Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C-H bond activation.

The development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of C(sp 3)-H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon-carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity. The compatibility with bioactive motifs and expedient synthesis of pharmaceutically relevant molecules highlight the synthetic potential of this protocol.

TCF12 Transcriptionally Activates SPHK1 to Induce Osteosarcoma Angiogenesis by Promoting the S1P/S1PR4/STAT3 Axis.

Transcription factor 12 (TCF12) is a known oncogene in many cancers. However, whether TCF12 can regulate malignant phenotypes and angiogenesis in osteosarcoma is not elucidated. In this study, we demonstrated increased expression of TCF12 in osteosarcoma tissues and cell lines. High TCF12 expression was associated with metastasis and poor survival rate of osteosarcoma patients. Knockdown of TCF12 reduced the proliferation, migration, and invasion of osteosarcoma cells. TCF12 was found to bind to the promoter region of sphingosine kinase 1 (SPHK1) to induce transcriptional activation of SPHK1 expression and enhance the secretion of sphingosine-1-phosphate (S1P), which eventually resulted in the malignant phenotypes of osteosarcoma cells. In addition, S1P secreted by osteosarcoma cells promoted the angiogenesis of HUVECs by targeting S1PR4 on the cell membrane to activate the STAT3 signaling pathway. These findings suggest that TCF12 may induce transcriptional activation of SPHK1 to promote the synthesis and secretion of S1P. This process likely enhances the malignant phenotypes of osteosarcoma cells and induces angiogenesis via the S1PR4/STAT3 signaling pathway.

Terminally differentiated cytotoxic CD4+ T cells were clonally expanded in the brain lesion of radiation-induced brain injury.

BACKGROUND: Accumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context. MAIN TEXT: Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI-related CD4+ CTLs from other subsets. CONCLUSION: The present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease.

Effect of topical 5-aminolevulinic acid-mediated photodynamic therapy combined with CO2 laser pretreatment for vaginal condyloma acuminate.

BACKGROUND: Condyloma acuminatum (CA) of the vagina is a sexually transmitted disease due to infection by human papilloma virus (HPV). The treatment efficacy of the conventional methods for vaginal CA is often unsatisfactory with a high recurrence rate. Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) combined with CO2 laser pretreatment is a feasible approach for vaginal CA, but the effectiveness and safety need further evaluation. METHODS: This study enrolled 15 patients with vaginal CA. All patients underwent CO2 laser ablation and then ALA-PDT for two or three cycles. The clinical efficacy and side effects were evaluated and analyzed during the treatment and 6 months after the treatment. RESULTS: The wart lesions in 4 cases (26.7 %) disappeared after the first treatment. The wart lesions in 5 cases (33.3 %) disappeared after the second treatment. And 6 cases (40 %) needed three treatment cycles before the lesions disappeared completely. The complete response (CR) rate was 93.3 % (14/15) at 2 weeks after three treatment cycles. There were 5 cases (83.3 %) which have complete remission after 2 treatments in warts diameter <1 cm group. There were only 4 cases (44.4 %) which have complete remission after 2 treatments in diameter>1 cm group. All patients had CR without reoccurrence at 6 months after treatment. The side effects mainly included a mild or moderate burning or stinging sensation (26.7 %). There were no infection, ulcers and scars after treatment. CONCLUSION: Topical 5-aminolevulinic acid-mediated photodynamic therapy combined with CO2 laser pretreatment is a safe and effective treatment for vaginal CA.

3-Hydroxythiophenol-Formaldehyde Resin Microspheres Modulated by Sulfhydryl Groups for Highly Efficient Photocatalytic Synthesis of H2 O2.

Resorcinol-formaldehyde (RF) resin represents a promising visible-light responding photocatalyst for oxygen reduction reaction (ORR) toward H2 O2 production. However, its photocatalytic ORR activity toward H2 O2 generation is still unsatisfied for practical application. Herein, 3-hydroxythiophenol-formaldehyde (3-HTPF) resin microspheres synthesized through polycondensation reaction between 3-HTP and formaldehyde at room temperature and subsequent hydrothermal treatment exhibit enhanced photocatalytic ORR activity is reported. The experimental results show that the partial substitution of hydroxy group (─OH) by sulfhydryl one (─SH) through using 3-HTP to replace resorcinol could slow the rates of nucleation and growth of the resin particles and lead to strongly π-stacked architecture in 3-HTPF. The introduction of ─SH group can also improve adsorption ability of 3-HTPF to O2 molecules and enhance ORR catalytic activity of the photocatalysts. Stronger built-in electric field, better adsorption ability to O2 molecules, and increased surface catalytic activity collectively boost photocatalytic activity of 3-HTPF microspheres. As a result, H2 O2 production rate of 2010 µm h-1 is achieved over 3-HTPF microspheres at 273 K, which is 3.4 times larger than that obtained using RF submicrospheres (591 µm h-1 ). The rational substituent group modulation provides a new strategy for designing polymeric photocatalysts at the molecular level toward high-efficiency artificial photosynthesis.

