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Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment. Several studies have shown that Fusobacterium nucleatum aggravates colorectal cancer (CRC) development and chemoresistance. Here the authors show that F. nucleatum is enriched preferentially in patients with KRAS p.G12D mutant CRC and that it promotes colorectal tumorigenesis in preclinical models by binding DHX15 on tumor cells. [ABSTRACT FROM AUTHOR]

The promise of precision medicine has been limited by the pervasive resistance to many targeted therapies for cancer. Inferring the timing (i.e., pre-existing or acquired) and mechanism (i.e., drug-induced) of such resistance is crucial for designing effective new therapeutics. This paper studies cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) using tumor volume data obtained from patient-derived tumor xenografts. We ask if resistance mechanisms can be determined from this data alone, and if not, what data would be needed to deduce the underlying mode(s) of resistance. To answer these questions, we propose a family of mathematical models, with each member of the family assuming a different timing and mechanism of resistance. We present a method for fitting these models to individual volumetric data, and utilize model selection and parameter sensitivity analyses to ask: which member(s) of the family of models best describes HNSCC response to cetuximab, and what does that tell us about the timing and mechanisms driving resistance? We find that along with time-course volumetric data to a single dose of cetuximab, the initial resistance fraction and, in some instances, dose escalation volumetric data are required to distinguish among the family of models and thereby infer the mechanisms of resistance. These findings can inform future experimental design so that we can best leverage the synergy of wet laboratory experimentation and mathematical modeling in the study of novel targeted cancer therapeutics. [ABSTRACT FROM AUTHOR]

The polymer separator is part of the gel polymer electrolyte (GPE) and plays a crucial role in battery. In this study, a novel PES-based separator for lithium-oxygen batteries was prepared using non-solvent-induced phase separation (NIPS) technique firstly and modified by doping Al2O3 nanoparticles. It is proved that the properties of the PES/Al2O3 separator are affected by the presence of Al2O3 nanoparticles. The results show that the PES/Al2O3 separator with Al2O3 content of 2 wt% and 4 wt% has lower crystallinity, higher electrolyte uptake, and better mechanical properties and thermal stability than PES-based separator without Al2O3. The resulting PES/Al2O3 separator containing 4 wt% Al2O3 has higher ionic conductivity (0.49 mS cm−1) and lithium ions transference number (0.28). Consequently, the assembled batteries with the PES/Al2O3 separator containing 4 wt% Al2O3 exhibit excellent cycling performance (75 cycles, 1000 mAh g−1 at 0.05 mA cm−2). Therefore, PES/Al2O3 separator has a significance meaning in the research of high-safety and long-cycle lithium-oxygen battery. [ABSTRACT FROM AUTHOR]

PARP enzymes utilise NAD+ as a co-substrate for their enzymatic activity. Inhibition of PARP1 is synthetic lethal with defects in either BRCA1 or BRCA2. In order to assess whether other genes implicated in NAD+ metabolism were synthetic lethal with BRCA1 or BRCA2 gene defects, we carried out a genetic screen, which identified a synthetic lethality between BRCA1 and genetic inhibition of either of two sirtuin (SIRT) enzymes, SIRT1 or SIRT6. This synthetic lethal interaction was replicated using small-molecule SIRT inhibitors and was associated with replication stress and increased cellular PARylation, in contrast to the decreased PARylation associated with BRCA-gene/PARP inhibitor synthetic lethality. SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of either PARP1 or the histone PARylation factor-coding gene HPF1, implicating PARP1/HPF1-mediated serine ADP-ribosylation as part of the mechanistic basis of this synthetic lethal effect. These observations suggest that PARP1/HPF1-mediated serine ADP-ribosylation, when driven by SIRT inhibition, can inadvertently inhibit the growth of BRCA-gene mutant cells. Bajrami, Walker et al. investigated the synthetic lethality between BRCA gene defects and inhibition of two sirtuin genes, SIRT1 or SIRT6, which was found to be associated with replication stress and increased PARylation. The authors demonstrated that the SIRT/BRCA1 synthetic lethality was reversed by genetic ablation of PARP1 or HPF1. [ABSTRACT FROM AUTHOR]

