of CO2 and bulk olefins compared to homopolymerization of bulk olefins, considerable research attention has been devoted to synthesis of polyester via the ring-opening polymerization (ROP) of a six-membered disubstituted lactone intermediate, 1,2-ethylidene-6-vinyl-tetrahydro-2H-pyran-2-one (𝜹-L), obtained from telomerization of CO2 and 1,3-butadiene. However, the conjugate olefin on the six-membered ring of 𝜹-L leads to serious Michael addition side reactions. Thus, the selective ROP of 𝜹-L, which can precisely control the repeating unit for the production of polyesters potentially amenable to efficient monomer recycling, remains an unresolved challenge. Herein, the first example of selective ROP of 𝜹-L is reported using a combination of organobase and N,N'-Bis[3,5-bis(trifluoromethyl)phenyl]urea as the catalytic system. Systematic modifications of the substituent of the urea show that the presence of electron-deficient 3,5-bis(trifluoromethyl)-phenyl groups is the key to the extraordinary selectivity of ring opening over Michael addition. Efficient monomer recovery of oligo(𝜹-L) is also achieved under mild catalytic conditions.

The effect of corneal power on the accuracy of 14 IOL power formulas.

BACKGROUND: This study evaluates the impact of corneal power on the accuracy of 14 newer intraocular lens (IOL) calculation formulas in cataract surgery. The aim is to assess how these formulas perform across different corneal curvature ranges, thereby guiding more precise IOL selection. METHODS: In this retrospective case series, 336 eyes from 336 patients who underwent cataract surgery were studied. The cohort was divided into three groups according to preoperative corneal power. Key metrics analyzed included mean prediction error (PE), standard deviation of PE (SD), mean absolute prediction error (MAE), median absolute error (MedAE), and the percentage of eyes with PE within ± 0.25 D, 0.50 D, ± 0.75 D, ± 1.00 D and ± 2.00 D. RESULTS: In the flat K group (Km < 43 D), VRF-G, Emmetropia Verifying Optical Version 2.0 (EVO2.0), Kane, and Hoffer QST demonstrated lower SDs (± 0.373D, ± 0.379D, ± 0.380D, ± 0.418D, respectively) compared to the VRF formula (all P < 0.05). EVO2.0 and K6 showed significantly different SDs compared to Barrett Universal II (BUII) (all P < 0.02). In the medium K group (43 D ≤ Km < 46 D), VRF-G, BUII, Karmona, K6, EVO2.0, Kane, and Pearl-DGS recorded lower MAEs (0.307D to 0.320D) than Olsen (OLCR) and Castrop (all P < 0.03), with RBF3.0 having the second lowest MAE (0.309D), significantly lower than VRF and Olsen (OLCR) (all P < 0.05). In the steep K group (Km ≥ 46D), RBF3.0, K6, and Kane achieved significantly lower MAEs (0.279D, 0.290D, 0.291D, respectively) than Castrop (all P < 0.001). CONCLUSIONS: The study highlights the varying accuracy of newer IOL formulas based on corneal power. VRF-G, EVO2.0, Kane, K6, and Hoffer QST are highly accurate for flat corneas, while VRF-G, RBF3.0, BUII, Karmona, K6, EVO2.0, Kane, and Pearl-DGS are recommended for medium K corneas. In steep corneas, RBF3.0, K6, and Kane show superior performance.

GATA3 mediates doxorubicin resistance by inhibiting CYB5R2-catalyzed iron reduction in breast cancer cells.

