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The application of electric vehicles (EVs) in the logistics industry has become more extensive. However, the mileage limitation of electric logistics vehicles (ELVs) and the long-distance distribution of ELVs have become urgent problems. Therefore, this paper proposes a long-distance distribution model for ELVs based on dynamic traffic information considering fleet mileage, distribution time and total distribution cost as the optimisation objectives, thus reasonably planning road selection and charging, and alleviating “mileage anxiety” in the long-distance distribution of ELVs. The model proposed in this paper comprehensively considers the characteristics of the high-speed and low-speed roads, the changes in road traffic flow on weekdays and non-weekdays, the time-of-use electricity price of electric vehicle charging stations (EVCSs) and uses the M/M/s queuing theory model to determine the charging waiting time. Finally, a real traffic network is taken as an example to verify the practicability and effectiveness of this model.

Stabilized hypochlorous acid (HOCl) is increasingly used as a hospital disinfectant and antiseptic, yet its effect on N95 filtration facemask respirators (FFR) is unknown. These FFRs could also contribute to fomite-based transmission of nosocomial infections if worn for extended use between patient rooms.Filtration performance of N95 FFR fabric swatches was assessed after various levels of HOCl exposure. N95 swatches were then contaminated with 10The size-dependent filtration efficiency of HOCl-sprayed N95 FFR fabric ranged from 96% to 100%, showing no significant change. Flow resistance testing revealed almost no change compared to control. Submersion in HOCl, but not spraying, had an excellent bactericidal effect on contaminated swatches.The role of the outer hydrophobic layer of N95 FFRs is discussed regarding the effects of HOCl on filtration and bacterial decontamination.N95 material, sprayed with or briefly submerged in HOCl, maintained its filtration function. HOCl delivery by spray pump, however, would not accomplish decontamination of extended use FFRs between patient encounters. HOCl submersion of intact FFRs, contaminated with various hospital pathogens, is worth further study.

The osteoid is the key structure in development of mature bone. The deposition of unmineralized osteoid along the trabeculae is from the defective mineralization which provide the homogeneous accumulation. The osteoblasts move over bone matrix, deposit osteoid with its major component collagen. In this study we use the mechanical overload simulation method to mimic the exercise-induced bone fatigue. We investigated the morpgological changes of trabecula, compared the variations of the bone under the simple mechanical overload simulation, and the 490 nm beam photodynamic force intervention. The results indicated that mechanical overload promoted the osteoclasts proliferation in tendon bone junction region. However the unmineralized osteoid is not significantly accumulated. The significant osteoclasts proliferation and osteoid accumulation observed in 490 nm photodynamic force intervention bone, which suggested osteoclasts were activated by phtodynamic force. Mechanical stress is the positive factor to maintain strength of the bone. The endurance exercises offer effects on bone. However excessive exercise lead to bone fatigue. In this study, we addressed the photodynamic force intervention to improve the bone neoformation from the exercise induced bone fatigue. Our results show phtodynamic force accelerated the osteoclasts proliferation and osteoid accumulation, that created the favorable conditions for the osteogenic process and maintaining bone structure under the mechanical overload.

A novel strategy was developed to fabricate FeNx-doped carbon quantum dots (Fe-N-CQDs) to detect Cu2+ ions selectively as a fluorescence probe. The Fe-N-CQDs were synthesized by an efficient electrolysis of a carbon cloth electrode, which was coated with monoatomic iron-anchored nitrogen-doped carbon (Fe-N-C). The obtained Fe-N-CQDs emitted blue fluorescence and possessed a quantum yield (QY) of 7.5%. An extremely wide linear relationship between the Cu2+ concentration and the fluorescence intensity was obtained in the range from 100 nM to 1000 nM (R2 = 0.997), and the detection limit was calculated as 59 nM. Moreover, the Fe-N-CQDs demonstrated wide range pH compatibility between 2 and 13 due to the coordination between pyridine nitrogen and Fe3+, which dramatically reduced the affection of the protonation and deprotonation process between H+ and Fe-N-CQDs. It is notable that the Fe-N-CQDs exhibited a rapid response in Cu2+ detection, where stable quenching can be completed in 7 s. The mechanism of excellent selective detection of Cu2+ was revealed by energy level simulation that the LUMO level of Fe-N-CQDs (−4.37 eV) was close to the redox potential of Cu2+, thus facilitating the electron transport from Fe-N-CQDs to Cu2+.

