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This paper proposes a nine-level switched-capacitor step-up inverter (9LSUI) which can achieve a quadruple voltage gain with single dc source. Differing from other switched-capacitor inverters, the voltage stress of switches is effectively reduced due to the elimination of H-bridge, and the peak inverse voltage of all switches is kept within 2Vdc. In addition, the proposed inverter is able to integrate inductive load, and the capacitor voltage self-balancing can be achieved without any auxiliary circuits. Moreover, the topology structure can be flexibly extended to raise the output levels, and the peak inverse voltage of switches can remain constant with the increase of sub-modules in the extended structure. Comprehensive comparisons are performed to verify the outstanding advantages of the proposed inverter. Finally, the steady-state and dynamic performance of the proposed inverter is validated through an experimental prototype, and the experimental results are provided to prove the theoretical analysis.

Purpose To develop a bidirectional slide guide to assist screw placement in the axial lamina and to preliminarily discuss the accuracy and feasibility of auxiliary screw placement. Methods CT data from 40 randomly selected patients were imported into the software for modelling, and cross-pinning was used to simulate pinning. According to the different crossing methods of the upper and lower laminar screws, they are divided into two groups. In the software, the position of the needlepoint of each screw is accurately measured, and the needle point is kept unchanged to simulate the movable range of the screw tail under the condition that the body does not penetrate the cortical bone. The data were compared by grouping and gender. Finally, the guide was designed by combining the screw exit point and fine adjustment angle data of all patients with the centripetal principle of the slide rail. Results The needle exit data L1/L2/L3/L4 were 6.44 ± 0.52 mm, 7.05 ± 0.48 mm, 3.55 ± 0.75 mm and 5.09 ± 0.74 mm, respectively, and the fine adjustment angle of the slide rail was 10.51° ± 0.87°. There was no significant difference between the two groups or between men and women (p > 0.05). Conclusion In this experiment, using the data obtained from the simulation of screw insertion, a two-way slide guide was designed to assist the insertion of axial laminar screws. The guide locks the screw outlet point to position and guides the screw inlet point, which improves the accuracy and safety of screw placement.

Background Cas12a (formerly known as Cpf1), the class II type V CRISPR nuclease, has been widely used for genome editing in mammalian cells and plants due to its distinct characteristics from Cas9. Despite being one of the most robust Cas12a nucleases, LbCas12a in general is less efficient than SpCas9 for genome editing in human cells, animals, and plants. Results To improve the editing efficiency of LbCas12a, we conduct saturation mutagenesis in E. coli and identify 1977 positive point mutations of LbCas12a. We selectively assess the editing efficiency of 56 LbCas12a variants in human cells, identifying an optimal LbCas12a variant (RVQ: G146R/R182V/E795Q) with the most robust editing activity. We further test LbCas12a-RV, LbCas12a-RRV, and LbCas12a-RVQ in plants and find LbCas12a-RV has robust editing activity in rice and tomato protoplasts. Interestingly, LbCas12a-RRV, resulting from the stacking of RV and D156R, displays improved editing efficiency in stably transformed rice and poplar plants, leading to up to 100% editing efficiency in T0 plants of both plant species. Moreover, this high-efficiency editing occurs even at the non-canonical TTV PAM sites. Conclusions Our results demonstrate that LbCas12a-RVQ is a powerful tool for genome editing in human cells while LbCas12a-RRV confers robust genome editing in plants. Our study reveals the tremendous potential of these LbCas12a variants for advancing precision genome editing applications across a wide range of organisms.

Transition metal-catalyzed C–H bond functionalization is an important method in organic synthesis, but the development of methods that are lower cost and have a less environmental impact is desirable. Here, a Cu-catalyzed asymmetric C(sp2)–H arylation is reported. With diaryliodonium salts as arylating reagents, a range of ortho-arylated P-chiral phosphonic diamides were obtained in moderate to excellent yields with high enantioselectivities (up to 92% ee). Meanwhile, enantioselective C-3 arylation of diarylphosphine oxide indoles was also realized under similar conditions to construct axial chirality.