AIMS: Neoadjuvant chemotherapy (NAC) is the primary preoperative therapy for breast cancer. The luminal subtype of breast cancer shows less NAC response than the basal subtype, with an inefficient NAC treatment effect. Understanding of the molecular and cellular mechanisms responsible for this chemoresistance is an important issue when determining optimal treatment. METHODS: Doxorubicin-induced apoptosis and ferroptosis was investigated using cytotoxicity, western blotting, and flow cytometry assays. The role of GATA3 in modulating doxorubicin-induced cell death was investigated both in vitro and in vivo. RNA-seq, qPCR, ChIP, and luciferase assay and association analyses were performed to investigate the regulation of CYB5R2 by GATA3. The function of GATA3 and CYB5R2 in regulating doxorubicin-induced ferroptosis was evaluated with iron, ROS, and lipid peroxidation detection assays. Immunohistochemistry was performed for results validation. RESULTS: Doxorubicin-induced basal breast cancer cell death is dependent on iron-mediated ferroptosis. Overexpression of the luminal signature transcriptional factor GATA3 mediates doxorubicin resistance. GATA3 promotes cell viability by decreasing ferroptosis-related gene CYB5R2 expression and by maintaining iron homeostasis. Analyzing data from the public and our cohorts demonstrates that GATA3 and CYB5R2 are associated with NAC response. CONCLUSIONS: GATA3 promotes doxorubicin resistance by inhibiting CYB5R2-mediated iron metabolism and ferroptosis. Therefore, patients with breast cancer who display high GATA3 expression do not benefit from doxorubicin-based NAC regimens.

The partnership between statisticians and the Institutional Animal Care and Use Committee (IACUC).

In this tutorial we explore the valuable partnership between statisticians and Institutional Animal Care and Use Committees (IACUCs) in the context of animal research, shedding light on the critical role statisticians play in ensuring the ethical and scientifically rigorous use of animals in research. Pharmaceutical statisticians have increasingly become vital members of these committees, contributing expertise in study design, data analysis, and interpretation, and working more generally to facilitate the integration of good statistical practices into experimental procedures. We review the "3Rs" principles (Replacement, Reduction, and Refinement) which are the foundation for the humane use of animals in scientific research, and how statisticians can partner with IACUC to help ensure robust and reproducible research while adhering to the 3Rs principles. We also highlight emerging areas of interest, such as the use of virtual control groups.

Effectiveness of immediate implant placement into defective sockets in the esthetic zone: A systematic review and meta-analysis.

STATEMENT OF PROBLEM: A defective socket is common after tooth extraction in the esthetic zone, but whether an implant can be immediately placed in a defective socket is unclear. PURPOSE: The purpose of this systematic review and meta-analysis was to summarize relevant studies within the last 20 years on implant survival and changes in soft and hard tissues after immediate implant placement in esthetic areas with socket defects. MATERIAL AND METHODS: A search was conducted for the relevant studies in the PubMed/Medline, the Cochrane Library, Web of Science, and Embase databases from January 2000 to March 2022. The literature review, data retrieval, and judgment whether the included studies had a risk of bias were handled independently by 2 reviewers, and a single-arm meta-analysis was performed using a statistical software program. RESULTS: A total of 23 studies evaluating the immediate implant placement of 630 implants (9 studies without a flap and 14 studies with a flap) were included. A 98.1% implant survival rate (95% confidence interval (CI): 96.2%, 100.0%) was determined. Marginal bone loss (MBL) at 6, 12, and ≥24 months were 1.03 mm (95%CI: 1.02, 1.03), 0.72 mm (0.72, 0.73), and 1.15 mm (1.14, 1.16). Gingival recession at 12 months was 0.25 mm (95%CI: 0.17, 0.33). The pink esthetic score (PES) were 12.34 (95%CI: 12.16, 12.52) at 12 months and 12.58 (12.39, 12.76) at ≥24 months. CONCLUSIONS: Current evidence shows that immediate implant placement into defective sockets in esthetic areas is feasible. Immediate implant placement can have a relatively good therapeutic effect in terms of implant survival rate, MBL, gingival recession, and PES.

Calix[4]arene-Derived 2D Covalent Organic Framework with an Electron Donor-Acceptor Structure: A Visible-Light-Driven Photocatalyst.

