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High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms. miR-22 cardiac-specific knockout (miR-22cKO) mice and miR-22 cardiac-specific transgenic (miR-22cOE) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The echocardiogram results suggested that miR-22cKO CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22cKO CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22cKO CLP mice, while it had contrary role in the miR-22cOE group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy in vitro. Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions. Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.

Identifying personalized driver genes is essential for discovering critical biomarkers and developing effective personalized therapies of cancers. However, few methods consider weights for different types of mutations and efficiently distinguish driver genes over a larger number of passenger genes. We propose MinNetRank (Minimum used for Network-based Ranking), a new method for prioritizing cancer genes that sets weights for different types of mutations, considers the incoming and outgoing degree of interaction network simultaneously, and uses minimum strategy to integrate multi-omics data. MinNetRank prioritizes cancer genes among multi-omics data for each sample. The sample-specific rankings of genes are then integrated into a population-level ranking. When evaluating the accuracy and robustness of prioritizing driver genes, our method almost always significantly outperforms other methods in terms of precision, F1 score, and partial area under the curve (AUC) on six cancer datasets. Importantly, MinNetRank is efficient in discovering novel driver genes. SP1 is selected as a candidate driver gene only by our method (ranked top three), and SP1 RNA and protein differential expression between tumor and normal samples are statistically significant in liver hepatocellular carcinoma. The top seven genes stratify patients into two subtypes exhibiting statistically significant survival differences in five cancer types. These top seven genes are associated with overall survival, as illustrated by previous researchers. MinNetRank can be very useful for identifying cancer driver genes, and these biologically relevant marker genes are associated with clinical outcome. The R package of MinNetRank is available at https://github.com/weitinging/MinNetRank.

Cadmium (Cd) is harmful to plant growth and can be easily transferred from soil to plants. Plant cell wall plays important role in preventing Cd from entering cells. Salicylic acid (SA) mediated defense response increases plant resistance to heavy metals. In this study, all tomato seedlings were pre-treated with 100 μM SA for 3 d, then seedlings were used to analyze the role of SA in regulating plant cell wall resistance to Cd stress. The results showed that exogenous SA significantly reduced Cd accumulation in tomato plants and changed Cd distribution. By analyzing the cell wall composition, it was found cellulose, hemicellulose, pectin, and lignin were induced by SA. Interestingly, the content of Cd in pectin decreased by SA pretreatment, however it was increased in cellulose. Gene expression analysis showed SA up-regulated the expression level of lignin and cellulose synthase genes, but down-regulated the expression of pectin methylesterase related genes. In addition, SA down-regulated the activity of pectin methylesterase. These results indicated that SA pretreatment up-regulated cell wall polysaccharide synthesis and related gene expression to thicken the cell wall and block Cd from passing through. Furthermore, SA decreased pectin methylesterase activity and content to reduce cell wall Cd accumulation and change the Cd partition ratio.

BackgroundImmune checkpoint inhibitors (ICIs) are an important treatment modality that must be considered for patients with lung adenocarcinoma (LUAD). However, ICIs are effective only in some of these patients. Therefore, identifying biomarkers that accurately predict the prognosis of patients with LUAD treated with ICIs can help maximize their therapeutic benefits. This study aimed to identify a new potential predictor to better select and optimally benefit LUAD patients.MethodsWe first collected and analyzed a discovery immunotherapy cohort comprising clinical and mutation data for LUAD patients. Then, we evaluated whether the specific mutated genes can act as predictive biomarkers in this discovery immunotherapy cohort and further validated the findings in The Cancer Genome Atlas (TCGA) project LUAD cohort. Gene set enrichment analysis (GSEA) was used to explore possible alterations in DNA damage response (DDR) pathways within the gene mutation. Moreover, we analyzed whole-exome sequencing (WES) and drug sensitivity response data for LUAD cell lines in the Genomics of Drug Sensitivity in Cancer (GDSC) database.ResultsAmong the mutated genes screened from both the ICI treatment and TCGA-LUAD cohorts, NTRK3 mutation (mutant-type NTRK3, NTRK3-MT) was strongly associated with immunotherapy. First, significant differences in overall survival (OS) were observed between patients with NTRK3-MT and those with NTRK3-WT in the ICI treatment cohort but not in the non-ICI-treated TCGA-LUAD cohort. We then analyzed the association of NTRK3-MT with clinical characteristics and found the tumor mutation burden (TMB) to be significantly higher in both NTRK3-MT cohorts. However, significant differences in neoantigen levels and smoking history were found only for NTRK3-MT in the LUAD cohort from TCGA. Furthermore, some immune-related genes and immune cell-related genes were significantly upregulated in patients with NTRK3-MT compared to those with NTRK3-WT. In addition, NTRK3 mutation affected the deregulation of some signaling pathways and the DDR pathway.ConclusionsOur findings suggest that NTRK3-MT can predict the prognosis of patients with LUAD treated by ICIs and that it may have clinical significance for immunotherapy.

