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Nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines and chiral ligands. However the direct enantioselective C-H amination to access optically pure N-C atropisomer is still difficult and rare. Here we report a π-π interaction and dual H-bond concerted control strategy to develop the chiral phosphoric acids (CPAs) catalyzed direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines with azodicarboxylates as amino sources for the construction of atroposelective naphthalene-1,2-diamines. This type of N-C atropisomers is stabilized by intramolecular hydrogen bond and the method features a broad range of substrates, high yields and ee values, providing a strategy to chirality transfer via the modification of N-C atropisomers. Atropisomers with a chiral C-N axis are useful for natural products synthesis and as ligands in asymmetric catalysis. Here, the authors reportt a π-π interaction and dual H-bond concerted control strategy in enantioselective C-H amination affording configurationally stable N-C atropisomers.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis -hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues. (‒)-Morphine is an essential medicine selected by the World Health Organization, however its catalytic asymmetric syntheses have been rarely reported. Here, the authors developed an intramolecular enantioselective Michael addition leading to (‒)-morphine in a longest linear sequence of 16 steps.

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps). As a practical application, the asymmetric total synthesis of naucleofficine I ( 1a ) and II ( 1b ) in ten steps have been accomplished. Natural products often contain complex N-fused polycyclic structures with multiple substituents and stereocentres. Here, the authors developed a bifunctional organocatalyst that is instrumental in obtaining such structures and applied it to the total synthesis of naucleofficine I and II in 6 steps.

Amyloid precursor protein (APP)-null mice exhibit significant deficits in motor performance, including reduced grip strength and impaired locomotion; however, the underlying neurophysiological mechanisms remain unclear. In this study, we show that conditional knockdown of APP selectively in Purkinje cells (PCs) recapitulates these motor deficits, while exogenous expression of APP in APP-null mice rescues motor function. Electrophysiological analysis revealed that APP deficiency leads to aberrant firing patterns in PCs and reduces inhibitory synaptic transmission onto neurons of the deep cerebellar nucleus (DCN). We identified a marked reduction in Nav1.6-mediated sodium currents as the key mechanism underlying abnormal action potential firing and propagation in APP-deficient PCs. Importantly, all electrophysiological and behavioral deficits were rescued by PC-specific APP reconstitution. These findings reveal a novel and essential role for APP in cerebellar motor control by regulating Nav1.6 channel activity and PC excitability.

Inflammasomes can identify endogenous danger signals as an inflammatory immune response. As the most common inflammasome, the NLR pyrin family domain containing 3 (NLRP3) inflammasome is associated with the pathogenesis of different tumors. However, the function of the NLRP3 inflammasome in esophageal cancer (EC) has rarely been reported. Herein, the expression levels of the components of NLRP3 inflammasome and Ki-67 were analyzed by immunohistochemistry. Furthermore, correlations between the NLRP3 inflammasome and Ki-67 along with the clinicopathological features of EC patients were evaluated. The components of the NLRP3 inflammasome were also assessed by western blot analysis and quantitative PCR. NLRP3 was silenced or overexpressed in different esophageal squamous cell carcinoma (ESCC) cell lines, and cell viability, migration and invasion were assessed by CCK-8 and Transwell assays. The present results showed that high NLRP3 expression in the tumor specimens was significantly associated with TNM stage and T category. Spearman's correlation analysis revealed a positive correlation between NLRP3 and the Ki-67 proliferation index. The mRNA and protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and interleukin (IL)-1β in tumor tissues were higher than those in non-cancerous tissues. The level of secreted IL-1β in tumor tissues was also increased, as compared to that in normal tissues. Silencing of NLRP3 in KYSE-70 and TE13 cells strongly attenuated cell viability, decreased cell mobility in wound-healing assays and greatly diminished the ability of cell migration and invasion in the Transwell system. Overexpression of NLRP3 in KYSE-510 and EC9706 cells markedly promoted the proliferation, migration and invasion. Collectively, these results revealed that the the NLRP3 inflammasome is upregulated in human ESCC tissues and promotes ESCC progression. Hence, NLRP3 could be a promising new candidate diagnostic and prognostic target.

目的：饲喂牛磺酸和降低饲养密度对蛋鸡肾脏功能的影响。创新点：通过研究日粮中添加牛磺酸对不同饲养方式蛋鸡肾脏功能的影响,证实日粮中添加牛磺酸和降低饲养密度均能降低蛋鸡肾脏损伤程度。方法：将15 000只绿壳蛋鸡随机分成散养组、笼养低密度组和笼养高密度组,每组又分成对照组（正常日粮）和实验组（日粮中添加0.1%牛磺酸）。十五天后,无菌采集血液及肾脏组织,分析组织病理学变化、炎症介质水平、氧化及抗氧化水平等。结论：结果表明,降低饲养密度和日粮中添加牛磺酸可以改善肾脏损伤,促进生产,提高蛋鸡健康和福利水平。

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer’s disease.

