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Background: Primary cilia are antenna‐like organelles that conduct physical and chemical signals, which affect cell proliferation, migration, and differentiation. Some researchers have reported the correlation between primary cilia‐related genes and prognosis of colorectal cancer (CRC). Methods: The association between single nucleotide polymorphisms (SNPs) of primary cilia‐related genes and outcome after the first‐line chemotherapy was explored by the Cox regression model. Expression qualitative trait locus (eQTL) analysis was performed to explore the impact of SNPs on gene expression. Tumor Immune Estimation Resource and TISIDB databases were used for investigating the relevance between ODF2L and tumor infiltration immune cells and immunomodulators. Results: We identified that rs4288473 C allele of ODF2L had poor progression‐free survival (PFS) and overall survival (OS) of CRC patients in the additive model (adjusted HRPFS = 1.39, 95% CI = 1.14–1.70, p = 1.36 × 10−3, and adjusted HROS = 1.31, 95% CI = 1.03–1.65, p = 2.62 × 10−2). The stratified analysis indicated that rs4288573 CC/CT genotype was involved with poor prognosis in the irinotecan‐treated subgroup (PPFS = 1.03 × 10−2, POS = 3.29 × 10−3). Besides, ODF2L mRNA expression level was notably up‐regrated in CRC tissues. The C allele of rs4288573 was notably related to higher ODF2L mRNA expression levels based on eQTL analysis. Functionally, knockdown of ODF2L inhibited cell proliferation and decrease the chemoresistance of HCT‐116 and DLD‐1 cells to irinotecan. Conclusion: Our study indicates that rs4288573 in ODF2L is a potential predictor of the chemotherapy prognosis of CRC. [ABSTRACT FROM AUTHOR]

Aim: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. Methods: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once‐daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24‐week double‐blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open‐label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all‐patients‐treated population using an analysis of co‐variance. Results: After 24 weeks, both add‐on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were −1.17 ± 0.794%, −1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment β‐function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. Conclusions: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. Materials and Methods: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double‐blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open‐label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. Results: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (−1.08%) and cetagliptin 100 mg (−1.07%) compared with placebo (−0.35%). The placebo‐subtracted HbA1c reduction was −0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2‐hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug‐related hypoglycaemia was reported. Conclusions: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet. [ABSTRACT FROM AUTHOR]

Biodiversity can stabilise productivity through different mechanisms, such as asynchronous species responses to environmental variability and species stability. Global changes, like intensified drought, could negatively affect species richness, species asynchrony and species stability, but it is unclear how changes in these mechanisms will affect the stability of above‐ground primary productivity (ANPP) across ecosystems.We studied the effects of a 4‐year extreme drought on ANPP stability and the underlying mechanisms (species richness, species asynchrony and species stability) across six grasslands in Northern China. We also assessed the relative importance of these mechanisms in determining ANPP stability under extreme drought.We found that extreme drought decreased ANPP stability, species richness, species asynchrony and species stability across the six grasslands. However, structural equation modelling revealed that species asynchrony, not species richness or species stability, was the most important mechanism promoting stability of ANPP, regardless of drought across the six grasslands.Synthesis. Our results suggest that species asynchrony, not species richness and species stability, consistently buffers ecosystem stability against extreme drought across and within grasslands spanning a broad precipitation gradient. Thus, species asynchrony may be a more general mechanism for promoting stability of ANPP in grasslands in the face of intensified drought. [ABSTRACT FROM AUTHOR]

Grasslands are subject to climate change, such as severe drought, and an important aspect of their functioning is temporal stability in response to extreme climate events. Previous research has explored the impacts of extreme drought and post‐drought periods on grassland stability, yet the mechanistic pathways behind these changes have rarely been studied.Here, we implemented an experiment with 4 years of drought and 3 years of recovery to assess the effects of drought and post‐drought on the temporal stability of above‐ground net primary productivity (ANPP) and its underlying mechanisms. To do so, we measured community‐weighted mean (CWM) of six plant growth and nine seed traits, functional diversity, population stability and species asynchrony across two cold, semiarid grasslands in northern China. We also performed piecewise structural equation models (SEMs) to assess the relationships between ANPP stability and its underlying mechanisms and how drought and post‐drought periods alter the relative contribution of these mechanisms to ANPP stability.We found that temporal stability of ANPP was not reduced during drought due to grasses maintaining productivity, which compensated for increased variation of forb productivity. Moreover, ANPP recovered rapidly after drought, and both grasses and forbs contributed to community stability during the post‐drought period. Overall, ANPP stability decreased during the combined drought and post‐drought periods because of rapid changes in ANPP from drought to post‐drought. SEMs revealed that the temporal stability of ANPP during drought and post‐drought periods was modulated by functional diversity and community‐weighted mean traits directly and indirectly by altering species asynchrony and population stability. Specifically, the temporal stability of ANPP was positively correlated with functional divergence of plant communities. CWMs of seed traits (e.g. seed width and thickness), rather than plant growth traits (e.g. specific leaf area and leaf nutrient content), stabilized grassland ANPP. Productivity of plant communities with large and thick seeds was less sensitive to precipitation changes over time.These results emphasize the importance of considering both the functional trait distribution among species and seed traits of dominant species since their combined effects can stabilize ecosystem functions under global climate change scenarios. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Asexual reproduction plays a fundamental role in the structure, dynamics and persistence of perennial grasslands. Thus, assessing how asexual reproductive traits of plant communities respond to drought may be key for understanding grassland resistance to drought and recovery following drought.Here, we quantified three asexual reproductive traits (i.e. above‐ground tiller abundance, below‐ground bud abundance and the ratio of tillers to buds) during a 4‐year severe drought and a 2‐year drought recovery period in four grasslands that spanned an aridity gradient in northern China. We also assessed the relationship between these traits and the resistance and recovery of above‐ground net primary productivity (ANPP).We found that drought had limited and largely inconsistent effects on asexual reproduction among drought and recovery years and grasslands overall. Drought increased tiller abundance in the first treatment year and reduced bud banks by the fourth treatment year across grasslands. However, neither of the three asexual reproductive traits were correlated with drought resistance of ANPP. Drought legacies differed among the four grasslands with positive, negative and no legacies evident for the three asexual reproductive traits, and no clear relationship with aridity. Bud banks and tiller to bud ratio decreased and increased, respectively, in the first recovery year, but not in the second recovery year. In contrast to drought resistance, community bud abundance was strongly related to recovery, such that communities with higher bud abundance had greater ANPP recovery following drought.Synthesis. These results suggest that asexual reproductive traits may be important drivers of ecosystem recovery after drought, but that variable responses of these asexual reproduction traits during drought complicates predictions of overall grassland responses. [ABSTRACT FROM AUTHOR]

How biodiversity affects terrestrial productivity is important to the maintenance of ecosystem services under global change. Although the crucial role of plant–soil feedbacks (PSF) in determining diversity–productivity relationship has been increasingly recognized in recent years, its legacy effects on subsequent diversity–productivity relationship are still unclear.We conducted a classic PSF experiment to assess how plant diversity‐conditioned soils influenced subsequent plant diversity–productivity relationships, where three plant diversity levels (1, 4 and 8 species) were planted in soils conditioned at three diversity levels (conditioned by 1, 4 and 8 species for 3 years). In addition, to test the role of soil microbial diversity in mediating the effects of soil conditioning diversity, the three plant diversity levels were planted with low, moderate and high soil biodiversity created by a soil inoculum dilution.The results showed that plant productivities were promoted by mixed‐conditioned soils (4 and 8 species) comparing to mono‐conditioned soils (1 species). Productivity was positively related to planted diversity in mixed‐conditioned soils, while showed no relation with planted diversity in mono‐conditioned soils. Productivity was promoted by soil biodiversity when 4 and 8 species were mixed planted, while did not change when 1 species was planted.Synthesis and applications. Our results highlight that PSF is crucial to strengthen the positive effects of biodiversity on productivity, implying that diversifying cropping systems should be encouraged in agroecosystem management to benefit from positive PSF effects. The importance of soil legacy for optimizing plant productivity is particularly important for conditioning soils with an intermediate number of plant species. [ABSTRACT FROM AUTHOR]

