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Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.

Chronic kidney disease (CKD) is a major risk factor for endstage renal disease, cardiovascular disease, and premature death. Here we estimated the global prevalence and absolute burden of CKD in 2010 by pooling data from population- based studies. We searched MEDLINE (January 1990 to December 2014), International Society of Nephrology Global Outreach Program-funded projects, and bibliographies of retrieved articles and selected 33 studies reporting gender- and age-specific prevalence of CKD in representative population samples. The age-standardized global prevalence of CKD stages 1–5 in adults aged 20 and older was 10.4% in men (95% confidence interval 9.3–11.9%) and 11.8% in women (11.2–12.6%). This consisted of 8.6% in men (7.3–9.8%) and 9.6% in women (7.7–11.1%) in high-income countries, and 10.6% in men (9.4–13.1%) and 12.5% in women (11.8–14.0%) in low- and middle-income countries. The total number of adults with CKD was 225.7 million (205.7–257.4 million) men and 271.8 million (258.0–293.7 million) women. This consisted of 48.3 million (42.3–53.3 million) men and 61.7 million (50.4–69.9 million) women in high-income countries, and 177.4 million (159.2–215.9 million) men and 210.1 million (200.8–231.7 million) women in low- and middle-income countries. Thus, CKD is an important global-health challenge, especially in low- and middle-income countries. National and international efforts for prevention, detection, and treatment of CKD are needed to reduce its morbidity and mortality worldwide.

The energy density of batteries with lithium cobalt oxide (LCO) can be maximized by increasing the cut‐off voltage to approach the theoretical capacity limit. However, it is not realized in the practical applications due to the restricted cycle life caused by vulnerable cathode surface in deep delithiation state, where severe side reactions, oxygen/cobalt loss and structure degradation often happen. Here, an outside‐in oriented nanostructure on LiCoO2 crystals is fabricated. The outer electrochemically stable LiF and Li2CoTi3O8 particles perform as physical barrier to prevent damage of both cathodes and electrolytes, while the inner F doping promote Li ions diffusivity and stabilize the lattice oxygen. With the spinel‐like transition layer between them, a solid and complete lithium‐ion transport channel generation along the lithium concentration gradient. Under the protection from this structure, the LiCoO2 withstand the high voltage of 4.6 V and the LCO/graphite pouch full cell with high loading density exhibits 81.52% energy density retention after 135 cycles at 4.5 V. To chase the long lifespan of LiCoO2 at 4.6 V, an outside‐in oriented nanostructure is fabricated on LiCoO2 crystals consisting of the outer electrochemically stable LiF and Li2CoTi3O8 particles, the inner F doping and the spinel‐like transition layer between them. A solid and complete lithium‐ion transport channel is generated along the lithium concentration gradient, keeping the integrity of LiCoO2 structure.

Extensive studies have been conducted to evaluate the effect of external organic Carbon on native soil organic carbon (SOC) decomposition. However, the direction and extent of this effect reported by different authors is inconsistent. The objective was to provide a synthesis of existing data that comprehensively and quantitatively evaluates how the soil chemical properties and incubation conditions interact with additional external organic C to affect the native SOC decomposition. A meta-analysis was conducted on previously published empirical studies that examined the effect of the addition of external organic carbon on the native SOC decomposition through isotopic techniques. The addition of external organic C, when averaged across all studies, enhanced the native SOC decomposition by 26.5%. The soil with higher SOC content and fine texture showed significantly higher priming effects, whereas the soil with higher total nitrogen content showed an opposite trend. The soils with higher C:N ratios had significantly stronger priming effects than those with low C:N ratios. The decomposition of native SOC was significantly enhanced more at early stage of incubation (<15d) than at the later stages (>15d). In addition, the incubation temperature and the addition rate of organic matter significantly influenced the native SOC decomposition in response to the addition of external organic C.

Images captured under poor lighting conditions often suffer from low brightness, low contrast, color distortion, and noise. The function of low-light image enhancement is to improve the visual effect of such images for subsequent processing. Recently, deep learning has been used more and more widely in image processing with the development of artificial intelligence technology, and we provide a comprehensive review of the field of low-light image enhancement in terms of network structure, training data, and evaluation metrics. In this paper, we systematically introduce low-light image enhancement based on deep learning in four aspects. First, we introduce the related methods of low-light image enhancement based on deep learning. We then describe the low-light image quality evaluation methods, organize the low-light image dataset, and finally compare and analyze the advantages and disadvantages of the related methods and give an outlook on the future development direction.

