FANCM AND FAAP24 MAINTAIN GENOMIC STABILITY THROUGH COOPERATIVE AND UNIQUE FUNCTIONS

Fanconi anemia (FA) is a rare recessive genetic disease with an array of clinical manifestations including multiple congenital abnormalities, progressive bone marrow failure and profound cancer susceptibility. A hallmark of cells derived from FA patients is hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin, suggesting that FA- and FA-associated proteins play important roles in protecting cells from DNA interstrand crosslink (ICL) damage. Two genes involved in the FA pathway, FANCM and FAAP24, are of particular interest because they contain DNA interacting domains. However, there are no definitive patient mutations for these two genes, and the resulting lack of human genetic model system renders their functional studies difficult. In this study, I established isogenic human FANCM- and FAAP24-null mutants through homologous replacement-mediated gene targeting in HCT-116 cells, and systematically investigated the functions of FANCM and FAAP24 inchromosome stability, FA pathway activation, DNA damage checkpoint signaling, and ICL repair. I found that the FANCM-/-/FAAP24-/- double mutant was much more sensitive to DNA crosslinking agents than FANCM-/- and FAAP24-/- single mutants, suggesting that FANCM and FAAP24 possess epistatic as well as unique functions in response to ICL damage. I demonstrated that FANCM and FAAP24 coordinately support the activation of FA pathway by promoting chromatin localization of FA core complex and FANCD2 monoubiqutination. They also cooperatively function to suppress sister chromatid exchange and radial chromosome formation, likely by limiting crossovers in recombination repair. In addition, I defined novel non-overlapping functions of FANCM and FAAP24 in response to ICL damage. FAAP24 plays a major role in activating ICL-induced ATR-dependent checkpoint, which is independent of its interaction with FANCM. On the other hand, FANCM promotes recombination-independent ICL repair independently of FAAP24. Mechanistically, FANCM facilitates recruitment of nucleotide excision repair machinery and lesion bypass factors to ICL damage sites through its translocase activity. Collectively, my studies provide mechanistic insights into how genome integrity is both coordinately and independently protected by FANCM and FAAP24

FDI Regimes in the Chinese Triangle

The existence of regimes on foreign direct investment (FDI) in the Chinese triangle (China, Hong Kong and Taiwan) is one of the most important elements that promote rapid FDI inter-flows and economic integration within the triangle. The economic policies and FDI inter-flows are leading to their regimes harmonize with international standards. Cultural backgrounds and ideological conflicts have an impact on shaping legalism towards their FDI regimes. Their FDI regimes also reflect the interaction between market and government. As their domestic markets being oriented toward a bigger and more competitive international market, FDI regimes in the triangle need to be, at least, harmonized with each other and with international standards. Learning from East Asian countries' past examples of rapid economic growth and recent lessons of financial crisis, governments within the triangle need to improve their FDI regimes to support the Chinese triangle to be more dynamic and harmony. In this thesis, after exploiting the backgrounds of FDI regimes in the triangle, I first compared the systems and effects of FDI regimes in the Chinese triangle, then analyzed their integration and harmonization trends. In conclusion, both market mechanisms and government strategies can and have played an important and effective role in the triangle in building regimes to attract FDI inflows to support their economic development and integration with each other. Meanwhile, as part of their legal systems that belong to three major different legal systems in the world, the integration and harmonization of FDI regimes in the triangle could be a useful preparation for the harmonization of international investment law

SIMULATION OF A SILICON NANOWIRE FET BIOSENSOR FOR DETECTING BIOTIN/STREPTAVIDIN BINDING

Silicon nanowire field-effect transistor (SiNW FET) biosensors have recently been demonstrated experimentally for direct, label free, high sensitive, high selective and real time detection of DNA and proteins at very low concentration. Among these experiments, the detection of biotin/streptavidin binding is of special interest since the biotin/streptavidin system exhibits one of the strongest noncovalent biological interactions known in nature. Thus, biotin/streptavidin system is widely demonstrated as a model system to study biorecognition between proteins and other biomolecules. Despite these promising experimental results and their enormous potential, it is somewhat surprising that the fundamental mechanism of electrical sensing of biomolecules and the design principles of SiNW FET biosensor remain poorly understood. In this work, a comprehensive modeling theory and simulation approach is presented to account for the underlying detection mechanism of biotin/Streptavidin binding using SiNW FET biosensor. The influence of parameters like the dimension of the SiNW, the doping of the SiNW, and surrounding environment (the ions concentration in the solvent) are investigated for the performance optimization of the SiNW FET biosensor. The preliminary simulation results indicate that the optimal sensor performance can be ensured by careful optimization of its parameters and it is feasible to detect binding of single streptavidin molecule when optimal parameters are chosen

