Solvent-Controlled Divergent Cyclization of 3-Ylideneoxindoles with Ethyl 2-Diazoacetate: Access to Spirocyclopropyl and Spiropyrazolines Oxindoles.

Herein a catalyst-free solvent-controlled method for the divergent synthesis of spirocyclopropyl and spiropyrazoline oxindoles from 3-ylideneoxindoles and ethyl diazoacetate was developed. With ClCH2CH2Cl as the solvent, spirocyclopropyl oxindoles were obtained in moderate to excellent yields, whereas the use of MeOH as solvent afforded spiropyrazoline oxindoles in moderate to good yields. The readily available substrates, simple operation and various product transformations further highlighted the utility of this method.

Long-term outcomes of pelvic exenterations for gynecological malignancies: a single-center retrospective cohort study.

BACKGROUND: Recently, with the advancement of medical technology, the postoperative morbidity of pelvic exenteration (PE) has gradually decreased, and it has become a curative treatment option for some patients with recurrent gynecological malignancies. However, more evidence is still needed to support its efficacy. This study aimed to explore the safety and long-term survival outcome of PE and the feasibility of umbilical single-port laparoscopic PE for gynecologic malignancies in a single medical center in China. PATIENTS AND METHODS: PE for gynecological cancers except for ovarian cancer conducted by a single surgical team in Sun Yat-sen University Cancer Center between July 2014 and December 2019 were included and the data were retrospectively analyzed. RESULTS: Forty-one cases were included and median age at diagnosis was 53 years. Cervical cancer accounted for 87.8% of all cases, and most of them received prior treatment (95.1%). Sixteen procedures were performed in 2016 and before, and 25 after 2016. Three anterior PE were performed by umbilical single-site laparoscopy. The median operation time was 460 min, and the median estimated blood loss was 600 ml. There was no perioperative death. The years of the operations was significantly associated with the length of the operation time (P = 0.0018). The overall morbidity was 52.4%, while the severe complications rate was 19.0%. The most common complication was pelvic and abdominal infection. The years of surgery was also significantly associated with the occurrence of severe complication (P = 0.040). The median follow-up time was 55.8 months. The median disease-free survival (DFS) was 17.9 months, and the median overall survival (OS) was 25.3 months. The 5-year DFS was 28.5%, and the 5-year OS was 30.8%. CONCLUSION: PE is safe for patient who is selected by a multi-disciplinary treatment, and can be a curative treatment for some patients. PE demands a high level of experience from the surgical team. Umbilical single-port laparoscopy was a technically feasible approach for APE, meriting further investigation.

Jeotgalibacillus haloalkalitolerans sp. nov., a novel alkalitolerant and halotolerant bacterium, isolated from the confluence of the Fenhe River and the Yellow River.

A Gram-stain positive, aerobic, alkalitolerant and halotolerant bacterium, designated HH7-29 T, was isolated from the confluence of the Fenhe River and the Yellow River in Shanxi Province, PR China. Growth occurred at pH 6.0-12.0 (optimum, pH 8.0-8.5) and 15-40℃ (optimum, 32℃) with 0.5-24% NaCl (optimum, 2-9%). The predominant fatty acids (> 10.0%) were iso-C15:0 and anteiso-C15:0. The major menaquinones were MK-7 and MK-8. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol and two unidentified phospholipids. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that strain HH7-29 T was a member of the genus Jeotgalibacillus, exhibiting high sequence similarity to the 16S rRNA gene sequences of Jeotgalibacillus alkaliphilus JC303T (98.4%), Jeotgalibacillus salarius ASL-1 T (98.1%) and Jeotgalibacillus alimentarius YKJ-13 T (98.1%). The genomic DNA G + C content was 43.0%. Gene annotation showed that strain HH7-29 T had lower protein isoelectric points (pIs) and possessed genes related to ion transport and organic osmoprotectant uptake, implying its potential tolerance to salt and alkali. The average nucleotide identity, digital DNA-DNA hybridization values, amino acid identity values, and percentage of conserved proteins values between strain HH7-29 T and its related species were 71.1-83.8%, 19.5-27.4%, 66.5-88.4% and 59.8-76.6%, respectively. Based on the analyses of phenotypic, chemotaxonomic, phylogenetic and genomic features, strain HH7-29 T represents a novel species of the genus Jeotgalibacillus, for which the name Jeotgalibacillus haloalkalitolerans sp. nov. is proposed. The type strain is HH7-29 T (= KCTC 43417 T = MCCC 1K07541T).

