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ObjectiveFirst-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia.MethodsEligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary).ResultsA total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35–0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53–1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21–0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45–1.64). The grade 3–5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively.ConclusionsThis post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1–positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.

The chromatin remodeler CHD8 represents a high-confidence risk factor in autism, a multistage progressive neurologic disorder, however the underlying stage-specific functions remain elusive. In this study, by analyzingChd8conditional knock-out mice (male and female), we find that CHD8 controls cortical neural stem/progenitor cell (NSC) proliferation and survival in a stage-dependent manner. Strikingly, inducible genetic deletion reveals that CHD8 is required for the production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in the embryonic cortex. p53 loss of function partially rescues apoptosis and neurogenesis defects in theChd8-deficient brain. Further, transcriptomic and epigenomic profiling indicates that CHD8 regulates the chromatin accessibility landscape to activate neurogenesis-promoting factors including TBR2, a key regulator of IPC neurogenesis, while repressing DNA damage- and p53-induced apoptotic programs. In the adult brain, CHD8 depletion impairs forebrain neurogenesis by impeding IPC differentiation from NSCs in both subventricular and subgranular zones; however, unlike in embryos, it does not affect NSC proliferation and survival. Treatment with an antidepressant approved by the Federal Drug Administration (FDA), fluoxetine, partially restores adult hippocampal neurogenesis inChd8-ablated mice. Together, our multistage functional studies identify temporally specific roles for CHD8 in developmental and adult neurogenesis, pointing to a potential strategy to enhance neurogenesis in the CHD8-deficient brain.SIGNIFICANCE STATEMENTThe role of the high-confidence autism geneCHD8in neurogenesis remains incompletely understood. Here, we identify a stage-specific function of CHD8 in development of NSCs in developing and adult brains by conserved, yet spatiotemporally distinct, mechanisms. In embryonic cortex, CHD8 is critical for the proliferation, survival, and differentiation of both NSC and IPCs during cortical neurogenesis. In adult brain, CHD8 is required for IPC generation but not the proliferation and survival of adult NSCs. Treatment with FDA-approved antidepressant fluoxetine partially rescues the adult neurogenesis defects in CHD8 mutants. Thus, our findings help resolve CHD8 functions throughout life during embryonic and adult neurogenesis and point to a potential avenue to promote neurogenesis in CHD8 deficiency.

In order to solve the problem of fast identification of the noise source of rotating machinery, the time-space complex envelope model of monopole sound source is studied, and a modulation method of the complex envelope is proposed. A method combining near-field acoustic holography technology and complex envelope information is proposed to reconstruct the sound field and realize the identification of rotating machinery noise sources. Using the overall fluctuation of the signal to identify the noise source of the rotating machinery greatly reduces the amount of calculation, and speeds up the positioning speed while ensuring the positioning accuracy. According to the sound field radiation characteristics of rotating machinery noise, different measurement distances, different sampling points numbers and different reconstruction distances are selected to reconstruct the sound field. The simulation data analysis results show that the near-field acoustic holography technology can still obtain high sound field reconstruction accuracy under the condition of large reconstruction distance, and does not require high sampling points numbers. Using the envelope information extracted by envelope modulation technology to reconstruct the sound field can accurately identify the number and geometric distribution of sound sources. This technology not only speeds up data processing, but also ensures the accuracy of sound field reconstruction. &nbsp

In order to reduce the induction noise of automobile engine, an active control system model of engine induction noise is established with the FXLMS algorithm, the off-line identification method is used to identify the secondary channel, and the engine speed signal is used to construct the sound source reference signal to avoid the interference from secondary sources to the reference signal. The influence of filter length and convergence factor on the convergence speed and stability of the system is studied by simulation, the average power of the noise signal and the error signal is calculated, the noise variation at different engine speeds is analyzed, and the noise reduction effect and system stability are evaluated. The results show that when the filter order L is 20 and the convergence factor is 0.01, the engine induction noise can be effectively reduced, the noise reduction can reach 15dB, and the system stability can be improved at the same time. This paper optimizes the convergence factor and the filter order in the FXLMS algorithm, and can effectively control the induction noise in the car and improve the indoor sound quality of the car. It has important reference significance for practical engineering applications.

