Pathogenic Mutations Differentially Regulate Cell-to-Cell Transmission of α-Synuclein

Recent studies suggest that the cell-to-cell spread of pathological α-synuclein (α-syn) plays important roles in the development of Parkinson’s disease (PD). PD patients who carry α-syn gene mutations often have an earlier onset and more severe clinical symptoms and pathology than sporadic PD cases who carry the wild-type (WT) α-syn gene. However, the molecular mechanism by which α-syn gene mutations promote PD remains unclear. Here, we hypothesized that pathogenic mutations facilitate the intercellular transfer and cytotoxicity of α-syn, favoring an early disease onset and faster progression. We investigated the effects of eight known pathogenic mutations in human α-syn (A18T, A29S, A30P, E46K, H50Q, G51D, A53E, and A53T) on its pathological transmission in terms of secretion, aggregation, intracellular level, cytotoxicity, seeding, and induction of neuroinflammation in SH-SY5Y neuroblastoma cells, cultured rat neurons, and microglia, and the rat substantia nigra pars compacta. We found that 2 of the 8 mutations (H50Q and A53T) significantly increased α-syn secretion while 6 mutations (A18T, A29S, A30P, G51D, A53E, and E46K) tended to enhance it. In vitroα-syn aggregation experiments showed that H50Q promoted while G51D delayed aggregation most strongly. Interestingly, 3 mutations (E46K, H50Q, and G51D) greatly increased the intracellular α-syn level when cultured cells were treated with preformed α-syn fibrils (PFFs) compared with the WT, while the other 5 had no effect. We also demonstrated that H50Q, G51D, and A53T PFFs, but not E46K PFFs, efficiently seeded in vivo and acutely induced neuroinflammation in rat substantia nigra pars compacta. Our data indicate that pathogenic mutations augment the prion-like spread of α-syn at different steps and blockade of this pathogenic propagation may serve as a promising therapeutic intervention for PD

The Evolving Role of Transcatheter Tricuspid Valve Edge-to-Edge Repair in Tricuspid Regurgitation

Growing evidence indicates that severe tricuspid regurgitation (TR) is independently associated with adverse clinical outcomes. The prognostic benefit of isolated TR surgery remains unclear, and medical therapy for decompensated right heart failure alone cannot delay disease progression. TR assessment and management have substantially evolved in recent years. Currently, minimally invasive catheter-based techniques have emerged as a feasible and effective option for TR treatment in high-risk surgical patients. Transcatheter tricuspid valve edge-to-edge repair (T-TEER) has been proposed and applied as an interventional treatment for TR, and has yielded promising preliminary results. This review provides an overview of the current state of T-TEER

An analysis of farmers' perception of the new cooperative medical system in Liaoning Province, China

<p>Abstract</p> <p>Background</p> <p>Since 2003, the number of pilot areas of the New Rural Cooperative Medical System (NRCMS) has increased in rural China. And the major efforts have been concentrated on the enrollment of prospective members. In this study, we examined the satisfaction of the rural residents with the NRCMS as well as factors affecting their attitudes towards the NRCMS.</p> <p>Methods</p> <p>The data for this study were collected from a survey involving twenty counties in Liaoning Province. Interviews and focus groups were conducted between 10^thJanuary and 20^thAugust 2008. A total of 2,780 people aged 18-72 were randomly selected and interviewed. Data were evaluated by nonparametric tests and ordinal regression models.</p> <p>Results</p> <p>71.6% of the study subjects were satisfied with the NRCMS. Single factor analysis showed that attitudes towards the NRCMS were influenced by gender, age, marital status, and self-rated health status. In the ordinal regression analysis, gender, age, and self-rated health status affect satisfaction (P < 0.05).</p> <p>Conclusions</p> <p>We found that a considerable proportion of farmers were satisfied with the NRCMS. Gender, age, and self-rated health status had significant effects on farmers' attitudes towards the NRCMS. The Chinese Central Government attempted to adopt active measures in the future to continuously improve the NRCMS, including initiating educational programs, building new medical facilities and increasing financial investment.</p

Melanoma NOS1 expression promotes dysfunctional IFN signaling.

In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells

Non-covalent interactions for directing self-assembly of supramolecular architectures towards nanocontainers