Alteromonas arenosi sp. nov., a novel bioflocculant-producing bacterium, isolated from intertidal sand.

A novel Gram-stain-negative, strictly aerobic and bioflocculant-producing bacterium, designated as ASW11-36T, was isolated from an intertidal sand collected from coastal areas of Qingdao, PR China. Growth occurred at 15-40 °C (optimum, 30 °C), pH 7.0-9.0 (optimum, pH 7.5) and with 1.5-7.0% (w/v) NaCl (optimum, 2.5-3.0%). In the whole-cell fatty acid pattern prevailed C16:0 and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The major isoprenoid quinone was determined to be Q-8 and the major polar lipids were phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), one unidentified aminolipid (AL), one unidentified glycolipid (GL), and two lipids (L1, L2). Based on the phylogenetic analyses of 16S rRNA gene sequences and 618 single-copy orthologous clusters, strain ASW11-36T could represent a novel member of the genus Alteromonas and was closely related to Alteromonas flava P0211T (98.4%) and Alteromonas facilis P0213T (98.3%). The pairwise average nucleotide identity and digital DNA-DNA hybridization values of the ASW11-36T genome assembly against the closely related species genomes were 71.8% and 21.7%, respectively, that clearly lower than the proposed thresholds for species. Based on phenotypic, phylogenetic, and chemotaxonomic analyses, strain ASW11-36T is considered to represent a novel species of the genus Alteromonas, for which the name Alteromonas arenosi sp. nov. is proposed. The type strain is ASW11-36T (= KCTC 82496T = MCCC 1K05585T). In addition, the strain yielded 65% of flocculating efficiency in kaolin suspension with CaCl2 addition. The draft genome of ASW11-36T shared abundant putative CAZy family related genes, especially involved in the biosynthesis of exopolysaccharides, implying its potential environmental and biological applications.

Nanoparticles as Drug Delivery Systems for the Targeted Treatment of Atherosclerosis.

Atherosclerosis continues to be a leading cause of morbidity and mortality globally. The precise evaluation of the extent of an atherosclerotic plaque is essential for forecasting its likelihood of causing health concerns and tracking treatment outcomes. When compared to conventional methods used, nanoparticles offer clear benefits and excellent development opportunities for the detection and characterisation of susceptible atherosclerotic plaques. In this review, we analyse the recent advancements of nanoparticles as theranostics in the management of atherosclerosis, with an emphasis on applications in drug delivery. Furthermore, the main issues that must be resolved in order to advance clinical utility and future developments of NP research are discussed. It is anticipated that medical NPs will develop into complex and advanced next-generation nanobotics that can carry out a variety of functions in the bloodstream.

Model-based hypothesis tests for the causal mediation of semi-competing risks.

Analyzing the causal mediation of semi-competing risks has become important in medical research. Semi-competing risks refers to a scenario wherein an intermediate event may be censored by a primary event but not vice versa. Causal mediation analyses decompose the effect of an exposure on the primary outcome into an indirect (mediation) effect: an effect mediated through a mediator, and a direct effect: an effect not through the mediator. Here we proposed a model-based testing procedure to examine the indirect effect of the exposure on the primary event through the intermediate event. Under the counterfactual outcome framework, we defined a causal mediation effect using counting process. To assess statistical evidence for the mediation effect, we proposed two tests: an intersection-union test (IUT) and a weighted log-rank test (WLR). The test statistic was developed from a semi-parametric estimator of the mediation effect using a Cox proportional hazards model for the primary event and a series of logistic regression models for the intermediate event. We built a connection between the IUT and WLR. Asymptotic properties of the two tests were derived, and the IUT was determined to be a size [Formula: see text] test and statistically more powerful than the WLR. In numerical simulations, both the model-based IUT and WLR can properly adjust for confounding covariates, and the Type I error rates of the proposed methods are well protected, with the IUT being more powerful than the WLR. Our methods demonstrate the strongly significant effects of hepatitis B or C on the risk of liver cancer mediated through liver cirrhosis incidence in a prospective cohort study. The proposed method is also applicable to surrogate endpoint analyses in clinical trials.