Background Both N6-methyladenosine (m6A) and ferroptosis-related genes are associated with the prognosis of lung adenocarcinoma. However, the predictive value of m6A-related ferroptosis genes remains unclear. Here, we aimed to identify the prognostic value of m6A-related ferroptosis genes in lung adenocarcinoma. Methods Lung adenocarcinoma sample data were downloaded from the University of California Santa Cruz Xena and Gene Expression Omnibus databases. Spearman’s correlation analysis was used to screen for m6A-related ferroptosis genes. Univariate Cox regression, Kaplan–Meier, and Lasso analyses were conducted to identify prognostic m6A-related ferroptosis genes, and stepwise regression was used to construct a prognostic gene signature. The predictive value of the gene signature was assessed using a multivariate Cox analysis. In the validation cohort, survival analysis was performed to verify gene signature stability. The training cohort was divided into high- and low-risk groups according to the median risk score to assess differences between the two groups in terms of gene set variation analysis, somatic mutations, and tumor immune infiltration cells. Results Six m6A-related ferroptosis genes were used to construct a gene signature in the training cohort and a multivariate Cox analysis was conducted to determine the independent prognostic value of these genes in lung adenocarcinoma. In the validation cohort, Kaplan–Meier and receiver operating characteristic analyses confirmed the strong predictive power of this signature for the prognosis of lung adenocarcinoma. Gene set variation analysis showed that the low-risk group was mainly related to immunity, and the high-risk group was mainly related to DNA replication. Somatic mutation analysis revealed that the TP53 gene had the highest mutation rate in the high-risk group. Tumor immune infiltration cell analysis showed that the low-risk group had higher levels of resting CD4 memory T cells and lower levels of M0 macrophages. Conclusion Our study identified a novel m6A-related ferroptosis-associated six-gene signature (comprising SLC2A1, HERPUD1, EIF2S1, ACSL3, NCOA4, and CISD1) for predicting lung adenocarcinoma prognosis, yielding a useful prognostic biomarker and potential therapeutic target.

Sleep is ubiquitous and essential, but its mechanisms remain unclear. Studies in animals and humans have provided insights of sleep at vastly different spatiotemporal scales. However, challenges remain to integrate local and global information of sleep. Therefore, we developed sleep fMRI based on simultaneous electrophysiology at 9.4 T in male mice. Optimized un-anesthetized mouse fMRI setup allowed manifestation of NREM and REM sleep, and a large sleep fMRI dataset was collected and openly accessible. State dependent global patterns were revealed, and state transitions were found to be global, asymmetrical and sequential, which can be predicted up to 17.8 s using LSTM models. Importantly, sleep fMRI with hippocampal recording revealed potentiated sharp-wave ripple triggered global patterns during NREM than awake state, potentially attributable to co-occurrence of spindle events. To conclude, we established mouse sleep fMRI with simultaneous electrophysiology, and demonstrated its capability by revealing global dynamics of state transitions and neural events.

Metastable ε-Fe2O3 was discovered on a ceramic ware of Deqing kiln of the Tang Dynasty, which coexists with α-Fe2O3 in the brown area between adjacent black glaze areas, and it is the earliest known artificially synthesized ε-Fe2O3. Based on the composition analysis of α-Fe2O3, ε-Fe2O3 and the glass phase around them, it is speculated that some Fe3+ ions were replaced by Al3+ ions during the formation of ε-Fe2O3, and a relatively low CaO content may be required for its crystallization. This work may promote researchers' understanding of ε-Fe2O3 crystals, and provide clues for the artificial synthesis of large ε-Fe2O3 crystals.

Objectives This study aimed to explore differences between psychological resilience and problem-solving ability in grade one junior middle school adolescents with and without suicidal ideation, focusing on the relationship between these factors and suicidal ideation. Methods Ninety-nine adolescents (aged 10 to 14) were divided into Suicidal Ideation (SI, n = 49) and Non-Suicidal Ideation (NSI, n = 50) grouped by the Self-rating Idea of Suicide Scale (SIOSS). The Psychological Resilience Scale (PRS) and Tower of Hanoi task (TOH) were applied to assess psychological resilience and problem-solving ability, respectively. Results The SI group scored significantly lower than the NSI group on PRS (p p p r = − 0.413, p r = − 0.361, − 0.360, − 0.382; p Conclusions This study profiled the characteristics and differences in psychological resilience and problem-solving ability between adolescents with and without suicidal ideation. The data suggested adolescents with SI might have deficits in psychological resilience and problem-solving ability, which may serve as potential targets for suicide intervention.