The Role of T-Type Calcium Channel Genes in Absence Seizures

The thalamic relay neurons, reticular thalamic nucleus, and neocortical pyramidal cells form a circuit that sustains oscillatory burst firing, and is regarded as the underlying mechanism of absence seizures. T-type calcium channels play a key role in this circuit. Here, we review the role of T-type calcium channel genes in the development of absence seizures, and emphasize gain or loss of function mutations, and other variations that alter both quantity and quality of transcripts, and methylation status of isoforms of T-type calcium channel proteins might be of equal importance in understanding the pathological mechanism of absence seizures

The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

Hematological toxicity; Infectious complicationsToxicidad hematológica; Complicaciones infecciosasToxicitat hematològica; Complicacions infecciosesCD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.KR received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK) and was funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP). This work was supported by a grant within the Gilead Research Scholar Program (to KR, MS), the Bruno & Helene Jöster foundation (to KR, MS), and by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/12021–452881907 and DFG research grant 451580403 (to MS). This work was in part supported by NCI/NIH P30CA076292. FLL is in part supported as a Clinical Scholar by the Leukemia and Lymphoma Society. The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF)

Mycotoxigenic potentials of Fusarium species in various culture matrices revealed by mycotoxin profiling

In this study, twenty of the most common Fusarium species were molecularly characterized and inoculated on potato dextrose agar (PDA), rice and maize medium, where thirty three targeted mycotoxins, which might be the secondary metabolites of the identified fungal species, were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analysis was performed with principal component analysis (PCA) to characterize the mycotoxin profiles for the twenty fungi, suggesting that these fungi species could be discriminated and divided into three groups as follows. Group I, the fusaric acid producers, were defined into two subgroups, namely subgroup I as producers of fusaric acid and fumonisins, comprising of F. proliferatum, F. verticillioides, F. fujikuroi and F. solani, and subgroup II considered to only produce fusaric acid, including F. temperatum, F. subglutinans, F. musae, F. tricinctum, F. oxysporum, F. equiseti, F. sacchari, F. concentricum, F. andiyazi. Group II, as type A trichothecenes producers, included F. langsethiae, F. sporotrichioides, F. polyphialidicum, while Group III were found to mainly produce type B trichothecenes, comprising of F. culmorum, F. poae, F. meridionale and F. graminearum. A comprehensive picture, which presents the mycotoxin-producing patterns by the selected fungal species in various matrices, is obtained for the first time, and thus from an application point of view, provides key information to explore mycotoxigenic potentials of Fusarium species and forecast the Fusarium infestation/mycotoxins contamination

Myrica rubra Extracts Protect the Liver from CCl4-Induced Damage

The relationship between the expression of mitochondrial voltage-dependent anion channels (VDACs) and the protective effects of Myrica rubra Sieb. Et Zucc fruit extract (MCE) against carbon tetrachloride (CCl4)-induced liver damage was investigated. Pretreatment with 50 mg kg−1, 150 mg kg−1 or 450 mg kg−1 MCE significantly blocked the CCl4-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels in mice (P < .05 or .01 versus CCl4 group). Ultrastructural observations of decreased nuclear condensation, ameliorated mitochondrial fragmentation of the cristae and less lipid deposition by an electron microscope confirmed the hepatoprotection. The mitochondrial membrane potential dropped from −191.94 ± 8.84 mV to −132.06 ± 12.26 mV (P < .01) after the mice had been treated with CCl4. MCE attenuated CCl4-induced mitochondrial membrane potential dissipation in a dose-dependent manner. At a dose of 150 or 450 mg kg−1 of MCE, the mitochondrial membrane potentials were restored (P < .05). Pretreatment with MCE also prevented the elevation of intra-mitochondrial free calcium as observed in the liver of the CCl4-insulted mice (P < .01 versus CCl4 group). In addition, MCE treatment (50–450 mg kg−1) significantly increased both transcription and translation of VDAC inhibited by CCl4. The above data suggest that MCE mitigates the damage to liver mitochondria induced by CCl4, possibly through the regulation of mitochondrial VDAC, one of the most important proteins in the mitochondrial outer membrane

Research Article Detect Adjacent Well by Analyzing Geomagnetic Anomalies

Abstract: This study describes a method of determining the position of adjacent well by analyzing geomagnetic anomalies in the drilling. In the experiment, put a casing in the geomagnetic field respectively to simulate 3 conditions, which are vertical well, deviated well and horizontal well. Study the interference of regional geomagnetic caused by casing, summary the law of the regional geomagnetic field anomalies caused by the adjacent casing. Experimental results show that: magnetic intensity distortion caused by deviated well is similar to that caused by horizontal well, but the distortion is different from vertical well. The scope and amplitude of N and E component magnetic intensity distortion will increase with the increase of casing inclination, meanwhile the scope and amplitude of V component distortion will decrease and the distortion value changes from negative to positive to the southwest of adjacent well. Through the analysis of geomagnetic anomalies, the position of the adjacent wells could be determined