China's Proposal for the Eastern Mediterranean Conflict Resolution: A "Developmental Peace"

The Eastern Mediterranean is one of the epicenters of Middle Eastern conflicts ranging from internal and bilateral to multilateral disputes. Outside powers adhere to diverse outlooks of peace initiatives. The western liberalists highlight "democratic peace", emphasizing that "democracy deficit" causes conflict. China favors the "developmental peace" proposal and argues that conflicting parties can achieve peace through domestic and regional development. China dispatched peacekeeping forces to Lebanon for humanitarian rescues for the Republic in 2020, offered developmental aid and economic assistance to Lebanon, Syria and Palestine to improve their capacity with key infrastructure and livelihood projects as the centerpiece, and participated in post-war reconstruction in the three war-torn countries as well. The "developmental peace" argument is based on China's four-decade-long Reform and Opening-up experience, a potentially new scenario for the Eastern Mediterranean conflict resolution

Pharmacogenetics of warfarin

Warfarin is one of the most commonly used oral anticoagulants worldwide and is highly efficacious for the treatment and prevention of thromboembolic disorders. However, due to its narrow therapeutic index and large interindividual variability, it remains a challenging drug to prescribe. Genetic factors (CYP2C9 and VKORCI), together with clinical factors (age and body weight), account for up to 60% of warfarin dose variance but the remaining ~40% variability remains unexplained. A polymorphism rs2108622 in CYP4F2, a vitamin K oxidase, has previously been associated with increased warfarin stable dose requirements, accounting for 1-7% dose variability. In our cohort of prospectively recruited patients (n = 311), we were unable to confirm these results. Interestingly, after fine mapping of the CYP4F2 gene region, we found a SNP rs2189784, which is in LD with rs2108622, to be associated with time to therapeutic INR (Pc = 0.03). Further fine mapping of the CYP4F gene cluster together with the utilisation a bank of well characterized Caucasian surgical liver samples (n = 149) and data from a genome-wide association study (n = 714), showed that CYP4F2 rs2108622 and rs2189784 SNPs were found to be associated with increasing CYP4F2 and decreasing CYP4FII or CYP4Fl2 mRNA expression, respectively. Interestingly, a CYP4Fll variant rsl060467 (in LD with rs2108622) was associated with reduced CYP4F2 rnRNA expression. Furthermore, rsl060467 contributes to 2.5% of warfarin dose variability and was associated with reduced warfarin dose requirement (~1 mg/day, Pc = 0.003), an effect in the opposite direction previously reported with CYP4F2 rs2108622 by Caldwell et al. (2008) and other studies. Warfarin-resistant patients have been reported to harbour VKORCI missense mutations. Extended regions of VKORCI were sequenced in our patients (n = 65) with resistance to warfarin, defined by clinical and pharmacodynamic criteria. Seven novel heterozygous mutations were identified and in silica analyses predicted the promoter c.-160G>C mutation creates a putative Spl transcription factor binding site and that the missense mutation c.79C>G to be deleterious. To confirm these predictions, in vitro functional studies were carried out using EMSA, transient transfection assays, and DNA methylation. c.-160G>C was found to create a weak binding site for Spl transcription factor, and caused an increase in promoter activity by ~20% (P = 0.003). The c.79C>G mutation reduced levels of PIVKA-II by ~10%. Associations of VKORCI genotypes with DNA methylation did not remain significant after correction for multiple testing. The effect of warfarin on the rate of decline of vitamin K-dependent clotting factors, and the role of SNPs in the clotting factor genes, is not known. Using a large prospective cohort of patients (n = 619), SNPs in F7 and F 10 genes showed association with variability in factor VII levels. The rate at which the plasma levels of factors II, X and protein C decline affect how patients respond to warfarin, in particular the achievement of warfarin stable dose and time to therapeutic INR. Furthermore, the change in clotting factor X level accounted for 1.4% of warfarin dose variability. In conclusion, the results presented in this thesis demonstrate that multiple genetic, clinical and biochemical factors account for the variability in warfarin response. Further understanding of such complex interactions, along with the advent of genomics technologies and development of new computational and conceptual tools, will yield insights to the accurate prediction of drug efficacy and toxicity, which will hopefully translate into improved outcomes for patients

Vivre avec les déchets :

