General Regio- and Diastereoselective Allylic C-H Oxygenation of Internal Alkenes.

Branched allylic esters and carboxylates are fundamental motifs prevalent in natural products and drug molecules. The direct allylic C-H oxygenation of internal alkenes represents one of the most straightforward approaches, bypassing the requirement for an allylic leaving group as in the classical Tsuji-Trost reaction. However, current methods suffer from limited scope─often accompanied by selectivity issues─thus hampering further development. Herein we report a photocatalytic platform as a general solution to these problems, enabling the coupling of diverse internal alkenes with carboxylic acids, alcohols, and other O-nucleophiles, typically in a highly regio- and diastereoselective manner.

Visible Light-Induced Transition Metal Catalysis.

In recent years, visible light-induced transition metal catalysis has emerged as a new paradigm in organic photocatalysis, which has led to the discovery of unprecedented transformations as well as the improvement of known reactions. In this subfield of photocatalysis, a transition metal complex serves a double duty by harvesting photon energy and then enabling bond forming/breaking events mostly via a single catalytic cycle, thus contrasting the established dual photocatalysis in which an exogenous photosensitizer is employed. In addition, this approach often synergistically combines catalyst-substrate interaction with photoinduced process, a feature that is uncommon in conventional photoredox chemistry. This Review describes the early development and recent advances of this emerging field.

Recent Advances in Visible Light Induced Palladium Catalysis.

Visible light-induced Pd catalysis has emerged as a promising subfield of photocatalysis. The hybrid nature of Pd radical species has enabled a wide array of radical-based transformations otherwise challenging or unknown via conventional Pd chemistry. In parallel to the ongoing pursuit of alternative, readily available radical precursors, notable discoveries have demonstrated that photoexcitation can alter not only oxidative addition but also other elementary steps. This Minireview highlights the recent progress in this area.

Photoinduced Palladium-Catalyzed Carbofunctionalization of Conjugated Dienes Proceeding via Radical-Polar Crossover Scenario: 1,2-Aminoalkylation and Beyond.

A photoinduced palladium-catalyzed 1,2-carbofunctionalization of conjugated dienes has been developed. This mild modular approach, which does not require employment of exogeneous photosensitizers and external oxidants, allows for efficient and highly regio- and stereoselective synthesis of a broad range of allylic amines from readily available 1,3-dienes, alkyl iodides, and amines. Employment of O- and C-nucleophiles toward oxyalkylation and dialkylation products was also demonstrated. A putative π-allyl palladium radical-polar crossover path is proposed as a key event in this three-component coupling process. The utility of this protocol is highlighted by its application for derivatization of several amine-containing drugs.

Poverty, deprivation, and depressive symptoms among older adults in Hong Kong.

OBJECTIVES: Examine the association of income poverty and material deprivation with depression in old age. METHODS: Our data contains a survey of 1,959 older Chinese adults in Hong Kong. We used the Geriatric Depression Scale - Short Form to assess their depressive symptoms. Income poverty was defined as having household income below half the median household income (adjusted by household size); material deprivation was measured by a validated 28-item material deprivation. In addition to income poverty and material deprivation, we also assessed the effect of socio-demographic variables, financial strain, health indicators, and social and community resources on depressive symptoms. RESULTS: Those who experienced material deprivation reported a significantly more severe depressive symptoms, even after income poverty and all other covariates were controlled for; the bivariate association between income poverty and depressive symptoms disappeared once material deprivation was controlled for. Further, we found a significant interaction effect between income poverty and material deprivation on depressive symptoms; and both engagement in cultural activities and neighborhood collective efficacy moderated the impact of being materially deprived on depressive symptoms. CONCLUSION: Our results have important policy implications for the measurement of poverty and for the development of anti-poverty measures for materially deprived older adults.

Matrix metallopeptidase 9 targeted by hsa-miR-494 promotes silybin-inhibited osteosarcoma.