Abstract Cellular protein eukaryotic translation elongation factor 1A (eEF1A) is an actin binding protein that plays a role in the formation of filamentous actin (F-actin) bundles. F-Actin regulates multiple stages of respiratory syncytial virus (RSV) replication including assembly and budding. Our previous study demonstrated that eEF1A knock-down significantly reduced RSV replication. Here we investigated if the eEF1A function in actin bundle formation was important for RSV replication and release. To investigate this, eEF1A function was impaired in HEp-2 cells by either knock-down of eEF1A with siRNA, or treatment with an eEF1A inhibitor, didemnin B (Did B). Cell staining and confocal microscopy analysis showed that both eEF1A knock-down and treatment with Did B resulted in disruption of cellular stress fiber formation and elevated accumulation of F-actin near the plasma membrane. When treated cells were then infected with RSV, there was also reduced formation of virus-induced cellular filopodia. Did B treatment, similarly to eEF1A knock-down, reduced the release of infectious RSV, but unlike eEF1A knock-down, did not significantly affect RSV genome replication. The lower infectious virus production in Did B treated cells also reduced RSV-induced cell death. In conclusion, the cellular factor eEF1A plays an important role in the regulation of F-actin stress fiber formation required for RSV assembly and release.

AIM: To study whether autophagy and paraptosis were activated in retinal ganglion cells(RGCs)after acute high intraocular pressure(IOP)in an experimental rat model and to explore the possible underlying mechanisms. METHODS: A total of 50 male Sprague-Dawley(SD)rats were randomly divided into normal control group, and 3d, 1, 4, 8wk group after acute elevated intraocular pressure(IOP)(n=10 per group). Acute intraocular hypertension model was established by anterior chamber perfusion of normal saline in the right eye. The expression levels of microtubule-associated protein 1 light chain 3(LC3)was measured by immumofluorescence method. To determine whether autophagy and paraptosis were activated. Retinal sections were examined by transmission electron microscopy(TEM). Autophagosomes and cytoplasmic vacuoles in the cytoplasm of RGCs were measured. RESULTS: TEM analysis revealed that double- and multiple-membrane vacuoles containing electron-dense materials of autophagosomes were found in RGCs. The number of autophagosomes per 50μm2 were 0.79±0.43, 2.14±0.36, 2.29±0.47, 1.57±0.51 and 1.21±0.43 in the normal control group and in acute IOP group at 3d, 1wk, 4wk, 8wk, respectively. The number of autophagosomes markedly increased in the cytoplasm of RGCs at 3d, 1wk, 4wk, 8wk groups than those in the normal control group(all at PPPCONCLUSION: Autophagy and paraptosis participate in the death of RGCs under transiently elevated intraocular pressure. Different types of programmed cell death(PCD), coexistence of multiple cell death forms or a single cell death form, participates in the pathogenesis of acute elevation of intraocular pressure.