Regular gastroscopy and colonoscopy during the evaluation of urachal cancer: do we really need them?

PURPOSE: Urachal cancer is similar to gastrointestinal adenocarcinoma in histology, and gastroscopy/colonoscopy is often administered during perioperative evaluation. However, gastroscopy and colonoscopy have corresponding disadvantages. This study discusses whether gastroscopy/colonoscopy is truly necessary for patients with urachal cancer. PATIENTS AND METHODS: A total of 166 bladder adenocarcinoma cases diagnosed at Sun Yat-sen University Cancer Center were retrospectively reviewed and divided into two groups (urachal cancer and nonurachal cancer), and perioperative evaluations were retrieved. RESULTS: There were 78 patients with urachal cancer, the median age was 48 years, and 59 were male. Perioperative gastroscopy/colonoscopy revealed 5 intestinal polyps and 1 adenoma during these evaluations, and no primary gastrointestinal cancer was found. Meanwhile, preoperative imaging evaluation did not detect significant gastrointestinal lesions. For 88 patients with nonurachal cancer, including primary bladder adenocarcinoma and metastatic tumors from gastrointestinal cancer, the median age was 56 years, and 64 were male. Preoperative imaging evaluation demonstrated 36 cases of gastrointestinal lesions, and 32 were confirmed by gastroscopy/colonoscopy; the other 4 were negative. Another 4 cases of colon cancer were detected by regular colonoscopy for suspected primary bladder adenocarcinoma. In all, 35 cases of colon cancer and 1 case of gastric cancer were identified by endoscopic examination. The diagnostic consistency of imaging and gastrointestinal endoscopy was favorable (P < 0.001), and the negative predictive value and diagnostic efficiency of imaging were 96.9% and 94.6%, respectively. CONCLUSIONS: The vast majority of gastrointestinal cancer cases can be identified by assessment of the patient's clinical symptoms, meticulous physical examination, and imaging evaluation. We recommend that gastroscopy/colonoscopy only be applied to patients with urachal cancer when the above examinations are positive.

Enterohemorrhagic Escherichia coli O157:H7 antigens produced in transgenic lettuce effective as an oral vaccine in mice.

KEY MESSAGE: Transgene with recombination sites to address biosafety concerns engineered into lettuce to produce EspB and γ-intimin C280 for oral vaccination against EHEC O157:H7. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a food-borne pathogen where ruminant farm animals, mainly bovine, serve as reservoirs. Bovine vaccination has been used to prevent disease outbreaks, and the current method relies on vaccines subcutaneously injected three times per year. Since EHEC O157:H7 colonizes mucosal surfaces, an oral vaccine that produces an IgA response could be more convenient. Here, we report on oral vaccination against EHEC O157:H7 in mice orally gavaged with transgenic lettuce that produces EHEC O157:H7 antigens EspB and γ-intimin C280. Younger leaves accumulated a higher concentration of antigens; and in unexpanded leaves of 30-day-old T2 plants, EspB and γ-intimin C280 were up to 32 and 51 µg/g fresh weight, respectively. Mice orally gavaged with lettuce powders containing < 3 µg antigens for 6 days showed a mucosal immune response with reduced colonization of EHEC O157:H7. This suggests that the transgenic lettuce has potential to be used for bovine vaccination. To promote the biosafety of crop plants producing medically relevant proteins, recombination sites were built into our transgenic lines that would permit optional marker removal by Cre-lox recombination, as well as transgene deletion in pollen by CinH-RS2 recombination. The ability to upgrade the transgenic lettuce by stacking additional antigen genes or replacing older genes with newer versions would also be possible through the combined use of Bxb-att and Cre-lox recombination systems.