Grasslands are expected to experience droughts of unprecedented frequency and magnitude in the future. Characterizing grassland responses and recovery from drought is therefore critical to predict the vulnerability of grassland ecosystems to climate change. Most previous studies have focused on ecosystem responses during drought while investigations of post‐drought recovery are rare. Few studies have used functional traits, and in particular bud or clonal traits, to explore the mechanisms underlying grassland responses to and recovery from drought.To address this issue, we experimentally imposed a four‐year drought in a C3‐dominated grassland in northeastern China and monitored recovery for 3 years post‐drought. We investigated the immediate and legacy effects of drought on total above‐ground net primary productivity (ANPP), ANPP of functional groups (rhizomatous grasses, bunch grasses and forbs), and how the legacy effects were driven by plant species diversity, clonal traits and vegetative traits.We found that drought progressively reduced total ANPP over the 4‐year period. The reductions in total ANPP in the first and third drought years were caused by the decrease in ANPP of bunch grasses only, while that of the second year was caused by declines in ANPP of bunch grasses and forbs, and the fourth year decline was linked to all three functional groups. The post‐drought recovery of ANPP, which occurred despite the continued loss of plant species diversity, was mainly driven by rapid recovery of rhizomatous and bunch grasses, which compensated for the slow response by forbs. The rapid post‐drought recovery of these grasses can be attributed to their relatively large, intact bud and shoot densities post‐drought, as well as the recovery of plant height and specific leaf area. The rapid recovery of grasses possibly restricted the growth and distribution of forbs, resulting in reduced forb ANPP and, consequently, lower species diversity during the recovery period.Synthesis. These results highlight the potential for positive legacy effects of drought on ANPP as well as the important and complementary roles of plant reproductive and vegetative traits in mediating ecosystem recovery from drought in a C3‐dominated grassland. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the optimal regimen for unresectable recurrent hepatocellular carcinoma (HCC), so this retrospective study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors (T-L-P) versus TACE combined with lenvatinib (T-L) or TACE alone. Method: Data were collected from 204 patients with unresectable recurrent HCC who received T-L-P, T-L, or TACE alone at three medical centers from January, 2019 to December, 2020 for analysis. The survival outcomes, tumor response, and adverse events were compared between three groups, and risk factors were further investigated. Results: The median overall survival in the T-L-P, T-L, and TACE alone groups were not reached, 25.6, and 15.7 months, respectively (p < 0.001). The median progression-free survival in the T-L-P, T-L, and TACE alone groups were 24.1, 17.3, and 13.7 months, respectively (p < 0.001). The best objective response rate in the T-L-P, T-L, and TACE alone groups were 70.4%, 48.9%, and 42.5%, respectively. The best disease control rate in the T-L-P, T-L, and TACE alone groups were 100.0%, 97.8%, and 87.5%, respectively. There was no significant difference between the T-L-P and T-L groups for Grade 3/4 adverse events. Conclusion: T-L-P regimen was safe and superior to T-L or TACE alone in improving survival for unresectable recurrent HCC patients. [ABSTRACT FROM AUTHOR]

Climate change is expected to increase the magnitude and frequency of extreme drought in most grassland ecosystems. Exploring the responses of below‐ground bud banks and their relationships with above‐ground plant structure and drought is need to explain how climate change will impact grassland ecosystems. However, studies on the response of community‐scale bud and shoot densities to experimental drought along an aridity gradient are rare.We experimentally removed 66% of growing season precipitation for 4 years in three temperate grasslands that spanned an aridity gradient in northern China. We quantified the legacy effects of drought on grass, forb and total community below‐ground bud density, above‐ground shoot density and the ratio of bud to shoot density 1 year following treatment.Below‐ground bud density was lowest at the highest aridity site for the entire community, while above‐ground shoot density was highest at the medium aridity site. Below‐ground bud and above‐ground shoot densities were the lowest at the high aridity site for grasses but the highest for forbs at this site. Bud:shoot ratios decreased with increasing aridity for grasses, yet remained constant for forbs along the aridity gradient. Below‐ground bud density in drought plots remained lower than controls a year following drought at each site. Experimental drought did not alter the below‐ground bud bank for grasses but decreased forb bud banks across sites. Experimental drought had little legacy effects on above‐ground shoot density and bud:shoot ratios for grasses, forbs and the total community at each site.Our results suggest that grass and forb bud banks can differ in their responses to both multi‐year drought along an aridity gradient, and that bud limitation for shoot generation may increase as grasslands get drier. Bud bank responses to climate will impact plant community functioning and resilience. Thus, incorporating bud bank dynamics will improve projections of grassland ecosystems under future climate change. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Background and Purpose: Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear.Experimental Approach: Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization.Key Results: The dopamine D1 receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of μ opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D1 receptor knockout (KO) mice, suggesting that SCH23390 modified μ receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of μ receptor-D1 receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D1 or μ receptor KO mice and thus unable to form μ receptor-D1 receptor heterodimers, failed to show locomotor sensitization to morphine.Conclusion and Implications: Our results suggest that μ receptor-D1 receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates. [ABSTRACT FROM AUTHOR]