In developing a bisulfite-free methylation assay with the use of restriction enzymes, self-ligation of next generation sequencing adapters (NGS-adapter) is a technological bottleneck to be overcome. In the experiments of this study, a variety of strategies designed to limit or abolish adapter’s self-ligation has been tested. Experimental data have showed that the three strategies tested can either substantially decrease or completely abolish the self-ligation of NGS-adapters. Minimization or elimination of NGS-adapter’s self-ligation is of importance in increasing the sensitivity, efficiency, and reproducibility of enzyme-mediated methylation assay. The strategies reported in the present study may find applications in some other nanotechnologies. In combination with nanotechnologies, either drop-digit PCR or microarray-based sequencing, the methylation-dependent endonuclease mediated methylation assays will facilitate applications of methylation analysis in both fundamental research and clinical epigenetic studies, particularly in early diagnosis of cancer.

China's legal education shoulders the historical mission of transporting talents for the comprehensive rule of law. The fundamental demand for the cultivation of legal talents comes from the implementation of the strategy of rule of law. The rule of law aims to promote the construction of national development layout, and the cultivation of legal talents should fully respond to the construction needs of the five in one overall layout. At present, China's legal education is limited to the path dependence of vocational education and the lack of practice in cultivating compound and innovative talents, which leads to the imbalance between the supply of legal talents and the national demand. Under the guidance of the new concept of law, we should highlight the paradigm of knowledge system construction of field law, enhance the depth of interdisciplinary integration, and build the "curriculum ideological and political" of law courses. In the undergraduate education stage of law, the core courses of this major are refined into basic courses and basic development courses, and the field law courses are opened according to the actual situation of the University, to expand the vision of practice. The postgraduate education focuses more on the cultivation of compound and innovative legal talents, and should adopt the project system of collaborative innovation, and carry out all-round reforms such as enrollment and training.

Magnetic-induction phase shift (MIPS) was rarely used in vivo and clinically because of low sensitivity and nonquantitative detection. The conventional single excitation coil and single detection coil (single coil-coil) generates divergent excitation magnetic field, resulting in different sensitivity of different object positions.To improve the sensitivity and linearity of MIPS and object volume to realize quantitative detection, a novel sensor system was proposed.The novel sensor system adopted uniform rotating magnetic field replacing the divergent magnetic field for the first time integrated with primary field cancellation. The uniform rotating magnetic field was generated by a birdcage coil excited by two orthogonal current; the primary field cancellation was realized by a specially arranged solenoid receiver coil installed co-axially with the birdcage coil detecting the z, not x and y-component of the secondary magnetic field.The saltwater simulation experiment showed that MIPS changed high linearity with the injection volume of all four different conductivity solutions. The experimental results of rabbit cerebral hemorrhage (CH) revealed that with injected blood volume increased to 3 ml, the MIPS linearly decreased to -1.916°, which was 5.5 times higher than that of the single coil-coil method.Compared with the single coil-coil method, this novel detection system was more sensitive and linearly correlated for the detection of bleeding volume. It provided the probability of quantitative detection of the CH volume and a series of brain-content diseases.

Velocity field products estimated from MODIS Aqua/Terra true reflectance images.

The ground space optical observation system considered as one of the main measurement methods to observe space object in Medium Earth Orbit (MEO), Highly Elliptical Orbit (HEO) and Geostationary Orbit (GEO) faces difficulties in forming high-solution images for objects located in GEO that only appears several light spots with limited pixels due to the impacts of observing distance, resolution ratio, and other atmospheric conditions. The light curve is the time history of an object’s observed brightness obtained from the ground-based optical observation system through light curves, right ascension, and declination of space objects. The characteristic of space objects such as position, velocity, size, shape, and material can be inverted. This paper has analyzed the principles, applications, merits, and demerits of several non-linear filtering methods in detail. Besides, the scientific description of inversion for characteristics of a non-resolved space object from ground photometric measurements and the essence of the non-linear filtering inversion method has also been clarified. A selection principle of the non-linear filtering inversion method for different space object characteristics is then proposed, and the developing direction of such inversion methods is also described in the end.