Base-Controlled Divergent Synthesis of Fluorine-Containing Benzo[4,5]imidazo[2,1-b][1,3]thiazines from 2-Mercaptobenzimidazoles and ß-CF3-1,3-Enynes.

A base-controlled divergent cyclization between 2-mercaptobenzimidazoles and ß-CF3-1,3-enynes providing either trifluoromethylated or fluorinated benzo[4,5]imidazo[2,1-b][1,3]thiazines has been developed. The ß-CF3-1,3-enyne, as a three-carbon synthon, underwent a 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU)-catalyzed tandem hydroamination/intramolecular hydrothiolation to give CF3-substituted 3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine, whereas reaction with KOH afforded fluorinated 4H-benzo[4,5]imidazo[2,1-b][1,3]thiazine exclusively. In addition, the synthetic utility of this methodology was showcased through a variety of downstream derivatizations.

The Protective Effect of (-)-Tetrahydroalstonine against OGD/R-Induced Neuronal Injury via Autophagy Regulation.

Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT assay, and the states of the autophagy-lysosomal pathway and Akt/mTOR pathway were monitored by Western blot analysis. The findings suggested that THA administration increased the cell viability of OGD/R-induced cortical neurons. Autophagic activity and lysosomal dysfunction were found at the early stage of OGD/R, which were significantly ameliorated by THA treatment. Meanwhile, the protective effect of THA was significantly reversed by the lysosome inhibitor. Additionally, THA significantly activated the Akt/mTOR pathway, which was suppressed after OGD/R induction. In summary, THA exhibited promising protective effects against OGD/R-induced neuronal injury by autophagy regulation through the Akt/mTOR pathway.

Structural Elucidation and Cytotoxic Activity of New Monoterpenoid Indoles from Gelsemium elegans.

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC50 values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1-2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC50 value of 57.02 uM.

How Community-Based Eldercare Services Adapt in Response to Covid-19 Restrictions: Evidence from Singapore.

This study investigated service adaptation strategies that community-based eldercare services (CES) in Singapore adopted in view of the COVID-19 pandemic restrictions. These strategies were also examined for their strengths and challenges. A qualitative study using semi-structured interviews was conducted individually with 11 social service staff from various CES in Singapore. Findings indicated that two main forms of service adaptation emerged: (1) increased engagement with clients and relevant stakeholders, and (2) increased use of telecommunication modalities. Resulting benefits included (1) perceived enhancement of social connectedness and social engagement for service users, and (2) new opportunities for CES to review operations and tap on increased visibility of service users. However, difficulties using telecommunications, resource constraints, and work stressors remain. It is recommended that CES providers implement supportive workplace practices, complement direct service provision with technology, and leverage on opportunities to improve the social environments of community-dwelling older adults.

N-Trifluoropropylation of Azoles through N-Vinylation and Sequential Hydrogenation.

Installing a fluoroalkyl group onto the nitrogen atom of azoles represents a potential strategy for lead optimization in medicinal chemistry. Herein, we describe a method for the N-trifluoropropylation of azoles. This process is accomplished using a combination of regioselective N-vinylation and sequential hydrogenation. The two-step sequence is applicable to a diverse set of azoles and tolerates a wide range of functionalities. In addition, we showcase its practicability and utility through the gram-scale synthesis and the late-stage modification of a complex molecule.

Catalytic divergent synthesis of imidazoles via reaction condition-dependent [3 + 2] cyclization of TosMIC.

A base-catalyzed divergent synthesis of multisubstituted imidazoles through TosMIC-based [3 + 2] cyclization reaction has been developed. In the presence of ketenimines and tBuONa, 1,4,5-trisubstituted imidazoles were obtained. Nonetheless, in the absence of ketenimines, 1,4-disubstituted imidazole was produced through cyclodimerization of TosMIC.