A Synthetic Steroid 5α-Androst-3ß, 5, 6ß-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis.

Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3ß, 5, 6ß-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL's potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.

Expression and bioinformatics analysis of RPL38 protein and mRNA in gastric cancer.

We aimed to clarify the expression of RPL38 in gastric cancer, explore the relationship between the expression level of RPL38 and the clinicopathological parameters and prognosis of gastric cancer patients, and explore whether RPL38 has the potential to be used as a therapeutic target for gastric cancer and a biomarker for assessing prognosis. The mRNA and protein expression of RPL38 in gastric cancer tissues and normal tissues were compared by TIMER, Kaplan-Meier plotter, CCLE and UALCAN databases, respectively. Next, the relationship between the expression level of RPL38 in gastric cancer tissues and clinicopathological features was analysed using the UALCAN database. The Kaplan-Meier plotter database was then used to predict the prognostic value of RPL38 in gastric cancer patients, and overall survival curves were plotted based on the follow-up information of clinical specimens. The relationship between RPL38 expression and the level of immune infiltration in gastric cancer was explored using the TIMER database. Finally, co-expression analysis as well as enrichment analysis of RPL38 was performed using LinkedOmics database and GSEA, respectively. Through comprehensive bioinformatics analysis and immunohistochemistry experiments, we comprehensively concluded that RPL38 was highly expressed in gastric cancer. Univariate analysis showed that TNM stage (P=0.008), radiotherapy (P=0.02), and RPL38 expression level (P=0.0006) were associated with prognosis. Multifactorial analysis showed that RPL38 expression level (P=0.019), TNM stage (P=0.015) and radiotherapy (P=0.039) were independent risk factors affecting the prognosis of gastric cancer. Gastric cancer patients with high expression of RPL38 had poorer OS. In addition, RPL38 was associated with immune infiltration in gastric cancer. RPL38 is highly expressed in gastric cancer tissues, and RPL38 protein plays an important role in the development of gastric cancer, which is one of the important factors in assessing the prognosis of gastric cancer patients.

Walnut Protein Peptides Ameliorate DSS-Induced Ulcerative Colitis Damage in Mice: An in Silico Analysis and in Vivo Investigation.

Walnut (Juglans regia L.) is a food with food-medicine homology, whose derived protein peptides have been shown to have anti-inflammatory activity in vitro. However, the effects and mechanisms of walnut protein peptides on ulcerative colitis (UC) in vivo have not been systematically and thoroughly investigated. In this study, we applied virtual screening and network pharmacology screening of bioactive peptides to obtain three novel WPPs (SHTLP, HYNLN, and LGTYP) that may alleviate UC through TLR4-MAPK signaling. In vivo studies have shown that WPPs improve intestinal mucosal barrier dysfunction and reduce inflammation by inhibiting activation of the TLR4-MAPK pathway. In addition, WPPs restore intestinal microbial homeostasis by reducing harmful bacteria (Helicobacter and Bacteroides) and increasing the relative abundance of beneficial bacteria (Candidatus_Saccharimonas). Our study showed that the WPPs obtained by virtual screening were effective in ameliorating colitis, which has important implications for future screening of bioactive peptides from medicinal food homologues as drugs or dietary supplements.

Moringa oleifera Lam. Isothiocyanate Quinazolinone Derivatives Inhibit U251 Glioma Cell Proliferation through Cell Cycle Regulation and Apoptosis Induction.

