2-甲酰(乙酰)取代喹啉缩氨基硫脲的合成

缩氨基硫脲类化合物有抗肿瘤、抗病毒和抗菌等多种药理活性。Barret等首次报道了乙二醛二缩氨基硫脲(Ⅰ)的抗疟活性。Klayman等研究了缩     

Socioeconomic deprivation is inversely associated with measles incidence: a longitudinal small-area analysis,Germany, 2001 to 2017

BackgroundAlthough measles is endemic throughout the World Health Organization European Region, few studies have analysed socioeconomic inequalities and spatiotemporal variations in the disease’s incidence.AimTo study the association between socioeconomic deprivation and measles incidence in Germany, while considering relevant demographic, spatial and temporal factors.MethodsWe conducted a longitudinal small-area analysis using nationally representative linked data in 401 districts (2001–2017). We used spatiotemporal Bayesian regression models to assess the potential effect of area deprivation on measles incidence, adjusted for demographic and geographical factors, as well as spatial and temporal effects. We estimated risk ratios (RR) for deprivation quintiles (Q1–Q5), and district-specific adjusted relative risks (ARR) to assess the area-level risk profile of measles in Germany.ResultsThe risk of measles incidence in areas with lowest deprivation quintile (Q1) was 1.58 times higher (95% credible interval (CrI): 1.32–2.00) than in those with highest deprivation (Q5). Areas with medium-low (Q2), medium (Q3) and medium-high deprivation (Q4) had higher adjusted risks of measles relative to areas with highest deprivation (Q5) (RR: 1.23, 95%CrI: 0.99–1.51; 1.05, 95%CrI: 0.87–1.26 and 1.23, 95%CrI: 1.05–1.43, respectively). We identified 54 districts at medium-high risk for measles (ARR > 2) in Germany, of which 22 were at high risk (ARR > 3).ConclusionSocioeconomic deprivation in Germany, one of Europe’s most populated countries, is inversely associated with measles incidence. This association persists after demographic and spatiotemporal factors are considered. The social, spatial and temporal patterns of elevated risk require targeted public health action and policy to address the complexity underlying measles epidemiology.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

Mesoporous-silica-coated palladium-nanocubes as recyclable nanocatalyst in C–C-coupling reaction – a green approach

We report the straightforward design of a recyclable palladium-core–silica-shell nanocatalyst showing an excellent balance between sufficient stability and permeability. The overall process – design, catalysis and purification – is characterized by its sustainability and simplicity accompanied by a great recycling potential and ultra high yields in C–C-coupling reactions.

A green approach: in a single-step coating process a mesoporous silica shell was tailored onto palladium-nanocubes. Along with a PEG-matrix this core–shell-nanocatalyst could be recovered after C–C-coupling reactions and reused without any significant decrease in product yield.