Plant traits are useful proxies of plant strategies and can influence community and ecosystem responses to climate extremes, such as severe drought. Few studies, however, have investigated both the immediate and lagged effects of drought on community‐weighted mean (CWM) plant traits, with even less research on the relative roles of interspecific vs. intraspecific trait variability in such responses.We experimentally reduced growing season precipitation by 66% in two cold‐semi‐arid grassland sites in northern China for four consecutive years to explore the drought resistance of CWM traits as well as their recovery 2 years following the drought. In addition, we isolated the effects of both interspecific and intraspecific trait variability on shifts in CWM traits.At both sites, we observed significant effects of drought on interspecific and intraspecific trait variability which, in some cases, led to significant changes in CWM traits. For example, drought led to reduced CWM plant height and leaf phosphorous content, but increased leaf carbon content at both sites, with responses primarily due to intraspecific trait shifts. Surprisingly, these CWM traits recovered completely 2 years after the extreme drought. Intraspecific trait variability influenced CWM traits via both positive and negative covariation with interspecific trait variability during drought and recovery phases.These findings highlight the important role of interspecific and intraspecific trait variability in driving the response and recovery of CWM traits following extreme, prolonged drought. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Recurrent droughts are an inevitable consequence of climate change, yet how grasslands respond to such events is unclear. We conducted a 6‐year rainfall manipulation experiment in a semiarid grassland that consisted of an initial 2‐year drought (2015–2016), followed by a recovery period (2017–2018) and, finally, a second 2‐year drought (2019–2020). In each year, we estimated aboveground net primary productivity (ANPP), species richness, community‐weighted mean (CWM) plant traits, and several indices of functional diversity. The initial drought led to reduced ANPP, which was primarily driven by limited growth of forbs in the first year and grasses in the second year. Total ANPP completely recovered as the rapid recovery of grass productivity compensated for the slow recovery of forb productivity. The subsequent drought led to a greater reduction in total ANPP than the initial drought due to the greater decline of both grass and forb productivity. The structural equation models revealed that soil moisture influenced ANPP responses directly during the initial drought, and indirectly during the subsequent drought by lowering functional diversity, which resulted in reduced total ANPP. Additionally, ANPP was positively influenced by CWM plant height and leaf nitrogen during the recovery period and recurrent drought, respectively. Overall, the greater impact of the second drought on ecosystem function than the initial drought, as well as the underlying differential mechanism, underscores the need for an understanding of how increased drought frequency may alter semiarid grassland functioning. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is one of the most common malignant digestive tract tumors with a poor prognosis. RNA 5‐methylcytosine (m5C) is an important posttranscriptional widespread modification involved in many biological processes. However, the association between genetic variations of m5C modification genes and the prognostic value of colorectal cancer remains unclear. Methods: We investigated the association between candidate single nucleotide polymorphisms (SNPs) in 13 m5C modification genes and colorectal cancer overall survival (OS) after chemotherapy by the Cox regression model. The combined effect of selected SNPs on OS, progression‐free survival (PFS), and disease control rate (DCR) was assessed by the number of risk alleles (NRA). The GTEx and TCGA database were used to perform expression qualitative trait locus (eQTL) analysis. Results: We identified that two SNPs in YBX1 were associated with OS after chemotherapy (HR = 1.43, p = 0.001 for rs10890208; HR = 1.36, p = 0.025 for rs3862218). A striking dose–response effect between NRA and OS after chemotherapy was found (ptrend = 0.002). The DCR of patients receiving oxaliplatin chemotherapy in the 3–4 NRA group was markedly reduced in comparison to that in the 0–2 NRA group (OR = 1.49, p = 0.036). Moreover, YBX1 mRNA expression was significantly overexpressed in tumor tissues (p < 0.05) in the TCGA database, and eQTL analysis demonstrated that the two SNPs were associated with YBX1 (p = 0.003 for rs10890208 and p = 0.024 for rs3862218). Conclusion: Our study indicates that genetic variants in m5C modification genes may mediate changes in YBX1 mRNA levels and affect the chemotherapeutic efficacy of colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Drought events induced by global climate change strongly modify ecosystem structure and function in grasslands. Higher plant biodiversity can enhance ecosystem resistance to drought; however, the potential effects of drought on the relationships between above‐ground productivity (ANPP) and biodiversity along a natural aridity gradient remain poorly understood.Here, we studied the effects of experimental drought on plant community structure and ANPP during the two different dry years (2015 and 2017) spanning three temperate steppe sites with low‐, medium‐ and high‐aridity levels. We also examined the effects of drought and aridity on the associations of plant species (richness and abundance), functional (community‐weighted trait means and functional dispersion) and phylogenetic diversity (evolutionary lineages) with ANPP. A structural equation modelling (SEM) was used to elucidate how the drought affected ANPP by altering biodiversity attributes.We found that experimental drought shaped the biodiversity–ANPP relationships, and the biodiversity–ANPP relationships differed among three sites. At the low‐aridity site, ANPP was correlated with plant functional traits, whereas ANPP was correlated with functional dispersion, species and phylogenetic diversity at the medium‐aridity site. At the high‐aridity site, ANPP was correlated with species richness, functional traits and phylogenetic diversity. Compared with 2015, natural drought in 2017 strengthened the associations of species diversity, functional dispersion, leaf dry matter content and leaf nitrogen content with ANPP across three sites. SEM further showed that both experimental and natural drought directly decreased ANPP and indirectly decreased ANPP by reducing community‐weighted mean of plant height.Synthesis. These results suggest that the aridity increase or drought occurrence is likely to induce the shifts in the associations of ANPP with species and functional diversity, highlighting the important role of water availability or precipitation conditions in regulating the biodiversity–ANPP relationships in temperate steppes. Overall, functional traits related to plant size play a crucial role in modulating the response of productivity to drought across three steppe sites. Thus, to buffer the negative effects of drought on steppe ANPP should pay attention to protect the species with large plant size. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Seeds provide the basis of genetic diversity in perennial grassland communities and their traits may influence ecosystem resistance to extreme drought. However, we know little about how drought effects the community functional composition of seed traits and the corresponding implications for ecosystem resistance to drought.We experimentally removed 66% of growing season precipitation for 4 years across five arid and semi‐arid grasslands in northern China and assessed how this multi‐year drought impacted community‐weighted means (CWMs) of seed traits, seed trait functional diversity and above‐ground net primary productivity (ANPP).Experimental drought had limited effects on CWM traits and the few effects that did occur varied by site and year. For three separate sites, and in different years, drought reduced seed length and phosphorus content but increased both seed and seed‐coat thickness. Additionally, drought led to increased seed functional evenness, divergence, dispersion and richness, but only in some sites, and mostly in later years following cumulative effects of water limitation. However, we observed a strong negative relationship between drought‐induced reductions in ANPP and CWMs of seed‐coat thickness, indicating that a high abundance of dominant species with thick seeds may increase ecosystem resistance to drought. Seed trait functional diversity was not significantly predictive of ANPP, providing little evidence for a diversity effect.Our results suggest that monitoring community composition with a focus on seed traits may provide a valuable indicator of ecosystem resistance to future droughts despite inconsistent responses of seed trait composition overall. This highlights the importance of developing a comprehensive seed and reproductive traits database for arid and semi‐arid grassland biomes. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

The present investigation is the first to provide information on the formation, process and influence factors for hydrocarbon generation and expulsion potential of the Cuizhuang Formation source rock in the Yuncheng sub‐basin to decipher the reason why no commercial petroleum resources have been found so far. In this study, data from the Jitan‐1 well in the Yuncheng sub‐basin were applied for the Cuizhuang Formation source rock basin modelling and organic geochemical analyses to reconstruct the burial and thermal evolution history and reveal the timing and process of hydrocarbon generation and expulsion. The modelling results indicate that the peak palaeotemperature of the Cuizhuang Formation source rock reached ~205°C in the Middle Carboniferous (~327 Ma) at a maximum burial depth of ~4000 m, when rapid burial subsidence and thermal events played a significant role in increasing thermal maturity. The Cuizhuang Formation generated and expelled small amounts of hydrocarbons from the Early Ordovician until the Middle Carboniferous, starting with the primary kerogen cracking and conversion to oil from the Early to Middle Ordovician (~476–461 Ma), corresponding to the thermal maturity values of 0.55–0.70 %VRo and transformation ratio (TR) <10%. The expulsion of most generated oil (0.70–1.30 %VRo, TR of 10%–90%) started from the Middle Ordovician to the Early Carboniferous (~461–351 Ma), before reaching the secondary cracking of the retained oil into gas (>1.30 %VRo and TR of 90%–100%) from the Early to Middle Carboniferous (~351–327 Ma). Destruction of the initial formation of hydrocarbon reservoirs in the Yuncheng sub‐basin was primarily controlled by the Middle Carboniferous tectonic event with its major uplift‐erosion, resulting in the absence of potential hydrocarbon reservoirs in recent exploration activities in some parts of the Yuncheng sub‐basin. [ABSTRACT FROM AUTHOR]

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The crystal structure of the title complex, [Ir(C10H15)(C4N2S2)], is composed of distinct [η5-Cp*Ir(mnt)] (Cp* is penta­methyl­cyclo­penta­dienyl and mnt is 1,2-dicyano­ethyl­ene­dithiol­ate) molecules separated by normal van der Waals contacts. The asymmetric unit consists of two molecules. The IrIII atom may be considered penta­coordinate since it is linked to a bidentate dithiol­ate ligand and a formally tridentate η5-Cp* ligand. Ir—S distances range from 2.238 (3) to 2.246 (3) Å. [ABSTRACT FROM AUTHOR]