In this paper, a gel polymer electrolyte based on sulfonated polyetherimide (SPEI)/polyetherimide (PEI) blending separator has been fabricated through non-solvent-induced phase separation (NIPS) method. The performance of the SPEI/PEI blending separator is investigated through the morphology and electrochemical analysis. The addition of SPEI polymer has great effect on the morphology of separator's top and bottom surface. When the SPEI mass ratio increases, the SPEI/PEI blending separator shows high porosity (up to 72.80%), ion conductivity (up to 2.63 mS cm−1), and low tensile strength (down to 7.98 MPa). The discharge specific capacity, capacity retention rate, and average capacity attenuation rate of lithium-sulfur battery using SPEI-2 (separator with the weight ratio of SPEI/PEI = 2:8) are 736.1 mAh g−1, 57.2%, and 0.21% after 200 cycles, respectively. The result shows that the SPEI/PEI blending separator has lower capacity decays compared with SPEI-0 (separator with the weight ratio of SPEI/PEI = 0:10) and the commercial Celgard 2320 separator, which indicates that the existence of sulfonic acid group is conducive to the stability of the lithium-sulfur battery cycle. Therefore, it is concluded that the SPEI/PEI blending separator prepared by NIPS method is a potential separator for high-performance rechargeable lithium-sulfur battery. [ABSTRACT FROM AUTHOR]

The high performance and safety of lithium-sulfur (Li-S) batteries are the focus of research in recent years. The separator is an important part of the battery, whose performance stability directly affects the performance of the battery. What's more, there are still many defects in the commercial polyolefin separator. In this work, a polyethylene/polyetherimide (PE/PEI) composite separator is designed by surface coating and non-solvent-induced phase separation (NIPS) method. The film breakage temperature and anti-puncture strength of the PE/PEI composite separator (181.96 °C, 7.90 N) are higher than those of the commercial PE separator (153.00 °C, 6.20 N), which will greatly ensure the safety problems caused by internal self-heating and external short circuit of Li-S batteries. The PE/PEI composite separator–based Li-S battery delivers a high initial specific capacity of 1265 mAh g−1 at 0.2 C and exhibits excellent rate capability compared with the commercial PE separator. Therefore, the PE/PEI composite separator is a candidate separator for the high-performance and high-safety Li-S battery. [ABSTRACT FROM AUTHOR]

A graph F is called a linear forest if V (F) = E (F) = ∅ or every component of F is a path. We denote by ω 1 (F) the number of components of order 1 in F. In this article, we prove the following theorem. Let k ≥ 5 and m ≥ 0 . Let G be a (k + m) -connected graph and F be a linear forest on a cycle of G with | E (F) | = m and k + 1 ≤ ω 1 (F) ≤ ⌊ 4 k - 1 3 ⌋ . Then G has a cycle of length at least min { σ 2 (G) - m , | V (G) | } passing through F, where σ 2 (G) denotes the minimum degree sum of two independent vertices. Our result generalizes the theorem of Hu and Song (J Graph Theory 87(3):374–393). [ABSTRACT FROM AUTHOR]