Shanghai is susceptible to land subsidence due to its unique geological environment and frequent human activities. Traditional leveling techniques are not sufficient for monitoring large areas of land subsidence due to the time-consuming, labor-intensive, and expensive nature of the process. Furthermore, the results of conventional methods may not be timely, rendering them ineffective for monitoring purposes. Interferometric Synthetic Aperture Radar (InSAR) technology is a widely used method for monitoring ground subsidence due to its low cost, high efficiency, and ability to cover large areas. To monitor the surface sink condition of Shanghai over the past 2 years, monitoring data were obtained through the technical processing of 24 images from Sentinel-1A data covering Shanghai from 2019 to 2020 using the Persistent Scatterer (PS-InSAR) and Small Baseline Subset (SBAS-InSAR) technique. The ground subsidence (GS) results were extracted via PS and SBAS interferometry processing, while Shuttle Radar Topography Mission data were used to correct the residual phase. According to PS and SBAS methods, the maximum ground subsidence in the study area reached 99.8 mm and 47.2 mm, respectively. The subsidence rate and the accumulated amount of subsidence derived from the monitoring results revealed the urban area in Shanghai to be principally characterized by uneven GS, with multiple settlement funnels being found to be distributed across the main urban area. Moreover, when compared with the historical subsidence data, geological data, and urban construction distribution data, the individual settlement funnels were observed to correspond to those data concerning the historical surface settlement funnel in Shanghai. By randomly selecting GS time-series data regarding three feature points, it was determined that the morphological variables of the GS remained largely consistent at all time points and that their change trends exhibited a high degree of consistency, which verified the reliability of the PS-InSAR and SBAS-InSAR monitoring method. The results can provide data support for decision making in terms of geological disaster prevention and control in Shanghai.

Defense against ultraviolet (UV) radiation exposure is essential for survival, especially in high-elevation species. Although some specific genes involved in UV response have been reported, the full view of UV defense mechanisms remains largely unexplored. Herein, we used integrated approaches to analyze UV responses in the highest-elevation frog, Nanorana parkeri . We show less damage and more efficient antioxidant activity in skin of this frog than those of its lower-elevation relatives after UV exposure. We also reveal genes related to UV defense and a corresponding temporal expression pattern in N. parkeri . Genomic and metabolomic analysis along with large-scale transcriptomic profiling revealed a time-dependent coordinated defense mechanism in N. parkeri . We also identified several microRNAs that play important regulatory roles, especially in decreasing the expression levels of cell cycle genes. Moreover, multiple defense genes (i.e., TYR for melanogenesis) exhibit positive selection with function-enhancing substitutions. Thus, both expression shifts and gene mutations contribute to UV adaptation in N. parkeri . Our work demonstrates a genetic framework for evolution of UV defense in a natural environment.

ObjectiveThis study aimed to detect circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in patients with advanced lung cancer, for describing the distribution characteristics of CTC and CTEC subtypes, exploring the correlation between CTC/CTEC subtypes and novel prognostic biomarkers.MethodsA total of 52 patients with advanced lung cancer were enrolled in this study. Using the subtraction enrichment-immunofluorescence in situ hybridization (SE-iFISH) system, CTCs and CTECs derived from these patients were identified.ResultsBased on cell size, there were 49.3% small and 50.7% large CTCs, and 23.0% small and 77.0% large CTECs. Triploidy, tetraploidy, and multiploidy varied in the small and large CTCs/CTECs. Besides these three aneuploid subtypes, monoploidy was found in the small and large CTECs. Triploid and multiploid small CTCs and tetraploid large CTCs were associated with shorter overall survival (OS) in patients with advanced lung cancer. However, none of the CTECs subtypes showed a significant correlation with patient prognosis. In addition, we found strong positive correlations (Pmultiploid small cell size CTECs, and multiploid small cell size CTCs and monoploid small cell size CTECs. Furthermore, combined detection of the specific subtypes, including triploid small CTC and monoploid small CTEC, triploid small CTC and triploid small CTEC, and multiploid small CTC and monoploid small CTEC, were associated with poor prognosis in advanced lung cancer.ConclusionsAneuploid small CTCs are associated with the outcome of patients with advanced lung cancer. In particular, the combined detection of triploid small CTCs and monoploid small CTECs, triploid small CTCs and triploid small CTECs, and multiploid small CTCs and monoploid small CTECs has clinical significance for predicting prognosis in patients with advanced lung cancer.