Osteosarcoma (OS) is the most common malignant tumor that develops in bone. Its mortality is very high. Therefore, study of mechanisms of pathogenesis of the OS is urgently required. Previous studies of microarray showed that the expression levels of matrix metallopeptidase 9 (MMP-9) altered significantly in OS. In addition, overexpression of MMP-9 is recognized as an indicator in cancer. However, the exact roles of MMP-9 in OS are not fully investigated. Thus, we firstly studied the roles of MMP-9 in OS and revealed that silence of MMP-9 inhibited OS cell proliferation as determined by MTT assay and colony formation assay. Secondly, we conducted TUNEL assay and confirmed loss of functions of MMP-9 induced OS cell apoptosis. Next, we used lentivector packaging method to overexpress MMP-9 and found that overexpression of MMP-9 promoted OS cell migration. Fourthly, the results of luciferase assay showed that MMP-9 was targeted by hsa-miR-494, which inhibited OS. Fifthly, we revealed that the levels of hsa-miR-494 were upregulated by the drug silybin which inhibited OS. Finally, we revealed that silybin inhibited OS cell viability by altering the protein levels of ß-catenin and Runt-related transcription factor 2 (RUNX2) as determined by western blot and immunocytochemistry (ICC).

Risk of tuberculosis in patients with solid cancers and haematological malignancies: a systematic review and meta-analysis.

There is uncertainty regarding whether patients with cancer should be screened for latent tuberculosis infection (LTBI). We performed a systematic review and meta-analysis to estimate the relative incidence of tuberculosis (TB) in cancer.We searched MEDLINE and Embase for studies published before December 21, 2016. We included studies that evaluated the incidence of TB in patients with solid cancers and haematological malignancies relative to a reference group (study control or general population). A pooled estimate of the incidence rate ratio (IRR) was obtained using standard meta-analysis methods.The search strategy identified 13 unique studies including 921 464 patients with cancer. The IRR of TB for adult patients with cancer was 2.61 (95% CI 2.12-3.22; I2=91%). In haematological cancers, the IRR was 3.53 (95% CI 1.63-7.64; I2=96%); and in solid cancers in adults, it was 2.25 (95% CI 1.96-2.58; I2=91%). The highest IRR was found in children with haematological malignancies or solid cancers (IRR 16.82, 95% CI 8.81-32.12; I2=79%).Considering the limited duration of maximum immunosuppression in cancer and reduced cumulative lifetime risk of TB because of reduced life expectancy, children, but not adults, appear to be at a sufficient level of risk to warrant systematic screening for LTBI.

Detergent sclerosants at sub-lytic concentrations induce endothelial cell apoptosis through a caspase dependent pathway.

To investigate the apoptotic effects of detergent sclerosants sodium tetradecylsulphate (STS) and polidocanol (POL) on endothelial cells at sub-lytic concentrations. Human umbilical vein endothelial cells (HUVECs) were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated HUVECs viability was assessed using propidium iodide staining. Early apoptosis was determined by increased phosphatidylserine exposure by lactadherin binding. Caspase 3, 8, 9 and Bax activation as well as inhibitory assays with Pan Caspase (Z-VAD-FMK) and Bax (BI-6C9) were assessed to identify apoptotic pathways. Porimin activation was used to assess cell membrane permeability. Cell lysis reached almost 100 % with STS at 0.3 % and with POL at 0.6 %. Apoptosis was seen with both STS and POL at concentrations ranging from 0.075 to 0.15 %. PS exposure increased with both STS and POL and exhibited a dose-dependent trend. Active Caspase 3, 8 and 9 but not Bax were increased in HUVECs stimulated with low concentrations of both STS and POL. Inhibitory assays demonstrated Caspase 3, 8, 9 inhibition at low concentrations (0.075 to 0.6 %) with both STS and POL. Both agents increased the activation of porimin at all concentrations. Both sclerosants induced endothelial cell (EC) apoptosis at sub-lytic concentrations through a caspase-dependant pathway. Both agents induced EC oncosis.

A single-cell atlas of conventional central chondrosarcoma reveals the role of endoplasmic reticulum stress in malignant transformation.