Cet article analyse le rôle des déchets et leurs significations dans la formation des communautés de récupérateurs dans les métropoles chinoises actuelles. Nous y montrons qu’en Chine, les récupérateurs de déchets rappellent, dans une certaine mesure, les conditions d’un travail précaire et stigmatisant typique des sociétés du Sud. Mais nous avons remarqué qu’en Chine, les raisons financières seules ne permettaient pas d’éclairer ce qui poussait les travailleurs migrants à se lancer dans cette activité. En fait, les récupérateurs de déchets de Pékin entraient aussi dans ce commerce car il procurait l’expérience d’une forme de citoyenneté urbaine, en s’affranchissant du régime de travail des usines et en s’adonnant à une forme d’entreprenariat rendant possible le fait de fonder un foyer dans la périphérie de la capitale du pays. Leurs techniques de travail avec les déchets offrent un prisme pour comprendre une dimension plus large de la vie sociale et culturelle au sein des communautés de récupérateurs d’une grande ville chinoise – ce que nous désignons par « vivre avec les déchets ». Dans cet article, l’expression s’entend comme un cadre qui englobe les efforts déployés pour travailler avec, faire l’expérience de, et vivre parmi les matières résiduelles au quotidien. Comment les récupérateurs de déchets parlent-ils de leur métier ? S’agit-il uniquement de stigmatisation et de souffrance ? Peut-il signifier commerce et mobilité ? Que pensent les récupérateurs du fait d’élever des enfants dans une cour remplie de déchets récupérés ? Si « la saleté est matière mal placée (dirt is matter out of place) » (Douglas 1966), comment gèrent-ils les impuretés et la contamination au quotidien ? Quels efforts font-ils pour normaliser ou établir des limites dans cet environnement indésirable de travail et de vie ? Vivre avec les déchets est donc profondément lié aux efforts produits non seulement pour gagner sa vie, mais aussi pour constamment renégocier sa position et tracer des frontières avec les déchets au sein de la famille et de la communauté, ceci afin de rendre ce travail supportable, voire porteur de sens

The contracting benefits of accounting conservatism to lenders and borrowers

Thesis (Ph. D.)--Massachusetts Institute of Technology, Sloan School of Management, 2005.Includes bibliographical references (leaves 55-57).In this paper, I examine the ex post and ex ante benefits of conservatism to lenders and borrowers in the debt contracting process. First, I argue that conservatism benefits lenders ex post through a timely signal of default risk in the form of accelerated covenant violations by more conservative borrowers. I present evidence that the likelihood of a covenant violation following a negative shock increases in borrower conservatism. Second, I argue that conservatism benefits borrowers ex ante through lower initial interest rates. I provide both in- sample and out-of-sample evidence that lenders offer lower interest rates to more conservative borrowers. The result is robust to controlling for a series of other earnings attributes.by Jieying Zhang.Ph.D

Deciphering the role of HPV-mediated metabolic regulation in shaping the tumor microenvironment and its implications for immunotherapy in HNSCC

Head and neck squamous cell carcinoma (HNSCC), as a complex and variable malignancy, poses a significant threat to human health. Since the intricate association between HPV and HNSCC emerged, its role within the TME has garnered extensive attention. HPV+HNSCC exhibits distinct immunological characteristics within the TME, intricately intertwined with mechanisms of immune evasion. HPV employs multifaceted pathways to intervene in metabolic regulation within the TME, exerting influence over immune cell functionality and neoplastic cell genesis. Furthermore, the heightened immune reactivity exhibited by HPV+HNSCC within the TME augments responses to immune interventions such as immune checkpoint inhibitors. Therefore, amidst the current limitations of therapeutic approaches, immunotherapy stands as a promising strategy to overcome the conventional confines of treating HNSCC. This article comprehensively outlines the impact of HPV on the inception and progression of HNSCC while discussing the amalgamation of metabolic regulation within the TME and immunotherapeutic strategies. By intervening in the reciprocal interactions between HPV and HNSCC within the TME, the potential to modulate the efficacy of immune-based treatments becomes evident. Concurrently, a synthesis of pertinent biomarker development is summarized. Such endeavors hold paramount significance for personalized therapeutic approaches and the more effective management of HNSCC patients

M2 macrophage inhibits the antitumor effects of Lenvatinib on intrahepatic cholangiocarcinoma