The calixarenes are ideal building blocks for constructing photocatalytic covalent organic frameworks (COFs), owing to their electron-rich and bowl-shaped π cavities that endow them with electron-donating and adsorption properties. However, the synthesis and structural confirmation of COFs based on calixarenes are still challenging due to their structural flexibility and conformational diversity. In this study, a calix[4]arene-derived 2D COF is synthesized using 5,11,17,23-tetrakis(p-formyl)-25,26,27,28-tetrahydroxycalix[4]arene (CHO-C4A) as the electron donor and 4,7-bis(4-aminophenyl)-2,1,3-benzothiadiazole (BTD) as the acceptor. The powder X-ray diffraction data and theoretical simulation of crystal structure indicate that COF-C4A-BTD exhibits high crystallinity and features a non-interpenetrating undulating 2D layered structure with AA-stacking. The density functional theory theoretical calculation, transient-state photocurrent tests, and electrochemical impedance spectroscopy confirm the intramolecular charge transfer behavior of COF-C4A-BTD with a donor-acceptor structure, leading to its superior visible-light-driven photocatalytic activity. COF-C4A-BTD exhibits a narrow band gap of 1.99 eV and a conduction band energy of -0.37 V versus normal hydrogen electrode. The appropriate energy band structure can facilitate the participation of ·O2- and h+ . COF-C4A-BTD demonstrates high efficacy in removing organic pollutants, such as bisphenol A, rhodamine B, and methylene blue, with removal rates of 66%, 85%, and 99% respectively.

Phenolipid JE improves metabolic profile and inhibits gluconeogenesis via modulating AKT-mediated insulin signaling in STZ-induced diabetic mice.

Phenolipids are characteristic phytochemicals of Syzygium genus. However, the antidiabetic potential and underlying molecular mechanism of these components are not fully elucidated. Herein, we studied the anti-diabetic effects of jambone E (JE), a phenolipid from S. cumini, with in vitro and in vivo models. Data from current study showed that JE enhanced glucose consumption and uptake, promoted glycogen synthesis, and suppressed gluconeogenesis in insulin resistant (IR)-HepG2 cells and primary mouse hepatocytes. JE also attenuated streptozotocin-induced hyperglycemia and hyperlipidemia in type 1 diabetic (T1D) mice. Eleven metabolites (e.g. trimethylamine n-oxide, 4-pyridoxic acid, phosphatidylinositol 39:4, phenaceturic acid, and hippuric acid) were identified as potential serum biomarkers for JE's antidiabetic effects by an untargeted metabolomics approach. The further molecular mechanistic study revealed that JE up-regulated phosphorylation levels of protein kinase B (AKT), glycogen synthase kinase 3 beta, and forkhead box O1 (FoxO1), promoted nuclear exclusion of FoxO1 whilst decreased gene expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase in IR-HepG2 cells and T1D mice. Our data suggested that JE might be a potent activator for AKT-mediated insulin signaling pathway, which was confirmed by the usage of AKT inhibitor and AKT-target siRNA interference, as well as the cellular thermal shift assay. Findings from the current study shed light on the anti-diabetic effects of phenolipids in the Syzygium species, which supports the use of medicinal plants in the Syzygium genus for potential pharmaceutical applications.

Novel biomarkers identified by weighted gene co-expression network analysis for atherosclerosis.

BACKGROUND: This study aimed to screen out the potential diagnostic biomarkers for atherosclerosis (AS). METHODS: We downloaded the gene expression profiles GSE66360, GSE28829, GSE41571, GSE71226, and GSE100927 from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the "limma" package in R. Weighted gene co-expression network analysis (WGCNA) was applied to reveal the correlation between genes in different samples. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The interaction pairs of proteins were retained by the STRING database, and the protein-protein interaction (PPI) network was visualized with the hub genes. Finally, the R packages "ggpubr" and "preprocessCore" were used to analyze immune cell infiltration. RESULTS: In total, 40 overlapping genes both in GSE66360 and GSE28829 were found to be related to the occurrence of AS. Further, the top 10 network hub genes including TYROBP, CSF1R, TLR2, CD14, CCL4, FCER1G, CD163, TREM1, PLEK, and C5AR1 were identified as significant key genes. Moreover, four genes (TYROBP, CSF1R, FCGR1B, and CD14) were verified that could efficiently diagnose AS. Finally, the gene TYROBP was found to have a strong correlation with immune-infiltrating cells. CONCLUSION: Our study identified four genes (TYROBP, CSF1R, FCGR1B, and CD14) that may be effective biomarkers for AS, with the potential to guide the clinical diagnosis of AS.