The transformation of benign lesions to malignant tumours is a crucial aspect of understanding chondrosarcomas, which are malignant cartilage tumours that could develop from benign chondroid lesions. However, the process of malignant transformation for chondroid lesions remains poorly understood, and no reliable markers are available to aid clinical decision-making. To address this issue, we conducted a study analysing 11 primary cartilage tumours and controls using single-cell RNA sequencing. By creating a single-cell atlas, we were able to identify the role of endoplasmic reticulum (ER) stress in the malignant transformation of conventional central chondrosarcomas (CCCS). Our research revealed that lower levels of ER stress promote chondrosarcoma growth in a patient-derived xenograft mouse model, while intensive ER stress reduces primary chondrosarcoma cell viability. Furthermore, we discovered that the NF-κB pathway alleviates ER stress-induced apoptosis during chondrosarcoma progression. Our single-cell signatures and large public data support the use of key ER stress regulators, such as DNA Damage Inducible Transcript 3 (DDIT3; also known as CHOP), as malignant markers for overall patient survival. Ultimately, our study highlights the significant role that ER stress plays in the malignant transformation of cartilaginous tumours and provides a valuable resource for future diagnostic markers and therapeutic strategies.

Major depressive disorder in vulnerable groups of older adults, their course and treatment, and psychiatric comorbidity.

BACKGROUND: Although a number of epidemiology studies of major depressive disorder (MDD) in older adults have been reported, most of them suffer four limitations: (1) the sample was not nationally representative; (2) the sample was relatively small or only one or two sociodemographic correlates of MDD were examined; (3) psychiatric comorbidity was not examined; and (4) the clinical characteristics of MDD were not reported. This study (1) examines the prevalence of DSM-IV MDD across different demographics, especially the vulnerable ones; (2) identifies clinical characteristics of DSM-IV MDD, such as onset, course, and treatment; and (3) evaluates the comorbidity of DSM-IV MDD with anxiety disorder, substance-use disorder, and personality disorder. METHODS: We analyzed data on 8,205 individuals aged 65 or older from the National Epidemiologic Survey on Alcohol and Related Conditions (2001-2002), a nationally representative survey of the noninstitutionalized U.S. household population. The Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV version assessed MDD, anxiety, substance use, personality disorders, and pathological gambling. The survey also included demographic characteristics: age, sex, race/ethnicity, marital status, education, employment status, personal income, urban vs. rural residence, and region of the country. RESULTS: Marital status and gender were associated with MDD, whereas race and socioeconomic characteristics were not. Specifically, the prevalence rates of past-year MDD were significant greater for females (3.6%) than males (2.0%) and higher for widowed (4.9%) or separated/divorced (3.5%) than married (1.85%). The mean onset age was 50 years and the average number of lifetime episodes was 4.4. Only half of older adults with MDD had received treatment, even though one-fourth had thought about suicide. Anxiety disorder, substance dependence, and pathological gambling were highly associated with MDD. CONCLUSION: Prevention could be targeted to older women and those who were widowed, separated, or divorced and low treatment rate was also alarming. More research is needed for the comorbid psychiatric disorders in late-life depression because of their impact on the course and prognosis of MDD.

Synthesis of Difluoromethylated Alkenes via Copper-Catalyzed Protodefluorination of ß-(Trifluoromethyl)styrenes.

Under typical copper-catalyzed hydroboration conditions, ß-(trifluoromethyl)styrenes demonstrate unusal reactivities by forming difluoromethylated alkenes via a net protodefluorination process. This is also distinct from trifluoromethyl alkenes with alkyl substituents where defluoroborylation products predominate.

Asymmetric intermolecular allylic C-H amination of alkenes with aliphatic amines.

Aliphatic allylic amines are found in a great variety of complex and biorelevant molecules. The direct allylic C-H amination of alkenes serves as the most straightforward method toward these motifs. However, use of widely available internal alkenes with aliphatic amines in this transformation remains a synthetic challenge. In particular, palladium catalysis faces the twin challenges of inefficient coordination of Pd(II) to internal alkenes but excessively tight and therefore inhibitory coordination of Pd(II) by basic aliphatic amines. We report a general solution to these problems. The developed protocol, in contrast to a classical Pd(II/0) scenario, operates through a blue light-induced Pd(0/I/II) manifold with mild aryl bromide oxidant. This open-shell approach also enables enantio- and diastereoselective allylic C-H amination.

Crystallization and preliminary diffraction analysis of truncated human pleckstrin.

