Visible-Light-Mediated Azidation of α-Diazoesters with TMSN3 via Direct Photoexcitation and SH2 Mechanism.

A visible light-mediated azidation of α-diazoesters with TMSN3 to synthesize valuable α-azidoesters has been developed. Without using any catalysts and additives, the reaction proceeded smoothly under visible light irradiation at room temperature. A variety of α-diazoesters were successfully converted to the desired α-azidoesters, showing good functional group tolerance. The products could be readily transformed into triazole, α-azidoacid, and α-azidoamide. Mechanistic studies suggested that the reaction is mainly carrying out via direct photoexcitation and SH2 mechanism. This work provides a novel, mild, and practical protocol for synthesizing α-azidoesters.

Synthesis of Acylhydroquinones through Visible-Light-Mediated Hydroacylation of Quinones with α-Keto Acids.

A mild and eco-friendly visible-light-induced protocol for the hydroacylation of quinones with α-keto acids has been developed. In the absence of any catalyst or additive, the decarboxylative hydroacylation proceeded smoothly under visible-light irradiation at room temperature. A wide range of quinones and α-keto acids were well-tolerated and afforded hydroacylation products up to 88% isolated yield. The reaction can be scaled up, and the induced groups are useful for further synthetic applications. Preliminarily, mechanistic studies indicated that photoactive quinones absorb visible light to facilitate the transformation.

Acupuncture combined with gonadotropin-releasing hormone agonists improves endometrial receptivity and pregnancy outcome in patients with recurrent implantation failure of in vitro fertilization-embryo transfer.

OBJECTIVE: Gonadotropin-releasing hormone agonists (GnRHa), combined with other auxiliary treatments, can improve pregnancy outcomes in in vitro fertilization-embryo transfer (IVF-ET). This research investigated the effect of acupuncture combined with GnRHa in patients with recurrent implantation failure (RIF) of IVF-ET. METHODS: A total of 164 patients who intended to undergo frozen-thawed embryo transfer after RIF of IVF-ET were selected for experiments and then divided into the control (received conventional hormone replacement therapy (HRT) for endometrial preparation) and study groups (received a combination of acupuncture, GnRHa, and HRT for endometrial preparation) (n = 82). Endometrial thickness (EMT), endometrial morphological classification, submucosal uterine blood flow classification, clinical pregnancy rate, embryo implantation rate, and early abortion rate for each transfer cycle were compared between the two groups. RESULTS: EMT of the study group was higher than that of the control group 1 day before transfer. There were more patients with linear endometrium (A + B type) in the study group on the day of endometrial transformation than in the control group. The number of patients with type I submucosal uterine blood flow in the study group was decreased and the number of patients with type III was increased compared with the control group on the day of endometrial transformation. The clinical pregnancy rate and embryo implantation rate of the study group were higher than those of the control group. CONCLUSION: Acupuncture combined with GnRHa improves the endometrial receptivity of patients with RIF of IVF-ET, thereby increasing clinical pregnancy rates and improving pregnancy outcomes.

GeoDILI: A Robust and Interpretable Model for Drug-Induced Liver Injury Prediction Using Graph Neural Network-Based Molecular Geometric Representation.

Drug-induced liver injury (DILI) is a significant cause of drug failure and withdrawal due to liver damage. Accurate prediction of hepatotoxic compounds is crucial for safe drug development. Several DILI prediction models have been published, but they are built on different data sets, making it difficult to compare model performance. Moreover, most existing models are based on molecular fingerprints or descriptors, neglecting molecular geometric properties and lacking interpretability. To address these limitations, we developed GeoDILI, an interpretable graph neural network that uses a molecular geometric representation. First, we utilized a geometry-based pretrained molecular representation and optimized it on the DILI data set to improve predictive performance. Second, we leveraged gradient information to obtain high-precision atomic-level weights and deduce the dominant substructure. We benchmarked GeoDILI against recently published DILI prediction models, as well as popular GNN models and fingerprint-based machine learning models using the same data set, showing superior predictive performance of our proposed model. We applied the interpretable method in the DILI data set and derived seven precise and mechanistically elucidated structural alerts. Overall, GeoDILI provides a promising approach for accurate and interpretable DILI prediction with potential applications in drug discovery and safety assessment. The data and source code are available at GitHub repository (https://github.com/CSU-QJY/GeoDILI).