In contrast to bulk materials, metal-nanocyrstals (NC) possess unique physical and chemical properties. Both, nano-scale and geometry can dictate their optical, electronic and catalytic behavior.^1–3 Consequently, nanomaterials have been implemented already in various fields like medicine,⁴ sensing,⁵ nano-electronics⁶ and organic synthesis.⁷ Smart strategies for a sustainable usage of limited resources such as precious metals and hydrocarbons are inevitable due to the consistently growing population and economy.^8–10 Generally, catalysis gives rise to novel and energy-saving synthetic routes. However, homogeneous catalysis is not widely used in industrial processes, due to the need of mostly toxic ligands and the costly purification along with a restricted reusability potential.^11–13 Heterogeneous catalysis based on the utilization of metal nanocrystals overcomes most of these limitations. Caused by its high surface-to-volume ratio, catalytic activities are drastically increased in comparison to bulk materials. However, the most common disadvantage in NC-based catalysis lies in the occurrence of aggregates during the reaction, which leads to a decrease of the catalytic active surface. Several studies were already presented in literature to delay that phenomenon using micelle-like- or core–shell-nanostructures as potential nanocatalytic systems.^14–20 However, these surfactants or shells are either potentially harmful for the environment or very step-inefficient to produce. Other approaches used the deposition of small NCs in a mesoporous support which offers a large active surface area.^21–24 In this context, it is crucial to find an adequate balance between permeability for small organic molecules and the overall stability of the nanocatalyst. Overcoming these obstacles can contribute to a sustainable supply of drugs and other organic substances.In the present work palladium-nanocubes (Pd-NCubes) were fabricated in aqueous solution using cetyltrimethyl-ammoniumbromide (CTAB) as surfactant. The procedure is adapted from a previously published study.^25,26 The respective transmission electron microscopy (TEM) image and the selected area electron diffraction (SAED) pattern of the as-obtained Pd-NCubes are depicted in Fig. S1.^† The SAED confirms the single-crystallinity of Pd-NCubes bound by {100}-facets. TE micrographs of Pd-NCubes revealed an average edge-length of (18 ± 2) nm (for histogram see Fig. S2^†). The formation of polyhedra and nanorods was found to be less than 1%.To the best of our knowledge, there is no procedure reported that showed the direct fabrication of a mesoporous silica (mSi) shell tailored on Pd-NCs. However, Matsuura et al. demonstrated a single-step coating approach of CTAB-capped gold-nanorods and CdSe/ZnS quantum dots obtaining a mesoporous silica shell.²⁷ The pores were determined to be 4 nm in width with 2 nm thick walls. Since the Pd-NCubes are covered by CTAB, already no surfactant exchange is necessary. Consequently, this procedure could be directly transferred to the as-obtained Pd-NCubes (∼10¹⁵ particles per L) of this study using tetraethyl orthosilicate (TEOS) as silica precursor in an alkaline solution. Here, CTAB serves as organic template for the formation of the mesoporous silica shell.TE micrographs of individual Pd-mSi-nanohybrids are depicted in Fig. 1 showing a spherical silica coating with a thickness of (17 ± 2) nm (for histogram see Fig. S3^†). The porosity is essential to ensure that vacant coordination sites on the palladium-core are present and accessible for catalysis. In contrast to other multistep approaches, pores are formed in situ with no additional etching step necessary.^28,29 This avoids the usage of harmful etching agents such as fluorides or ammonia.³⁰ The silica shell then served as platform for further surface modification using two different PEG-silanes (M_n = 5000 g mol⁻¹ and M_n = 20 000 g mol⁻¹). TE microscopy did not reveal any changes in the structure of the PEG functionalized Pd-mSi-nanohybrids opposed to the unfunctionalized nanocatalyst, since the contrast of polymer is too low (see Fig. S4^†). However, dynamic light scattering (DLS) measurements in diluted aqueous solutions proved an increased hydrodynamic radius with increasing molecular weight of the PEG-chain grafted onto the silica shell (see Fig. 2). These results provide evidence that only individual nanostructures are formed while no larger aggregates are present.Open in a separate windowFig. 1Exemplary TE micrographs of Pd-mSi-nanohybrids.Open in a separate windowFig. 2DLS results along the different stages of the hierarchal fabrication process of the nanocatalyst.The successful functionalization of the Pd-mSi-nanohybrid with PEG provides the dispersibility for the overall nanocatalyst in a PEG matrix. Due to its lack of toxicity and its simple recovery, caused by its melting point at ∼50 °C, PEG is considered as a “green” reaction medium.³¹ It has already been shown that PEG can act as suitable solvent for both homogeneous and heterogeneous catalysis.