Aim: Transarterial chemoembolization (TACE) combined with a PD‐1 inhibitor and TACE combined with a PD‐1 inhibitor and lenvatinib have recently been reported as promising treatments to improve the prognosis of hepatocellular carcinoma (HCC) patients. This study aims to compare the efficacy of these two treatments. Methods: A retrospective study was conducted, and patients were recruited from two centers in China. Progression‐free survival (PFS) and overall survival (OS) were compared, and the objective response rate (ORR) and disease control rate (DCR) were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment‐related adverse events (AEs) were analyzed to assess safety. Results: The median follow‐up for the entire cohort was 11.4 months. Of the 103 patients included in this study, 56 received triple therapy, and 47 received doublet therapy. PFS was significantly higher in the triple therapy group than in the doublet therapy group (mPFS 22.5 vs. 14.0 months, P < 0.001). Similar results were obtained in terms of OS (P = 0.001). The ORR and DCR were also better in the triple therapy group (64.3% vs. 38.3%, P = 0.010; 85.7% vs. 57.4%, P = 0.002). The most common AEs in the triple therapy group were decreased albumin (55.3%), decreased platelet count (51.8%) and hypertension (44.6%). Conclusions: The combination of TACE with a PD‐1 inhibitor and lenvatinib in patients with BCLC stage B HCC might result in significantly improved clinical outcomes with a manageable safety profile compared with TACE with a PD‐1 inhibitor. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the role of tagging single nucleotide polymorphisms (tagSNPs) in the adiponectin gene in the natural course of nonalcoholic fatty liver disease (NAFLD). METHODS: The participants were chosen from our previous survey containing 3543 individuals. Finally, a total of 696 participants who had been followed up for a median of 4 years were included. Each participant was administered with an interview, physical examination, blood tests and ultrasonic examination at both baseline and end-point. Polymerase chain reaction-restriction fragment length polymorphism was applied to determine seven tagSNPs in the adiponectin gene, namely, rs182052, rs16861205, rs822396, rs7627128, rs1501299, rs2241767 and rs3774261. Ordinal logistic regression was used to screen risk factors of NAFLD progression as well as the susceptibility to the disease. Haplotypes analyses were performed to confirm the results. RESULTS: After adjusting for age and gender, rs1501299 (G276T), rs2241767 (A45G) and rs3774261 (A712G) were found to be risk factors of both susceptibility (OR 5.040, 7.471 and 3.546, respectively) and progression (OR 3.83, 3.51 and 3.30, respectively) to NAFLD. Nevertheless, rs182052, rs16861205, rs822396 and rs7627128 had no impact on them. These findings were confirmed by haplotype analysis. CONCLUSION: The tagSNPs rs2241767, rs1501299 and rs3774261 in the adiponectin gene are risk factors for the individuals' susceptibility to and progression of NAFLD. [ABSTRACT FROM AUTHOR]

Although Notch signalling pathway could control the proliferation and differentiation of neural stem cells (NSCs), it is largely unknown about the effect of Notch signalling pathway on the neurogenesis of CD133‐positive cells. By using the primary cultured ependymal cells and the transgenic mouse, we found that CD133 immunoreactivity was exclusively localized in the ependymal layer of ventricles; moreover, most CD133‐positive cells were co‐labelled with Nestin. In addition, recombination signal binding protein J (RBP‐J), a key nuclear effector of Notch signalling pathway, was highly active in CD133‐positive cells. CD133‐positive cells can differentiate into the immature and mature neurons; in particular, the number of CD133‐positive cells differentiating into the immature and mature neurons was significantly increased following the deficiency or interference of RBP‐J in vivo or in vitro. By using real‐time qPCR and Western blot, we found that RBP‐J and Hes1 were downregulated, whereas Notch1 was upregulated in the expression levels of mRNAs and proteins following the deficiency or interference of RBP‐J. These results demonstrated RBP‐J deficiency promoted the proliferation and differentiation of CD133‐positive cells. Therefore, we speculated that RBP‐J could maintain CD133‐positive cells in the characteristics of NSCs possibly by regulating Notch1/RBP‐J/Hes1 pathway. It will provide a novel molecular insight into the function of RBP‐J as well as facilitate a future investigation of CD133‐positive cells with respect to their potential application in neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

The extent to which individuals experience interspecific and intraspecific interactions through their spatial arrangements within diverse plant communities, whether because of confounding effects of species richness, evenness or direct changes in species patch sizes on their neighbourhood relationships, could affect grassland biomass production and its stability at community scales. Elucidating the ways in which neighbourhood effects and species richness contribute to such community responses has important implications for how practitioners establish grasslands to meet forage production and conservation goals.We assessed the effects of altering plant species richness (3 levels: 2, 4 or 8 forage species per plot) and seed arrangements (4 levels: species mixed and seeded or seeded in 0.0625, 0.25 or 1.0 m2 single‐species patches while maintaining plot‐scale species evenness) on above‐ground biomass production and its temporal stability in developing grasslands seeded with a suite of globally common forage species (three legumes, three cool‐season grasses and two warm‐season grasses).Communities seeded with more species and those with their seeds arranged into smaller conspecific patches produced more biomass and were more temporally stable than those seeded with fewer species and larger conspecific patches. The effect of manipulating species arrangements is attributable to greater neighbourhood‐scale interspecific interactions and stronger complementary effects. Furthermore, seeding species into conspecific patches resulted in communities that were 34% more productive, that were just as temporally stable, and that had similar diversity effects as those seeded with a species mixture, as is common in grassland reconstruction efforts.Synthesis. In comparison with conventional mixed‐seeding methods, seeding grasslands with high species richness and small, single‐species patches may promote grassland reconstruction through increased biomass production, temporal stability and complementarity effects. Our study highlights the importance of regulating intraspecific interactions within diverse communities for improving grassland biomass production and suggests that efforts to re‐evaluate methods used to establish forage and conservation grasslands could result in greater biomass production and stability in these systems. [ABSTRACT FROM AUTHOR]

Summary: Climate extremes pose enormous threats to natural ecosystems. Arbuscular mycorrhizal (AM) fungi are key plant symbionts that can affect plant community dynamics and ecosystem stability. However, knowledge about how AM fungal communities respond to climate extremes in natural ecosystems remains elusive.Based on a grassland extreme drought experiment in Inner Mongolia, we investigated the response of AM fungal communities to extreme drought in association with plant communities. The experiment simulated two types of extreme drought (chronic/intense) of once‐in‐20‐year occurrence.AM fungal richness and community composition exhibited high sensitivity to extreme drought and were more sensitive to intense drought than chronic drought. This community sensitivity (i.e. decline in richness and shifts in community composition) of AM fungi can be jointly explained by soil moisture, plant richness, and aboveground productivity. Notably, the robustness of the plant–AM fungal community co‐response increased with drought intensity.Our results indicate that AM fungal communities are sensitive to climate extremes, and we propose that the plant community mediates AM fungal community responses. Given the ubiquitous nature of AM associations, their climate sensitivity may have profound consequences on plant communities and ecosystem stability under climate change. [ABSTRACT FROM AUTHOR]

Aims: This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin. Methods: Forty‐eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study. Results: Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0–1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase‐4 (DPP‐4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP‐4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon‐like‐1 peptide (GLP‐1) concentrations were significantly increased in the cetagliptin groups by 2.3‐ to 3.1‐fold at day 1 and 3.1‐ to 3.6‐fold at steady state compared with that of placebo, and active GLP‐1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP‐1 level and induced to long‐lasting glucose‐lowering efficacy. Cetagliptin was well tolerated across all doses studied. Conclusion: Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP‐4, the increase in GLP‐1 and insulin, the decrease in glucose, and might be more effective in DPP‐4 inhibition than sitagliptin. [ABSTRACT FROM AUTHOR]

The translocation of hexa-arginine peptides across the asymmetric lipid bilayer in both random and bundled state was studied by coarse-grained molecular dynamics simulations. It was found that the peptides pass through the membrane by a pore-mediated mechanism when their concentration exceeds a critical value. However, the translocation efficiency of the bundled peptides is much higher than that of the random case at the same concentration. The pore formation results from the cumulative effects of each peptide in random case, while the bundled ones disturb the membrane locally. Furthermore, we show that the role of the hydrophobic group of peptide amphiphiles is facilitating the formation of aggregation for improving their penetration efficiency. [ABSTRACT FROM AUTHOR]