The preimplantation genetic testing for monogenic disorders strategy for blocking the transmission of hereditary cancers through haplotype linkage analysis by karyomapping.

PURPOSE: Providing feasible preimplantation genetic testing strategies for monogenic disorders (PGT-M) for prevention and control of genetic cancers. METHODS: Inclusion of families with a specific pathogenic mutation or a clear family history of genetic cancers. Identification of the distribution of hereditary cancer-related mutations in families through genetic testing. After a series of assisted reproductive measures such as down-regulation, stimulation, egg retrieval, and in vitro fertilization, a biopsy of trophectoderm cells from a blastocyst was performed for single-cell level whole-genome amplification (WGA). Then, the detection of chromosomal aneuploidies was performed by karyomapping. Construction of a haplotype-based linkage analysis to determine whether the embryo carries the mutation. Meanwhile, we performed CNV testing. Finally, embryos can be selected for transfer, and the results will be verified in 18-22 weeks after pregnancy. RESULTS: Six couples with a total of 7 cycles were included in our study. Except for cycle 1 of case 5 which did not result in a transferable embryo, the remaining 6 cycles produced transferable embryos and had a successful pregnancy. Four couples have had amniotic fluid tests to confirm that the fetus does not carry the mutation, while 1 couple was not tested due to insufficient pregnancy weeks. And the remaining couples had to induce labor due to fetal megacystis during pregnancy. CONCLUSION: Our strategy has been proven to be feasible. It can effectively prevent transmission of hereditary cancer-related mutations to offspring during the prenatal stage.

Identification of carrier status of Xp22.31 microdeletions associated with X-linked ichthyosis at the single-cell level using haplotype linkage analysis by karyomapping.

PURPOSE: Currently, owing to the limitations of high-throughput sequencing depth and the allele dropout caused by the whole-genome amplification, detection of chromosomal variants in embryos with CNVs <5 Mb is unsatisfactory at the single-cell level using only conventional sequencing methods. Therefore, here we aimed to use a strategy of preimplantation genetic testing for monogenic (PGT-M) to compensate for the shortcomings of conventional sequencing methods. The purpose of this study is to report the effectiveness of haplotype linkage analysis by karyomapping for preimplantation diagnosis microdeletion diseases. METHODS: Six couples carrying chromosomal microdeletions associated with X-linked ichthyosis were recruited, and all couples entered the PGT process. Multiple displacement amplification (MDA) method was used to amplify the whole-genome DNA of trophectoderm cells. Then karyomapping based on single nucleotide polymorphism (SNP) was used for haplotype linkage analysis to detect alleles carrying microdeletions, and CNVs of embryos were identified to determine euploid identity. Amniotic fluid tests were performed in the second trimester to verify the PGT-M results. RESULTS: All couples were tested for chromosomal microdeletions, with deletion fragments ranging in size from 1.60 to 1.73 Mb, and one partner in each couple did not carry the microdeletion. Three couples successfully underwent PGT-M assisted conception and obtained healthy live births. CONCLUSION: This study shows that haplotype linkage analysis by karyomapping could effectively detect the carrier status of embryos with microdeletions at the single-cell level. This approach may be applied to the preimplantation diagnosis of various chromosomal microvariation diseases.

MAIT cells and their implication in human oral diseases.

OBJECTIVE: Mucosal-associated invariant T (MAIT) cells are unique innate-like T cells that are abundant in humans, accounting for 1-10% of circulating T cells and about 2% of total T cells in human oral cavity. MAIT cells can mount a strong immune response quickly without exogenous antigens and undergo a phenotypic transformation in the development of diseases. They produce cytokines involved in the Th1 and Th17 immune response and cytotoxic proteins, promote the dysfunction of autoreactive B cell and inhibit the function of NK cells. MAIT cells have been widely explored in autoimmune diseases, inflammatory diseases and tumors, and these mechanisms may also be involved in the pathogenesis of some oral diseases, while MAIT cells have not been systematically discussed in oral diseases. METHODS: We searched PubMed/MEDLINE, EMBASE and Microsoft Bing databases to review and analyze relevant literatures on the impact of MAIT cells in the pathogenesis of human oral diseases. CONCLUSION: Collected evidence elucidated the characteristics of MAIT cells and emphasized the potential roles of MAIT cells in oral lichen planus (OLP), chronic graft-versus-host disease (cGVHD), oral squamous cell carcinoma (OSCC), apical periodontitis (AP) and primary Sjogren's syndrome (pSS).