Exposure to emamectin benzoate confers cytotoxic effects on human molt-4 T-cells and possible ameliorative role of vitamin E and dithiothreitol.

Emamectin benzoate (EMB) is an avermectin insecticide that is extensively used for pest control, but there are few reports concerning its cytotoxic effects on human lymphocytes. In the current study, the hematotoxicity of EMB was evaluated in Molt-4 T-cells, a human T-lymphoblastic cell line with high motility, and the role of vitamin E (VitE) and dithiothreitol (DTT) in attenuating EMB cytotoxicity was characterized. Exposure of Molt-4 cells to EMB decreased cell viability and proliferation, induced a loss of cell clusters, and significantly increased membrane collapse and chromatin condensation. Moreover, EMB significantly increased cell death and suppressed transglutaminase activity. EMB treatment modulated the NF-κB signaling pathway, decreased the expression of p105, p50, and p65/RelA in cytosolic and nuclear fractions, and increased nuclear IκBα expression. EMB increased oxidative stress, as demonstrated by a significant increase in the levels of reactive oxygen species (ROS). Treatment with non-cytotoxic concentrations of VitE or DTT ameliorated the hematotoxicity induced by pretreatment with EMB, increased Molt-4 cell viability, raised the IC50 values of EMB, limited intracellular ROS generation, and mitigated EMB-mediated effects on NF-κB signaling. The results indicate the potential cytotoxicity of EMB on human lymphocytes, and demonstrate that VitE and DTT treatment can reduce the cytotoxic effects of EMB.

The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor (TCR)-mediated signaling pathway, such as the lymphocyte-specific protein tyrosine kinase (Lck), Src family tyrosine kinases Fyn, and the phosphorylation levels of Zeta-chain-associated protein kinase-70 (ZAP70). For the first time, we have successfully produced PTPN22 CS transgenic mice in which the tyrosine phosphatase activity of PTPN22 is suppressed. Notably, the number of thymocytes in the PTPN22 CS mice was significantly reduced, and the expression of cytokines in the spleen and lymph nodes was changed significantly. Furthermore, PTPN22 CS facilitated the positive and negative selection of developing thymocytes, increased the expression of the TCRαß-CD3 complex on the thymus cell surface, and regulated their internalization and recycling. ZAP70, Lck, Phospholipase C gamma1(PLCγ1), and other proteins were observed to be reduced in PTPN22 CS mouse thymocytes. In summary, PTPN22 regulates TCR internalization and recycling via the modulation of the TCR signaling pathway and affects TCR expression on the T cell surface to regulate negative and positive selection. PTPN22 affected the development of the thymus, spleen, lymph nodes, and other peripheral immune organs in mice. Our study demonstrated that PTPN22 plays a crucial role in T cell development and provides a theoretical basis for immune system construction.

A Multi-Scale Temporal Convolutional Network with Attention Mechanism for Force Level Classification during Motor Imagery of Unilateral Upper-Limb Movements.