Dielectric capacitors with high energy storage performance are highly desired for next-generation advanced high/pulsed power capacitors that demand miniaturization and integration. However, the poor energy-storage density that results from the low breakdown strength, has been the major challenge for practical applications of dielectric capacitors. Herein, we propose a heterovalent-doping-enabled atom-displacement fluctuation strategy for the design of low-atom-displacements regions in the antiferroelectric matrix to achieve the increase in breakdown strength and enhancement of the energy-storage density for AgNbO3-based multilayer capacitors. An ultrahigh breakdown strength ~1450 kV·cm−1 is realized in the Sm0.05Ag0.85Nb0.7Ta0.3O3 multilayer capacitors, especially with an ultrahigh Urec ~14 J·cm−3, excellent η ~ 85% and PD,max ~ 102.84 MW·cm−3, manifesting a breakthrough in the comprehensive energy storage performance for lead-free antiferroelectric capacitors. This work offers a good paradigm for improving the energy storage properties of antiferroelectric multilayer capacitors to meet the demanding requirements of advanced energy storage applications.

Klebsiella pneumoniae carbapenemase (KPC)-2, metallo-beta-lactamases (MBL), and oxacillinase (OXA)-48-like carbapenemases are considered the most important carbapenemases. In vitro studies have demonstrated that the carbapenemase activity of KPC-2 and MBL can be inhibited by 3-aminophenylboronic acid and ethylenediaminetetraacetic acid (EDTA), respectively. Understanding the carbapenemase types expressed in carbapenem-resistant Enterobacterales (CRE) is of great significance to clinical therapies. Liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) is fast, stable, and specific; and is considered the gold standard method for measuring small molecules. In this study, we developed carbapenemase inhibition tests combined with LC-MS/MS to rapidly identify carbapenemase types. A total of 295 clinical isolates were examined, including 212 KPC-2 producers, 29 MBL producers, 15 OXA-48-like producers, 3 KPC-2 + OXA-232 producers, and 36 carbapenem-sensitive strains. We used LC-MS/MS to determine the carbapenemase types by measuring the ratio of the hydrolyzed meropenem peak areas in the presence and absence of different inhibitors. The sensitivity and specificity of LC-MS/MS in detecting single KPC-2 producers were 97.64% and 100.00%, respectively, and 96.55% and 100.00% for MBL producers, respectively. In addition, the sensitivity and specificity of LC-MS/MS in detecting single OXA-48-like producers were both 100.00% when extending incubation time up to 2.5 h. LC-MS/MS showed excellent agreement in detecting carbapenemase types using the modified carbapenem inactivation (mCIM)/EDTA-carbapenem inactivation assay (eCIM) (kappa = 0.93 for serine carbapenemases and kappa = 0.98 for MBL carbapenemases). In this study, LC-MS/MS demonstrated excellent detection of different carbapenemase types, showing potential reliability in future clinical applications.

In consideration of the abundant moisture of limonitic nickel laterite mined, it is essential to determine whether the self-possessed moisture of limonitic nickel laterite after pre-dried is appropriate for sintering. Thus, based on the characterization of limonitic nickel laterite, the influence of its self-possessed moisture on sintering performance was expounded by sinter pot tests and the relevant mechanism was revealed by the systematical analyses of the granulation properties of sinter mixture, thermodynamic conditions during sintering and mineralogy of product sinter. The results indicate that the self-possessed moisture of limonitic nickel laterite indeed has significant influence on its sintering performance. At the optimum self-possessed moisture of 21 mass%, sinter indices are relatively better with tumble index, productivity and solid fuel rate of 48.87%, 1.04 t m−2 h−1 and 136.52 kg t−1, respectively, due to the superior granulation properties of sinter mixture and thermodynamic conditions during sintering, relatively large amount of silico-ferrite of calcium and alumina and tighter sinter microstructure. However, sintering performance of limonitic nickel laterite is still much poorer than that of ordinary iron ores. It is feasible to strengthen limonitic nickel laterite sintering by inhibiting the over-fast sintering speed and improving the thermodynamic conditions during sintering.