Quantum entanglement between an interfering particle and a detector for acquiring the which-path information plays a central role for enforcing Bohr's complementarity principle. However, the quantitative relation between this entanglement and the fringe visibility remains untouched upon for an initial mixed state. Here we find an equality for quantifying this relation. Our equality characterizes how well the interference pattern can be preserved when an interfering particle, initially carrying a definite amount of coherence, is entangled, to a certain degree, with a which-path detector. This equality provides a connection between entanglement and interference in the unified framework of coherence, revealing the quantitative entanglement-interference complementarity. We experimentally demonstrate this relation with a superconducting circuit, where a resonator serves as a which-path detector for an interfering qubit. The measured fringe visibility of the qubit's Ramsey signal and the qubit-resonator entanglement exhibit a complementary relation, in well agreement with the theoretical prediction., 19 pages, 9 figures, 1 table

The move to online learning during COVID-19 deprived first-year students of friendships and other sources of social support that could buffer against stress during their transition to university. These effects may have been worse for international students than domestic students as many were subjected to travel restrictions or quarantine in addition to the usual stressors. This study examined the impact of COVID-19 on social connectedness and mental health of first-year students enrolled in a metropolitan university in Australia. The study involved 1239 students (30.4% international) and used a 3 (cohorts: 2019, 2020, 2021) × 2 (enrolment status: domestic and international) between-group design. Results showed that both loneliness and university belonging were significantly worse during the first year of COVID-19 compared to the year before or after. Contrary to expectation, domestic students were lonelier than international students across all cohorts. Multiple-group memberships did not change. As predicted, loneliness was moderately to highly correlated with the number of stressors, psychological distress, and (lower) well-being, whereas university belonging and multiple-group memberships were related to positive mental health outcomes. These findings highlight the need for initiatives that promote student connectedness and mental health as the university sector recovers from COVID-19.

Antimicrobial peptides (AMP) are small proteins that play critical roles in host defense against microbe invasion. Many AMPs disrupt the cellular membrane of microbe, while the mechanism of action of AMPs can be very sophisticated. Solid-state NMR (SSNMR) technique is powerful in characterizing the mechanism of AMPs in vivo and in vitro. This review summarizes the recent advance of SSNMR technique in AMP mechanisms characterization. We highlight the sample preparation approaches, the SSNMR spectroscopic methods, and a number of outstanding examples of AMP mechanisms elucidated via SSNMR spectroscopy.

The Fuling shale gas field in China is one of the largest shale gas fields outside of North America. After a long period of production, some gas wells showed significant production decline and an effective refracturing treatment is designed to rejuvenate production. This Casing-in-Casing (CiC) refracturing method with customized design was successfully implemented with production increase beyond expectation. It was the first successful trial of a CiC refracturing treatment on a horizontal shale gas well in China.Bullheading (BH) refracturing with diverting balls was attempted in this field in past years, with high initial production observed. However, the production was inconsistent and declined quickly. The operator investigated and decided to attempt a CiC refracturing method in an under-stimulated candidate well. The CiC refracturing method is to cement a 3.5-in. liner in the legacy 5.5-in. casing to isolate the perforations, and new plugging and perforating (P-n-P) operations can be performed in the reconstructed wellbore. A refracturing design was customized integrating the production profile, residual recoverable reserves, and the specific 5.5- × 3.5-in. reconstructed wellbore limitation.During the BH refracturing, the treating pressure gradually increased with the drops of diverting balls, but the proppant placement became more and more difficult accordingly. The BH refracturing was finally completed with five cycles which was less than the design. High initial production after the BH treatment was observed but it declined quickly. In the CiC refracturing, a new 5.5-in × 3.5-in wellbore was constructed successfully, and it passed pressure test for stage frac. New clusters were added between the original clusters and stimulated with more intensive fracturing treatment in the new wellbore. Dissolvable particulate diverting agent was used for even cluster initiation and fracture geometry. The pressure response of the diverting agent was obvious indicating good diversion result and new reservoir contact. The initial production recovery rate was 88.1% compared to that of the original fracturing and the production increased 819% compared to the production before the CiC refracturing, which was much higher than BH refracturing.This case study illustrates that the CiC refracturing method is an effective method for refracturing. It overcomes the uncertainty and difficulty of proppant placement, achieves a higher intensity of fracturing treatment, and enables stimulation of the previously bypassed reservoir to improve the recovery of the well. The method has provided the industry with a new and reliable option to rejuvenate the aging wells.

