An allelic variation in the promoter of the LRR-RLK gene,qSS6.1,is associated with melon seed size

Seed size is an important agronomic trait in melons that directly affects seed germination and subsequent seedling growth.However,the genetic mechanism underlying seed size in melon remains unclear.In the present study,we employed Bulked-Segregant Analysis sequencing(BSA-seq)to identify a candidate region(~1.35 Mb)on chromosome 6 that corresponds to seed size.This interval was confirmed by QTL mapping of three seed size-related traits from an F2 population across three environments.This mapping region represented nine QTLs that shared an overlapping region on chromosome 6,collectively referred to as qSS6.1.New InDel markers were developed in the qSS6.1 region,narrowing it down to a 68.35 kb interval that contains eight annotated genes.Sequence variation analysis of the eight genes identified a SNP with a C to T transition mutation in the promoter region of MELO3C014002,a leucine-rich repeat receptor-like kinase(LRR-RLK)gene.This mutation affected the promoter activity of the MELO3C014002 gene and was successfully used to differentiate the large-seeded accessions(C-allele)from the small-seeded accessions(T-allele).qRT-PCR revealed differential expression of MELO3C014002 between the two parental lines.Its predicted protein has typical LRR-RLK family domains,and phylogenetic analyses reveled its similarity with the homologs in several plant species.Altogether,these findings suggest MELO3C014002 as the most likely candidate gene involved in melon seed size regulation.Our results will be helpful for better understanding the genetic mechanism regulating seed size in melons and for genetically improving this important trait through molecular breeding pathways.

Terrestrial water storage changes over the Pearl River Basin from GRACE and connections with Pacific climate variability

Time-variable gravity data from the Gravity Recovery and Climate Experiment （GRACE） satellite mission are used to study terrestrial water storage （TWS） changes over the Pearl River Basin （PRB） for the period 2003-Nov. 2014. TWS estimates from GRACE generally show good agreement with those from two hydrological models GLDAS and WGHM. But they show different capability of detecting significant TWS changes over the PRB. Among them, WGHM is likely to underestimate the seasonal variability of TWS, while GRACE detects long- term water depletions over the upper PRB as was done by hydrological models, and observes significant water increases around the Longtan Reservoir （LTR） due to water impoundment. The heavy drought in 2011 caused by the persistent precipitation deficit has resulted in extreme low surface runoff and water level of the LTR. Moreover, large variability of summer and autumn precipitation may easily trigger floods and droughts in the rainy season in the PRB, especially for summer, as a high correlation of 0.89 was found between precipitation and surface runoff. Generally, the PRB TWS was negatively correlated with El Nifio-Southern Oscillation （ENSO） events. However, the modulation of the Pacific Decadal Oscillation （PDO） may impact this relationship, and the significant TWS anomaly was likely to occur in the peak of PDO phase as they agree well in both of the magnitude and timing of peaks. This indicates that GRACE-based TWS could be a valuable parameter for studying climatic in- fluences in the PRB.

Simulation analysis of regional surface mass anomalies inversion based on different types of constraints

Surface mass anomalies estimated by mass concentration(mascon)approach using Gravity Recovery and Climate Experiment(GRACE)observations with regularization constraints generally present higher spatial resolution than the spheric harmonic(SH)solutions.To analyze the influence of different types of constraints on the estimation of mascon solutions,we carried out a closed-loop simulation experiment to estimate surface mass anomalies over South America based on simulated GRACE intersatellite geopotential differences.Tikhonov regularization with spatial constraint(SC),uniform weighting constraint(UWC),and a prior information constraint(APC)were employed to stabilize the mascon solutions,and the corresponding optimal regularization parameters were determined based on the minimum residual root-mean-square(RMS)criterion.The results show that mascon solutions estimated under different types of constraints are consistent and equivalent when the optimal regularization parameters are selected.The spatial distributions and main characteristics of regional surface mass anomalies estimated by the three types of constraints agree well,and the values of residual RMS with different constraints are very close.But due to the smoothing effect of regularization,the signal strength of mascon solutions is a bit weaker than that of original true signal,especially in the regions with strong signals.In addition,due to the ill-conditioned problem is more serious for higher grid resolution,the relative contribution of the three types of constraints to the final mascon solutions would be stronger.The results show that the averages of relative contribution percentages of these constraints for 2°×2° mascon grids are 80%-90%,while the corresponding values for 4°×4° mascon grids are 30%-60%.However,based on the minimum residual RMS criterion,the accuracy of estimation results is not affected by the type of constraints and their relative contribution to the final mascon solutions.