Summary: Inhibition of RNA polymerase I (Pol I) is a promising strategy for modern cancer therapy. BMH-21 is a first-in-class small molecule that inhibits Pol I transcription and induces degradation of the enzyme, but how this exceptional response is enforced is not known. Here, we define key elements requisite for the response. We show that Pol I preinitiation factors and polymerase subunits (e.g., RPA135) are required for BMH-21-mediated degradation of RPA194. We further find that Pol I inhibition and induced degradation by BMH-21 are conserved in yeast. Genetic analyses demonstrate that mutations that induce transcription elongation defects in Pol I result in hypersensitivity to BMH-21. Using a fully reconstituted Pol I transcription assay, we show that BMH-21 directly impairs transcription elongation by Pol I, resulting in long-lived polymerase pausing. These studies define a conserved regulatory checkpoint that monitors Pol I transcription and is activated by therapeutic intervention. : Targeting of RNA polymerase I is currently being explored for cancer therapeutics. Wei et al. show that small-molecule BMH-21 activates a conserved RNA polymerase I checkpoint that monitors efficiency of transcription. Transcription inhibition and checkpoint activation by BMH-21 disengages the polymerase from chromatin and causes enzyme destruction. Keywords: transcription, elongation, cancer therapeutics, rRNA, nucleolus, yeast

Senecavirus A (SVA) is a newly porcine virus that has been detected in many countries since its first detection in pigs in Canada in 2007, and it remains endemic in many countries in Asia and America, which has become a substantial problem for the pig industry. Vaccination is a potentially effective strategy for the prevention and control of SVA infection. Our lab has developed a SVA vaccine candidate previously. In this study, the antibody response to the prepared vaccine in sows and their offspring was evaluated. Vaccination of sows with inactivated SVA vaccines during pregnancy elicited SVA-specific virus-neutralizing antibodies. Vaccination with a high dose of SVA vaccine followed a booster immunization contributed to a long-term duration of the persistence of maternally derived neutralizing antibodies (MDAs) in the milk of the sows (>14 days). In contrast, vaccination with a single low dose of SVA vaccine resulted in a short-term persistence of MDAs in the milk (2–7 days). The MDAs could be efficiently transferred from the sows to their offspring through the colostrum/milk but not the umbilical cord blood. The antibody titers and the duration of the persistence of MDAs in the offspring are highly associated with the antibody levels in the milk from the sows. Vaccination of sows with a booster dose of SVA vaccine resulted in a longer-lasting MDAs in their offspring (persisted for at least 90 days). However, vaccination with the single low dose of vaccine only brought about 42 days of MDAs persistence in their offspring. The effect of MDAs on active immunization with SVA vaccine in offspring was further evaluated, which showed that vaccination of the SVA vaccine in the presence of MDAs at the titer of ≈1:64 or less could overcome the MDAs’ interference and give rise to effective antibody response. This will help for establishing the optimal times and schedules for SVA vaccination in pigs.

AIM: To discuss the effect of the cystotome-assisted prechop technique performed in hard nuclear cataract phacoemulsification. METHODS: One hundred and twenty-six patients(158 eyes)of age-related cataracts with nucleus density at grade Ⅲ-Ⅳ were randomly divided into two groups. Group A was performed a manual prechop technique using a surgeon-bent cystotome after the capsulorhexis, while group B was performed traditional phaco-chop without prechop technique. The average power(AP), actual ultrasonic time(U/S time), accumulated energy complex parameter(AECP)of machine, average density of endothelial cells, endothelial cells loss, uncorrected visual acuity(UCVA), corneal edema and intraoperative complications were compared between groups. RESULTS: The AP, U/S time and AECP of Group A were significantly lower than that of Group B(PPCONCLUSION: Compared with traditional phaco-chop, the cystotome-assisted prechop technique presents shorter intraoperative ultrasound time and lower energy, while contributes to less corneal endothelial cell loss and better early postoperative UCVA.

AIM: To observe the clinical effect of vitrectomy combined with cataract surgery in the treatment of proliferative diabetic retinopathy(PDR). METHODS: Totally 80 patients(83 eyes)with PDR who underwent treatment in the hospital during the period from February 2013 to February 2017 were selected and divided into the control group and the observation group according to the treatment method. The control group was treated by vitrectomy combined with lensectomy while the observation group was treated by vitrectomy combined with phacoemulsification. The clinical curative effect was compared between the two groups. RESULTS: After surgery, the visual acuity of the two groups was improved significantly, and the visual acuity of the observation group was better than that of the control group(PPCONCLUSION: The clinical effect of vitrectomy combined with phacoemulsification is better than that of vitrectomy combined with lensectomy in the treatment of PDR.

