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The aim of local path planning for unmanned surface vehicles (USVs) is to avoid unknown dynamic or static obstacles. However, current relative studies have not fully considered the impact of ocean environmental factors which significantly increase the control difficulty and collision risk of USVs. Therefore, this work studies two ocean environmental factors, namely, wave and current, given that they both have a significant impact on USVs. Furthermore, we redesign a kinematic model of an USV and the evaluation function of a classical and practical local path planning method based on the dynamic window approach (DWA). As shown by the results of the simulations, the path length was impacted mainly by the intensity of the environmental load and slightly by the direction of the environmental load, but the navigation time was significantly influenced by both. Taking the situation in still water as a benchmark in terms of the intensity and direction of the environmental factors, the maximum change rates of the path length were 8.6% and 0.6%, respectively, but the maximum change rates of the navigating time were 17.9% and 25.6%, separately. In addition, the average calculation time of each cycle was only 0.0418 s, and the longest time did not exceed the simulation time corresponding to a single cycle of 0.1 s. This method has proven to be a good candidate for real-time local path planning of USVs since it systematically considers the impact of waves and currents on the navigation of USVs, and thus ensures that USVs can adjust to the planned path in time and avoid obstacles when navigating in the real ocean environment.

DNA double strand breaks (DSBs) have detrimental effects on cell survival and genomic stability, and are related to cancer and other human diseases. In this study, we identified microtubule-depolymerizing kinesin Kif2C as a protein associated with DSB-mimicking DNA templates and known DSB repair proteins in Xenopus egg extracts and mammalian cells. The recruitment of Kif2C to DNA damage sites was dependent on both PARP and ATM activities. Kif2C knockdown or knockout led to accumulation of endogenous DNA damage, DNA damage hypersensitivity, and reduced DSB repair via both NHEJ and HR. Interestingly, Kif2C depletion, or inhibition of its microtubule depolymerase activity, reduced the mobility of DSBs, impaired the formation of DNA damage foci, and decreased the occurrence of foci fusion and resolution. Taken together, our study established Kif2C as a new player of the DNA damage response, and presented a new mechanism that governs DSB dynamics and repair. DNA can be damaged in many ways, and a double strand break is one of the most dangerous. This occurs when both strands of the double helix snap at the same time, leaving two broken ends. When cells detect this kind of damage, they race to get it fixed as quickly as possible. Fixing these double strand breaks is thought to involve the broken ends being moved to 'repair centers’ in the nucleus of the cell, but it was unclear how the broken ends were moved. One possibility was that the cells transport the broken ends along protein filaments called microtubules. Cells can assemble these track-like filaments on-demand to carry cargo attached to molecular motors called kinesins. However, this type of transport happens outside of the cell’s nucleus, and while there are different kinesin proteins localized inside the nucleus, their roles are largely unknown. In an effort to understand how broken DNA ends are repaired, Zhu, Paydar et al. conducted experiments that simulated double strand breaks and examined the proteins that responded. The first set of experiments involved mixing cut pieces of DNA with extracts taken from frog eggs or human cells. Zhu, Paydar et al. found that one kinesin called Kif2C stuck to the DNA fragments, and attached to many proteins known to play a role in DNA damage repair. Kif2C had previously been shown to help separate the chromosomes during cell division. To find out more about its potential role in DNA repair, Zhu, Paydar et al. then used a laser to create breaks in the DNA of living human cells and tracked Kif2C movement. The kinesin arrived within 60 seconds of the DNA damage and appeared to transport the cut DNA ends to 'repair centers'. Getting rid of Kif2C, or blocking its activity, had dire effects on the cells' abilities to mobilize and repair breaks to its DNA. Without the molecular motor, fewer double strand breaks were repaired, and so DNA damage started to build up. Defects in double strand break repair happen in many human diseases, including cancer. Many cancer treatments damage the DNA of cancer cells, sometimes in combination with drugs that stop cells from building and using their microtubule transport systems. Understanding the new role of Kif2C in DNA damage repair could therefore help optimize these treatment combinations.

BackgroundFibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc’s role in FLC tumour growth remains enigmatic.ObjectiveWe sought to determine the protein kinase-mediated signalling networks that drive growth and proliferation in FLC.DesignWe integrated a combination of newly established preclinical models of FLC and an unbiased polypharmacology-based approach to identify downstream kinases involved in DNAJ-PKAc-mediated FLC cell growth. We validated our findings in multiple patient-derived mouse models and patient tumours.ResultsFunctional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc’s centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumour growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues.ConclusionOur findings underscore the role of DNAJ-PKAc in rewiring signalling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi’s sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identify specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu ), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.