The autonomous exploration task we consider requires Unmanned Aerial Vehicles (UAVs) to actively navigate through unknown environments with the goal of fully perceiving and mapping the environments. Some existing exploration strategies suffer from rough cost budgets, ambiguous Information Gain (IG), and unnecessary backtracking exploration caused by Fragmented Regions (FRs). In our work, a hierarchical spatio-temporal aware exploration framework is proposed to alleviate these problems. At the local exploration level, the Asymmetrical Traveling Salesman Problem (ATSP) are solved by comprehensively considering exploration time, IG, and heading consistency to avoid blindly exploring. Specifically, the exploration time is reasonably budgeted by fast marching in an artificial potential field. Meanwhile, a transformer-based map occupancy predictor is designed to assist in IG calculation by imagining spatial clues out of the Field of View (FoV), facilitating the prescient exploration. We verify that our local exploration is effective in alleviating the unnecessary back-and-forth movements caused by FRs and the interference of potential obstacle occlusion on the IG calculation. At the global exploration level, the classical Next Best View Points (NBVP) are generalized to Next Best Sub-Regions (NBSR) to choose informative sub-regions for further forward-looking exploration based on a well-designed utility function. Safe flight paths and dynamically feasible trajectories are reasonably generated throughout the exploration process by fast marching and B-spline curve optimization. Comparative simulations and benchmark tests demonstrate that our proposed exploration strategy is quite competitive in terms of exploration path length, total exploration time, and exploration ratio.

Regeneration of biological tissues in medicine is challenging, and 3D bioprinting offers an innovative way to create functional multicellular tissues. One common way in bioprinting is bioink which is one type of the cell-loaded hydrogel. For clinical application, however, the bioprinting still suffers from satisfactory performance, e.g. in vascularization, effective antibacterial, immunomodulation and regulation of collagen deposition. Many studies have incorporated different bioactive materials into the 3D printed scaffolds to optimize the bioprinting. Here, we review a variety of additives added to the 3D bioprinting hydrogel. The underlying mechanisms and methodology for biological regeneration are important and will provide useful basis for future research.

BackgroundHypergravity environment is a kind of extreme environment that human beings will inevitably encounter when they realize space navigation. When the body is affected by a hypergravity load, the instantaneous changes in fluid distribution cause abnormalities in the physiological functions of the heart and blood vessels. Whether to adapt to these extreme conditions is an important link for humans to break through the Earth’s exploration of space.MethodThis study adopts the experimental method of simulating hypergravity, using amphibian frog larvae as the research object, to observe the structural changes of the unique single ventricle of amphibian frog larvae after being subjected to hypergravity load. Combining digital simulation technology, this study explores the possible impact of hypergravity load on ventricular function. The experiment selected frog larvae (Larvae, commonly known as tadpoles) and subjected them to a continuous load of 10 minutes under a rotating supergravity state of +3Gz for 3wks. The hypergravity load experiment ends when the larvae develop into young frogs (Metamorphs). After the specimen is subjected to histochemical fixation treatment, it is then embedded, sliced, stained, and subjected to computer-assisted microscopy to obtain heart slice images. With the help of computer-assisted image analysis, the length, axis, and ratio of the ventricles are calculated, and the morphological changes of the ventricles are analyzed.ResultsResearch shows that the impact of hypergravity fields on the heart is multifaceted. Due to prolonged and intermittent hypergravity load stimulation, the swimming mode of juvenile frogs has changed from a normal symmetrical swing of the tail to a dominant swimming mode on one side. The vestibular nucleus discharge record shows that after hypergravity load, the activity of vestibular nucleus discharge in juvenile frogs is lower than that in the control group, indicating that simulated hypergravity load has an effective stimulating effect on the development of amphibian frogs from larvae to juveniles. Hypergravity also causes the heart to shift to the right within the chest cavity, resulting in elongated ventricles with an imbalance in the ratio between the longitudinal and transverse axes, indicating a possible decrease in filling capacity.ConclusionThe experimental results of this study suggest that the hypergravity loading environment during space navigation can affect ventricular structure, and changes in this structure can reduce cardiac ejection function. Starting from the conclusion that prolonged intermittent hypergravity loads can affect heart development, it is necessary to consider how to develop protective equipment to alleviate the thoracic space bearing hypergravity loads, reduce cardiac anatomical displacement and ventricular structural imbalance, and ensure that the body maintains normal cardiac blood supply function in the airspace environment. This is a topic that needs further exploration in the future.

Existing research analysing properties available for short-term rental on Airbnb focuses on long-term impacts. There is still a gap to examine abrupt market growth due to mega events like COP26 in Glasgow. By employing Airbnb daily scrapings, this paper summarized spatiotemporal trends and patterns of new Airbnb entire home listings and their impact on neighbourhoods with different social characteristics. We found growth in both deprived and affluent areas during the event. The growth in deprived neighbourhoods, with a smaller Airbnb market in 2020, is consistent. The benefit of responding to the surge in demand, however, is more enjoyed by affluent neighbourhoods.