Treatment with cisplatin (DDP) is one of the standard therapies used to treat non-small-cell lung cancer (NSCLC) and fundamentally causes resistance in cancer cells, which eventually poses as an obstacle to the efficacy of chemotherapy in NSCLC. Efforts are on all over the world to explore a sensitizer of NSCLC to DDP. Here, we studied the effect of IL-7 on the resistance of NSCLC to chemotherapy. We observed that IL-7 treatment significantly enhanced DDP-induced effects in A549 and A549/DDP cells (DDP-resistant cells), including decreased cell viability and proliferation, as well as increased cell apoptosis and S arrest, indicating that IL-7 treatment resensitized DDP-resistant NSCLC cells to DDP. Subsequently, IL-7 enhanced the sensitivity of PI3K/AKT signaling and expressions of ABCG2 to DDP. By inhibiting IL-7 signaling via IL-7R knockdown or activating PI3K/AKT signaling via PI3K activation, the resensitization to DDP by IL-7 was abrogated, and the expression levels of ABCG2, p-PI3K, and p-AKT were found to be significantly higher. In vivo results also confirmed that IL-7 only in combination with DDP could remarkably induce tumor regression with reduced levels of ABCG2 in tumorous tissues. These findings indicate that IL-7, apart from its adjuvant effect, could overcome multidrug resistance of DDP to restore its chemotherapy sensitivity.

User experience plays an indispensable role in intelligent product design. Building a system for user research, capturing firsthand information from users and turning insights into achievable product design solutions is the key to innovation. This article introduces service design into product design and studies the design cue construction method through intelligent product design case. First, the authors capture customer touchpoints in the process of user interaction with the product by observing the user behavior and perform the correlation analysis of the customer touchpoint to obtain the user’s complaints and dissatisfaction. Second, the authors use positive creation theory to transform requirements and turn the complaints collected in user research into achievable functional requirements. Third, the authors use the KANO model for sensitivity analysis of functional requirements and select high-sensitivity requirements for priority development. Finally, using the service design innovation methods to analyze the user experience and stakeholders, the design cue map can be exported, and a new service system was established to enhance the overall user experience.

Massive open online courses (MOOCs; online courses delivered over the Internet) enable distance learning without time and place constraints. MOOCs are popular; however, active participation level among students who take MOOCs is generally lower than that among students who take in-person courses. Students who take MOOCs often lack guidance, and the courses often fail to provide personalized learning materials. Artificial intelligence (AI) has been applied to manage increasing amounts of learning data in learners' online activity records. Driven by the trend in big data, AI technology has drawn increasing attention in various fields. AI-based recommendation systems (RSs) are powerful tools for improving resource acquisition through supply customization, and they can provide personalized learning materials as study guides. In this study, a personalized learning path for MOOCs based on long short-term memory (LSTM) was proposed to meet students' personal needs for learning. According to students' video-watching behaviors, we proposed an MOOC material RS that identifies students with similar learning behaviors through clustering and then uses the clustering results and the learning paths of each group of students to construct an LSTM model to recommend learning paths. The system's learning path recommendations can effectively improve the online participation of learners, and students who received recommendations progressed from the slow-progress group to the medium-progress or fast-progress group. In addition, the learning attitude questionnaire results indicated that the proposed system not only motivated learners to continue learning and achieve high learning capacity but also supported their study planning according to their individual learning needs.

The capacity of an optical communication system can be greatly increased by using separate orbital angular momentum (OAM) modes as independent channels for signal transmission and encryption. At present, a transmissive OAM mode generator compatible with wavelength division multiplexing is being highly pursued. Here, we introduce a specific double-layer reverse-twist configuration into liquid crystal polymer (LCP) to overcome wavelength dependency. With this design, broadband-applicable OAM array generators are proposed and demonstrated. A Damman vortex grating and a Damman q-plate were encoded via photopatterning two subsequent LCP layers adopted with oppositely handed chiral dopants. Rectangular and hexagonal OAM arrays with mode conversion efficiencies exceeding 40.1% and 51.0% in the ranges of 530 to 930 nm, respectively, are presented. This provides a simple and broadband efficient strategy for beam shaping.