High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma

The role of autologous hematopoietic stem cell transplantation(auto-HSCT)following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma(DLBCL).However,its clinical efficacy as frontline therapy remains to be elucidated.This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients.We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone(year 2008-2014)from four hospitals.The median follow-up time was 29.4 months.Between the two treatment arms among the intermediate/high-risk DLBCL patients,the 3-year overall survival(OS)and progression-free survival(PFS)rates of patients given frontline auto-HSCT were 87.6%and 81.9%,respectively,and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9%and 59.59%,respectively.Compared with the chemotherapy-alone group,the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell(GCB)type.In addition,in the frontline auto-HSCT group,patients who achieved complete response(CR)at auto-HSCT had a longer survival time than those who did not achieve CR.Our results suggested that frontline auto-HSCT could improve the prognosis of intennediate/high-risk DLBCL patients.

Identification of candidate genes that regulate the trade-off between seedling cold tolerance and fruit quality in melon (Cucumis melo L.)

Trade-offs between survival and growth are widely observed in plants.Melon is an annual,trailing herb that produces economically valuable fruits that are traditionally cultivated in early spring in China.Melon seedlings are sensitive to low temperatures,and thus usually suffer from cold stress during the early growth period.However,little is known about the mechanism behind the trade-offs between seedling cold tolerance and fruit quality in melon.In this study,a total of 31 primary metabolites were detected from the mature fruits of eight melon lines that differ with respect to seedling cold tolerance;these included 12 amino acids,10 organic acids,and 9 soluble sugars.Our results showed that concentrations of most of the primary metabolites in the cold-resistant melons were generally lower than in the cold-sensitive melons;the greatest difference in metabolite levels was observed between the cold-resistant line H581 and the moderately cold-resistant line HH09.The metabolite and transcriptome data for these two lines were then subjected to weighted correlation network analysis,resulting in the identification of five key candidate genes underlying the balancing between seedling cold tolerance and fruit quality.Among these genes,CmEAF7 might play multiple roles in regulating chloroplast development,photosynthesis,and the ABA pathway.Furthermore,multi-method functional analysis showed that CmEAF7 can certainly improve both seedling cold tolerance and fruit quality in melon.Our study identified an agriculturally important gene,CmEAF7,and provides a new insight into breeding methods to develop melon cultivars with seedling cold tolerance and high fruit quality.

Spatial-temporal characteristics of the coupling coordination of social security and economic development in China during 2002–2018

Clarifying the relationship between social security and economic development is helpful to realize the sustainable social security system and the stable function of sustainable economic development.In this paper,the entropy method,coupling coordination degree,standard deviation ellipse model,and spatial autocorrelation were used to study the spatial-temporal characteristics of coupling coordination of social security and economic development in China from 2002 to 2018.The results indicate that the relationship between social security and economic development in China has been gradually strengthened in the process of mutual adaptation and common development.The benign interaction between the two was unstable,though the coupling coordination degree gradually transitioned to the primary coupling coordination type.Besides,from a spatial perspective,first,the coupling coordination degree of social security and economic development in China contracted in the east-west and north-south directions,and the coupling coordination clustered in the central region in this period;second,the coupling coordination degree generally presented a positive spatial autocorrelation,and regions with similar coupling coordination degrees were in a state of agglomeration;finally,the hot spots clumped together to form a continuous area in the eastern coastal area while the cold spots expanded toward the northwest and northeast.Furthermore,the random distribution areas exhibited a trend of contraction.

Clean-energy utilization technology in the transformation of existing urban residences in China

Clean-energy substitution technology for existing residential buildings in cities is an inevitable choice for sustainable development and low-carbon ecological city construction.In this paper,the current status of energy-saving renovation and renewable-energy applications for existing residential buildings in various cities in China was summarized by using statistical methods.The geographical distribution of clean-energy power generation in primary energy production in China was explored in depth.According to different climatic divisions for existing urban residences,clean-energy production and consumption were analyzed and predicted based on the STIRPAT model.The results show that the energy consumption of urban residential buildings in 2016 increased by 43.6%compared with 2009,and the percentage of clean energy also increased from 7.9%to 13.4%.Different climatic regions have different advantages regarding clean energy:nuclear power generation leads in the region that experiences hot summers and warm winters,whereas wind and solar power generation lead in the cold and severely cold regions.The present results provide basic data support for the planning and implementation of clean-energy upgrading and transformation systems in existing urban residences in China.

