Search

Mutations in the hereditary breast/ovarian cancer genes BRCA1/2 were shown to be synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). This toxicity is assumed to derive from PARPi-induced DNA double strand breaks (DSBs) that necessitate BRCA function in homologous recombination (HR) and/or fork protection (FP). However, PARPi accelerates replication forks. While high-speed replication could cause DSBs, the finding that PARPi leads to single-stranded DNA (ssDNA) gaps/nicks suggests replication gaps could also or alone be the cause of synthetic lethality. Here, we demonstrate that PARPi toxicity derives from replication gaps. Isogenic cells deficient in BRCA1 or the BRCA1-associated FANCJ, with common DNA repair defects in HR and FP, exhibit opposite responses to PARPi. Deficiency in FANCJ, a helicase also mutated in hereditary breast/ovarian cancer and Fanconi anemia, causes aberrant accumulation of fork remodeling factor HLTF and limits unrestrained DNA synthesis with ssDNA gaps. Thus, we predict replication gaps as a distinguishing factor and further uncouple HR, FP and fork speed from PARPi response. BRCA-deficient cells display excessive gaps that are diminished upon resistance, restored upon re-sensitization and when targeted augment synthetic lethality with PARPi. Furthermore, we define the source of gaps to defects in Okazaki fragment processing (OFP). Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1 but aberrantly low XRCC1 indicating a defective backup OFP pathway. Remarkably, 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. Collectively, our study highlights unprotected lagging strand gaps as a determinant of synthetic lethality, providing a new paradigm and biomarker for PARPi toxicity.

This thesis was scanned from the print manuscript for digital preservation and is copyright the author. Researchers can access this thesis by asking their local university, institution or public library to make a request on their behalf. Monash staff and postgraduate students can use the link in the References field.

To obtain the normative values of the testis volume of 0－14 years old Chinese boys by ultrasound measurement.We collected the testicular ultrasound data on 1607 Chinese boys with normal testes between January 2016 and June 2019. The boys were aged 0－14 years and divided into 14 age groups, with at least 100 cases in each group. We compared the mean, standard deviation and median of the testis volume among different age groups.The testis grew slowly in volume before 8 years old (0.372－0.678 ml), faster after 9 years old (1.040－4.600 ml), (1.040 ± 0.970) ml at 9－10 years, (1.876 ± 1.631) ml at 10－11 years, (2.831 ± 2.155) ml at 11－12 years, (3.640 ± 2.376) ml at 12－13 years, and (4.600 ± 3.559) ml at 13－14 years, larger in the 0－1 than in the 1－2 years group (［0.403 ± 0.130］ vs ［0.372 ± 0.110］ ml, P = 0.04), negatively correlated in age between the two groups.Ultrasonography is an effective method for the measurement of the testis volume, which can provide the normative values of the testis volume of the 0－14 years old Chinese boys and some evidence for clinical diagnosis and consultation.

It is a key problem to be solved urgently in the current agricultural production and resource utilization in China, to reduce the content of heavy metals in the environment matrix and its bioavailability by transforming the heavy metal from higher-activity form to less active form. Patent literature is the most effective carrier of technical information. This article took the passivation technology invention patents as research object, and made a bibliometric analysis of 95 patents on passivation of heavy metal disclosed by the State Intellectual Property Office of China. The number of patents on heavy metal passivation technology kept increasing, and entered a period of rapid growth after 2014. Beijing was the main application area. Soils, municipal sludge and livestock manure were the three key application fields. Most studies were pot experiments or batches of composting experiments. The inorganic passivating material mainly reduced the effective concentration of heavy metals in the soil by chemical reactions and adjusting the pH of the soil. Organic passivation technology reduced the water soluble and exchangeable components of heavy metals and reduced their bioavailability and mobility, by chemical actions with heavy metals to form insoluble metal-organic complex, to increase the amount of soil cation exchange. The passivation of microbes was related to the redox environment. The passivating effect of different passivating agents on different heavy metals was different, and the combination of different passivating agents also had a great influence on the morphology of heavy metals. Therefore, large-scale applications faced great difficulties in practice. With the aid of materials science, it still needs further study to refine the efficient adsorbent screening and improve the separation technology.