Human activities have significantly altered nitrogen (N) availability in most terrestrial ecosystems, with consequences for community composition and ecosystem functioning. Although studies of how changes in N availability affect biodiversity and community composition are relatively common, much less remains known about the effects of N inputs on the coupled biogeochemical cycling of N and phosphorus (P), and still fewer data exist regarding how increased N inputs affect the internal cycling of these two elements in plants. Nutrient resorption is an important driver of plant nutrient economies and of the quality of litter plants produce. Accordingly, resorption patterns have marked ecological implications for plant population and community fitness, as well as for ecosystem nutrient cycling. In a semiarid grassland in northern China, we studied the effects of a wide range of N inputs on foliar nutrient resorption of two dominant grasses, Leymus chinensis and Stipa grandis. After 4 years of treatments, N and P availability in soil and N and P concentrations in green and senesced grass leaves increased with increasing rates of N addition. Foliar N and P resorption significantly decreased along the N addition gradient, implying a resorption-mediated, positive plant-soil feedback induced by N inputs. Furthermore, N : P resorption ratios were negatively correlated with the rates of N addition, indicating the sensitivity of plant N and P stoichiometry to N inputs. Taken together, the results demonstrate that N additions accelerate ecosystem uptake and turnover of both N and P in the temperate steppe and that N and P cycles are coupled in dynamic ways. The convergence of N and P resorption in response to N inputs emphasizes the importance of nutrient resorption as a pathway by which plants and ecosystems adjust in the face of increasing N availability. [ABSTRACT FROM AUTHOR]

Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo‐like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle‐related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle‐related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1‐MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti‐tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1‐MYC‐CDC7 axis in the treatment of oxaliplatin‐based chemotherapy. [ABSTRACT FROM AUTHOR]

Background: 1q21.3 amplification, which is frequently observed in metastatic melanoma, is associated with cancer progression. Interleukin enhancer‐binding factor 2 (ILF2) is located in the 1q21.3 amplified region, but its functional role or contribution to tumour aggressiveness in cutaneous melanoma is unknown. Methods: In silico analyses were performed using the TCGA SKCM dataset with clinical annotations and three melanoma microarray cohorts from the GEO datasets. RNA in situ hybridisation and immunohistochemistry were utilised to validate the gene expression in melanoma tissues. Four stable melanoma cell lines were established for in vitro ILF2 functional characterisation. Results: Our results showed that the ILF2 copy number variation (CNV) is positively correlated with ILF2 mRNA expression (r = 0.68, p <.0001). Additionally, ILF2 expression is significantly increased with melanoma progression (p <.0001), and significantly associated with poor overall survival for metastatic melanoma patients (p =.026). The overexpression of ILF2 (ILF2‐OV) promotes proliferation in metastatic melanoma cells, whereas ILF2 knockdown decreases proliferation by blocking the cell cycle. Mechanistically, we demonstrated the interaction between ILF2 and the splicing factor U2AF2, whose knockdown reverses the proliferation effects mediated by ILF2‐OV. Stage IIIB–C melanoma patients with high ILF2‐U2AF2 expression showed significantly shorter overall survival (p =.024). Enhanced ILF2/U2AF2 expression promotes a more efficient DNA‐damage repair by increasing RAD50 and ATM mRNA expression. Paradoxically, metastatic melanoma cells with ILF2‐OV were more sensitive to ATM inhibitors. Conclusion: Our study uncovered that ILF2 amplification of the 1q21.3 chromosome is associated with melanoma progression and triggers a functional downstream pathway in metastatic melanoma promoting drug resistance. [ABSTRACT FROM AUTHOR]

Investigated in this paper is the (2 + 1)-dimensional coupled nonlinear Schrödinger system, which describes the propagation of the optical soliton through the Kerr nonlinear fiber in which each component diffracts in two transverse dimensions. By virtue of the Kadomtsev-Petviashvili hierarchy reduction, we obtain the bright, dark and mixed vector soliton solutions in terms of the Gramian. We investigate the vector solitons graphically: (1) Bright-dark one solitons with one of the components being gray or black are shown. Bouncing, beating, oscillating and breathing effects which appear during the interactions between the bright-dark two solitons are discussed, and those interactions are shape-preserving; (2) Degenerate and non-degenerate dark-dark one solitons are presented. Interaction of the dark-dark two solitons is discussed and the two solitons keep their amplitudes and velocities invariant except for some phase shifts during the interaction; (3) Bound-state and complexes of the bright-bright solitons are presented. [ABSTRACT FROM AUTHOR]

Extreme drought decreases aboveground net primary production (ANPP) in most grasslands, but the magnitude of ANPP reductions varies especially in C3‐dominated grasslands. Because the mechanisms underlying such differential ecosystem responses to drought are not well resolved, we experimentally imposed an extreme 4‐yr drought (2015–2018) in two C3 grasslands that differed in aridity. These sites had similar annual precipitation and dominant grass species (Leymus chinensis) but different annual temperatures and thus water availability. Drought treatments differentially affected these two semiarid grasslands, with ANPP of the drier site reduced more than at the wetter site. Structural equation modeling revealed that community‐weighted means for some traits modified relationships between soil moisture and ANPP, often due to intraspecific variation. Specifically, drought reduced community mean plant height at both sites, resulting in a reduction in ANPP beyond that attributable to reduced soil moisture alone. Higher community mean leaf carbon content enhanced the negative effects of drought on ANPP at the drier site, and ANPP–soil‐moisture relationships were influenced by soil C:N ratio at the wetter site. Importantly, neither species richness nor functional dispersion were significantly correlated with ANPP at either site. Overall, as expected, soil moisture was a dominant, direct driver of ANPP response to drought, but differential sensitivity to drought in these two grasslands was also related to soil fertility and plant traits. [ABSTRACT FROM AUTHOR]

Background: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood.Methods: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated.Results: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; Pdifference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess.Conclusions: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened. [ABSTRACT FROM AUTHOR]

Background: Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high incidence of local recurrence and metastasis. Circular RNAs (circRNAs) are implicated in the pathomechanism of TNBC. Here, we investigated the function of circ_0000520 in TNBC and its associated mechanism. Methods: Reverse transcription quantitative polymerase chain reaction (RT‐qPCR) and Western blot assay were used to measure RNA and protein expression. Cell proliferation was analyzed by cell counting kit‐8 (CCK8) assay, flow cytometry and colony formation assay. Cell apoptosis was assessed by flow cytometry. Cell migration ability was analyzed by transwell migration and wound healing assays. Transwell invasion assay was conducted to analyze the invasion ability. Dual‐luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA‐pulldown assay were performed to verify the interaction between microRNA‐1296 (miR‐1296) and circ_0000520 or zinc finger protein X‐linked (ZFX). Xenograft mice model was established to analyze the role of circ_0000520 in xenograft tumor growth in vivo. Results: Circ_0000520 expression was upregulated in TNBC tissues and cell lines. Circ_0000520 knockdown suppressed the proliferation, migration, and invasion whereas induced the apoptosis of TNBC cells. miR‐1296 was verified as a target of circ_0000520, and circ_0000520 silencing‐mediated suppressive effects on the malignant potential of TNBC cells were partly overturned by miR‐1296 knockdown. miR‐1296 interacted with the 3′ untranslated region (3′UTR) of ZFX, and ZFX overexpression partly reversed miR‐1296 overexpression‐mediated effects in TNBC cells. Circ_0000520 absence reduced ZFX expression by upregulating miR‐1296 in TNBC cells. Circ_0000520 silencing suppressed xenograft tumor growth in vivo. Conclusions: Circ_0000520 contributed to TNBC development by binding to miR‐1296 to induce ZFX expression. [ABSTRACT FROM AUTHOR]