The central China summer precipitation (CCSP) is of great importance to the people’s livelihood of this densely populated region, including the agriculture, ecosystems, water resources, economies, and health. Based on the observed precipitation, sea surface temperature (SST), and atmospheric reanalysis datasets, the present study investigates the effects of El Nino in the developing stage on the CCSP during 1960–2014. The results show that the CCSP anomalies exhibit significant negative correlations with the El Nino-related SST anomalies in both the simultaneous summer and the following winter, implying that the developing El Nino is important for modulating the CCSP. However, this climatic teleconnection of El Nino is unstable, with an obvious interdecadal change around the late 1980s. Specifically, the negative correlation is not statistically significant in the previous epoch before the late 1980s (1960–1988), but dramatically strengthens since the late 1980s (the post epoch for 1989–2014). Such an interdecadal change is closely associated with the change of the El Nino-related SST anomaly pattern. Compared to the previous epoch, the central Pacific El Nino occurs more frequently in the post epoch, leading to an interdecadal shift of the maximum warm SST anomalies from the eastern Pacific to the central Pacific. The resultant westward extension of the atmospheric circulation responses induces an anomalous low-level cyclone covering South China in the post epoch. It would prevent the southwest monsoon from delivering the moisture to the north and hence reduce the CCSP. While, in the previous epoch, the anomalous cyclone locates east of South China, exerting insignificant influence on the CCSP. This work highlights a strengthening effect of El Nino on the CCSP since the late 1980s, with great implications for the regional seasonal climate prediction.

The failure and instability of a kind of specific rock structural bodies, such as the spalling-induced thin rock plates and the slender rock pillars, are the key inducing factors of rock engineering disasters and they are closely related to the shape effect, i.e., the height-to-width (H/W) ratio. For application in engineering practice, the strength characteristics and failure modes of the rock structural bodies when their H/W ratios vary in a wide range should be specially concerned, whereas this seems to be seriously ignored in previous studies. To support this purpose, a numerical scheme that integrates the statistical meso-damage constitutive model and the finite deformation formulation is proposed, to consider both the material failure and buckling instability of the rock structural bodies. The numerical results of a series of uniaxial compression tests of rock samples with relatively low H/W ratios (0.5–4) are completely consistent with the findings obtained from experiments. The behaviors of rock samples with high H/W ratios (6–28) show that the failure of rock samples is affected by both the H/W ratio and the strength of the rock material. That is, as the H/W ratio increases, the failure of rock samples gradually transforms from material failure dominated to structural (buckling) instability dominated, and the increase of the strength of rock material can facilitate this transition. The presented results have established an envelope about the failure and instability of rocks, and obtained the critical boundary line (CBL) for distinguishing different failure modes and determining the boundary between low and high H/W ratio.

Background Abnormal lipid metabolism is one of the most prominent metabolic changes in cancer. Studies have shown that lipid metabolism also plays an important role in neuroblastoma. We recently discovered that the insulinoma-associated 2 gene (INSM2) could regulate lipid metabolism in neuroblastoma (NB) and is improperly controlled by super enhancers, a mammalian genome region that has been shown to control the expression of NB cell identity genes. However, the specific molecular pathways by which INSM2 leads to NB disease development are unknown. Results We identified INSM2 as a gene regulated by super enhancers in NB. In addition, INSM2 expression levels were significantly upregulated in NB and correlated with poor prognosis in patients. We found that INSM2 drives the growth of NB cell lines both in vitro and in vivo. Knocking down INSM2 inhibited fatty acid metabolism in NB cells. Mechanistically, INSM2 regulates the expression of SREBP1 by regulating the mTOR signaling pathway, which in turn affects lipid metabolism, thereby mediating the occurrence and development of neuroblastoma. Conclusion INSM2 as a super-enhancer-associated gene could regulates lipid metabolism by modulating mTOR signaling pathway in neuroblastoma.

Aflatoxin B1 (AFB1) contamination in feed and food seriously threatens the healthy growth of animals and humans, and it may lead to huge economic losses in livestock and poultry production. Therefore, screening of high-efficient AFB1-degrading bacteria is necessary to ensure the safety of feed and food. The study aims to isolate and characterize bacteria from various sources to explore its AFB1 degradation potential. Fifteen bacterial were obtained using a medium containing coumarin as the sole carbon source; only one strain showed a good-degrading ability in culture media by adding AFB1 and it was selected for further studies. A gram-negative and spore-forming, designated E1, was identified as Paenibacillus pabuli, with the highest sequence similarity to P. pabuli NBRC13638T (98.97%). The growth of the strain E1 was observed under 22–47 °C, pH 5.5–9.5 and NaCl concentration 0–6% (w/v), with optimum growth at 37 °C, pH 7.5 and 1% NaCl. The biodegradation characteristics of object strain were detected by high performance liquid chromatography (HPLC). The degradation ratio of AFB1 reached 55% at 24 h and 70.2% at 48 h. After 96 h, the degradation rate of AFB1 reached 85.9%. The active degradation components were present in the cell-free supernatant of strain E1, and the degradation ratio of AFB1 reached 80.0% after 96 h. It is the first report that genus Paenibacillus could degrade AFB1. Moreover, E1 has highly adaptable to diverse environmental conditions. It will be a potential candidate for biodegradation of mycotoxins in feed and food.