Understanding the response of soil respiration to global warming in agro-ecosystem is crucial for simulating terrestrial carbon (C) cycle. We conducted an infrared warming experiment under conventional tillage (CT) and no-tillage (NT) farmland for winter wheat and summer maize rotation system in North China Plain (NCP). Treatments include CT with and without warming (CTW and CTN), NT with and without warming (NTW and NTN). The results indicated that warming had no significant effect on soil moisture in irrigated farmland of NCP (P>0.05). The elevated average soil temperature of 1.1–1.6°C in crop growing periods could increase annual soil CO2 emission by 10.3% in CT filed (P>0.05), but significantly increase it by 12.7% in NT field (P

In this paper, we reconsider the problem of low computational efficiency in traditional superpixel segmentation methods based on clustering. We propose a superpixel segmentation method based on autonomous attachment named ALIC, which use a simpler and more efficient distance measurement method to accelerate the algorithm. Simultaneously, the allocation of pixel autonomous attached fully considers the natural continuity between pixels, and each pixel can share label with its neighbors, which allows us to obtain better boundary performance. In the experiment, our method only achieves convergence in five iterations. On the basis of obtaining more sensitive boundaries, our algorithm improves the operation speed. (On a simple CPU core, it only takes about 0.1s to segment a 481×321 image into 400 homogenic superpixels).

BACKGROUND Renal fibrosis occurs in the end-stage of all chronic kidney disease. Transforming growth factor-s1 (TGF-s1) is a central contributor in fibrosis. Identifying effective biomarkers that targets TGF-s1 is necessary for the development of therapeutic agents for kidney disease. In this study, we investigated the effects and mechanism of long non-coding RNA (LncRNA)-ATB in TGF-s1 induced human kidney 2 (HK-2) cells. MATERIAL AND METHODS We investigated the effects of either overexpression or knockdown of LncRNA-ATB on inflammation, cell apoptosis, and senescence in TGF-s1 induced HK-2 cells. TGF-s1 induced HK-2 cells served as the cell model. The gene level was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and protein expressions by western blot. Cell Counting Kit-8 (CCK-8) assay was performed for assessment of cell viability. Flow cytometry was applied for detection of cell apoptosis. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1s, and IL-6 were measured by corresponding kits. RESULTS LncRNA-ATB was highly expressed in TGF-s1 induced HK-2 cells. Inflammation, cell apoptosis, and senescence were enhanced by TGF-s1 and these effects were all reduced by knockdown of LncRNA-ATB. Whereas overexpression of LncRNA-ATB had the opposite effects with knockdown of LncRNA-ATB. The TGFs/SMAD2/3 signaling pathway was activated by TGF-s1 and this effect was further enhanced by LncRNA-ATB overexpression. Silencing LncRNA-ATB inhibited the TGFs/SMAD2/3 signaling pathway in TGF-s1 induced cells. The effects of LncRNA-ATB overexpression aforementioned in TGF-s1 induced cells were abolished by blockage of the TGFs/S0MAD2/3 signaling pathway. CONCLUSIONS LncRNA-ATB overexpression have promoting effects on inflammation, cell apoptosis and senescence in TGF-s1 induced HK-2 cells via activating the TGFs/SMAD2/3 signaling pathway. LncRNA-ATB act as a key downstream mediator via activating the TGFs/SMAD2/3 signaling pathway and silencing LncRNA-ATB might be a new strategy for chronic kidney disease treatment.

With the wide application of infrared sensors and visible sensors, the registration of two heterogeneous images has caused widespread concern. Multi-angle comprehensive analysis of multi-sensor imaging systems can obtain more accurate image information. However, the main challenge of image registration is the detection of feature points and the acquisition of the correct feature point matching pairs. A Geometric constraint method is proposed to obtain the correct feature matching pairs. Three feature point matching pairs are randomly selected in the two images, and the ratio of the corresponding line segment lengths is obtained according to the coordinates of the three feature points to find the most three similar feature point matching pairs. Compared with the RANSAC algorithm, the method can obtain the correct feature point matching pair better. The algorithm runs on the DSP platform for about 30s, the error is 1 pixel, and the correct rate reaches 80%.

In this article, the influence of the churning technology on the average diameter of xonotlite particle and the micro-structure of xonotlite particle during the hydrothermal synthesis progress of the heat insulating material of xonotlite were researched. The influence of fiber adding process on the strength and density of calcium silicate insulation material was studied. The complexity and the macro mechanical properties of the fiber dispersed in the matrix with different fiber adding way were discussed. The microstructure of xonotlite was observed and analyzed by scanning electron microscope and the related mechanisms were studied.

The hard silicon calcium stone slurry were synthesized by dynamic hydrothermal synthesis in this article, the influence of water solid ratio and carbon fiber on the performance of the calcium silicate thermal insulation material was studied. The results showed that when the water-solid ratio of 40, sodium dodecyl benzene sulfonate cited as a foaming agent, the sphericity of spherical particles was well, and xonotlite fiber developed well. The added carbon fiber could significantly increase the flexural and compressive strength and coefficient of thermal conductivity of the material. The microstructure of calcium silicate insulation material was observed and analyzed by scanning electron microscope.