Alpha-Synuclein Disrupted Dopamine Homeostasis Leads to Dopaminergic Neuron Degeneration in Caenorhabditis elegans

This is the publisher's version, also available electronically from http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009312Disruption of dopamine homeostasis may lead to dopaminergic neuron degeneration, a proposed explanation for the specific vulnerability of dopaminergic neurons in Parkinson's disease. While expression of human α-synuclein in C. elegans results in dopaminergic neuron degeneration, the effects of α-synuclein on dopamine homeostasis and its contribution to dopaminergic neuron degeneration in C. elegans have not been reported. Here, we examined the effects of α-synuclein overexpression on worm dopamine homeostasis. We found that α-synuclein expression results in upregulation of dopamine synthesis and content, and redistribution of dopaminergic synaptic vesicles, which significantly contribute to dopaminergic neuron degeneration. These results provide in vivo evidence supporting a critical role for dopamine homeostasis in supporting dopaminergic neuron integrity

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer

Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer

Small Molecule Inhibitors of 15-PGDH Exploit a Physiologic Induced-Fit Closing System

15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine

The impact of dyslipidemia on prognosis of patients after endovascular abdominal aortic aneurysm repair

IntroductionDyslipidemia is common in patients with abdominal aortic aneurysm (AAA). However, there is insufficient research on the impact of dyslipidemia on the postoperative outcomes of patients with AAA after endovascular aortic aneurysm repair (EVAR). This study aimed to determine the impact of dyslipidemia on the prognosis of patients with AAA treated with EVAR.MethodWe retrospectively reviewed patients with AAA who underwent EVAR at our hospital between 2010 and 2020. The baseline characteristics and prognoses of patients in the dyslipidemia and non-dyslipidemia groups were analyzed.ResultsA total of 641 patients were included; the prevalence of dyslipidemia in patients with AAA was 42.3% (271/641), and the mean follow-up time was 63.37 ± 26.49 months. The prevalence of diabetes (10.0% vs. 15.1%, P = 0.050), peripheral arterial disease (17.3% vs. 25.8%, P = 0.018), and chronic kidney disease (3.0% vs. 6.3%, P = 0.043) was higher in the dyslipidemia group. The three-year all-cause mortality rate after EVAR was 9.98% (64/641), and there was no difference in the incidence of all-cause mortality (10.27% vs. 9.59%, P = 0.778) between the two groups. A total of 36 (5.62%) major adverse cardiovascular and cerebrovascular events (MACCEs) were observed within 3 years and were more common in patients with dyslipidemia (2.97% vs. 9.59%, P < 0.001). The incidence of stent-related complications in all patients was 19.97% (128/641), and there was no difference in the incidence of stent-related complications between the two groups (22.16% vs. 16.97%, P = 0.105); however, the incidence of type I endoleak in the dyslipidemia group was lower than that in the non-dyslipidemia group (9.19% vs. 4.06%, P = 0.012). Cox-regression analysis showed that high level of high-density lipoprotein cholesterol (HDL-C) was the protective factor (HR, 0.203, 95% CI, 0.067–0.616, P = 0.005) for MACCES, but it was the risk factor for type I endoleak (HR, 2.317, 95% CI, 1.202–4.466, P = 0.012).ConclusionDyslipidemia did not affect the mortality of patients with AAA who underwent EVAR; however, it may increase the incidence of MACCEs. Dyslipidemia may decrease the incidence of type I endoleaks after EVAR; however, further studies are warranted. We should strengthen the postoperative management of patients with dyslipidemia, prevent the occurrence of MACCEs

(Li0.84Fe0.16)OHFe0.98Se superconductor: Ion-exchange synthesis of large single crystal and highly two-dimensional electron properties

A large and high-quality single crystal (Li0.84Fe0.16)OHFe0.98Se, the optimal superconductor of newly reported (Li1-xFex)OHFe1-ySe system, has been successfully synthesized via a hydrothermal ion-exchange technique. The superconducting transition temperature (Tc) of 42 K is determined by magnetic susceptibility and electric resistivity measurements, and the zero-temperature upper critical magnetic fields are evaluated as 79 and 313 Tesla for the field along the c-axis and the ab-plane, respectively. The ratio of out-of-plane to in-plane electric resistivity,\r{ho}c/\r{ho}ab, is found to increases with decreasing temperature and to reach a high value of 2500 at 50 K, with an evident kink occurring at a characteristic temperature T*=120 K. The negative in-plane Hall coefficient indicates that electron carriers dominate in the charge transport, and the hole contribution is significantly reduced as the temperature is lowered to approach T*. From T* down to Tc, we observe the linear temperature dependences of the in-plane electric resistivity and the magnetic susceptibility for the FeSe layers. Our findings thus reveal that the normal state of (Li0.84Fe0.16)OHFe0.98Se becomes highly two-dimensional and anomalous prior to the superconducting transition, providing a new insight into the mechanism of high-Tc superconductivity.Comment: 11 pages, 4 figures, supplementary information is not uploade