Due to the highly contagious and spreads quickly of respiratory infectious diseases (ADR), the availability of rapid, sensitive, and reliable diagnostic methods is essential for disease control. Here, we develop an approach based on loop-mediated isothermal amplification (LAMP) for the detection of influenza A virus (Flu A), Flu A subtypes H1N1and H3N2, influenza B virus (Flu B), respiratory syncytial virus (RSV) subtypes A and B, human adenovirus (HAdV), parainfluenza virus (PIV) subtypes 1 and 3, and human rhinovirus (HRV) simultaneously. We designed primers specific to detect respiratory viruses above, optimized the RT-LAMP assay and evaluated it for its sensitivity and specificity of detection using real-time monitoring based on SYBR Green I. We also evaluated the result of our RT-LAMP assay on 638 nasopharyngeal swab specimens with the commercial RT-PCR by Cohen’s Kappa. The inconsistent results were verified by Sanger sequencing furtherly. The developed RT-LAMP assay displayed a detection limit of 1 × 102 copies/ml RNA close to that of RT-PCR; no cross-reactivity was observed in the 10 kinds of viruses studied. The results obtained with 638 clinical samples indicate that the developed method has high specificity (0.988–1) and sensitivity (0.863–1) for viruses studied, and the Kappa value of all viruses was more than 0.85 revealed an excellent agreement between the two methods. We developed an RT-LAMP-based method and optimized for the detection of common respiratory viruses. It may be a powerful tool for rapid and reliable clinical diagnosis of ADR in primary hospitals. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-021-04300-8.

Essential tremor (ET) is the most common movement disorder and share overlapping symptoms with Parkinson’s disease (PD), making differential diagnosis challenging. Gut dysbiosis is regarded crucial in the pathogenesis of PD. Since ET patients also has comorbidity in gastrointestinal disorders, the relationship between gut microbiota and ET really worth investigating and may help distinguishing ET from PD. Fecal samples from 54 ET, 67 de novo PD and 54 normal controls (NC) were collected for 16S ribosomal RNA gene sequencing and quantitative real-time PCR. ET showed lower species richness (Chao1 index) than NC and PD. ET was with Bacteroides-dominant enterotype, while PD was with Ruminococcus-dominant enterotype. Compared with NC, 7 genera were significantly reduced in ET, 4 of which (Ruminococcus, Romboutsia, Mucispirillum, and Aeromonas) were identified to be distinctive with an area under the curve (AUC) of 0.705. Compared to PD, 26 genera were found significantly different from ET, 4 of which (Bacteroides, Fusobacterium, Phascolarctobacterium, and Lachnospira) were found distinguishable with an AUC of 0.756. Clinical association results indicated that Proteus was associated with disease severity (TETRAS) of ET, while Klebsiella was linked to depression and anxiety in ET. Functional predictions revealed that 4 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were altered in ET. This study reveals gut dysbiosis in ET and it provides new insight into the pathogenesis of ET and helps distinguishing ET from PD.

Background Transmissible viral proventriculitis (TVP) causes significant economic loss to the poultry industry. However, the exact causative agents are obscure. Here we examine the virome of proventriculus from specified pathogen free (SPF) chickens that reproduced by infection of proventricular homogenate from broiler chicken with TVP using long read sequencing of the Pacific Biosciences RSII platform. The normal SPF chickens were used as control. Results Our investigation reveals a virome of proventriculitis, including three Gyrovirus genera of the Aneloviridae: Gyrovirus homsa1 (GyH1) (also known as Gyrovirus 3, GyV3) (n = 2662), chicken anemia virus (CAV) (n = 482) and Gyrovirus galga1 (GyG1) (also known as avian Gyrovirus 2, AGV2) (n = 11); a plethora of novel CRESS viral genomes (n = 26) and a novel genomovirus. The 27 novel viruses were divided into three clusters. Phylogenetic analysis showed that the GyH1 strain was more closely related to the strains from chicken (MG366592) than mammalian (human and cat), the GyG1 strain was closely related to the strains from cat in China (MK089245) and from chicken in Brazil (HM590588), and the CAV strain was more closely related to the strains from Germany (AJ297684) and United Kingdom (U66304) than that previously found in China. Conclusion In this study, we revealed that Gyrovirus virome showed high abundance in chickens with TVP, suggesting their potential role in TVP, especially GyH1. This study is expected to contribute to the knowledge of the etiology of TVP.