Establishment and application of a TaqMan probe-based qPCR for the detection of Enterocytozoon hepatopenaei in shrimp Litopenaeus vannamei.

Enterocytozoon hepatopenaei (EHP) is a common parasite that invades the epithelial cytoplasm in the hepatopancreas of shrimp Litopenaeus vannamei and results in slow growth of the host shrimps to cause significant economic loss in shrimp aquaculture. In this study, a TaqMan probe-based qPCR for quantitative detection of EHP was established. A pair of specific primers and a TaqMan probe were designed based on the sequence of cysteine desulfurase gene (NFS1) of EHP. The standard curve between cycle threshold (Ct) and the logarithmic starting quantity (SQ) of the template was determined as Ct = - 3.231 lg (SQ) + 40.638, with a correlation coefficient (R2) of 0.998 and an amplification efficiency of 103.9%. The lower limit of quantification was 1.67 × 101 copies/µL for this TaqMan probe-based qPCR and 1.67 × 103 copies/µL for the conventional PCR. The TaqMan probe-based qPCR established in the research was 100 times more sensitive than the conventional PCR method. In addition, the results of clinical sample detection indicated that the present technique was efficient in detecting EHP in the hepatopancreas, feces, water, and pond bottom mud samples. Therefore, the established TaqMan probe-based qPCR is a suitable technique for detecting EHP in both shrimp and aquatic environment samples.

A nomogram based on CHADS2 score for predicting atrial fibrillation recurrence after cryoballoon ablation.

BACKGROUND: As reported, CHADS2 scoring system moderately predicts the atrial fibrillation (AF) recurrence, a common event after cryoballoon ablation. We aimed to improve the diagnostic accuracy of the CHADS2 score by adding several routine auxiliary detection indicators into the scoring system and constructing a CHADS2 score-based nomogram to predict AF recurrence in patients with paroxysmal AF undergoing cryoballoon ablation. METHODS: Eighty-four patients with paroxysmal AF undergoing cryoballoon ablation were enrolled. Baseline characteristics were collected. The multivariable Cox proportional hazards model was used to identify the significantly related predictors of recurrence and to construct the nomogram whose performance was evaluated by the discrimination and calibration tests. RESULTS: Thirty-five patients developed AF recurrence after a mean follow up of 19.0 ± 15.77 months. In the Cox multivariate model, CHADS2 (>2) (hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.14-4.98, p = .021) and albumin-to-globulin ratio (AGR) (HR: 2.49; 95% CI: 1.26-4.92, p < .008) were independent risk factors associated with AF recurrence. In addition to CHADS2 , AGR and red blood cell distribution width were used to construct the nomogram. As a result, the discrimination of the concordance index for the predictive model of AF recurrence was increased from 0.56 (95% CI: 0.494-0.632) to 0.712 (95% CI: 0.631-0.811). The 24-month one well matched the ideal 45° line among the calibration plots for 6, 12, and 24 months' recurrence-free survival. CONCLUSION: This novel easy-to-use CHADS2 score-based nomogram may be used to predict AF recurrence for patient of paroxysmal AF undergoing cryoballoon ablation. Further external validation is still needed.

A panel of eight autophagy-related long non-coding RNAs is a good predictive parameter for clear cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) carries a variable prognosis. Prognostic biomarkers can stratify patients according to risk, and can provide crucial information for clinical decision-making. We screened for an autophagy-related long non-coding lncRNA (lncRNA) signature to improve postoperative risk stratification in The Cancer Genome Atlas (TCGA) database. We confirmed this model in ICGC and SYSU cohorts as a significant and independent prognostic signature. Western blotting, autophagic-flux assay and transmission electron microscopy were used to verify that regulation of expression of 8 lncRNAs related to autophagy affected changes in autophagic flow in vitro. Our data suggest that 8-lncRNA signature related to autophagy is a promising prognostic tool in predicting the survival of patients with ccRCC. Combination of this signature with clinical and pathologic parameters could aid accurate risk assessment to guide clinical management, and this 8-lncRNAs signature related to autophagy may serve as a therapeutic target.