Objective: Anxiety symptoms are persistent in Parkinson’s disease (PD), but the underlying neural substrates are still unclear. In the current study, we aimed to explore the underlying neural mechanisms in PD patients with anxiety symptoms. Methods: 42 PD-A patients, 41 PD patients without anxiety symptoms (PD-NA), and 40 healthy controls (HCs) were recruited in the present study. All the subjects performed 3.0T fMRI scans. The fractional amplitude of low-frequency fluctuation (fALFF) analysis was used to investigate the alterations in neural activity among the three groups. A Pearson correlation analysis was performed between the altered fALFF value of the PD-A group and anxiety scores. Results: Compared with HCs, PD-A patients had higher fALFF values in the left cerebellum, cerebellum posterior lobe, bilateral temporal cortex, and brainstem and lower fALFF values in the bilateral inferior gyrus, bilateral basal ganglia areas, and left inferior parietal lobule. Moreover, between the two PD groups, PD-A patients showed higher fALFF values in the right precuneus and lower fALFF values in the bilateral inferior gyrus, bilateral basal ganglia areas, left inferior parietal lobule, and left occipital lobe. Furthermore, Pearson’s correlation analysis demonstrated that the right precuneus and left caudate were correlated with the Hamilton Anxiety Rating Scale scores. Conclusion: Our study found that anxiety symptoms in PD patients may be related to alterations of neurological activities in multiple brain regions. Furthermore, these may be critical radiological biomarkers for PD-A patients. Therefore, these findings can improve our understanding of the pathophysiological mechanisms underlying PD-A.

Sea water intrusion is an environmental problem cause by the irrational exploitation of coastal groundwater resources and has attracted the attention of many coastal countries. In this study, we used time series monitoring data of groundwater levels and tidal waves to analyze the influence of tide flow on groundwater dynamics in the southern Laizhou Bay. The auto-correlation and cross-correlation coefficients between groundwater level and tidal wave level were calculated specifically to measure the boundary conditions along the coastline. In addition, spectrum analysis was employed to assess the periodicity and hysteresis of various tide and groundwater level fluctuations. The results of time series analysis show that groundwater level fluctuation is noticeably influenced by tides, but the influence is limited to a certain distance and cannot reach the saltwater-freshwater interface in the southern Laizhou Bay. There are three main periodic components of groundwater level in tidal effect range (i.e. 23.804 h, 12.500 h and 12.046 h), the pattern of which is the same as the tides. The affected groundwater level fluctuations lag behind the tides. The dynamic analysis of groundwater indicates that the coastal aquifer has a hydraulic connection with seawater but not in a direct way. Owing to the existence of the groundwater mound between the salty groundwater (brine) and fresh groundwater, the maximum influencing distance of the tide on the groundwater is 8.85 km. Considering that the fresh-saline groundwater interface is about 30 km away from the coastline, modern seawater has a limited contribution to sea-salt water intrusion in Laizhou Bay. The results of this study are expected to provide a reference for the study on sea water intrusion.

Background Acute diarrhea is one of the most serious problems in global public health that causes considerable morbidity and mortality worldwide. Human caliciviruses (HuCV) including norovirus (NoV, genogroup GI and GII) and sapovirus (SaV), is a leading cause of acute sporadic diarrhea in individuals across all age groups. However, few studies had been conducted clarifying the characteristics of HuCV in diarrhea cases across all age groups in China. Our study was aimed at assessing the HuCV-related diarrhea burden and NoV genotypes distribution in southwest China. Methods The study was conducted in four hospitals in Kunming city, Yunnan province, from June 2014 to July 2015. Stool specimens were collected from 1,121 diarrhea cases and 319 healthy controls in outpatient departments. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect NoV (GI, GII) and SaV. Sequencing was applied to confirm the three viral infections and phylogenetic analysis was performed to determine their genotypes. A structured questionnaire was used to record the demographic information and clinical symptoms of subjects. Results HuCV was detected at an 11.0 % infection rate in 1,121 diarrhea cases and at 3.4 % rate in 319 non-diarrhea subjects ( p  < 0.0001, OR = 3.5, 95 % CI 1.8–6.5). The prevalence of the NoV genogroup GII and genotype GII.4 in diarrhea cases was significantly higher than that found in healthy controls ( p  < 0.0001, p  = 0.018, respectively). NoV GII ( n  = 118, 10.5 %) was the most common HuCV subtype in diarrhea cases, followed by SaV ( n  = 3, 0.3 %) and NoV GI ( n  = 2, 0.2 %). Of 118 NoV GII strains isolated from diarrhea patients. GII.4 ( n  = 55, 46.6 %) was the predominant strain, followed by GII.3 ( n  = 28, 23.7 %), GII.12 ( n  = 25, 21.2 %), GII.17 ( n  = 8, 6.8 %), and GII.5 ( n  = 2, 1.7 %). Of the 55 GII.4 strains, the GII.4 Sydney 2012 variant had absolutely predominant prevalence ( n  = 52, 94.5 %), followed by the NoV GII.4-2006b variant ( n  = 3, 5.5 %). The GII.4 Orleans 2009 variant was not found in diarrhea cases of the study. Conclusions NoV GII was the major genogroup and GII.4 was the most predominant strain detected in diarrhea patients. The GII.17 is an emergent variant in sporadic diarrhea and might become the predominant strain in diarrhea cases in the near future. Rapid, accurate detection kits need to be developed to help us find and treat NoV-associated diarrhea in clinical settings in a timely manner.