A major active constituent of Moringa oleifera Lam. is 4-[(α-L-rhamnose oxy) benzyl] isothiocyanate (MITC). To broaden MITC's application and improve its biological activity, we synthesized a series of MITC quinazolinone derivatives and evaluated their anticancer activity. The anticancer effects and mechanisms of the compound with the most potent anticancer activity were investigated further. Among 16 MITC quinazolinone derivatives which were analyzed, MITC-12 significantly inhibited the growth of U251, A375, A431, HCT-116, HeLa, and MDA-MB-231 cells. MITC-12 significantly inhibited U251 cell proliferation in a time- and dose-dependent manner and decreased the number of EdU-positive cells, but was not toxic to normal human gastric mucosal cells (GES-1). Further, MITC-12 induced apoptosis of U251 cells, and increased caspase-3 expression levels and the Bax:Bcl-2 ratio. In addition, MITC-12 significantly decreased the proportion of U251 cells in the G1 phase and increased it in S and G2 phases. Transcriptome sequencing showed that MITC-12 had a significant regulatory effect on pathways regulating the cell cycle. Further, MITC-12 significantly decreased the expression levels of the cell cycle-related proteins CDK2, cyclinD1, and cyclinE, and increased those of cyclinA2, as well as the p-JNK:JNK ratio. These results indicate that MITC-12 inhibits U251 cell proliferation by inducing apoptosis and cell cycle arrest, activating JNK, and regulating cell cycle-associated proteins. MITC-12 has potential for use in the prevention and treatment of glioma.

LINC00853 contributes to tumor stemness of gastric cancer through FOXP3-mediated transcription of PDZK1IP1.

BACKGROUND: The incidence and mortality of gastric cancer (GC) are high worldwide. Tumor stemness is a major contributor to tumorigenesis and development of GC, in which long non-coding RNAs (lncRNAs) are deeply involved. The purpose of this study was to investigate the influences and mechanisms of LINC00853 in the progression and stemness of GC. METHODS: The level of LINC00853 was assessed based on The Cancer Genome Atlas (TCGA) database and GC cell lines by RT-PCR and in situ hybridization. An evaluation of biological functions of LINC00853 including cell proliferation, migration, and tumor stemness was conducted via gain-and loss-of-function experiments. Furthermore, RNA pull-down and RNA immunoprecipitation (RIP) assay were utilized to validate the connection between LINC00853 and the transcription factor Forkhead Box P3 (FOXP3). Nude mouse xenograft model was used to identify the impacts of LINC00853 on tumor development. RESULTS: We identified the up-regulated levels of lncRNA-LINC00853 in GC, and its overexpression correlates with poor prognosis in GC patients. Further study indicated that LINC00853 promoted cell proliferation, migration and cancer stemness while suppressed cell apoptosis. Mechanistically, LINC00853 directly bind to FOXP3 and promoted FOXP3-mediated transcription of PDZK1 interacting protein 1(PDZK1IP1). Alterations of FOXP3 or PDZK1IP1 reversed the LINC00853-induced biological effects on cell proliferation, migration and stemness. Moreover, xenograft tumor assay was used to investigate the function of LINC00853 in vivo. CONCLUSIONS: Taken together, these findings revealed the tumor-promoting activity of LINC00853 in GC, expanding our understanding of lncRNAs regulation on GC pathogenesis.

Binding behavior and antioxidant study of spice extract piperine with respect to meat myoglobin.

It has been reported in many studies that piperine (PIP) has multiple activity properties, the most prominent of which is antioxidant activity. This work reports the binding behavior and antioxidant activity of the spice extract piperine towards myoglobin (Mb) using spectroscopic and fluorescence spectra analysis, and computational approaches. Antioxidant activity studies have shown that the antioxidant effect of the Mb-PIP complex system depends on the concentration of PIP added. An appropriate concentration of PIP can successfully prevent the release of free iron from Mb. The fluorescence results indicated that the binding of PIP to Mb was via static quenching. After binding to PIP, the α-helix content of Mb decreased by about 5%. Synchronous fluorescence results indicate that PIP is closer to Trp, and MD simulations also demonstrate that PIP enters the hydrophobic cavity of Mb and binds stably. This explains the structural changes in proteins that lead to changes in antioxidant properties. The results of this study provide a reference for the quality control of additives of plant origin in the processing and storage of meat and meat products.

Strictly-controlled techniques are required in laparoscopic appendectomy for elemental mercury sequestration in the appendix: a case report.

Elemental mercury impaction in the appendix can cause subsequent local and systemic complications. We present a case of a teenage boy who ingested approximately 10 mL of elemental mercury, resulting in residual mercury sequestration in the appendix after conservative management. We performed laparoscopic appendectomy to remove the residual mercury. The patient made a complete clinical recovery without adverse events related to mercury poisoning over the 6-month follow-up. We highlight the advantages of laparoscopic appendectomy, abdominal computed tomography (CT), negative pressure operating rooms, and surgeon protection to improve surgical success rates. This case report adds to the literature on the management of elemental mercury impaction in the appendix and provides valuable insights for clinical decision-making.