Precipitation is a primary determinant of plant community structure in drylands. However, the empirical evidence and predictions are lacking for how plant functional diversity in desert and steppe communities respond to altered precipitation regimes.We examined how precipitation changes along the natural and experimental gradients affect different components of functional diversity in desert‐shrub and steppe‐grass communities. We compared the associations of precipitation changes with community‐weighted means (CWMs) of six traits, functional divergence (FDvar) of each single‐trait and multi‐trait functional richness (FRic) and dispersion (FDis) for shrub and grass communities along the natural and experimental gradients. We also disentangle the roles of species turnover and intraspecific variations in affecting the responses of different functional diversity to precipitation changes.We found that in general, the similar responses of functional traits or diversity to both the natural and experimental precipitation gradients were dependent on plant community type. Across both two gradients, precipitation was positively associated with CWM of plant height and negatively associated with the CWM of SLA and leaf thickness in grass community, while positively associated with FDvar of four traits and FDis in shrub communities. Both species turnover and intraspecific variations contributed to the responses of grass community traits to precipitation changes across both two gradients, and to FDvar of traits and FDis in shrub community along the natural gradient. In contrast, species turnover variations contributed to FDvar of traits and FDis in shrub community in experiment.These results suggest that there is better concordance between the effects of naturally and experimentally increased precipitation on functional diversity of plant communities, but different mechanisms behind the relationship of functional diversity–precipitation between shrub and grass communities. Grass communities can adapt to precipitation changes by average trait differences, while shrub communities persist through FDvar of single‐trait and multi‐trait dispersion, thus highlighting the important differences in adaptive strategies between shrub and grass communities. Our findings demonstrate that short‐term responses of plant communities to manipulative precipitation changes can reflect long‐term shifts at spatial scales depending on the specific functional trait and diversity. A free Plain Language Summary can be found within the Supporting Information of this article. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, the natural course of which has not been well documented. This study aimed to perform a prospective cohort study to investigate NAFLD in a Chinese population. METHODS: Using our previous epidemiological survey, 3543 patients were followed-up for a median of 4 years (range 3.6-4.8 years). Of these patients, 624 participated in a new survey. Interviews, physical examinations, biochemical tests and abdominal ultrasonography were repeated for these patient. RESULTS: The annual incidence of NAFLD was 9.1% (male 7.3% vs female 9.7%, P = 0.047). Among 117 NAFLD patients at baseline, 51 (43.6%) remained unchanged, 26 (22.2%) became worse, and 40 (34.2%) improved. Patients with simultaneous metabolic syndrome (MS) showed accelerated progression ( P = 0.026). For the NAFLD patients, both general annual mortality rates and cardiovascular disease deaths (both 0.54%) were significantly higher than those of patients without NAFLD (0.19% and 0.17%, P = 0.005). Age and several variables related to MS were risk factors for NAFLD progression. CONCLUSIONS: The incidence of NAFLD in southern China is relatively lower in comparison with that of the developed countries. Patients with NAFLD have a benign prognosis. Variables related to MS are risk factors for NAFLD occurrence and progression. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this study was to investigate the influence of polygenetic polymorphisms, which play a role in the pathogenesis of metabolic syndrome, on the susceptibility to non-alcoholic fatty liver disease (NAFLD) of Chinese people. Methods: The subjects were selected from an epidemiological survey in the Guangdong province of southern China. In each polymorphism study, 50–117 subjects who met the diagnostic criteria of NAFLD and had typical clinical and ultrasonographic findings were placed into the case group. Using a nested case–control design, the same numbers of matched people without NAFLD were included as controls. Single nucleotide polymorphisms (SNP) at nine positions in seven candidate genes were tested. These SNP were found to be associated with the pathogenesis of metabolic syndrome. Genetic analyses were performed using genomic DNA extracted from peripheral blood leukocytes. Polymerase chain reaction–restriction fragment length polymorphism was applied to detect SNP. Results: Most candidate genes' SNP were associated with susceptibility to NAFLD. Some showed positive relationships (increased risk): tumor necrosis factor-α-238, adiponectin-45, leptin-2548, peroxisome proliferator-activated receptors-161 and phosphatidyletha-nolamine N-methyltransferase-175. Other SNP demonstrated a negative association (decreased risk): adiponectin-276 and hepatic lipase-514. Only two were not associated: tumor necrosis factor-α-380 and peroxisome proliferator-activated receptors-γ co-activator-1α-482. Conclusion: Most candidate genes' SNP examined in metabolic syndrome patients were associated with susceptibility to NAFLD. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic retinopathy is a chronic low-grade inflammatory disease; however, the mechanisms remain elusive. In the present study, we demonstrated that endoplasmic reticulum (ER) stress was activated in the retina in animal models of diabetes and oxygen-induced retinopathy (OIR). Induction of ER stress by tunicamycin resulted in significantly increased expression of inflammatory molecules in the retina. Inhibition of ER stress by chemical chaperone 4-phenyl butyric acid ameliorated inflammation in cultured human retinal endothelial cells exposed to hypoxia, and in the retinas of diabetic and OIR mice. These findings indicate that ER stress is a potential mediator of retinal inflammation in diabetic retinopathy. [Copyright &y& Elsevier]

The LIM (Lin-1, Isl-1 and Mec-3)-homeodomain transcription factor 1 beta ( Lmx1b) is widely expressed in vertebrate embryos, and is implicated in the development of diverse structures such as limbs, kidneys, eyes and brains. LMX1B mutations in humans cause an autosomal dominant inherited disease called nail-patella syndrome (NPS), which is characterized by abnormalities of the arms and legs as well as kidney disease and glaucoma. Expression of Lmx1b in the dorsal compartment of growing limb buds is critical for specification of dorsal limb cell fates and consequently dorsoventral patterning of limbs. In addition, Lmx1b is involved in the differentiation of anterior eye structures, formation of the glomerular basement membrane in kidneys and development of the skeleton, especially calvarial bones. In the central nervous system, Lmx1b controls the inductive activity of isthmic organizer, differentiation and maintenance of central serotonergic neurons, as well as the differentiation and migration of spinal dorsal horn neurons. Although details of the genetic programs involved in these developmental events are largely unknown, it is suggested that Lmx1b plays central roles in fate determination or cell differentiation in these tissues. Sustained expression of Lmx1b in the postnatal and mature mouse brain suggests that it also plays important roles in brain maturation and in the regulation of normal brain functions. This review aims to highlight recent insights into the many activities of Lmx1b in vertebrates. [ABSTRACT FROM AUTHOR]

Background/Aims: Peroxisome proliferator-activated receptors-γ (PPAR-γ) and its co-activator-1α (PGC-1α) are involved in the regulation of lipid and glucose metabolisms. This study aimed to investigate the genetic polymorphisms of PPAR-γ and PGC-1α in Chinese people and their influence on plasma adiponectin levels and non-alcoholic fatty liver disease (NAFLD) susceptibility. Methods: Ninety-six patients with NAFLD and 96 healthy controls were included. The single nucleotide polymorphisms (SNPs) of C161T PPAR-γand Gly482Ser PGC-1α genes were analysed by polymerase chain reaction and restriction fragment length polymorphism. Result: The CC, CT and TT genotypic distributions of the NAFLD group were significantly different from those of controls (55.2, 39.6, 5.2 vs. 74.0, 25.0, 1.0%; P=0.015). The allelic frequencies of C and T were also different between the two groups ( P=0.004). As for the PGC-1α gene, there was no difference of the genotypic and allelic frequencies between the two groups ( P>0.05). In NAFLD patients, the plasma adiponectin concentrations were lower in the PPAR-γ CT/TT genotypes compared with those in the CC genotype group (3.0±0.6 vs. 4.3±0.9, P=0.02). Multivariate logistic regression analysis showed that CT/TT genotypes of PPAR-γ, TG, waist hip ratio, hypoadiponectinaemia and homoeostasis model assessment (HOMA)-IR were the risk factors for NAFLD. Conclusion: SNPs in the PPAR-γ, but not PGC-1α, gene are associated with NAFLD susceptibility possibly through the adiponectin pathway. [ABSTRACT FROM AUTHOR]