In China, Energy transition was proposed in the “12th Five-Year Plan” and gained resilient support by “Energy Revolution” announced by President Xi Jinping in 2014. In Paris Agreement, there are targets set up for 2100 to be well below 2 °C, with ambitious target on 1.5 °C. China signed the agreement and will support the global target. In the meantime, large-scale actions were initiated in 2013 by the national action plan on air pollution control for the period from 2013 to 2017. None of these strategies has clear long-term target. In our studies, energy transition will be decided by the long-term target of CO2 emission reduction, air pollutant reduction, and energy security. This paper will present the analysis from IPAC model, by setting up reduction target for CO2 emission under the global 2 °C and 1.5 °C target. Energy transition, CO2 emission, and air pollutant reduction will be discussed based on these targets. For air pollutants, SO2, NOx, PM2.5, black carbon, and mercury will be included. From the results, there will be a significant energy transition by large-scale use of renewable energy, nuclear and the share of coal will be reduced to less than 20% in 2050 from 66% in 2015. Energy transition will also contribute to a drastic reduction in air pollutants.

The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1AA98V, rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/β-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated β-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1AA98V variant plus a HFD promotes the formation of colonic polyps by activating β-catenin via decreasing Cdx2 expression.

Fermentation at higher temperatures can potentially reduce the cooling cost in large-scale fermentation and reduce the contamination risk. Thus, the thermotolerant yeast, Kluyveromyces marxianus , which can grow and ferment at elevated temperatures, is a promising biotechnological tool for future applications. However, the promoters used in K. marxianus are not well characterized, especially at elevated temperatures, which is important in efficient metabolic pathway construction. In this study, six constitutive promoters (P TDH3 , P PGK , and P ADH1 from both Saccharomyces cerevisiae and K. marxianus ) were evaluated in K. marxianus through the heterologous expression of the KlLAC4 , GUSA, and SH BLE genes at various temperatures, with various carbon sources and oxygen conditions. The expression was evaluated at the transcription and protein level using real-time PCR and protein activity determination to eliminate the effect of heterologous protein stability. While the transcription of all the promoters decreased at higher temperatures, the order of their promoting strength at various temperatures with glucose as the carbon source was P KmPGK  > P KmTDH3  > P ScPGK  > P ScTDH3  > P KmADH1  > P ScADH1 . When glycerol or xylose was supplied as the carbon source at 42 °C, the order of promoter strength was P KmPGK  > P ScPGK  > P KmADH1  > P ScADH1  > P ScTDH3  > P KmTDH3 . The promoter activity of P TDH3 decreased significantly, while the promoter activity of both of the P ADH1 promoters increased. Oxygen conditions had non-significant effect. The results of this study provide important information for fine-tuned pathway construction for the metabolic engineering of K. marxianus.

Background The tumor microenvironment (TME), including infiltrating T‐cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death‐1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B‐cell lymphoma. Methods Adults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200 mg IV in 21‐day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)‐positron emission tomography‐computed tomography (PET‐CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1. Results Nine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high‐tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET‐CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow‐up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune‐related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected. Conclusion Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.

Non-homologous end joining (NHEJ) is a major DNA double-strand break (DSB) repair mechanism. We characterized here a series of plasmid-based DSB templates that were repaired in Xenopus egg extracts via the canonical, Ku-dependent NHEJ pathway. We showed that the template with compatible ends was efficiently repaired without end processing, in a manner that required the kinase activity of DNA-PKcs but not ATM. Moreover, non-compatible ends with blunt/3′-overhang, blunt/5′-overhang and 3′-overhang/5′-overhang were predominantly repaired with fill-in and ligation without the removal of end nucleotides. In contrast, 3′-overhang/3′-overhang and 5′-overhang/5′-overhang templates were processed by resection of 3–5 bases and fill-in of 1–4 bases prior to end ligation. Therefore, the NHEJ machinery exhibited a strong preference for precise repair; the presence of neither non-compatible ends nor protruding single strand DNA sufficiently warranted the action of nucleases. ATM was required for the efficient repair of all non-compatible ends including those repaired without end processing by nucleases, suggesting its role beyond phosphorylation and regulation of Artemis. Finally, dephosphorylation of the 5′-overhang/3′-overhang template reduced the efficiency of DNA repair without increasing the risk of end resection, indicating that end protection via prompt end ligation is not the sole mechanism that suppresses the action of nucleases.

By recognizing the importance of non-CO₃ gases mitigation for climate change abatement, modeling study for multi-gas scenarios was conducted by using IPAC model. This is also part of EMF-21 study for comparing the cost for CO₃ mitigation and multi-gas mitigation. The main objective of this analysis is to evaluate the international potential and costs of non-CO₃ greenhouse gas abatement. Three scenarios were defined by EMF-21 study including modeler reference, CO₃ only mitigation scenario and multi-gas mitigation scenario. By comparing the results for the three scenarios, it is found that there is quite large potential for non-CO₃ mitigation potential. Multi-gas mitigation policies could have lower cost compared with CO₃ only mitigation policies. In order to reach same mitigation target level of GHG emission, there could be 30% lower carbon tax rate for multi-gas mitigation, and therefore GDP loss could be reduced by 23% in 2100. Multi-gas mitigation could give less pressure for energy system to transform.