Background Gyrovirus homsa1 (GyH1) (also known as Gyrovirus 3, GyV3) is a non-enveloped, small, single-stranded DNA virus, which was first identified in children with acute diarrhea, and was subsequently detected in marketed chickens, broilers with transmissible viral proventriculitis (TVP), and mammals. GyH1 is a pathogenic virus in chickens, causing aplastic anemia, immunosuppression, and multisystem damage. However, the seroepidemiology of GyH1 infection in chickens remains unclear. Here, we investigated the seroprevalence of GyH1 in chickens by ELISA to reveal the endemic status of GyH1 in China. Results An indirect ELISA with high sensitivity and specificity was developed for investigation of seroepidemiology of GyH1 in chickens in China. The seropositive rate of GyH1 ranged from 0.6% to 7.7% in thirteen provinces, and ranged from 4.1% to 8.1% in eight species chickens. The seropositive rate of GyH1 in broiler breeders was significantly higher than that of in layers. There was a negative correlation between seropositive rate and age of chickens. The highest and lowest seropositive rate were present in chickens at 30–60 days and over 180 days, respectively. Conclusions The seroepidemiological investigation results demonstrated that natural GyH1 infection is widespread in chickens in China. Different species showed different susceptibility for GyH1. Aged chickens showed obvious age-resistance to GyH1. GyH1 has shown a high risk to the poultry industry and should be highly concerned.

Safe and effective autonomous navigation in dynamic environments is challenging for four-wheel independently driven steered mobile robots (FWIDSMRs) due to the flexible allocation of multiple maneuver modes. To address this problem, this study proposes a novel multiple mode-based navigation system, which can achieve efficient motion planning and accurate tracking control. To reduce the calculation burden and obtain a comprehensive optimized global path, a kinodynamic interior-exterior cell exploration planning method, which leverages the hybrid space of available modes with an incorporated exploration guiding algorithm, is designed. By utilizing the sampled subgoals and the constructed global path, local planning is then performed to avoid unexpected obstacles and potential collisions. With the desired profile curvature and preselected mode, a fuzzy adaptive receding horizon control is proposed such that the online updating of the predictive horizon is realized to enhance the trajectory-following precision. The tracking controller design is achieved using the quadratic programming (QP) technique, and the primal-dual neural network optimization technique is used to solve the QP problem. Experimental results on a real-time FWIDSMR validate that the proposed method shows superior features over some existing methods in terms of efficiency and accuracy.

Infection by Enterotoxigenic Escherichia coli is a common cause of diarrhea in animals. The development of vaccines against enterotoxins can effectively control the infection. We have previously constructed a recombinant antigen SLS fused by STa, LTB and STb enterotoxin and it showed a high immunogenicity in mice. Herein, we evaluated the expression of SLS in three different E. coli cells with corresponding plasmids. SLS proteins expressed in E. coli BL21 (DE3) and Rosetta-gami B (DE3) were aggregated as inclusion bodies, and the proteins solubility were not obviously promoted in low temperature combined with adjustment of inducer concentration. In contrast, SLS protein with maltose-binding protein (MBP) yielded from TB1 (DE3) cells were partially soluble. After increasing the IPTG concentration in the medium up to 2 mM and incubating at 37 ℃ for 4 h, the soluble protein yield reached the highest level (4.533 mg/0.2 L culture), which was significantly higher than the expression of SLS protein in Rosetta-gami B (DE3) (P