Beneficial reuse of drinking water treatment plant residues (WTRs) has been intensively studied worldwide in the last decades, but few engineering applications can be found. The majority of WTRs were directly reused in cake form (after dewatering), e.g., alum sludge cake as main substrate used in constructed wetlands (CWs), or oven dried and ground powdery form, e.g., sorbent for pollutant removal. However, WTRs reuse in such forms has several drawbacks, i.e., difficulty of recovering and easy clogging (in CWs), which result in limited WTRs engineering applications. Granulation or pelleting could widen and be a wiser WTRs reuse route and also seems to be a promising strategy to overcome the “application bottleneck” issues. In the literature, a number of trials of WTRs granulation have been reported since 2008, including sintering ceramsite, gel entrapment and newly emerged techniques. Hence, there is a need to overlook these studies and promote WTRs granulation for further development. To this end, this review firstly provides a piece of updated comprehensive information and critical analysis regarding WTRs granulation/pelleting technology. It aims to enhance WTRs granulation studies in the developing stage and thus enlarge WTRs engineering applications.

The accelerated decline in Arctic sea ice in recent decades suggests the possibility of future trans-Arctic shipping routes linking the Atlantic and Pacific oceans, with significant implications for the global economy. We present a projection of Arctic sea ice conditions and shipping activities during the 21st century based on 16 CMIP6 models calibrated to remove spatial biases. The multimodel ensemble mean shows that the Arctic is likely to be ice-free in September by 2076 and 2055 under the SSP2-4.5 and SSP5-8.5 scenarios, respectively, whereas the extent of sea ice is >2 × 10 ^6 km ^2 throughout the 21st century under the SSP1-2.6 scenario. The Arctic sea ice in September thins over time, leading to a reduction in the area with an ice thickness >120 cm (i.e. the threshold over which sea ice is inaccessible to Type A vessels) by 34–100% by the late 21st century (2086–2100) under the three scenarios. Given the declines in the extent and thickness of sea ice, the most commonly traversed route along the North West Passage tends to migrate from the southern to the northern route during the 21st century. The optimum route along the Northern Sea Route shifts northward with time, with the Transpolar Sea Route becoming available. Quantitatively, the maritime accessibility to Type A vessels via the Transpolar Sea Route increases from ∼6.7, 4.2 and 2.1% in 2021–2035 to 14.7, 29.2 and 67.5% in 2086–2100 under the SSP1-2.6, SSP2-4.5 and SSP5-8.5 scenarios, respectively. The season for trans-Arctic shipping extends from 5 to ∼7.5 (9) months by the late 21st century under the SSP1-2.6 (SSP2-4.5) scenario and the Arctic becomes navigable all year round under the SSP5-8.5 scenario. These findings may aid in developing strategic planning by governments for the Arctic and providing strategic advice for the global maritime industry.

Brassinosteroids (BRs), a class of steroidal phytohormones are essential for many biological processes in plant. However, little is known about their roles in fruit development. Tomato is a highly valuable vegetable and has been adopted as the model species for studying fruit growth, development, and ripening. To understand the role of endogenous BRs in the development of tomato fruit, the expression patterns of three homologues of DWF4 gene were investigated and the transgenic tomato plants were generated in which the GhDWF4 gene from upland cotton (Gossypium hirsutum L.) was ectopically expressed. The contents of main quality components were analyzed in fruits of transgenic tomato line and non-transgenic line (control plant, CP) when the fruit was mature. SlCYP90B3 that possesses high homology with GhDWF4 preferentially expressed in mature fruit. Significantly higher contents of soluble sugar, soluble proteins, and vitamin C were obtained in fruit of transgenic tomato lines compared with those in the CP. Furthermore, overexpressing GhDWF4 promoted fruit growth and ripening. The weight per fruit was increased by about 23% in transgenic lines. In addition, overexpressing GhDWF4 promoted the germination of transgenic tomato seeds and hypocotyl elongation of seedlings. These results indicated that overexpressing GhDWF4 gene in tomato could increase the contents of many nutrients in fruit and accelerate fruit ripening. It is suggested that increased endogenous BRs in fruit affect the growth and development of tomato fruit and therefore improved the nutrient quality of tomato.