N,N-Diisopropylethylamine-Mediated Electrochemical Reduction of Azobenzenes in Dichloromethane.

We report a cathodic reduction-dominated electrochemical approach for the hydrogenation of azobenzenes in dichloromethane. With cheap and readily available N,N-diisopropylethylamine as a catalytic mediator, the reaction proceeded smoothly in a simple undivided cell under constant-current electrolysis. A series of azobenzenes were successfully reduced to the corresponding hydrazobenzenes in moderate to high yields at room temperature. Preliminarily mechanistic studies indicate that solvent dichloromethane acts as a hydrogen source. The use of a common solvent as a hydrogen source, no need for stoichiometric mediators or metallic reductants, and mild conditions make this work a more straightforward and sustainable protocol for hydrogenation of azobenzenes.

Characterization and function of circulating mucosal-associated invariant T cells and γδT cells in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disease with uncertain aetiology. Mucosal-associated invariant T (MAIT) cells and γδT cells are unconventional, innate-like T cells with immunoregulatory capacity. This study aimed to investigate the potential effects of MAIT and γδT cells on the pathogenesis of OLP. METHODS: Circulating MAIT cells and γδT cells were identified using flow cytometry. Surface proteins including CD4, CD8, CD69, CD103, CD49d, programmed death-1 (PD-1) and its ligand PD-L1 were assessed. Cytokines containing interleukin (IL)-4, IL-17, interferon (IFN)-γ, granzyme B and tumour necrosis factor (TNF)-α released by MAIT and γδT cells were measured following PMA and ionomycin stimulation. RESULTS: Circulating MAIT and γδT cells were deficient in OLP. The percentage of CD4+ , CD69+ , CD103+ and PD-1+ MAIT cells was increased in OLP, while that of CD8+ and CD49d+ MAIT cells was decreased. The percentage of CD103+ , PD-1+ and PD-L1+ γδT cells was upregulated in OLP. Both the MAIT and γδT cells in OLP produced less IL-4 than controls. The granzyme B-producing MAIT cells were increased, while γδT cells secreting granzyme B and TNF-α were reduced in OLP. IL-17 and IFN-γ in OLP MAIT and γδT cells were not significantly different from that in controls. The frequency of OLP MAIT cells and the MAIT/γδT rate were positively associated with the disease severity. CONCLUSION: The deficient MAIT and γδT cells expressing functional proteins and releasing cytokines may play an immunoregulatory role in the pathogenesis of OLP.

T cell-derived exosomes containing cytokines induced keratinocytes apoptosis in oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is a T cell-mediated inflammatory disease with uncertain etiology. Exosomes are cell-derived vesicles containing biological cargo, being associated with the development of multiple inflammatory diseases. The present study aims to investigate the role of T cell-derived exosomes in the pathogenesis of OLP. METHODS: Exosomal marker CD63 was detected in OLP lesions by immunohistochemistry. Twenty-three cytokines in T cell-derived exosomes were assessed using luminex xMAP-based assay. After co-incubating with exosomes, the apoptosis of keratinocytes and the proliferation of Jurkat cells were assessed via flow cytometry and cell counting kit-8 assay, respectively. RESULTS: CD63 was highly expressed in the lymphocyte infiltrated areas of OLP lesions. OLP T cell-derived exosomes contained upregulated interleukin-7, -10, -12, -17 and downregulated interleukin-1ß, -5, and interferon-γ. Both exosomes from OLP patients and controls induced the apoptosis of keratinocytes and altered their morphology. Moreover, healthy control-derived exosomes markedly inhibited the proliferation of Jurkat cells, whereas OLP-derived exosomes exhibited no inhibitory effect. CONCLUSIONS: OLP T cell-derived exosomes have an aberrant cytokine profile and could trigger the apoptosis of keratinocytes in vitro, which may be involved in the pathogenesis of OLP.

Comparative Transcriptomics Analysis of Roots and Leaves under Cd Stress in Calotropis gigantea L.