Pleckstrin is a major substrate of protein kinase C in platelets and leukocytes and appears to play an important role in exocytosis through a currently unknown mechanism. Pleckstrin function is regulated by phosphorylation, which is thought to cause dissociation of pleckstrin dimers, thereby facilitating phosphoinositide interactions and membrane localization. Evidence also exists suggesting that phosphorylation causes a subtle conformational change in pleckstrin. Structural studies of pleckstrin have been initiated in order to characterize these structural changes and ultimately advance understanding of pleckstrin function. Here, the crystallization and preliminary X-ray diffraction analysis of a truncated version of pleckstrin consisting of the N-terminal PH domain, the protein kinase C phosphorylation sites and the DEP domain (NPHDEP) are reported. In addition, the oligomeric state and phospholipid-binding properties of NPHDEP were analyzed. This work demonstrates that NPHDEP behaves as a monomer in solution and suggests that all three pleckstrin domains contribute to the dimerization interface. Furthermore, based on the binding properties of NPHDEP, the C-terminal PH domain appears to increase the specificity of pleckstrin for phosphoinositides. This work represents a significant step towards determining the structure of pleckstrin.

C-H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals.

Selective functionalization of ubiquitous unactivated C-H bonds is a continuous quest for synthetic organic chemists. In addition to transition metal catalysis, which typically operates under a two-electron manifold, a recent renaissance in the radical approach relying on the hydrogen atom transfer (HAT) process has led to tremendous growth in the area. Despite several challenges, protocols proceeding via HAT are highly sought after as they allow for relatively easy activation of inert C-H bonds under mild conditions leading to a broader scope and higher functional group tolerance and sometimes complementary reactivity over methods relying on traditional transition metal catalysis. A number of methods operating via heteroatom-based HAT have been extensively reported over the past few years, while methods employing more challenging carbon analogues have been less explored. Recent developments of mild methodologies for generation of various carbon-centered radical species enabled their utilization in the HAT process, which, in turn, led to the development of remote C(sp3)-H functionalization reactions of alcohols, amines, amides and related compounds. This review covers mostly recent advances in C-H functionalization reactions involving the HAT step to carbon-centered radicals.

Sirolimus and propranolol inhibit endothelial proliferation while detergent sclerosants induce endothelial activation, microparticle release and apoptosis in vitro.

OBJECTIVES: To investigate the effects of detergent sclerosants, sodium tetradecyl sulphate and polidocanol, on endothelial cell activation and microparticle release and the effects of detergent sclerosants, sirolimus and propranolol, on apoptosis in vitro. METHODS: Cultured human umbilical vein endothelial cells and murine haemangioendothelioma (EOMA) cell lines were incubated with different concentrations of sodium tetradecyl sulphate and polidocanol, as well as sirolimus and propranolol. Endothelial activation was assessed using flow cytometry for CD62e (E-Selectin), CD54 (ICAM-1), CD105 (endoglin), CD144 (VE-Cadherin), CD146 (MCAM) and the release of endothelial microparticles. Cell proliferation was assessed using [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] and carboxyfluorescein succinimidyl ester assays. Apoptosis was assessed using flow cytometry for lactadherin/propidium iodide staining and for Caspase-3 expression. RESULTS: Sublytic concentrations of sodium tetradecyl sulphate and polidocanol (0.075%-0.3%) increased the expression of the activation markers CD62e and CD54. The expression of CD105 decreased in sclerosant treated cultured human umbilical vein endothelial cells. Both sodium tetradecyl sulphate and polidocanol induced the release of endothelial microparticles. All agents inhibited cell proliferation. Sodium tetradecyl sulphate and polidocanol-induced apoptosis as evidenced by increased phosphatidylserine exposure and caspase-3 expression, whereas sirolimus and propranolol increased caspase-3 expression only. CONCLUSION: Sublytic concentrations of detergent sclerosants induce endothelial activation and the release of endothelial microparticles. All agents were anti-proliferative in EOMA cell lines, with sodium tetradecyl sulphate and polidocanol inducing cellular apoptosis.

Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation.