In this study, a Ni-based sludge coke catalyst was prepared by mechanical ball-milling and mild injection to produce high-quality hydrogen-rich gas through the gasification of sludge. The effects of different factors, such as ball milling time, gasification temperature, NiO loading rate and steam flow rate on the gasification characteristics of the Ni-based sludge coke were investigated. The results showed that the optimum process conditions were the ball-milling time of 10 min, gasification temperature of 900 °C, NiO loading rate of 20% and steam flow rate of 1 g min−1. Under these conditions, the gas production efficiency was improved, with gas and H2 production rates of 0.76 m3 kg−1 and 0.34 m3 kg−1, respectively. Temperature is a key factor of gasification. The gas yield and H2 yield at 900 °C were 38 times and 85 times higher than those at 500 °C, respectively. The FTIR and XRD analysis further revealed that the selection of an appropriate ball-milling time caused the NiO to be evenly distributed on the biochar, thereby improving its catalytic performance. While, increasing the temperature promoted the full pyrolysis of organic matter and the secondary decomposition of tar, which improved the gasification efficiency. The results obtained here allow optimization of the technical parameters for the generation of hydrogen-rich gas by sludge gasification, thereby providing a theoretical basis for the production of high-quality gas through the catalytic gasification of Ni-based biochar.

Four new N-methyl-4-quinolones (1–4) and a new citrinin dimer derivative (10) with fourteen known compounds (5–9, 11–19) were isolated from the sponge-derived fungus Penicillium sp. SCSIO41303. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and X-ray single-crystal diffraction. Most of the isolated compounds were evaluated for their cytotoxic, antibacterial, anti-virus, and enzyme inhibitory activities against acetylcholinesterase (AChE), and pancreatic lipase (PL). Compounds 2 and 11 exhibited enzyme inhibition activity against PL with IC50 values of 24.6 and 7.2 μg/mL, respectively. Besides, compound 11 showed enzyme inhibition activity against AChE with IC50 value of 16.5 μg/mL. Compound 15 showed moderate inhibition activities with 52.2% at the concentration of 50 μg/mL against PL and antibacterial activity against Staphylococcus aureus displaying diameter of about 10 mm.

Iron-catalyzed direct SN2' dehydroxyboration of allylic alcohols has been developed to access (E)-stereoselective allylboronates. Allylic alcohols with diverse structures and functional groups, especially derived from natural products, underwent smooth transformation. The six-membered ring transition state formed by allylic alcohols and iron-boron intermediate was indicated to be the key component involved in transfer of the boron group, activation of the C-OH bond, and control of the stereoselectivity.

One new citrinin monomer derivative (1), and two new natural products α-pyrone analogues (2a and 2b), were isolated from the sponge derived fungus Penicillium sp. SCSIO 41302. Their structures were determined by extensive spectroscopic analysis, chiral-phase HPLC analysis, modified Mosher's method, ECD calculations, and X-ray single-crystal diffraction. Bioactivity screening showed that compounds 2b and 8 exhibited obvious inhibitory activities against pancreatic lipase and acetyl cholinesterase with IC50 values of 48.5 and 4.8 μM, respectively, which indicated that different chiral center between enantiomers (2a and 2b) might result in different biological activities (IC50 value against PL for 2a >100 μg/ml).

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval [CI], 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11‐0.65]; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 [95% CI, 0.17‐0.91]; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738., This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.

Background Workplace heat exposure can cause a series of heat-related illnesses and injuries. Protecting workers especially those undertake work outdoors from the risk of heat strain is a great challenge for many workplaces in China under the context of climate change. The aim of this study is to investigate the perceptions and adaptation behaviors of heat exposure among construction workers and to provide evidence for the development of targeted heat adaptation strategies nationally and internationally. Methods In 2020, we conducted a cross-sectional online questionnaire survey via WeChat Survey Star in China, using a purposive snowball sampling approach. A total of 326 construction workers submitted completed questionnaires. The perceptions of workplace heat exposure were measured using seven indicators: concerns over high temperature, perception of high temperature injury, attitudes towards both heat-related training and regulations, adjustment of working habits during heat, heat prevention measures in the workplace, and reduction of work efficiency. Bivariate and multivariate regression analyses were used to identify the factors significantly associated with workers’ heat perceptions and behavioral responses. Results 33.3% of the respondents were moderately or very concerned about heat exposure in the workplace. Less than half of the workers (43.8%) were worried about heat-related injuries. Workers who have either experienced work-related injuries (OR = 1.30, 95% CI 1.03–1.62) or witnessed injuries to others during high temperatures (OR = 1.12, 95% CI 1.02–1.27) were more concerned about heat exposure compared to other workers. Most respondents (63.5%) stated that their work efficiency declined during extremely hot weather. The factors significantly associated with a reduction of work efficiency included undertaking physically demanding jobs (OR = 1.28, 95% CI 1.07–1.54) and witnessing other workers’ injuries during high temperatures (OR = 1.26, 95% CI 1.11–1.43). More than half of the workers were willing to adjust their work habits to adapt to the impact of high temperatures (81.6%). The internet was the most common method to obtain heat prevention information (44.7%), and the most frequently used heat prevention measure was the provision of cool drinking water (64.8%). Conclusions Chinese construction workers lack heat risk awareness and are not well prepared for the likely increasing heat exposure in the workplace due to global warming. Therefore, there is a need to improve their awareness of heat-related injuries, strengthen high temperature related education and training, and update the current heat prevention policies to ensure compliance and implementation.