Background Cardamonin, a chalcone isolated from Alpiniae katsumadai , has anti-inflammatory and anti-tumor activities. However, the molecular mechanism by which cardamonin inhibits breast cancer progression largely remains to be determined. Methods CCK-8 and Hoechst 33258 staining were used to detect cell growth and apoptosis, respectively. HIF-1α driven transcription was measured by luciferase reporter assay. Glucose uptake and lactate content were detected with 2-NBDG and L-Lactate Assay Kit. Cell metabolism assays were performed on Agilent’s Seahorse Bioscience XF96 Extracellular Flux Analyzer. Mitochondrial membrane potential was measured with JC-1 probe. DCFH-DA was used to measure ROS level. Protein expression was detected by western blotting assay. Immunohistochemistry was performed to measure the expression of HIF-1α, LDHA and CD31 in tumor tissues. Results Cardamonin inhibited growth of the triple negative breast cancer cell line MDA-MB-231 in vitro and in vivo by suppressing HIF-1α mediated cell metabolism. Cardamonin inhibited the expression of HIF-1α at mRNA and protein levels by repressing the mTOR/p70S6K pathway, and subsequently enhanced mitochondrial oxidative phosphorylation and induced reactive oxygen species (ROS) accumulation. We also found that cardamonin inhibited the Nrf2-dependent ROS scavenging system which further increased intracellular ROS levels. Eventually, accumulation of the intracellular ROS induced apoptosis in breast cancer cells. In addition, cardamonin treatment reduced glucose uptake as well as lactic acid production and efflux, suggesting its function in repressing the glycolysis process. Conclusions These results reveal novel function of cardamonin in modulating cancer cell metabolism and suppressing breast cancer progression, and suggest its potential for breast cancer treatment.

We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial ( n  = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC. Biomarker analysis of the phase 3 JAVELIN Renal 101 trial uncovers molecular determinants of therapy-specific outcomes, which may inform personalized treatment strategies for patients with advanced renal cell carcinoma.

Detecting and classifying real-life small traffic signs from large input images is difficult due to their occupying fewer pixels relative to larger targets. To address this challenge, we proposed a deep-learning-based model (Dense-RefineDet) that applies a single-shot, object-detection framework (RefineDet) to maintain a suitable accuracy–speed trade-off. We constructed a dense connection-related transfer-connection block to combine high-level feature layers with low-level feature layers to optimize the use of the higher layers to obtain additional contextual information. Additionally, we presented an anchor-design method to provide suitable anchors for detecting small traffic signs. Experiments using the Tsinghua-Tencent 100K dataset demonstrated that Dense-RefineDet achieved competitive accuracy at high-speed detection (0.13 s/frame) of small-, medium-, and large-scale traffic signs (recall: 84.3%, 95.2%, and 92.6%; precision: 83.9%, 95.6%, and 94.0%). Moreover, experiments using the Caltech pedestrian dataset indicated that the miss rate of Dense-RefineDet was 54.03% (pedestrian height > 20 pixels), which outperformed other state-of-the-art methods.

Temple of Hmongism is a membership-based non-profit, new religious organization first launched in 2012 from St Paul, Minnesota, to promote Hmongism, a simplified version of traditional religion \"Dab Qhuas Hmoob\" in Hmong immigrant communities around the US. This is a group of Hmong men and women who, through research and deliberation, strive to consolidate and institutionalize the indigenous Hmong beliefs taken with them from Asia, while at the same time, reform various religious rituals and practices in all areas, including Shamanism, weddings, and funerals, in the hope of making them \"much simpler, less costly, and more friendly\" and \"full of Hmong identity and pride\" in their newly adopted land. How does Temple of Hmongism revamp a system of traditional religious beliefs? What does it mean to a transnational Hmong community? Does it signify a continuous traditionalist or culturalist move, a move to search for Hmong identity, and a cultural resistance to the encircle and encroachment of traditional Hmong society by contesting and combating a dominant mainstream power from outside? In what way does Temple of Hmongism redefine Hmongness, the meaning of being Hmong? And how is it performed in religious rituals and everyday lives? Through in-depth interviews and focus group discussions with members of this religious organization, as well as participant observation at different religious practices, this study strives to understand this growing new religious movement in the transnational Hmong community, and see how religious faith, cultural heritage, and ethnic identity intersect and interact with each other. Keywords: Temple of Hmongism, Beliefs, Rituals, Hmongness

Aiming to alleviate traffic congestion, many congestion avoidance and traffic optimization systems have been proposed recently. However, most of them suffer from three main problems. Firstly scalability: they rely on a centralized server, which has to perform intensive communication and computational tasks. Secondly unpredictability: they use smartphones and other sensors to detect the congested roads and warn upcoming vehicles accordingly. In other words, they are used to solve the problem rather than avoiding it. Lastly, infrastructure dependency: they assume the presence of pre-installed infrastructures such as roadside unit (RSU) or cellular 3G/4G networks. Motivated by the above-mentioned reasons, in this paper, we proposed a fully distributed and infrastructure-less congestion avoidance and traffic optimization system for VANET (Vehicular Ad-hoc Networks) in urban environments named DIFTOS (Distributed Infrastructure-Free Traffic Optimization System), in which the city map is divided into a hierarchy of servers. The vehicles that are located in the busy road intersections play the role of servers, thus DIFTOS does not rely on any centralized server and does not need internet connectivity or RSU or any kind of infrastructure. As far as we know, in the literature of congestion avoidance using VANET, DIFTOS is the first completely infrastructure-free congestion avoidance system. The effectiveness and scalability of DIFTOS have been proved by simulation under different traffic conditions.