STUDY QUESTION Is sperm telomere length (STL) associated with sperm nuclear DNA damage and mitochondrial DNA abnormalities? SUMMARY ANSWER Sperm telomere length is related to sperm nuclear DNA integrity and mitochondrial DNA abnormalities in healthy young college students. WHAT IS KNOWN ALREADY Many studies have revealed the correlations between sperm genetic alterations in both the nucleus and mitochondria and sperm functionality, however, the possible associations between the telomere, an important component of chromosome, and conventional indicators of mitochondrial DNA and nuclear DNA changes have not been investigated. STUDY DESIGN, SIZE, DURATION A prospective cohort study, Male Reproductive Health in Chongqing College Students (MARHCS), was conducted from June 2013 to June 2015. We pooled data collected from the follow-up study in 2014 and a total of 444 participants were included. PARTICIPANTS/MATERIALS, SETTING, METHODS STL was measured by quantitative (Q)-PCR. Sperm nuclear DNA integrity was determined using sperm chromatin structure assay (SCSA) and comet assay. Mitochondrial DNA damage was assessed by mitochondrial DNA copy number (mtDNAcn) evaluated with Q-PCR, and mtDNA integrity was determined with long PCR. MAIN RESULTS AND THE ROLE OF CHANCE The univariable-linear regression analysis revealed that STL was significantly positively correlated with markers of sperm nuclear DNA damage including the DNA fragmentation index (DFI) and comet parameters (the percentage of DNA in the tail, tail length, comet length, and tail moment). Additionally, STL was also significantly positively correlated with mtDNAcn and significantly negatively correlated with mtDNA integrity. After adjustment for potential confounders, these relationships remained appreciable. Moreover, we investigated potential effects of biometric factors, including age, parental age at conception, and BMI on STL and found that STL was increased with paternal age at conception. LIMITATIONS, REASONS FOR CAUTION A mechanistic explanation of the correlation between STL, sperm nuclear DNA integrity, and mtDNA abnormalities cannot be provided with a cross-sectional study design, so well-designed longitudinal studies are still necessary. In addition, a single semen samples were provided and were not all obtained at the same time point, which may increase the intraindividual bias in this study. WIDER IMPLICATIONS OF THE FINDINGS The findings extend the literature including assessment of mitochondrial dysfunction, sperm nuclear DNA damage, and telomere length and provide new insights into the relevance of STL in male reproduction. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (No. 82073590), the National Natural Science Foundation of China (No. 81903363), the National Natural Science Foundation of China (No. 82130097), and the National Key R&D Program of China (2022YFC2702900). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Backgrounds & aimsLiver inflammation is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. To replace biopsy, additional non-invasive biomarkers to diagnose and grade liver necroinflammation are urgently required in clinical practice.MethodNinety-four CHB patients, including 74 HBeAg-positive and 20 HBeAg-negative patients, were enrolled and started entecavir or adefovir therapy. Serum HBV RNA, HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), ALT and AST levels, as well as intrahepatic HBV DNA and cccDNA were measured at baseline and during treatment. Liver inflammation was assessed at baseline and month 60 by liver biopsy. Inflammation regression was defined as a ≥1-grade decrease according to the Scheuer scoring system.ResultsIn HBeAg-positive CHB patients, at baseline, serum HBsAg and HBcrAg levels negatively correlated with inflammation grade, while ALT and AST levels positively correlated with inflammation grade. AST plus HBsAg exhibited excellent diagnostic ability for significant inflammation with an AUROC of 0.896. After 60 months of antiviral treatment, almost all the patients’ liver inflammation ameliorated to G1, and no patients had inflammation progression.ConclusionBesides ALT and AST, serum HBsAg and HBcrAg correlated with inflammation grade in HBeAg-positive CHB patients before NAs treatment. Moreover, the combination of HBsAg and AST exhibited excellent diagnostic ability for significant inflammation.

Supplementary figures showing that the gut microbiome variations over the course of nCRT associated with therapeutic response.