53BP1 is a chromatin-binding protein that regulates the repair of DNA double-strand breaks by suppressing the nucleolytic resection of DNA termini [1], [2]. This function of 53BP1 requires interactions with PTIP [3] and RIF1 [4]- [9], the latter of which recruits REV7 (also known as MAD2L2) to break sites [10], [11]. How 53BP1-pathway proteins shield DNA ends is currently unknown, but there are two models that provide the best potential explanation of their action. In one model the 53BP1 complex strengthens the nucleosomal barrier to end-resection nucleases [12], [13], and in the other 53BP1 recruits effector proteins with end-protection activity. Here we identify a 53BP1 effector complex, shieldin, that includes C20orf196 (also known as SHLD1), FAM35A (SHLD2), CTC-534A2.2 (SHLD3) and REV7. Shieldin localizes to double-strand-break sites in a 53BP1- and RIF1-dependent manner, and its SHLD2 subunit binds to single-stranded DNA via OB-fold domains that are analogous to those of RPA1 and POT1. Loss of shieldin impairs non-homologous end-joining, leads to defective immunoglobulin class switching and causes hyper-resection. Mutations in genes that encode shieldin subunits also cause resistance to poly(ADP-ribose) polymerase inhibition in BRCA1-deficient cells and tumours, owing to restoration of homologous recombination. Finally, we show that binding of single-stranded DNA by SHLD2 is critical for shieldin function, consistent with a model in which shieldin protects DNA ends to mediate 53BP1-dependent DNA repair. The 53BP1 effector complex shieldin is involved in non-homologous end-joining and immunoglobulin class switching, and acts to protect DNA ends to facilitate the repair of DNA by 53BP1. [ABSTRACT FROM AUTHOR]

Thrombocytopenia or chronic depletion of platelets in blood, could create life-threatening conditions in patients who receive aggressive systemic radiation and chemotherapy. Currently there are no approved agents for the rapid treatment of thrombocytopenia. In the present study, we demonstrate that administration of Orientin, a glycosidic flavonoid or dietary administration of Orientin containing Tulsi (Holy Basil) leaves, results in a significant increase in circulating platelets in a clinically relevant mouse model. No noticeable effects were observed on red blood cells, white blood cells or other hematologic parameters in treated animals indicating that Orientin specificity enhances platelet formation. The gene expression and immunophenotyping of bone marrow revealed that Orientin stimulates megakaryopoiesis specific transcriptional program. A significant increase in colony formation in bone marrow cells from Orientin pretreated mice further complemented the effect of Orientin on progenitor cells. The ex-vivo differentiation of irradiated human peripheral blood CD34+stem cells demonstrated stimulatory effects of Orientin on megakaryocyte erythrocyte progenitors (MEP). The results show that Orientin, a non-toxic readily available natural product can counter platelet imbalances. Thrombocytopenia also develop as a consequence of multiple hematologic malignancies and side effects of treatments. Dietary supplementation of Orientin containing phytochemicals could be effective as countermeasures and viable therapeutics. [ABSTRACT FROM AUTHOR]

Primitive streak formation in the chick embryo involves large-scale highly coordinated flows of more than 100,000 cells in the epiblast. These large-scale tissue flows and deformations can be correlated with specific anisotropic cell behaviours in the forming mesendoderm through a combination of light-sheet microscopy and computational analysis. Relevant behaviours include apical contraction, elongation along the apical-basal axis followed by ingression, and asynchronous directional cell intercalation of small groups of mesendoderm cells. Cell intercalation is associated with sequential, directional contraction of apical junctions, the onset, localization and direction of which correlate strongly with the appearance of active myosin II cables in aligned apical junctions in neighbouring cells. Use of class specific myosin inhibitors and gene-specific knockdown shows that apical contraction and intercalation are myosin II dependent and also reveal critical roles for myosin I and myosin V family members in the assembly of junctional myosin II cables. [ABSTRACT FROM AUTHOR]

Traditional parametric models of solid mechanics have disadvantages such as poor lightweight level of cloud data and low integrity of operations of solid mechanics. To solve the above problems, a parametric model for solid mechanics in engineering research based on cloud computing models is designed. By calculating the number of cloud data copy optimizations, the upper limit of resources required for engineering research is estimated, and the specific values is assessed by continuously cycling the demand, so as to complete the basic conflict analysis, and set up a cloud computing engineering research environment. On this basis, the modeling index is selected. By analyzing the sensitivity of the index, the purpose of optimizing the modeling parameters is achieved, and a new solid mechanics parametric model is constructed. Analyzing and contrasting the experimental data shows that after applying the parametric model of solid mechanics in the engineering research based on the cloud computing model, the lightweight level of cloud data can be increased by up to 24 levels, and the operational integrity of solid mechanics can be increased by about 30%. [ABSTRACT FROM AUTHOR]