Stage III deficient mismatch repair colon patients get greater benefit from earlier starting oxaliplatin-based chemotherapy regimen.

We evaluate the prognostic value of chemotherapy and other prognostic factors on overall survival among colon patients with deficient mismatch repair (dMMR), and determine the optimum time to start chemotherapy after surgery. Data of 306 colon cancer patients with dMMR who received radical surgery were collected from three Chinese centers between August 2012 and January 2018. Overall survival (OS) was assessed with the Kaplan-Meier method and log-rank. Cox regression analysis were used to assess influencing prognosis factors. The median follow-up time for all patients was 45.0 months (range, 1.0-100). There was a nonsignificant OS benefit from chemotherapy for patients with stage I and stage II disease, including high-risk stage II disease (log-rank p: 0.386, 0.779, 0.921), and a significant OS benefit for patients with stage III and stage IV disease for receiving post-operation chemotherapy (log-rank p = 0.002, 0.019). Stage III patients benefitted from chemotherapy regimens that contained oxaliplatin (log-rank p = 0.004), and Starting chemotherapy with oxaliplatin treatment earlier resulted in better outcomes (95% CI 0.013-0.857; p = 0.035). Chemotherapy regimens containing oxaliplatin can prolong the survival time of stage III and IV dMMR colon cancer patients. This beneficial manifestation was more pronounced after starting chemotherapy treatment early post operation. High risk stage II dMMR colon patients including T4N0M0 cannot benefit from chemotherapy.

In Vitro Cytotoxicity of Antiresorptive and Antiangiogenic Compounds on Oral Tissues Contributing to MRONJ: Systematic Review.

BACKGROUND: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear. METHODS: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells. RESULTS: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration. CONCLUSIONS: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.

Correlation analysis between renal anatomical factors and residual stones after an ultrasound-guided PCNL.

Introduction: To predict the factors of residual stones after percutaneous nephrolithotomy (PCNL) by analyzing the characteristics of the renal anatomical structure in intravenous urography, so as to make a reasonable operation plan, reduce the risk of residual stones in PCNL, and improve the stone-free rate (SFR). Methods: A retrospective study was performed between January 2019 and September 2020 for patients treated with PCNL. According to the results of a kidney ureter bladder review after PCNL, 245 patients were divided into a residual stone group (71 patients, stone size >4 mm) and a stone-free group (174 patients, stone size ≤4 mm). An independent sample t-test was used to analyze the age, the length and width of channel calices, the angle between the channel calices and the involved calices, and the length and width of the involved calices. The gender, the channel types, the number of channels, the degree of hydronephrosis, and the number of involved calices were analyzed by using the chi-square test. A score of p < 0.05 was considered statistically significant. At the same time, logistic regression analysis was carried out to explore the independent influencing factors of the SFR after PCNL. Results: A total of 71 patients developed residual stones after surgery. The overall residual rate was 29.0%. The width of the channel calices (p = 0.003), the angle between the channel calices and the involved calices (p = 0.007), the width of the involved calices (p < 0.001), the channel types (p = 0.008), and the number of involved calices (p < 0.001) were all significantly correlated with residual stones after PCNL. Logistic regression analysis showed that the width of the channel calices (p = 0.003), the angle between the channel calices and the involved calices (p = 0.012), the width of the involved calices (p < 0.001), the channel types (p = 0.008), and the number of involved calyces (p < 0.001) were all independent influencing factors of the SFR after PCNL. Conclusion: A larger caliceal neck width and angle can reduce the risk of residual stones. The more calyces that are involved, the higher the risk of residual stones. There was no difference between F16 and F18, but F16 had a higher SFR than F24.

Porcine Epidemic Diarrhea Virus Replication in Human Intestinal Cells Reveals Potential Susceptibility to Cross-Species Infection.