Calotropis gigantea is often found in mining areas with heavy metal pollution. However, little is known about the physiological and molecular response mechanism of C. gigantea to Cd stress. In the present study, Cd tolerance characteristic of C. gigantea and the potential mechanisms were explored. Seed germination test results showed that C. gigantea had a certain Cd tolerance capacity. Biochemical and transcriptomic analysis indicated that the roots and leaves of C. gigantea had different responses to early Cd stress. A total of 176 and 1618 DEGs were identified in the roots and leaves of C. gigantea treated with Cd compared to the control samples, respectively. Results indicated that oxidative stress was mainly initiated in the roots of C. gigantea, whereas the leaves activated several Cd detoxification processes to cope with Cd, including the upregulation of genes involved in Cd transport (i.e., absorption, efflux, or compartmentalization), cell wall remodeling, antioxidant system, and chelation. This study provides preliminary information to understand how C. gigantea respond to Cd stress, which is useful for evaluating the potential of C. gigantea in the remediation of Cd-contaminated soils.

LHPP exerts a tumor-inhibiting role in glioblastoma via the downregulation of Akt and Wnt/ß-catenin signaling.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been recently identified as a novel inhibitor of multiple tumors; however, its role in glioblastoma (GBM) has not been investigated. This study aimed to evaluate whether LHPP exerts a potential tumor-inhibiting role in GBM. Compared with that in normal tissues, LHPP expression was lower in GBM tissues and various GBM cell lines. LHPP up-regulation in GBM cells markedly reduced their proliferation and invasion, and its knockdown had an oncogenic effect on these cells. Further studies revealed that overexpressed LHPP decreased the levels of Akt and glycogen synthase-3ß phosphorylation and down-regulated Wnt/ß-catenin signaling. By contrast, LHPP knockdown produced opposite effects. Akt suppression markedly abrogated the activation of Wnt/ß-catenin signaling induced by LHPP knockdown. The reactivation of Wnt/ß-catenin signaling partially reversed the inhibition of tumor growth in GBM mediated by LHPP overexpression. In addition, LHPP overexpression markedly retarded the tumorigenesis of GBM cells in vivo. These findings revealed that LHPP acts a potential inhibitor of tumor growth in GBM, and its overexpression represses GBM proliferation and invasion by down-regulating Akt and Wnt/ß-catenin signaling. This work highlights the crucial role of LHPP in GBM progression and suggests its potential as an anticancer target for the treatment of this disease.

Visible-Light-Promoted Diboron-Mediated Transfer Hydrogenation of Azobenzenes to Hydrazobenzenes.

A visible-light-promoted transfer hydrogenation of azobenzenes has been developed. In the presence of B2pin2 and upon visible-light irradiation, the reactions proceeded smoothly in methanol at ambient temperature. The azobenzenes with diverse functional groups have been reduced to the corresponding hydrazobenzenes with a yield of up to 96%. Preliminary mechanistic studies indicated that the hydrogen atom comes from the solvent and the transformation is achieved through a radical pathway.

Visible-light-promoted α-methoxymethylation and aminomethylation of ketones with methanol as the C1 source.

Visible-light-promoted α-methoxymethylation and aminomethylation of ketones using methanol as a sustainable C1 source have been developed. With rose bengal as the photosensitizer and air as the green oxidant, the methoxymethylation reactions proceeded smoothly under visible light irradiation at ambient temperature. Additionally, a one-pot one-step α-aminomethylation of ketones was achieved by adding N-nucleophiles. Preliminary mechanism studies suggest that the reaction mainly proceeds via a radical pathway.

Visible-light-promoted selective O-alkylation of 2-pyridones with α-aryldiazoacetates.

A visible-light-promoted O-H insertion reaction between 2-pyridones and α-aryldiazoacetates has been developed. Upon visible light irradiation, the reaction proceeds smoothly under mild and catalyst-free conditions. A wide scope of 2-pyridones and α-aryldiazoacetates are well tolerated, and various O-alkylated 2-pyridones are obtained with perfect selectivity and good functional group tolerance. A photoinduced radical process is probably responsible for the excellent selectivity.