The two major aggrecanases involved in osteoarthritis (OA) are ADAMTS-4 and ADAMTS-5. Knock-out studies suggested that ADAMTS-5, but not ADAMTS-4, is the major aggrecanase in murine OA. However, studies of human articular cartilage suggest that ADAMTS-4 also contributes to aggrecan degradation in human OA. This study investigated ADAMTS-4 in human OA. While ADAMTS-4 was virtually absent in control cartilage, numerous ADAMTS-4 immuno-positive chondrocytes were present in OA cartilage and their numbers increased with disease severity. RT-PCR confirmed expression, especially in the surface zone. DNA methylation was lost at specific CpG sites in the ADAMTS-4 promoter in OA chondrocytes, suggesting that the increased gene expression was more than a simple up-regulation, but involved loss of DNA methylation at specific CpG sites, resulting in a heritable and permanent expression of ADAMTS-4 in OA chondrocytes. These results suggest that ADAMTS-4 is epigenetically regulated and plays a role in aggrecan degradation in human OA.

Synthesis of 2-(Trifluoromethyl)indoles via Domino Trifluoromethylation/Cyclization of 2-Alkynylanilines.

A new method for the synthesis of 2-(trifluoromethyl)indoles using easily accessible 2-alkynylanilines and a well-established fluoroform-derived CuCF3 reagent is described. This method utilizes a domino trifluoromethylation/cyclization strategy to construct the indole cores with no ambiguity of the CF3 position. The intriguing 3-formyl-2-(trifluoromethyl)indoles can also be synthesized by this protocol, which are useful intermediates for the preparation of trifluoromethylated drug analogues. The ultimate CF3 source is the inexpensive industrial byproduct fluoroform.

Molecular epidemiology of coxsackievirus A6 circulating in Hong Kong reveals common neurological manifestations and emergence of novel recombinant groups.

BACKGROUND: Coxsackievirus A6 (CV-A6) represents the predominant enterovirus serotype in Hong Kong, but its epidemiology in our population was unknown. OBJECTIVES: To examine the clinical and molecular epidemiology of CV-A6 and detect emerging recombinant strains in Hong Kong. STUDY DESIGN: Nasopharyngeal aspirates (NPAs) from patients with febrile or respiratory illness were subject to RT-PCR for CV-A6 and sequencing of 5'-NCR and VP1. CV-A6-positive samples were further subject to 2C and 3D gene sequencing. Complete genome sequencing was performed on potential recombinant strains. RESULTS: Thirty-six (0.35%) NPAs were positive for CV-A6 by 5'-NCR RT-PCR and sequencing, 28 of which confirmed by partial VP1 gene sequencing. Among the 28 patients (mainly young children) with CV-A6 infection, hand-foot-and-mouth disease (HFMD) (43%), herpangina (18%) and tonsillitis (11%) were the most common diagnoses. Seven (25%) patients had neurological manifestations, including febrile seizures, encephalitis and meningitis. VP1 gene analysis showed that 24 CV-A6 strains circulating in Hong Kong belonged to genotype D5, while 4 strains belonged to D4. Further 2C and 3D gene analysis revealed eight potential recombinant strains. Genome sequencing of five selected strains confirmed four recombinant strains: HK459455/2013 belonging to recombination group RJ arisen from CV-A6/CV-A4, HK458288/2015 and HK446377/2015 representing novel group RL arisen from CV-A6/CV-A4, and HK462069/2015 representing novel group RM arisen from CV-A6/EV-A71. Recombination breakpoints located at 3D were identified in the latter three recombinant strains, with HK462069/2015 (from a child with encephalitis) having acquired 3D region from EV-A71. CONCLUSIONS: We identified novel recombinant CV-A6 strains in Hong Kong, with 3D being a common recombination site.

Copper(I)-Catalyzed Interrupted Click Reaction with TMSCF3: Synthesis of 5-Trifluoromethyl 1,2,3-Triazoles.

We herein describe a Cu(I)-catalyzed interrupted click reaction, using (trifluoromethyl)trimethylsilane (TMSCF3) as a nucleophilic CF3 source, to synthesize 5-trifluoromethyl 1,2,3-triazoles in one step from readily available terminal alkynes and azides. The reaction shows complete regioselectivity, broad substrate scope, and good functional group tolerability. The application of the reaction has been demonstrated in the synthesis of a trifluoromethylated analog of antiepileptic drug rufinamide.