Various coronaviruses have emerged as a result of cross-species transmission among humans and domestic animals. Porcine epidemic diarrhea virus (PEDV; family Coronaviridae, genus Alphacoronavirus) causes acute diarrhea, vomiting, dehydration, and high mortality in neonatal piglets. Porcine small intestinal epithelial cells (IPEC-J2 cells) can be used as target cells for PEDV infection. However, the origin of PEDV in pigs, the host range, and cross-species infection of PEDV remain unclear. To determine whether PEDV has the ability to infect human cells in vitro, human small intestinal epithelial cells (FHs 74 Int cells) were inoculated with PEDV LJX and PEDV CV777 strains. The results indicated that PEDV LJX, but not PEDV CV777, could infect FHs 74 Int cells. Furthermore, we observed M gene mRNA transcripts and N protein expression in infected FHs 74 Int cells. A one-step growth curve showed that the highest viral titer of PEDV occurred at 12 h post infection. Viral particles in vacuoles were observed in FHs 74 Int cells at 24 h post infection. The results proved that human small intestinal epithelial cells are susceptible to PEDV infection, suggesting the possibility of cross-species transmission of PEDV.

Effects of antimony exposure on DNA damage and genome-wide variation in zebrafish (Danio rerio) liver.

Antimony (Sb) is a potentially toxic and carcinogenic cumulative contaminant that poses a serious threat to aquatic ecosystems. To better clarify the genotoxicity of Sb and its mechanism of action. In this study, we investigated DNA damage and genome-wide variation in the liver of a model organism, zebrafish (Danio rerio), under subacute Sb exposure and explored its potential toxicological mechanisms. The results showed that medium and high concentrations of Sb significantly reduced the total antioxidant capacity and increased the content of reactive oxygen species in zebrafish liver, and further studies revealed that it increased oxidative DNA damage and DNA-DNA cross-link (DDC), but had little effect on DNA-protein cross-link (DPC). The result of resequencing showed that the mutation sites of the genes with high concentrations of Sb were higher than those with medium concentrations, and the mutation was mainly a single nucleotide. The pathways significantly enriched for nonsynonymous single nucleotide polymorphisms (SNPs) and insertion/deletion mutations (InDels) variant genes in the coding regions of both the medium and high Sb-treated groups were ECM-receptor interactions, and the high Sb-treated group also included lysine degradation, hematopoietic cell lineage, and cytokine-cytokine receptor interactions. This suggests that ECM-receptor interactions play an important role in the mechanism of antimony toxicity to the liver of zebrafish.

Nickel-Catalyzed Enantioselective Electrochemical Reductive Cross-Coupling of Aryl Aziridines with Alkenyl Bromides.

An electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording enantioenriched ß-aryl homoallylic amines with excellent E-selectivity. This electroreductive strategy proceeds in the absence of heterogeneous metal reductants and sacrificial anodes by employing constant current electrolysis in an undivided cell with triethylamine as a terminal reductant. The reaction features mild conditions, remarkable stereocontrol, broad substrate scope, and excellent functional group compatibility, which was illustrated by the late-stage functionalization of bioactive molecules. Mechanistic studies indicate that this transformation conforms with a stereoconvergent mechanism in which the aziridine is activated through a nucleophilic halide ring-opening process.

Heterologous Expression and Bioactivity Determination of Monochamus alternatus Antibacterial Peptide Gene in Komagataella phaffii (Pichia pastoris).

Insects have evolved to form a variety of complex natural compounds to prevent pathogen infection in the process of a long-term attack and defense game with various pathogens in nature. Antimicrobial Peptides (AMPs) are important effector molecules of the insect immune response to the pathogen invasion involved in bacteria, fungi, viruses and nematodes. The discovery and creation of new nematicides from these natural compounds is a key path to pest control. A total of 11 AMPs from Monochamus alternatus were classified into 3 categories, including Attacin, Cecropin and Defensin. Four AMP genes were successfully expressed by Komagataella phaffii KM71. The bioassay results showed that the exogenous expressed AMPs represented antimicrobial activity against Serratia (G-), Bacillus thuringiensis (G+) and Beauveria bassiana and high nematicide activity against Bursaphelenchus xylophilus. All four purified AMPs' protein against B. xylophilus reached LC50 at 3 h (LC50 = 0.19 mg·mL-1 of MaltAtt-1, LC50 = 0.20 mg·mL-1 of MaltAtt-2 and MaltCec-2, LC50 = 0.25 mg·mL-1 of MaltDef-1). Furthermore, the AMPs could cause significant reduction of the thrashing frequency and egg hatching rate, and the deformation or fracture of the body wall of B. xylophilus. Therefore, this study is a foundation for further study of insect biological control and provides a theoretical basis for the research and development of new insecticidal pesticides.

A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon's minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery-magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues-Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor ß (PDGFRß) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.