T cell-derived exosomes induced macrophage inflammatory protein-1α/ß drive the trafficking of CD8+ T cells in oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disease with uncertain aetiology. Exosomes are nanosized particles with biological capacities. Here, we aimed to study the effects of T cell-derived exosomes (T-exos) on the pathogenesis of OLP and its mechanism. T-exos were incubated with Jurkat cells for 48 hours, and 26 cytokines in the supernatant were measured by luminex assay. The expression of macrophage inflammatory protein (MIP)-1α/ß was detected using immunohistochemistry and ELISA; that of CCR1/3/5 on peripheral T cells was determined by flow cytometry. Transwell assay was performed to investigate the chemotactic effect of MIP-1α/ß, and cells in the lower chambers were examinated by flow cytometry. As a result, OLP T-exos elevated the production of MIP-1α/ß, which were highly expressed in OLP tissues and plasma. CCR1/5 were markedly expressed on OLP peripheral T cells, and the majority of CCR1/5+ T cells were CD8+ T cells. Besides, MIP-1α/ß promoted the migration of OLP mononuclear cells, while inhibiting CCR1/5 significantly decreased the trafficking of mononuclear cells, especially that of CD8+ T cells. Conclusively, OLP T-exos-induced MIP-1α/ß may drive the trafficking of CD8+ T cells after binding with CCR1/5 in OLP, contributing to the development of OLP.

Omega-3 polyunsaturated fatty acids: a promising approach for the management of oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T-cell-mediated inflammatory disease with a risk of malignant transformation. Although the etiology of OLP is still uncertain, growing evidence suggests that oral microbiota, antigen-specific, and non-specific mechanisms are involved in the pathogenesis of OLP. Antigen-specific mechanisms include antigen presentation, T-cell activation, nuclear factor-kappa B signaling pathway, and cytokine secretion, while non-specific mechanisms consist of matrix metalloproteinases (MMP)-9 upregulation, psychological pressure, oxidative damage, aberrant expression of microRNAs (miRNAs), and autophagy. Till now, there is no cure for OLP, and the main purpose of OLP therapy is symptomatic control. FINDING: Seafood and its derivative omega-3 polyunsaturated fatty acids (n-3 PUFAs) can suppress antigen presentation, T-cell activation, and nuclear factor-kappa B signaling pathway, modulate the overexpressed inflammatory cytokines, inhibit the expression of MMP-9, as well as regulate the expression of miRNAs and autophagy. And they are possible agents for ameliorating psychological disorder and oxidative damage. Moreover, n-3 PUFAs supplementation has a beneficial effect on preventing tumorigenesis. CONCLUSION: n-3 PUFAs consumption may provide a non-toxic, inexpensive administration for OLP.

Room temperature iron(ii)-catalyzed radical cyclization of unsaturated oximes with hypervalent iodine reagents.

Here, we disclose an iron(ii)-catalyzed I-O bond cleavage of Koser's hypervalent iodine reagents (HIRs) that initiated the radical cyclization of unsaturated oximes at room temperature. This strategy is successfully applied for the construction of the isoxazoline backbone in an efficient manner. In particular, the direct introduction of a TsO group into products facilitates their late-stage transformations in organic synthesis.

Catalyst-free, visible-light-promoted S-H insertion reaction between thiols and α-diazoesters.

A visible-light-promoted S-H insertion reaction between thiols and α-diazoesters was developed. The reaction proceeded smoothly at room temperature with a broad substrate scope, affording various thioethers in moderate to excellent yields. The catalyst- and additive-free nature, sustainable energy source and mild reaction conditions make this strategy more eco-friendly.

A nonspecific ulcer on upper lip presented as the first and sole sign of syphilis.

Syphilis, a sexually transmitted disease, can be categorized as acquired syphilis and congenital syphilis, manifesting diverse lesions involving multiple sites. Oral manifestations at the primary stage of acquired syphilis are usually characterized by its short period and non-specific varied presentations. And oral ulcers as initial and the only presentation of syphilis oral lesions are infrequent and occur in less than 2% of patients. Because of its transient nature and variable manifestations which could mimic other oral ulcerative lesions, oral syphilis presenting as sole ulceration at early stage can be easily neglected and rather difficult to diagnose. Herein, we report a 35-year-old female patient manifested a sole atypical ulceration on her upper lip for approximately 1 month. We highlighted the importance of early and accurate diagnosis, focused on the characteristics of oral chancre, and gave an insight to the differential diagnoses, which would be enlightening and useful in clinical practice.