^32–34 Consequently, further experiments were performed using only the Pd-mSi-nanohybrid functionalized with PEG-silane having an average molecular weight of M_n = 5000 g mol⁻¹ (PEG-5k). For catalytic reactions, Pd-mSi-PEG-5k was dispersed in a PEG matrix (PEG-2000, M_n = 2000 g mol⁻¹) and charged into a Teflon centrifuge tube. Using only one tube for the reaction and the product separation avoids an additional transfer step and prevents any loss of the nanocatalyst between reaction cycles (see recycling Scheme 1). Here, the C–C-coupling between ethyl acrylate and p-iodoanisole served as model Heck-reaction to prove the catalytic activity of the designed catalyst (4.4 mol% overall Pd conc. equal to ca. 0.3 mol% surface-available Pd; conc. is determined by ICP-MS measurements, see Table S1^†). Sodium phosphate was used as base providing the largest product yield when compared to other bases, such as Na₂CO₃, K₂CO₃ and K₃PO₄. Once the catalysis was performed and the PEG-2000 was cooled down, diethyl ether was added to extract the product and separated from the reaction medium via centrifugation.Open in a separate windowScheme 1Recycling process of the Pd-mSi-PEG-5k-nanocatalyst and PEG-2000 as solvent after the Heck-reaction between ethyl acrylate and p-iodoanisole to form ethyl p-methoxycinnamate.To exclude any suspended compounds from the desired product, the mixture was passed through a PTFE-filter. Et₂O was removed in vacuo without the need of column chromatography. Comparing the ¹H-NMR spectra of the as-obtained product with the educts indicate a yield of 98% with only small amounts of PEG-2000 present (identified by the signal at ∼3.6 ppm, < 1 weight-%). The results show that both educts and the base Na₃PO₄ are able to diffuse through the mesoporous silica shell to the palladium core (see Fig. 3). A detailed ¹H-NMR signal assignment of the product is given in Fig. S5.^†Open in a separate windowFig. 3 ¹H-NMR spectra of the educts ethyl acrylate (top) and p-iodoanisole (center) and the product ethyl p-methoxycinnamate (bottom).After recovering the reaction mixture containing Pd-mSi-PEG-5k and PEG-2000, seven further Heck-reaction-cycles were conducted under the same conditions. Results obtained from ¹H-NMR and gravimetry indicate no significant decrease in catalytic activity (see ¹H-NMR spectra in Fig. 4). Along the eight Heck-reactions, product yields were determined between 94% and 99%. Only small traces of p-iodoanisole (identified by the signal at ∼6.75 ppm) were still present while ethyl acrylate could be fully removed in vacuo. The yields obtained after each cycle are displayed in Fig. 5. ICP-MS measurements of the catalysis product were performed to determine the palladium leaching out of the catalytic system. The results are displayed in Table S1^† indicating that leaching is strongly suppressed since the overall Pd-content in the product ranges from 0.3–5.7 ng, only. This corresponds to 0.002–0.044 ppm palladium with respect to the product mass. The data are in good agreement with the high product yields along the eight Heck-reactions. To trace the evolution of the nanocatalyst along the cycles, TE micrographs were taken after the 1^st and the 8^th Heck-cycle (see Fig. 6). It can be seen that the cubical structure of the palladium vanishes during the first reaction (left TEM image). Inside the silica shell spherical palladium particles were formed. An explanation for this rearrangement lies in the suggested Heck-mechanism.³⁵ Here, a Pd²⁺-species forms after the oxidative addition of the p-iodoanisole which can desorb from the Pd-NCube. Once the reductive elimination of the product occurs the Pd⁰-species is generated again that can re-deposit on the palladium-core.²¹ Since the spherical geometry possesses the lowest free surface energy, globules were eventually formed.³ The mesoporous silica shell is not affected significantly by the catalysis and the rearrangement of the palladium. The porosity appears to stay intact, enabling the penetration of further small organic molecules. Control experiments were performed to validate whether these observations are based on either a thermally or a chemically induced rearrangement process of the palladium core. Therefore, only the nanocatalyst was dispersed in PEG-2000 and heated at 110 °C for 24 h without any conducted catalysis reaction. TEM results showed no changes in the structure of neither the palladium core nor the silica shell (see Fig. S6^†). After the 8^th reaction, no core–shell-nanostructures could be detected anymore via TEM. Only small randomly shaped Pd-nanoparticles (≤20 nm) were found indicating a slow leaching of the palladium out of the silica shell. However, no larger aggregates were formed (see right TE micrograph in Fig. 6) which explains the continuously high catalytic activity.Open in a separate windowFig. 4 ¹H-NMR spectra of the product ethyl p-methoxycinnamate after the 1^st Heck-reaction (bottom) up to the 8^th reaction (top).Open in a separate windowFig. 5Conversions of ethyl p-methoxycinnamate obtained via NMR and gravimetry after each respective Heck-reaction (1–8).Open in a separate windowFig. 6TE micrographs of the Pd-mSi-PEG-5k-nanocatalyst taken after the 1^st (left) and the 8^th Heck-reaction (right).     