In motor imagery (MI) brain-computer interface (BCI) research, some researchers have designed MI paradigms of force under a unilateral upper-limb static state. It is difficult to apply these paradigms to the dynamic force interaction process between the robot and the patient in a brain-controlled rehabilitation robot system, which needs to induce thinking states of the patient's demand for assistance. Therefore, in our research, according to the movement of wiping the table in human daily life, we designed a three-level-force MI paradigm under a unilateral upper-limb dynamic state. Based on the event-related de-synchronization (ERD) feature analysis of the electroencephalography (EEG) signals generated by the brain's force change motor imagination, we proposed a multi-scale temporal convolutional network with attention mechanism (MSTCN-AM) algorithm to recognize ERD features of MI-EEG signals. Aiming at the slight feature differences of single-trial MI-EEG signals among different levels of force, the MSTCN module was designed to extract fine-grained features of different dimensions in the time-frequency domain. The spatial convolution module was then used to learn the area differences of space domain features. Finally, the attention mechanism dynamically weighted the time-frequency-space domain features to improve the algorithm's sensitivity. The results showed that the accuracy of the algorithm was 86.4 ± 14.0% for the three-level-force MI-EEG data collected experimentally. Compared with the baseline algorithms (OVR-CSP+SVM (77.6 ± 14.5%), Deep ConvNet (75.3 ± 12.3%), Shallow ConvNet (77.6 ± 11.8%), EEGNet (82.3 ± 13.8%), and SCNN-BiLSTM (69.1 ± 16.8%)), our algorithm had higher classification accuracy with significant differences and better fitting performance.

Chemically Recyclable CO2 -Based Solid Polyesters with Facile Property Tunability.

Synthesizing chemically recyclable solid polymeric materials is a significant strategy to potentially achieve carbon neutral production of new polymers and alleviate plastic pollution, especially when the synthesis is based on CO2 and inexpensive co-feedstocks available in large scales. Additionally, polymeric materials should have high enough molecular weight to exhibit distinguished properties from low molar mass polymers to serve for a broader range of application scenarios. However, up to now, strategies for developing solid-state CO2 -based chemically recyclable polyesters with both high molecular weight and facile property tunability are still unprecedented. Herein, a brand-new synthetic route is developed to synthesize chemically recyclable CO2 -based solid polyesters with high molecular weight (Mn up to 587.7 kg mol-1 ) and narrow dispersity (D < 1.2), which should further broaden the potential application scenarios of new CO2 -based polyesters. Additionally, complete monomer recovery from poly(δLH2 ) material is also achieved. The preserved terminal alkene groups allow facile property tuning of the polyesters via photo-initiated thiol-ene click reactions, enabling more potential utilities and further functionalizations.

Synergy of cystamine and pyraclostrobin against Fusarium graminearum involves membrane permeability mitigation and autophagy enhancement.

The application of fungicide mixture is one of the most important measures to extend the service life of highly selective fungicides. Pyraclostrobin (PYR), which has been extensively used to control plant diseases by inhibiting mitochondrial respiration of pathogenic fungi, is at a high risk of resistance development. In this study, the potential of PYR alone or in combination with cystamine, an inhibitor of microbial transglutaminase, to suppress Fusarium graminearum was tested in vitro and in vivo. A synergistic effect of PYR/CYS mixture was observed both in vitro and when applied to etiolated wheat coleoptile. The control effect of PYR/CYS mixture on F. graminearum was better than that of PYR alone, which was reflected by the increased protection effect. The discrepancies of membrane permeability and the redox-physiological state were observed between PYR and PYR/CYS treatments, suggesting that an increased PYR availability in F. graminearum mycelia could be related with the observed synergistic action. Moreover, a synergistic profile was observed between PYR and CYS in regard of massive autophagosomes in mycelia, indicating that enhanced autophagy could be involved in the mode of action of PYR/CYS mixture. The differential content of mitochondrial metabolites between PYR and PYR/CYS treatments also provided evidence for CYS contribution to the fungicidal action of PYR/CYS mixture. The results provide insight into the synergistic mechanism of action of PYR/CYS mixture and an effective way to enhance the efficiency of PYR to combat F. graminearum.

A Novel Muscle Synergy Extraction Method Used for Motor Function Evaluation of Stroke Patients: A Pilot Study.