In this short review, we have presented a brief overview on major web resources relevant to stem cell research. To facilitate more efficient use of these resources, we have provided a preliminary rating based on our own user experience of the overall quality for each resource. We plan to update the information on an annual basis.

Background: Date palm (Phoenix dactylifera L.) is a cultivated woody plant with agricultural and economic importance in many countries around the world. With the advantages of next generation sequencing technologies, genome sequences for many date palm cultivars have been released recently. Short sequence repeat (SSR) and single nucleotide polymorphism (SNP) can be identified from these genomic data, and have been proven to be very useful biomarkers in plant genome analysis and breeding.Results: Here, we first improved the date palm genome assembly using 130X of HiSeq data generated in our lab. Then 246,445 SSRs (214,901 SSRs and 31,544 compound SSRs) were annotated in this genome assembly; among the SSRs, mononucleotide SSRs (58.92%) were the most abundant, followed by di- (29.92%), tri- (8.14%), tetra- (2.47%), penta- (0.36%), and hexa-nucleotide SSRs (0.19%). The high-quality PCR primer pairs were designed for most (174,497; 70.81% out of total) SSRs. We also annotated 6,375,806 SNPs with raw read depth≥3 in 90% cultivars. To further reduce false positive SNPs, we only kept 5,572,650 (87.40% out of total) SNPs with at least 20% cultivars support for downstream analyses. The high-quality PCR primer pairs were also obtained for 4,177,778 (65.53%) SNPs. We reconstructed the phylogenetic relationships among the 62 cultivars using these variants and found that they can be divided into three clusters, namely North Africa, Egypt – Sudan, and Middle East – South Asian, with Egypt – Sudan being the admixture of North Africa and Middle East – South Asian cultivars; we further confirmed these clusters using principal component analysis. Moreover, 34,346 SSRs and 4,177,778 SNPs with PCR primers were assigned to shared cultivars for cultivar classification and diversity analysis. All these SSRs, SNPs and their classification are available in our database, and can be used for cultivar identification, comparison, and molecular breeding.Conclusion:DRDB is a comprehensive genomic resource database of date palm. It can serve as a bioinformatics platform for date palm genomics, genetics, and molecular breeding. DRDB is freely available at http://drdb.big.ac.cn/home.

In China, the ridge-furrow water conservation planting (RC) system is advantageous for improving crop yields and rainwater use efficiency. In RC planting system, plastic film-mulched ridges are employed for water harvesting while the furrows serve as infiltration and planting belts. To optimize the RC system and to overcome problems due to the lack of water in semi-humid areas at risk of drought, we mulched the furrows with 8% biodegradable film (RCSB), liquid film (RCSL), or no mulching in the furrows (RCSN), while conventional flat planting (CF) was employed as the control. After 4 year (2007–2010) consecutive field study, the results showed that the soil water storage level in the 0–100 cm layer with four treatments was ranked as follow: RCSB > RCSL > RCSN > CF, while the RCSB and RCSL were 26.3 and 12.2 mm greater than RCSN, respectively. Compared with CF, the average soil temperature was significantly (P < 0.05) higher by 3.1, 1.7, and 1.5°C under the RC planting treatments (RCSB, RCSL, and RCSN) during each year, respectively. The average ET rate of RC treatments were all lower than CF in each experimental year, and the average decreased by 8.0% (P < 0.05). The average yields with RCSB, RCSL, and RCSN increased by 2,665, 1,444, and 1,235 kg ha−1, respectively, and the water use efficiency (WUE) increased by 51.6, 25.6, and 21.1%, compared with CF. RCSB obtained the highest economic benefit, the average net income was higher than CF by 4,020 Yuan ha−1. In conclusion, we found that RC planting with biodegradable film mulching in the furrows is the best cultivation pattern in the semi-humid areas of China in terms of both environmental and economic benefits.