BACKGROUND Under the trend of normalization of the follow-up epidemic prevention and control, whether the function of intelligent technology will be continuously explored and expanded to reduce the social isolation of the elderly, or whether it will restrict the participation of the elderly in social life and aggravate the social isolation in the post-epidemic era, has become an important issue to be investigated. Based on this background, this paper conducts an in-depth study on the impact of the using intelligent technology on the social isolation of the elderly. OBJECTIVE To understand the impact of intelligent technology use on social isolation of the elderly. METHODS In 2021, we conducted a cross-sectional online questionnaire with 229 valid samples in China using the purposeful snowball sampling method. Using logistic regression model, this paper analyzed the impacts and differences of using intelligent technology on the social isolation of the elderly, and the robustness test was conducted. RESULTS The use of intelligent technology can significantly reduce the social isolation of the elderly. The result is still valid after overcoming the robustness test. Women, middle-aged and elderly people can benefit more from the using intelligent technology to reduce social isolation, and there is no urban-rural difference in the effectiveness of use. CONCLUSIONS These results suggest that intelligent technology can become an effective tool to eliminate the digital divide of the elderly and decrease the social isolation of the elderly.

This study aimed to explore the prevalence of prenatal depression and to determine the dyadic relationship between perceived stress, marital satisfaction, and prenatal depression in pregnant women with gestational diabetes mellitus (GDM) and their partners.GDM during pregnancy is a very stressful event for couples. However, previous studies have largely focused on pregnant women, with few including their partners.A cross-sectional study was conducted in Guangzhou, China, from 30 July to 2 December 2021. Three hundred fourteen couples with GDM completed the Perceived Stress Scale, Locke-Wallace Marital Adjustment Scale, and Edinburgh Postnatal Depression Scale. Dyadic analysis was conducted using the actor-partner interdependence mediation model.The prevalence of depressive symptoms was 13.4% in pregnant women with GDM and 8.3% in their partners. Regarding the actor effects, perceived stress was positively associated with prenatal depression in pregnant women with GDM and their partners, respectively, and marital satisfaction acted as a mediating role. Regarding the partner effects, paternal perceived stress was negatively associated with maternal marital satisfaction, and maternal marital satisfaction mediated the association between paternal perceived stress and maternal prenatal depression.Dyadic effects of perceived stress, marital satisfaction, and prenatal depression exist in couples with GDM.

Due to the widespread application of rare earth oxide nanoparticles in various fields, their release into the environment is inevitable, and their potential toxicity and ecological impact have become a concern. Yttrium oxide nanoparticles are important rare earth oxide nanoparticles; however, their impact on plants and the molecular mechanism underlying their influence on plant growth and development are unclear. In this study, we found that yttrium oxide nanoparticles at concentrations exceeding 2 mM significantly inhibited the growth of Arabidopsis seedlings. Using Arabidopsis marker lines for auxin signaling, we found that the application of yttrium oxide nanoparticles resulted in disordered auxin signaling in root cells. Auxin signaling in the cells of the quiescent center and columella stem cells decreased, while auxin signaling in the cells of the stele was enhanced. In addition, trypan blue staining showed that yttrium oxide nanoparticles induced root cell death. Transcriptome analysis showed that the nanoparticles specifically inhibited the expression of lignin synthesis-related genes, activated the MAPK signaling pathway, and enhanced the ethylene and abscisic acid signaling pathways in plants. This study demonstrates the phytotoxicity of yttrium oxide nanoparticles at the molecular level in Arabidopsis, and it provides a new perspective on how plants respond to rare earth oxide stress.