In this paper, we present a novel muscle synergy extraction method based on multivariate curve resolution-alternating least squares (MCR-ALS) to overcome the limitation of the nonnegative matrix factorization (NMF) method for extracting non-sparse muscle synergy, and we study its potential application for evaluating motor function of stroke survivors. Nonnegative matrix factorization (NMF) is the most widely used method for muscle synergy extraction. However, NMF is susceptible to components' sparseness and usually provides inferior reliability, which significantly limits the promotion of muscle synergy. In this study, MCR-ALS was employed to extract muscle synergy from electromyography (EMG) data. Its performance was compared with two other matrix factorization algorithms, NMF and self-modeling mixture analysis (SMMA). Simulated data sets were utilized to explore the influences of the sparseness and noise on the extracted synergies. As a result, the synergies estimated by MCR-ALS were the most similar to true synergies as compared with SMMA and NMF. MCR-ALS was used to analyze the muscle synergy characteristics of upper limb movements performed by healthy (n = 11) and stroke (n = 5) subjects. The repeatability and intra-subject consistency were used to evaluate the performance of MCR-ALS. As a result, MCR-ALS provided much higher repeatability and intra-subject consistency as compared with NMF, which were important for the reliability of the motor function evaluation. The stroke subjects had lower intra-subject consistency and seemingly had more synergies as compared with the healthy subjects. Thus, MCR-ALS is a promising muscle synergy analysis method for motor function evaluation of stroke patients.

Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice.

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 µmol/g tissue in WT mice vs. 0.85 ± 0.14 µmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.

24.6 kW near diffraction limit quasi-continuous-wave Nd:YAG slab laser based on a stable-unstable hybrid cavity.

A 24.6 kW quasi-continuous-wave (QCW) Nd-doped yttrium aluminum garnet (Nd:YAG) slab laser is proposed in this Letter. The laser is based on a stable-unstable hybrid cavity. A stable and an unstable resonator were constructed along orthogonal directions in the aperture of the slab. Due to features of the hybrid cavity, the slab laser achieves both high efficiency of power extraction with excellent beam quality and compactness with simplicity. Average output power of 24.6 kW with 47% optical-to-optical efficiency is achieved in the experiment. The beam quality of the output beam is 1.5 times diffraction limits after correction of adaptive optics. The repetition frequency and pulse width of the laser are 400 Hz and 200 µs.

Void-free bonding for a large slab laser crystal.

A void-free bonding technique was demonstrated for a large slab Nd: YAG crystal with a bonding surface dimension of ∼160mm×70mm. By using the novel fluxless oxide layer removal technology, the indium-oxide barrier problem was resolved. With the help of electrochemical-polished indium solder and a plasma-cleaned heat sink, the solderability of the indium was enhanced; in particular, the contact angle of the solder was improved from 51° to 31°. With the largest-bonding-size slab, a single-slab laser created a maximum output power of 7.3 kW under an absorbed pump power of 12.8 kW, corresponding to an optical to optical efficiency of 57% and a slope conversion of 67.8%. By detecting the wavefront of the interferometer before and after bonding, the RMS of wavefront was 0.192λ and 0.434λ (λ=633nm), respectively. To the best of our knowledge, this is the largest void-free bonding size for a laser slab and the highest output power achieved from a single-slab crystal laser oscillator.

Universal Anticancer Cu(DTC)2 Discriminates between Thiols and Zinc(II) Thiolates Oxidatively.

Aerobic organisms must rely on abundant intracellular thiols to reductively protect various vital functional units, especially ubiquitous zinc(II) thiolate sites of proteins, from deleterious oxidations resulting from oxidizing environments. Disclosed here is the first well-defined model study for reactions between zinc(II) thiolate complexes and copper(II) complexes. Among all the studied ligands of copper(II), diethyldithiocarbamate (DTC) displays a unique redox-tuning ability that enables copper(II) to resist the reduction by thiols while retaining its ability to oxidize zinc(II) thiolates to form disulfides. This work proves for the first time that it is possible to develop oxidants to discriminate between thiols and zinc(II) thiolates, alluding to a new chemical principle for how oxidants, especially universal anticancer Cu(DTC)2 , might circumvent the intracellular reductive defense around certain zinc(II) thiolate sites of proteins to kill malignant cells.