Purpose:The gut microbiome is involved in antitumor immunotherapy and chemotherapy responses; however, evidence-based research on the role of gut microbiome in predicting response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) remains scarce. This prospective, longitudinal study aimed to evaluate the feasibility of the gut microbiome in predicting nCRT responses.Experimental Design:We collected 167 fecal samples from 84 patients with LARC before and after nCRT and 31 specimens from healthy individuals for 16S rRNA sequencing. Patients were divided into responders and nonresponders according to pathologic response to nCRT. After identifying microbial biomarkers related to nCRT responses, we constructed a random forest classifier for nCRT response prediction of a training cohort of baseline samples from 37 patients and validated the classifier in another cohort of 47 patients.Results:We observed significant microbiome alterations represented by a decrease in LARC-related pathogens and an increase in Lactobacillus and Streptococcus during nCRT. Furthermore, a prominent microbiota difference between responders and nonresponders was noticed in the baseline samples. Microbes related with butyrate production, including Roseburia, Dorea, and Anaerostipes, were overrepresented in responders, whereas Coriobacteriaceae and Fusobacterium were overrepresented in nonresponders. Ten biomarkers were selected for the response-prediction classifier, including Dorea, Anaerostipes, and Streptococcus, which yielded an area under the curve value of 93.57% [95% confidence interval (CI), 85.76%–100%] in the training cohort and 73.53% (95% CI, 58.96%–88.11%) in the validation cohort.Conclusions:The gut microbiome offers novel potential biomarkers for predicting nCRT responses, which has important manifestations in the clinical management of these patients.

Details on inclusion and exclusion criteria, and supplementary table showing the frequency of patients with discriminatory taxa in fecal samples.

BackgroundLung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism.MethodsChinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher’s exact test. The enriched pathways in each grade of tumors were also inferred.ResultsThe study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein–Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors.ConclusionPatients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein–Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein–Barr virus, pathway analysis

RNA-guided genome editing based on the CRISPR-Cas system is currently the most effective genome editing technique. Here, we report that SviCas3 from the subtype I-B-Svi Cas system in Streptomyces virginiae IBL14 is an RNA-guided and DNA-guided DNA endonuclease suitable for the gene and/or base editing of prokaryotic and eukaryotic cell genomes. The genome editing efficiency of SviCas3 guided by DNA was no less than that of SviCas3 guided by RNA. It should be noted that no off-target effects or indel-formation were detected in targeted sequencing. In particular, t-DNA, as a template and a guide, does not require a proto-spacer-adjacent motif, demonstrating that CRISPR, as the basis for crRNA design, is not required for SviCas3-mediated gene and base editing. This discovery will provide important tools for the creation and modification of living things and the treatment of human genetic diseases, and will usher in a new era of DNA-guided genome editing.

Background: Postmenstrual spotting and chronic pelvic pain after cesarean delivery are associated with the presence of niches. Levonorgestrel intrauterine system (52 mg) and hysteroscopic niche resection have been shown to relieve niche-related symptoms at 6 months after the intervention. Objective: This trial aimed to compare the effectiveness of 52-mg levonorgestrel intrauterine system with that of hysteroscopic niche resection in reducing niche-related postmenstrual spotting. Study Design: This randomized, open-label, controlled trial was conducted at a medical center in Shanghai, China. Women with symptoms of postmenstrual spotting after cesarean delivery, with a niche depth of at least 2 mm and residual myometrium of at least 2.2 mm on magnetic resonance imaging, and no intention to conceive within the next year were randomly assigned to receive treatment with 52-mg levonorgestrel intrauterine system or hysteroscopic niche resection. The primary outcome was the reduction in postmenstrual spotting at 6 months after randomization, defined as the percentage of women with a reduction of at least 50% in spotting days relative to baseline. Efficacy and safety were assessed using intention-to-treat analysis. Results: Between September 2019 and January 2022, 208 women were randomized into the levonorgestrel intrauterine system group (N=104) or the hysteroscopic niche resection group (N=104). At the 6-month follow-up, a 50% reduction in spotting had occurred in 78.4% (80/102) of women in the levonorgestrel intrauterine system group and in 73.1% (76/104) of women in the hysteroscopic niche resection group (relative risk, 1.07 [95% confidence interval, 0.92–1.25]; P=.370). Spotting decreased over time (P trend=.001), with a stronger reduction observed in the levonorgestrel intrauterine system group (P=.001). There was also a significant interaction between time and treatment (P=.007). From 9 months onward, a more significant reduction in spotting was observed in the levonorgestrel intrauterine system group than in the hysteroscopic niche resection group (9 months, 89.2% vs 72.1%; relative risk, 1.24 [95% confidence interval, 1.08–1.42]; 12 months, 90.2% vs 70.2%; relative risk, 1.29 [95% confidence interval, 1.12–1.48]). Moreover, compared with the hysteroscopic niche resection group, the levonorgestrel intrauterine system group had significantly fewer postmenstrual spotting days and total bleeding days from 6 months onward (all P

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.