Quantitative comparison of the expression of antimicrobial peptides in the oral mucosa and extraoral skin

Antimicrobial peptides (AMP) defend epithelial surfaces against pathological micro-organisms. We know of no comparison of their expression between the oral mucosa and extraoral epithelium, but knowledge of differences in their quantities is of interest, possibly as a starting point for new treatments. Expression of AMP human beta-defensin (hBD)-1/-2/-3 and psoriasin in the oral mucosa and extraoral epithelium of the head and neck were measured by real-time polymerase chain reaction (RT-PCR) (n=14), immunohistochemistry (n=6), and western blot (n=8). RT-PCR showed that all the genes investigated were expressed significantly more in the oral mucosa than in the skin (hBD-1: p=0.002; hBD-2: p=0.006; hBD-3: p=0.035; psoriasin: p=0.02). Immunohistochemistry and western blot showed differential concentrations of proteins: hBD-2 (p=0.021) and hBD-3 (p=0.043) were pronounced in the oral mucosa, whereas psoriasin was raised in the extraoral skin (p=0.021). There was no difference in protein concentrations for hBD-1 (p=0.08). The observed differences in the expression of AMP may be important for new treatments such as topical application of AMP derivatives.     

Fatty acid ethanolamide levels are altered in borderline personality and complex posttraumatic stress disorders

Borderline personality (BPD) and complex posttraumatic stress disorders (PTSD) are both powerfully associated with the experience of interpersonal violence during childhood and adolescence. The disorders frequently co-occur and often result in pervasive problems in, e.g., emotion regulation and altered pain perception, where the endocannabinoid system is deeply involved. We hypothesize an endocannabinoid role in both disorders. We investigated serum levels of the endocannabinoids anandamide and 2-arachidonoylglycerol and related fatty acid ethanolamides (FAEs) in BPD, PTSD, and controls. Significant alterations were found for both endocannabinoids in BPD and for the FAE oleoylethanolamide in PTSD suggesting a respective link to both disorders.     

Identification of Candida species in the clinical laboratory: a review of conventional,commercial, and molecular techniques

In healthy individuals, Candida species are considered commensal yeasts of the oral cavity. However, these microorganisms can also act as opportunist pathogens, particularly the so‐called non‐albicans Candida species that are increasingly recognized as important agents of human infection. Several surveys have documented increased rates of C. glabrata, C. tropicalis, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. krusei in local and systemic fungal infections. Some of these species are resistant to antifungal agents. Consequently, rapid and correct identification of species can play an important role in the management of candidiasis. Conventional methods for identification of Candida species are based on morphological and physiological attributes. However, accurate identification of all isolates from clinical samples is often complex and time‐consuming. Hence, several manual and automated rapid commercial systems for identifying these organisms have been developed, some of which may have significant sensitivity issues. To overcome these limitations, newer molecular typing techniques have been developed that allow accurate and rapid identification of Candida species. This study reviewed the current state of identification methods for yeasts, particularly Candida species.     

Grafting assay distinguishes promotion sensitive from promotion resistant JB6 cells

The JB6 mouse epidermal cell system has been used extensively as an in vitro transformation model for the study of tumor promotion. The standard JB6 cell assay for promotion of transformation is carried out in soft agar or other anchorage independent conditions. The present study was directed to the development of an in vivo model to distinguish the promotion resistant (P-) and promotion sensitive (P+) progression phenotypes. Results indicate that the grafting assay distinguishes P- and P+ cells in vivo with P+ but not P- cells forming tumors within 7-9 weeks. Expression of dominant negative mutant jun TAM67 blocks both anchorage independent transformation response and graft bed tumor formation by P+ cells, suggesting that the requirement for AP-1 activation in transformation now applies in vivo. Expression of mutated p53 produced a gain of P+ phenotype in P- cells in vitro, but not in vivo. Histochemical and Northern blot analysis for expression of various keratinocyte markers revealed no evidence for expression, suggesting a loss of keratinocyte markers following establishment in culture. In summary, the skin-grafting assay described in this study appears to be a valid in vivo assay for distinguishing the preneoplastic progression phenotypes represented by JB6 P- and P+ cells.