Self-assembly and folding with primary oligomers rely on various non-covalent interactions are important for generating higher-order secondary or tertiary structures of large biological molecules, from which emerge their sophisticated functions. Mimicking this approach for the self-assembly of complex artificial supramolecular structures is still challenging. Building blocks with characteristics like low symmetry and flexibility, while common in biological systems, pose numerous problems for synthetic self-assembly. In this thesis, the research aims to advance knowledge of how non-covalent interactions designed into aromatic amide based building blocks for self-assembly can be used to control conformation and generate complementary shapes for directing self-assembly of larger structures and through this to develop an approach that could allow the formation of more complex structures with interesting properties and reactivities. This work is divided into two different but complementary approaches: 1) Metal-based self-assembly of aromatic amide units and 2) The use of multiple helix formation in aromatic oligoamides as a driving force for self-assembly of larger systems. In chapter 3, a series of heteroaromatic amide-based ligands (L1-L5) were synthesized and used for coordination-driven self-assembly of MnL2n polyhedral cages. Despite the flexibility around the amide bonds, non-covalent interactions in the ligands lead to preferential curved conformational states that orient the coordination sites and allow sufficient control over the bend angles of the ligands giving access to M2(L1)4, M6(L2)12, and M12(L2)24 cages. Additionally, the multiple endohedral hydrogen bonding sites on the ligand were found to play a role in the binding and discrimination of neutral guests. The subsequent work in chapter 4 studied the more complex novel dual curvature ligands (L6-L18). These were obtained using a Diels-Alder reaction to break the symmetry of the ligands and incorporate additional steric constraints and complementary shapes for self-assembly. Mixing the dual curvature ligands with Pd2+ ions demonstrates that these constraints could help direct self-assembly towards a single M2L4 cage or M4L8 double-walled metallomacrocycle out of hundreds of possible isomers. Moreover, this gives access to endohedrally functionalized M4L8 cages for different applications. Next, using the idea of the Diels-Alder reaction, we studied covalent post-modification in chapter 5 as a shorter alternative pathway to achieve similar complex structural and functional diversity. Two dienophiles, 4-Phenyl-1,2,4-triazoline-3,5-dione and 1-Methyl-1H-pyrrole-2,5-dione used for the synthesis of ligands (L19 and L20) and their self-assembly studied. Importantly, the ligand L19, due to the high dynamic exchange between its enantiomers, simplified the self-assembled mixtures, allowing easy NMR characterization and crystallization. Using this as a reference, we were able to covalently post-modify the metal-organic architectures at room temperature using 4-phenyl-1,2,4-triazoline-3,5-dione 5.01 and found that a new cage species could be formed. Although the nature of this cage species still requires further study, it demonstrates a rapid and facile approach to tune structures and functionalities of metal-organic architectures through covalent post-modification. Finally, in chapter 6, we describe another important advance in this thesis, a proof of concept work on the use of multiple helix formation with aromatic oligoamide foldamers as a driving force for the self-assembly of higher-ordered architectures. Based on the results and experience from coordination-driven self-assembly, two kinds of ligands were designed with central linkers differing in bend angles and rigidity. An optimized synthetic method was established and allowed us to obtain two foldamer-based ligands, L22 and L23. Importantly, NMR and MS studies for ligand L22 showed promising results suggesting it can assemble into larger structures, providing a proof of concept for our idea.(SC - Sciences) -- UCL, 202

Dividend Problems in the Diffusion Model with Interest and Exponentially Distributed Observation Time

Consider dividend problems in the diffusion model with interest and exponentially distributed observation time where dividends are paid according to a barrier strategy. Assume that dividends can only be paid with a certain probability at each point of time; that is, on each observation, if the surplus exceeds the barrier level, the excess is paid as dividend. In this paper, integrodifferential equations for the moment-generating function, the nth moment function, and the Laplace transform of ruin time are derived; explicit expressions for the expected discounted dividends paid until ruin and the Laplace transform of ruin time are also obtained

Mapping the Paths from Styles of Anger Experience and Expression to Obsessive–Compulsive Symptoms: The Moderating Roles of Family Cohesion and Adaptability

Previous research has shown strong connections of anger experience and expression with obsessive–compulsive (OC) symptoms. Additionally, studies have demonstrated links between family environment variables and obsessive–compulsive disorder (OCD). Our study aims to integrate the perspectives from these two literatures by exploring the moderating roles of family cohesion and family adaptability in the relationship between anger proneness and suppression and OCD symptoms. A total of 2008 college students were recruited from a comprehensive university in Shanghai, China between February and May 2016. The subjects completed self-report inventories, including the Symptom Check List-90, State-Trait Anger Expression Inventory 2 (Chinese version), and Family Adaptability and Cohesion Scale, second edition (Chinese Version). Controlling for age, one-child family status, ethnicity, family income, current depression, and anxiety, our analyses showed that the association between anger proneness and OC symptoms was moderated by family cohesion among men and that family adaptability moderated the connection between anger suppression and OC complaints among women. The findings imply that a more cohesive and empathic family environment may protect male students with high levels of anger proneness from developing OC behaviors or thoughts. The results suggest that for female subjects who are accustomed to suppressing angry feelings, flexible family coping strategies and communication atmospheres would reduce their vulnerability to OC symptoms. The findings are somewhat consistent with those of previous studies on psychotherapy outcomes that showed that OCD patients benefitted from psychotherapeutic interventions that cultivated the clients’ family cohesion and adaptability

The involvement of MiR-1-clathrin pathway in the regulation of phagocytosis.

Phagocytosis, one of the most powerful immune responses, is a complicated process regulated by many factors. However the regulation of phagocytosis mediated by microRNAs has not been extensively investigated. To address this issue, the regulation of phagocytosis by miR-1 was characterized in this study. The results showed that miR-1 played an important role in the phagocytosis regulation in shrimp in vivo. The sequence analysis indicated that miR-1 was highly conserved from invertebrates to mammals, suggesting that miR-1 might share the similar or same functions in phagocytosis of shrimp hemocytes and mammalian macrophages. The data presented that miR-1 was significantly downregulated in cancerous macrophage RAW264.7 cells compared with those in the isolated murine macrophage and in the immortalized macrophage ANA-1. The findings showed that miR-1 had a great effect on the regulation of phagocytosis in cancerous macrophage by the inhibition of clathrin heavy chain 1 (CLTC1) gene. Therefore our study presented a novel miR-1-mediated regulation of phagocytosis both in invertebrate and in vertebrate

Vulnerability Evaluation of Port Logistics System Under Public Health Emergencies

It is the goal that evaluating scientifically port logistics system vulnerability level under public health emergencies, exploring the influencing factors of brittleness and improving the production operation and management efficiency of port logistics system. According to the production practice of port logistics system and vulnerability theory, a vulnerability evaluation index system of port logistics system under public health emergencies is established in five aspects, including external risk disturbance, human resource management level, infrastructure level, operation and management level, and intelligence level. The combinatorial weights are obtained by combinatorial empowerment method of game theory, and it is used to process data that evidence theory improved by conflict correction process and mass function with normal cloud model. The vulnerability of Dalian port logistics system is analyzed empirically, and the result is better effectiveness