Cloud computing-enabled IIOT system for neurosurgical simulation using augmented reality data acces

In recent years,statistics have indicated that the number of patients with malignant brain tumors has increased sharply.However,most surgeons still perform surgical training using the traditional autopsy and prosthesis model,which encounters many problems,such as insufficient corpse resources,low efficiency,and high cost.With the advent of the 5G era,a wide range of Industrial Internet of Things(IIOT)applications have been developed.Virtual Reality(VR)and Augmented Reality(AR)technologies that emerged with 5G are developing rapidly for intelligent medical training.To address the challenges encountered during neurosurgery training,and combining with cloud computing,in this paper,a highly immersive AR-based brain tumor neurosurgery remote collaborative virtual surgery training system is developed,in which a VR simulator is embedded.The system enables real-time remote surgery training interaction through 5G transmission.Six experts and 18 novices were invited to participate in the experiment to verify the system.Subsequently,the two simulators were evaluated using face and construction validation methods.The results obtained by training the novices 50 times were further analyzed using the Learning Curve-Cumulative Sum(LC-CUSUM)evaluation method to validate the effectiveness of the two simulators.The results of the face and content validation demonstrated that the AR simulator in the system was superior to the VR simulator in terms of vision and scene authenticity,and had a better effect on the improvement of surgical skills.Moreover,the surgical training scheme proposed in this paper is effective,and the remote collaborative training effect of the system is ideal.

Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

An Analysis of the Patents concerning Hevea brasiliensis

This paper mainly analyzes the application data of patents concerning Hevea brasiliensis in the world and China from the perspectives of time,research field,and the geographical distribution of applicants. It also interprets the patents for invention in China from time,research field,and types of applicants. Based on the study,it shows that although the patent applications fluctuate,the general trend is rising. And the patents are mostly concentrated in plant protection,and agricultural biotechnology. The Chinese applicants of patents for invention largely work in the research institutes,and most of these patents focus on the field of plant protection,agricultural biotechnology,and agro-processing.However,the foreign applicants mainly work in companies,and most of these patents only focus on plant protection. These findings will provide a reference for formulating development policies about natural rubber industry in China.

Application of artificial intelligence in liver diseases: From diagnosis to treatment

Infectious or noninfectious liver disease has inexorably risen as one of the leading causes of global death and disease burden.There were an estimated 2.14 million liver-related deaths in 2017,representing an 11.4%increase since 2012.Traditional diagnosis and treatment methods have various dilemmas in different causes of liver disease.As a hot research topic in recent years,the application of artificial intelligence(AI)in different fields has attracted extensive attention,and new technologies have brought more ideas for the diagnosis and treatment of some liver diseases.Machine learning(ML)is the core of AI and the basic way to make a computer intelligent.ML technology has many potential uses in hepatology,ranging from exploring new noninvasive means to predict or diagnose different liver diseases to automated image analysis.The application of ML in liver diseases can help clinical staff to diagnose and treat different liver diseases quickly,accurately and scientifically,which is of importance for reducing the incidence and mortality of liver diseases,reducing medical errors,and promoting the development of medicine.This paper reviews the application and prospects of AI in liver diseases,and aims to improve clinicians’awareness of the importance of AI in the diagnosis and treatment of liver diseases.

The MtRGF6 Peptide Differentially Regulates Root Development and Symbiotic Nodulation of Medicago truncatula and Lotus japonicus

Rhizobia induces nitrogen-fixing nodules in legumes used in agricultural production,providing a direct source of combined nitrogen to leguminous crops.Small peptides,such as CLAVATA3/EMBRYO SURROUNDING REGION peptides(CLE),are known to regulate the formation and development of nitrogen-fixing nodules in legumes.Root meristem growth factor(RGF)peptides from Medicago truncatula not only regulate root develop-ment but also modulate nodulation symbiosis with Sinorhizobium meliloti.However,the impact of RGF peptides from one leguminous species on the others remains unclear.In this study,we investigate the effects of the RGF family peptide MtRGF6p from M.truncatula on nodulation symbiosis and root development in Lotus japonicus.The MtRGF6 gene is predominantly expressed in the root nodules of M.truncatula and shows low identity with RGF homologous genes from L.japonicus.The gene promoter is active in the primordia of root nodules and lat-eral roots,as well as in young nodules and roots,and the meristem,infection,and nitrogen-fixing regions of the mature nodule.Chemically synthesized MtRGF6p promoted primary root growth in M.truncatula but sup-pressed the growth of L.japonicus primary roots.The peptide negatively affected the initiation of nodule primor-dia,the formation of infection threads,and nodulation in both legumes,with a low dosage showing effects on L.japonicus compared to M.truncatula.These results suggest that the MtRGF6 peptide from M.truncatula may serve as an inter-species signal affecting the root organ development of L.japonicus.