Previous studies suggested that the dry–wet surface state over the Indo-China Peninsula (ICP), closely associated with the local spring precipitation, is an important seasonal predictor for the East Asian summer monsoon and extreme climate. Hence, this work investigates the inter-annual variability of spring precipitation over the ICP and its relationship with El Nino-Southern Oscillation (ENSO) during 1958–2019. The results show that the spring precipitation anomalies over the ICP are highly linked to the ENSO-induced atmospheric circulation anomalies. In particular, there are large asymmetries in the precipitation anomalies for the spring following ENSO. During the decaying spring of the El Nino events, the precipitation decrease mainly occurs over the Western ICP associated with an anomalous low-level anticyclone over the western North Pacific. In contrast, during the decaying spring of the La Nina events, a stronger precipitation increase broadly extends into the Southeastern ICP. This is owing to a nonlinear effect of ENSO on the atmospheric circulation. Compared to El Nino, the abnormal center of La Nina extends too far westwards, inducing a westward movement of the anomalous atmospheric circulation, which results in a stronger effect on the spring ICP precipitation. Our findings emphasize the nonlinear responses of the spring ICP precipitation to ENSO. This has important implications for the seasonal climate prediction over the ICP, especially for the Southeastern ICP countries/regions.

Nutrient availability is central for T-cell functions and immune responses. Here we report that CD8+ T-cell activation and anti-tumour responses are strongly potentiated by the non-essential amino acid Asn. Increased Asn levels enhance CD8+ T-cell activation and effector functions against tumour cells in vitro and in vivo. Conversely, restriction of dietary Asn, ASNase administration or inhibition of the Asn transporter SLC1A5 impairs the activity and responses of CD8+ T cells. Mechanistically, Asn does not directly alter cellular metabolic fluxes; it instead binds the SRC-family protein tyrosine kinase LCK and orchestrates LCK phosphorylation at Tyr 394 and 505, thereby leading to enhanced LCK activity and T-cell-receptor signalling. Thus, our findings reveal a critical and metabolism-independent role for Asn in the direct modulation of the adaptive immune response by controlling T-cell activation and efficacy, and further uncover that LCK is a natural Asn sensor signalling Asn sufficiency to T-cell functions. Wu et al. show that instead of altering cellular metabolism, asparagine directly binds to LCK and enhances T-cell-receptor signalling, thereby promoting CD8+ T-cell-mediated anti-tumour responses.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Background Chemodynamic therapy (CDT) relying on intracellular iron ions and H2O2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H2O2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H2O2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy. Results The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity. Conclusion In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine. Graphical Abstract

Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.

To meet the low warming targets proposed in the 2015 Paris Agreement, substantial reduction in carbon emissions is needed in the future. It is important to know how surface climates respond under low warming targets. The present study investigates the surface temperature changes under the low-forcing scenario of Representative Concentration Pathways (RCP2.6) and its updated version (Shared Socioeconomic Pathways, SSP1-2.6) by the Flexible Global Ocean-Atmosphere-Land System (FGOALS) models participating in phases 5 and 6 of the Coupled Model Intercomparison Project (CMIP5 and CMIP6, respectively). In both scenarios, radiative forcing (RF) first increases to a peak of 3 W m−2 around 2045 and then decreases to 2.6 W m−2 by 2100. Global mean surface air temperature rises in all FGOALS models when RF increases (RF increasing stage) and declines or holds nearly constant when RF decreases (RF decreasing stage). The surface temperature change is distinct in its sign and magnitude between the RF increasing and decreasing stages over the land, Arctic, North Atlantic subpolar region, and Southern Ocean. Besides, the regional surface temperature change pattern displays pronounced model-to-model spread during both the RF increasing and decreasing stages, mainly due to large intermodel differences in climatological surface temperature, ice-albedo feedback, natural variability, and Atlantic Meridional Overturning Circulation change. The pattern of tropical precipitation change is generally anchored by the spatial variations of relative surface temperature change (deviations from the tropical mean value) in the FGOALS models. Moreover, the projected changes in the updated FGOALS models are closer to the multi-model ensemble mean results than their predecessors, suggesting that there are noticeable improvements in the future projections of FGOALS models from CMIP5 to CMIP6.

To investigate the effects of multidisciplinary and comprehensive Chinese medicine (CM) treatments on progression-free survival (PFS) and median survival time (MST) in patients with advanced non-small cell lung cancer (NSCLC) and identify factors that influence progression and prognosis. Clinical data of 855 patients with advanced NSCLC who received multidisciplinary and comprehensive CM treatments at Longhua Hospital from January 2009 to December 2018 were retrospectively analyzed. Univariate analysis was performed by the Kaplan-Meier method and log-rank sequential inspection. Multivariate analysis of significant variables from the univariate analysis was performed with Cox regression modeling. Key factors correlated to progression and prognosis were screened out, and a Cox proportional hazard model was established to calculate the prognostic index. The PFS and MST of 855 advanced NSCLC patients were 9.0 and 26.0 months, respectively. The 1-, 2-, 3-, and 5-year survival rates were 79.2%, 54%, 36.2%, and 17.1%, respectively. Gender, pathologic type, and clinical stage were independent prognostic risk factors; surgical history, radiotherapy, treatment course of Chinese patent medicine, intravenous drip of Chinese herbal preparation, duration of oral administration of Chinese herbal decoction (CHD), and intervention measures were independent prognostic protective factors. Gender was an independent risk factor for progression, while operation history and oral CHD administration duration were independent protective factors (all P