Crop yield and water use efficiency (WUE) in a wheat-maize double cropping system are influenced by short and uneven rainfalls in the North China Plain (NCP). A 2-year experiment was conducted to investigate the effects of irrigation on soil water balance, crop yield and WUE to improve irrigation use efficiency in the cropping system. Soil water depletion (ΔSWS) by crop generally decreased with the increase of irrigation and rainfall, while ΔSWS for the whole rotation was relatively stable among these irrigation treatments. High irrigations in wheat season increased initial soil moisture and ΔSWS for subsequent maize especially in the drought season. Initial soil water influenced mainly by the irrigation and rainfall in the previous crop season, is essential to high yield in such cropping systems. Grain yield decreased prior to evapotranspiration (ET) when ET reached about 300 mm for wheat, while maize showed various WUEs with similar seasonal ET. For whole rotation, WUE declined when ET exceeded about 650 mm. These results indicate great potential for improving irrigation use efficiency in such wheat- maize cropping system in the NCP. Based on the present results, reasonable irrigation schedules according to different annual rainfall conditions are presented for such a cropping system. [ABSTRACT FROM AUTHOR]

OBJECTIVE: S-mephenytoin hydroxylase is a polymorphic cytochrome P450 (CYP) enzyme that catalyzes the metabolism of omeprazole, a proton-pump inhibitor, and some other drugs. The aim of this survey was to investigate the distribution of the genotype of S-mephenytoin hydroxylase in Chinese people. METHODS: One hundred and fifty-five unrelated healthy volunteers were selected and their blood samples were used for genotyping by PCR-restriction enzyme analysis. DNA from homozygous extensive metabolizers (EM) could be digested into two fragments, whereas poor metabolizers (PM) could not be digested and heterozygous EM could be partly digested. RESULTS: Two mutations of CYP2C19 were found; that is, m1 and m2. The frequency of the PM (m/m) genotype was 15.5% (24/155) and that of EM was 84.5% (131/155). The EM included 36.8% (57/155) homo-EM (wt/wt) and 47.7% (74/155) hetero-EM (wt/m). CONCLUSIONS: There were two forms of CYP2C19 mutations. The frequency of PM (m/m) and heterozygous EM genotype (w/m) in Chinese people were significantly higher than those of Western white people. Hetero-EM were more common than homo-EM in the Chinese population. The genotyping variation might explain the different effect of PPI on individuals. [ABSTRACT FROM AUTHOR]

Metal/CFRP hybrid material system has been recently introduced as an effective alternative for automotive applications. This study aimed to investigate tensile responses and flexural behaviors of aluminum/carbon fiber reinforced plastic (CFRP) hybrid laminated plates by comparing with their counterparts made of net CFRP or aluminum materials. The experimental results showed that for the hybrid specimens the tensile strength increased and the tensile modulus decreased with increasing number of CFRP layers. Further, it was found that the bending indicators of the hybrid specimens were in between those of pure CFRP specimen and pure aluminum specimen. With the increasing number of CFRP layers, a reduction in flexural modulus could be observed in the hybrid specimens, while the flexural strength increased. A parametric study was further conducted numerically and it was found that tensile modulus was less influenced by the fiber stacking sequences when the number of 45° CFRP layers was the same, and both tensile modulus and tensile strength decreased with increasing number of 45° CFRP layers. Type II hybrid specimen, fabricated by upper and lower CFRP plates sandwiched with aluminum core, showed the lowest flexural modulus but the highest flexural strength. When the configurational scheme changed from symmetric distribution (type II) into Type I (fabricated by upper CFRP plate and lower aluminum sheet) or Type III (fabricated by upper aluminum sheet and lower CFRP plate), flexural modulus increased but flexural strength decreased. As for the Type II hybrid specimens, the flexural modulus decreased with increasing number of 45° CFRP layers. [ABSTRACT FROM AUTHOR]

Summary: The Chinese jujube (Ziziphus jujuba Mill.), a member of the Rhamnaceae family, is an important perennial fruit tree crop of substantial economic, ecological and nutritional value, and is also used as a traditional herbal medicine. Here, we report the resequencing of 493 jujube accessions, including 202 wild and 291 cultivated accessions at >16× depth. Our population genomic analyses revealed that the Shanxi–Shaanxi area of China was jujube's primary domestication centre and that jujube was then disseminated into East China before finally extending into South China. Divergence events analysis indicated that Ziziphus acidojujuba and Ziziphus jujuba diverged around 2.7 Mya, suggesting the interesting possibility that a long pre‐domestication period may have occurred prior to human intervention. Using the large genetic polymorphism data set, we identified a 15‐bp tandem insertion in the promoter of the jujube ortholog of the POLLEN DEFECTIVE IN GUIDANCE 1 (POD1) gene, which was strongly associated with seed‐setting rate. Integrating genome‐wide association study (GWAS), transcriptome data, expression analysis and transgenic validation in tomato, we identified a DA3/UBIQUITIN‐SPECIFIC PROTEASE 14 (UBP14) ortholog, which negatively regulate fruit weight in jujube. We also identified candidate genes, which have likely influenced the selection of fruit sweetness and crispness texture traits among fresh and dry jujubes. Our study not only illuminates the genetic basis of jujube evolution and domestication and provides a deep and rich genomic resource to facilitate both crop improvement and hypothesis‐driven basic research, but also identifies multiple agriculturally important genes for this unique perennial tree fruit species. [ABSTRACT FROM AUTHOR]

An approach to 2,3‐dihydrobenzo[f]isoindolones by a Ag‐catalyzed Ugi 4CR/cascade radical cyclization sequence under mild conditions has been developed. The reaction of (E)‐2‐benzylidene‐4‐arylbut‐3‐ynoic acids, aldehydes, amines, and isocyanides produced 2,3‐dihydro‐benzo[f]isoindolones regioselectively in 60–85% yields via sequential Ugi 4CR/cascade radical cyclization reaction in the presence of Cs2CO3 and AgOTf. The method achieved the formation of two C−C bonds under air atmosphere in one‐pot fashion. [ABSTRACT FROM AUTHOR]

Background:LAR is a transmembrane receptor-like protein tyrosine phosphatase (PTP). Genetic studies of Drosophila LAR suggest that LAR may function to regulate cell adhesions or adhesion-mediated signal transduction. The over-expression of LAR in mammalian tissue culture cells does not affect cell adhesion but induces caspase-dependent apoptosis. This study investigates molecular mechanisms of LAR-induced apoptosis by searching for in vivo substrates of LAR which are responsible for LAR-induced apoptosis. Results:The over-expression of LAR in tissue culture cells specifically decreased the steady state protein level of p130Cas, a multifunctional signal assembly protein in signal transduction, by reducing the tyrosine phosphorylation and protein stability of p130Cas. The reduction of p130Cas protein level could be inhibited by tyrosine phosphatase inhibitors. Phosphatase domain-deleted mutant LARs had no effect on p130Cas. LAR also preferentially dephosphorylated p130Cas in vitro. Subcellularly, LAR and p130Cas were co-localized along stress fibres and at focal adhesions. LAR over-expression eliminated p130Cas from focal adhesions without affecting focal adhesion assembly. Restoring the level of p130Cas alleviated LAR-induced apoptosis. Conclusions:p130Cas is an in vivo substrate of LAR. LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival. The function of p130Cas in focal adhesions may not be to regulate focal adhesion assembly and cell adhesion but rather to transduce the cell adhesion-generated signals which are essential for cell survival. [ABSTRACT FROM AUTHOR]