Background and objectivesThe relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors. Tumor-associated macrophages (TAMs) are important inflammatory cells in the tumor microenvironment and play an important role in tumorigenesis and progression. Macrophages in malignant tumors, mainly the M2 subtype, promote tumor progression by producing cytokines and down-regulating anti-inflammatory immune responses. Several articles have investigated the effect of macrophages on the sensitivity of cancer chemotherapeutic agents, but few such articles have been reported in cholangiocarcinoma, so we investigated the effect of M2 macrophage on the sensitivity of cholangiocarcinoma cells to Lenvatinib compared to M1.MethodsTHP-1 monocytes were polarized to M0 macrophage by phorbol 12-myristate 13-acetate (PMA) and then induced to differentiate into M1 and M2 macrophages by LPS, IFN-γ and IL-4 and IL-13, respectively. Macrophages and cholangiocarcinoma cells were co-cultured prior to 24 hours of Lenvatinib administration, cancer cell apoptosis was detected by western-blot, FACS analysis of Annexin V and PI staining. Furthermore, we use xCELLigence RTCA SP Instrument (ACEA Bio-sciences) to monitor cell viability of Lenvatinib administration in co-culture of cholangiocarcinoma cells and macrophages. After tumorigenesis in immunodeficient mice, Lenvatinib was administered, and the effects of M2 on biological characteristics of cholangiocarcinoma cells were investigated by immuno-histochemistry.ResultsmRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1 derived macrophages, which provided a successful and efficient model of monocyte polarization to TAMs. Lenvatinib-induced apoptosis of cholangiocarcinoma cells was significantly reduced when co-cultured with M2 macrophage, whereas apoptosis of cholangiocarcinoma cells co-cultured with M1 macrophage was increased. In the CDX model, Lenvatinib-induced cancer cell apoptosis was markedly reduced, and proliferative cells increased in the presence of M2 macrophages. Angiogenesis related factors was significantly increased in cholangiocarcinoma cells co-cultured with M2.ConclusionCompared with M1, M2 macrophages can inhibit the anti-tumor effect of Lenvatinib on cholangiocarcinoma through immune regulation, which may be related to the tumor angiogenesis factor effect of M2 macrophage

Sampling strategies and integrated reconstruction for reducing distortion and boundary slice aliasing in high-resolution 3D diffusion MRI

Purpose: To develop a new method for high-fidelity, high-resolution 3D multi-slab diffusion MRI with minimal distortion and boundary slice aliasing. Methods: Our method modifies 3D multi-slab imaging to integrate blip-reversed acquisitions for distortion correction and oversampling in the slice direction (kz) for reducing boundary slice aliasing. Our aim is to achieve robust acceleration to keep the scan time the same as conventional 3D multi-slab acquisitions, in which data are acquired with a single direction of blip traversal and without kz-oversampling. We employ a two-stage reconstruction. In the first stage, the blip-up/down images are respectively reconstructed and analyzed to produce a field map for each diffusion direction. In the second stage, the blip-reversed data and the field map are incorporated into a joint reconstruction to produce images that are corrected for distortion and boundary slice aliasing. Results: We conducted experiments at 7T in six healthy subjects. Stage 1 reconstruction produces images from highly under-sampled data (R = 7.2) with sufficient quality to provide accurate field map estimation. Stage 2 joint reconstruction substantially reduces distortion artifacts with comparable quality to fully-sampled blip-reversed results (2.4× scan time). Whole-brain in-vivo results acquired at 1.22 mm and 1.05 mm isotropic resolutions demonstrate improved anatomical fidelity compared to conventional 3D multi-slab imaging. Data demonstrate good reliability and reproducibility of the proposed method over multiple subjects. Conclusion: The proposed acquisition and reconstruction framework provide major reductions in distortion and boundary slice aliasing for 3D multi-slab diffusion MRI without increasing the scan time, which can potentially produce high-quality, high-resolution diffusion MRI

Hybrid-space reconstruction with add-on distortion correction for simultaneous multi-slab diffusion MRI

Purpose: This study aims to propose a model-based reconstruction algorithm for simultaneous multi-slab diffusion MRI acquired with blipped-CAIPI gradients (blipped-SMSlab), which can also incorporate distortion correction. Methods: We formulate blipped-SMSlab in a 4D k-space with kz gradients for the intra-slab slice encoding and km (blipped-CAIPI) gradients for the inter-slab encoding. Because kz and km gradients share the same physical axis, the blipped-CAIPI gradients introduce phase interference in the z-km domain while motion induces phase variations in the kz-m domain. Thus, our previous k-space-based reconstruction would need multiple steps to transform data back and forth between k-space and image space for phase correction. Here we propose a model-based hybrid-space reconstruction algorithm to correct the phase errors simultaneously. Moreover, the proposed algorithm is combined with distortion correction, and jointly reconstructs data acquired with the blip-up/down acquisition to reduce the g-factor penalty. Results: The blipped-CAIPI-induced phase interference is corrected by the hybrid-space reconstruction. Blipped-CAIPI can reduce the g-factor penalty compared to the non-blipped acquisition in the basic reconstruction. Additionally, the joint reconstruction simultaneously corrects the image distortions and improves the 1/g-factors by around 50%. Furthermore, through the joint reconstruction, SMSlab acquisitions without the blipped-CAIPI gradients also show comparable correction performance with blipped-SMSlab. Conclusion: The proposed model-based hybrid-space reconstruction can reconstruct blipped-SMSlab diffusion MRI successfully. Its extension to a joint reconstruction of the blip-up/down acquisition can correct EPI distortions and further reduce the g-factor penalty compared with the separate reconstruction.Comment: 10 figures+tables, 8 supplementary figure