Although endoscopic thyroidectomy via the bilateral areola approach (ETBAA) has shown cosmetic advantage over open surgery, the risk factors of conversion to open surgery and its impact on patients remain unknown. The objective of this study is to analyze the predictors for conversion to open procedure in patients who underwent ETBAA and its related outcomes. The clinical data of patients who underwent ETBAA from May 2010 to May 2019 were analyzed retrospectively. The patients were divided into two groups according to operation notes: the conversion group and the non-conversion group. Univariate and multivariate logistic regression analyses were performed to investigate the risk factors for conversion to open surgery. Altogether, 140 patients were included in this study. Sixteen (11.4%) patients underwent conversion during ETBAA. Four factors demonstrated significant difference between the two groups: sex (P = 0.001), body mass index (BMI) (P = 0.021), thyroid peroxidase antibody (TPOAb) level (P = 0), and antithyroglobulin antibody (ATG) level (P = 0). Further univariate and multivariate logistic regression analysis revealed that male sex (P = 0.006), TPOAb level>7.8 IU/ml (P = 0.005), and ATG level>79 IU/ml (P = 0.003) had a significant correlation with conversion to open surgery in ETBAA. Prolonged operative time, increased surgical cost, and less patient cosmetic satisfaction were demonstrated in the conversion group (P

This study was designed to investigate the roles of numbing of positive and negative emotions in PTSD symptomology and related functional impairments. 14,465 Chinese children and adolescents who personally experienced the 2008 Wenchuan earthquake (in Sichuan province, China) took part in the study. Emotional numbing and other PTSD symptoms were assessed by the University of California-Los Angeles PTSD Reaction Index for Children. Functional impairment was measured by the Pediatric Quality of Life Inventory 4.0 Generic Core Scales. Item response theory (IRT) analysis showed that both numbing of positive and negative emotions demonstrated acceptable item response characteristics; numbing of positive emotions had better discrimination. Group comparisons revealed that participants who reported numbing of both positive and negative emotions had the highest risk of developing PTSD, most severe PTSD symptoms and functional impairments, with large effect sizes when compared with participants with no emotional numbing symptoms. Reporting only numbing of positive emotions had moderate effects, and reporting only numbing of negative emotions had smaller effects. The results revealed associations between emotional numbing patterns, posttraumatic stress symptoms and impairments in quality of life, and suggests that additional research is needed to explore generalized emotional numbing in children and adolescents in future PTSD research.

Extreme precipitation events (EPEs) over the Yangtze River basin (YRB) exert widespread impacts on regional ecological environment and people’s life. Using observed precipitation, atmospheric reanalysis, and land assimilation datasets, the present study explores the relationship between the summer EPEs over the YRB and the Meiyu front and their possible linkages with the preceding spring soil moisture anomalies over the Indo-China Peninsula (ICP). The analyses show that both the frequency and intensity of summer EPEs over the YRB are closely associated with the mean intensity of the Meiyu front, which exhibits a significant negative correlation with the soil moisture anomalies in the preceding spring over the ICP. An abnormally drier soil over the ICP in spring would evidently raise air temperature by suppressing local evapotranspiration, and vice versa. Owing to a strong memory of the ICP soil moisture, the persistent anomalous heating would elevate local geopotential height in summer, inducing an excessive westward extension of the Western Pacific subtropical high. Accordingly, a strengthened southwesterly wind at the lower troposphere brings abundant warm–wet air to the YRB, intensifying the mean Meiyu front. This is also verified by the diagnosis of vertical motion (omega) equation. As a result, the risk of summer EPEs (both the frequency and intensity) over the YRB would increase (decrease) with an abnormally drier (wetter) ICP soil during the preceding spring. For the summer EPEs over the YRB, our results suggest that the spring ICP soil moisture can be used as an important seasonal predictor.