[Expressions of FOXO1/3a/4/6 in human testis and their roles in testicular aging].

OBJECTIVE: To investigate the expression rules of FOXO1a, FOXO3a, FOXO4 and FOXO6 proteins in the human testis, and explore their roles in the development and progression of testicular aging. METHODS: We collected the para-carcinoma testis tissue from 4 testis cancer patients aged 28, 31, 32 and 46 years, and the testis tissue from another 2 PCa patients aged 66 and 81 years after castration surgery from January 2018 to December 2020. We detected the expressions of FOXO1a, FOXO3a, FOXO4 and FOXO6 proteins in the testis tissue by Western blot, determined the locations of FOXO1a, FOXO3a, FOXO4 and FOXO6 in the testis cells by immunofluorescence staining, and performed semi-quantitative and statistical analyses using image J and SPSS 23.0 software, respectively. RESULTS: The expression levels of FOXO1a and FOXO3a proteins were significantly decreased in the testis tissue of the elderly patients (P < 0.01), with an age-dependent reduction in the proportion of the positive cells. No statistically significant difference was observed in the expression levels of FOXO4 and FOXO6 between different age groups. FOXO1a was mainly expressed at the base of the seminiferous tubules, FOXO3a and FOXO4 in the Leydig cells, and FOXO6 in the seminiferous tubules. In addition, FOXO4 underwent age-related nuclear translocation in the senescent Leydig cells, suggesting its involvement in the aging of Leydig cells. CONCLUSION: FOXO1a/3a/4 may be closely related to human testicular aging and corresponding pathological changes, but its underlying mechanism remains to be further explored.

Female developmental environment delays development of male honeybee (Apis mellifera).

BACKGROUND: Nutrition and cell size play an important role in the determination of caste differentiation in queen and worker of honeybees (Apis mellifera), whereas the haploid genome dominates the differentiation of drones. However, the effects of female developmental environment on the development of males remain unclear. In this study, young drone larvae were transferred into worker cells (WCs) or remained in drone cells (DCs) to rear drones. The drone larvae were also grafted into queen cells (QCs) for 48 h and then transplanted into drone cells until emerging. Morphological indexes and reproductive organs of these three types of newly emerged drones were measured. Newly emerged drones and third instar drone larvae from WCs, DCs and QCs were sequenced by RNA sequencing (RNA-Seq). RESULTS: The amount of food remaining in cells of the QC and WC groups was significantly different to that in the DC group at the early larval stage. Morphological results showed that newly emerged DC drones had bigger body sizes and more well-developed reproductive tissues than WC and QC drones, whereas the reproductive tissues of QC drones were larger than those of WC drones. Additionally, whole body gene expression results showed a clear difference among three groups. At larval stage there were 889, 1761 and 1927 significantly differentially expressed genes (DEGs) in WC/DC, QC/DC and WC/QC comparisons, respectively. The number of DEGs decreased in adult drones of these three comparisons [678 (WC/DC), 338 (QC/DC) and 518 (WC/QC)]. A high number of DEGs were involved in sex differentiation, growth, olfaction, vision, mammalian target of rapamycin (mTOR), Wnt signaling pathways, and other processes. CONCLUSIONS: This study demonstrated that the developmental environment of honeybee females can delay male development, which may serve as a model for understanding the regulation of sex differentiation and male development in social insects by environmental factors.

Catalytic Enantioselective Isocyanide-Based Reactions: Beyond Passerini and Ugi Multicomponent Reactions.

The development of catalytic enantioselective isocyanide-based reactions is currently of great interest because the resulting products are valuable in organic synthesis, pharmacological chemistry, and materials science. This review assembles and comprehensively summarizes the recent achievements in this rapidly growing area according to the reaction types. Special attention is paid to the advantages, limitations, possible mechanisms, and synthetic applications of each reaction. In addition, a personal outlook on the opportunities for further exploration is given at the end.