Plasmonic metasurfaces show great potential to manipulate the wavefront of surface plasmons (SPs) and enable realization of various chip‐level photonic devices. However, the current configurations can merely operate under specific incident polarization state and/or have limitation in independently tuning the phase and amplitude of SPs, although arbitrary incident polarization state is allowed. There is still the lack of a metasurface scheme that not only can couple spatial light waves into SPs under arbitrary polarization states, but also can independently modulate the amplitude and phase of the generated SPs. Here, it is proposed and experimentally demonstrated that double‐lined metallic nanoslits can be well designed to overcome these limitations. Practical metadevices are designed and fabricated for generating polarization‐independent plasmonic Airy beams, near‐field focusing, and intensity‐preserved "lossless" beams, and their excellent performances at 633 nm are characterized with near‐field scanning optical microscope. The presented results will offer opportunities for the practical plasmonic devices and applications based on the plasmonic metasurfaces. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Long non‐coding RNAs (lncRNAs) are widely involved in the progression of Hirschsprung's disease (HSCR), but the role of actin filament associated protein 1 antisense RNA1 (AFAP1‐AS1), an lncRNA, in HSCR has not been explored before.What is the main finding and its importance?Downregulation of AFAP1‐AS1 blocks enteric neural crest stem cell proliferation, differentiation, migration and invasion and promotes the occurrence of HSCR via the miR‐195/E2F3 axis, indicating thatAFAP1‐AS might be a potential biomarker for HSCR patients. Long non‐coding RNAs (lncRNAs) are involved in several human disorders. Nevertheless, it remains unclear whether they are implicated in the phenotypes of enteric neural crest stem cells (ENCSCs) in Hirschsprung's disease (HSCR). Therefore, we designed this study to explore the pathogenicity of AFAP1‐AS1 for HSCR. Microarray analysis and bioinformatic tools were used to screen out the differentially lncRNAs and microRNAs (miRNAs) in patients with HSCR. Small interference RNA transfection was applied to carry out functional experiments in ENCSCs. Cellular activities were detected by cell counting kit‐8, 5‐ethynyl‐2′‐deoxyuridine, Transwell assays and flow cytometry. Finally, rescue experiments were performed to examine the cofunction of AFAP1‐AS1 and miR‐195 and of miR‐195 and E2F transcription factor 3 (E2F3). AFAP1‐AS1 was reduced in HSCR patients. Meanwhile, knockdown of AFAP1‐AS1 reduced the cell migratory and proliferative capacities and facilitated cell apoptosis along with G0/G1 phase arrest. E2F3 was diminished when miR‐195 was upregulated, and AFAP1‐AS1 inhibition reduced its ability to bind to miR‐195. Altogether, AFAP1‐AS1 silencing acts as an endogenous RNA by interacting with miR‐195 to alter E2F3 expression, thus conferring repressive effects on ENCSC activity and promoting HSCR progression. [ABSTRACT FROM AUTHOR]

Endothelial glycocalyx degradation, critical for increased pulmonary vascular permeability, is thought to facilitate the development of sepsis into the multiple organ failure. Maresin conjugates in tissue regeneration 1 (MCTR1), a macrophage‐derived lipid mediator, which exhibits potentially beneficial effects via the regulation of bacterial phagocytosis, promotion of inflammation resolution, and regeneration of tissue. In this study, we show that MCTR1 (100 ng/mouse) enhances the survival of mice with lipopolysaccharide (LPS)‐induced (15 mg/kg) sepsis. MCTR1 alleviates LPS (10 mg/kg)‐induced lung dysfunction and lung tissue inflammatory response by decreasing inflammatory cytokines (tumor necrosis factor‐α, interleukin‐1β [IL‐1β], and IL‐6) expression in serum and reducing the serum levels of heparan sulfate (HS) and syndecan‐1. In human umbilical vein endothelial cells (HUVECs) experiments, MCTR1 (100 nM) was added to the culture medium with LPS for 6 hr. MCTR1 treatment markedly inhibited HS degradation by downregulating heparanase (HPA) protein expression in vivo and in vitro. Further analyses indicated that MCTR1 upregulates sirtuin 1 (SIRT1) expression and decreases NF‐κB p65 phosphorylation. In the presence of BOC‐2 or EX527, the above effects of MCTR1 were abolished. These results suggest that MCTR1 protects against LPS‐induced sepsis in mice by attenuating pulmonary endothelial glycocalyx injury via the ALX/SIRT1/NF‐κB/HPA pathway. [ABSTRACT FROM AUTHOR]

Aims: It has been reported that allopregnanolone (APα) promotes the neurogenesis of the neural progenitor cells (NPCs) in the subventricular zone (SVZ) and prevents the decrease of dopaminergic neurons in 6‐hydroxydopamine (6‐OHDA)‐treated mice by binding to γ‐aminobutyric acid A receptor (GABAAR) and then opening voltage‐gated L‐type Ca2+ channel, but the underlying mechanisms remain elusive. The aim of this study was to explore the possible involvement of GABAAR and calcium/calmodulin‐dependent protein kinase II delta 3 (CaMKIIδ3) in this process. Methods: 6‐OHDA‐treated mice and primary cultured midbrain cells were administrated with APα and GABAAR antagonist bicuculline (Bic), and the proliferation and differentiation of NPCs, the tyrosine hydroxylase (TH)‐positive neurons and their fibers, the expression levels of CaMKIIδ3 and brain‐derived neurotrophic factor (BDNF), and motor functions were measured using ELISA, immunohistochemical staining, real‐time RT‐PCR, Western blot, and behavioral test. Results: Allopregnanolone significantly promoted the phosphorylation of cytoplasmic CaMKIIδ3 and its nuclear translocation by binding to GABAAR, which, in turn, increased the expression levels of BDNF. This may account for the findings that the exogenous APα enhanced the proliferation and differentiation of NPCs, and ameliorated the nigrostriatal system and behavioral performance in 6‐OHDA‐treated mice. Conclusions: Allopregnanolone may directly activate GABAAR, which, in turn, enhance the proliferation and differentiation of NPCs via upregulating the expression levels of CaMKIIδ3, and finally contribute to the restoration of dopaminergic neurons in 6‐OHDA‐treated mice. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effect of donor selection, stool procedures and pretreatment with antibiotics on the efficacy and safety of fecal microbiota transplantation (FMT)‐treated ulcerative colitis (UC). Methods: A systematic review and meta‐analysis was conducted including studies on UC treated with FMT as the primary therapeutic agent published up to June 30, 2020. Primary end‐point data included clinical remission (CR) or CR combined with endoscopic remission. Results: A total of 37 studies (seven random controlled trials [RCTs], five controlled and 25 uncontrolled cohort studies) and 959 patients with UC were enrolled. In controlled cohort studies and RCTs, FMT had a significantly greater benefit than placebo (pooled odds ratio [P‐OR] 3.392, 95% CI 2.196‐5.240, P < 0.001), with no heterogeneity (I2 = 0%). Furthermore, administration of FMT via the lower gastrointestinal (GI) tract was more effective in achieving CR than via the upper GI tract (44.3% vs 31.7%). The remission rate was also higher when the total stool dosage was over 275 g compared with less than 275 g (51.9% vs 29.5%). Overall, the incidence of serious adverse events of FMT was 5.9%. There was no significant difference between single and multiple donors, fresh and frozen stool sample used, and whether or not antibiotic pretreatment was administered before FMT. Conclusion: FMT administration via the lower GI tract and using higher dosage appear to be effective and safe in inducing remission of active UC. [ABSTRACT FROM AUTHOR]