Simulation Analysis of CO Concentration Distribution in Beijing Yuntong Tunnel

In this paper, the concentration distribution of CO emitted by motor vehicles in Beijing Yuntong Tunnel is simulated and analyzed based on Fluent numerical simulation software. Firstly, the physical model of tunnel geometry is established. Secondly, the suitable control equations and boundary conditions are selected to describe the diffusion distribution of pollutants in the tunnel. At the same time, the reliability of the model is verified according to the measured data, and the distribution law of CO concentration in the tunnel is observed through the simulation results. The tunnel is unorganized at the entrance of the tunnel. In the simulation results, the CO concentration at the entrance of the tunnel is far more than the CO unorganized emission limit in Beijing. The CO emission of the tunnel should be purified to prevent pollution of the urban environment.

Snyder希望理论结合医护一体化精细化护理对结直肠癌术后患者的影响

目的 分析应用Snyder希望理论结合医护一体化精细化护理对结直肠癌术后患者疼痛评分及生活质量的影响。方法 选取2021年1月至2022年12月温州医科大学附属第一医院收治的92例结直肠癌(colorectal cancer,CRC)患者作为研究对象,分为对照组与研究组,每组各46例。对照组采用常规护理,研究组采用Snyder希望理论结合医护一体化精细化护理,采用焦虑自评量表(Self-Rating Anxiety Scale,SAS)、抑郁自评量表(Self-Rating Depression Scale,SDS)评估患者心理状态,采用数字等级评分法(Numerical Rating Scale,NRS)评估患者疼痛程度,采用Herth希望量表(Herth Hope Scale,HHI)评估患者希望水平,采用简明健康问卷(SF-36)评估患者生活质量,比较两组心理状态、疼痛程度、生活质量、希望水平及护理满意度。结果 研究组护理后SAS评分、SDS评分较对照组低(P <0.001);研究组术后1 d、术后3 d、术后5 d及术后7 d NRS评分较对照组低(P <0.05);研究组护理后采取积极行动、与他人保持亲密关系、对现实及未来积极态度评分较对照组高(P <0.001);研究组护理后SF-36各项评分较对照组高(P <0.05);研究组满意率较对照组高(95.65%vs. 76.09%,P <0.05)。结论结直肠术后患者应用Snyder希望理论结合医护一体化精细化护理,有利于减轻疼痛度,促进生活质量提高,可改善患者心理状态,提高患者希望水平,并促进满意度提高。

清热调血汤加减联合缩宫素治疗湿热瘀阻型产后恶露不绝临床观察

目的观察清热调血汤加减联合缩宫素对湿热瘀阻型产后恶露不绝的临床疗效,及对患者贫血和凝血功能指标的影响。方法110例湿热瘀阻型产后恶露不绝患者随机分为试验组(清热调血汤加减联合缩宫素)和对照组(单用缩宫素)各55例,疗程7 d。比较两组患者治疗后临床总有效率、恶露排净时间,以及治疗前后中医证候积分、子宫三径之和、红细胞压积、血红蛋白、血纤维蛋白原和D-二聚体水平等指标变化;记录治疗期间两组药品不良反应发生率。结果试验组临床总有效率明显高于对照组,恶露排净时间明显短于对照组(P<0.05)。治疗后,两组患者各项中医证候评分的例数分布均较前明显改善,总积分明显下降(P<0.01);血红蛋白和红细胞压积较前明显升高,血纤维蛋白原和D-二聚体水平以及子宫三径之和较前明显降低(P<0.01);且试验组上述各项指标均优于对照组(P<0.01)。两组药品不良反应发生率差异无统计学意义(P>0.05)。结论清热调血汤加减与缩宫素联合使用可进一步改善湿热瘀阻型产后恶露不绝患者的临床症状,促进产后子宫恢复,纠正贫血症状和血液高凝状态,疗效显著且不增加患者用药安全风险。

GPC3在肝癌诊治中的研究进展

磷脂酰肌醇蛋白聚糖3(glypican3,GPC3)是一种包含硫酸乙酰肝素(heparan sulfate,HS)链和核心蛋白的细胞表面糖蛋白,通过磷脂酰肌醇锚(glycosylphosphatidylinositol,GPI)连接于细胞表面,与多种肿瘤的发生发展密切相关,对肿瘤细胞的增殖、凋亡及侵袭转移有着重要的调控作用。GPC3在肝细胞癌(hepatocellular carcinoma,HCC)中高表达,且可以通过影响Wnt和YAP等信号通路控制HCC细胞的增殖,进而影响肿瘤的生长和转移。临床上GPC3已被用于HCC的诊断,靶向GPC3的治疗研究包括靶向抗体、免疫毒素、细胞免疫和基因治疗也正在开展。本文将阐述GPC3的结构以及在HCC发生发展中的作用,对GPC3在HCC中的诊断应用和以其为靶点的免疫疗法和基因疗法的研究进展进行综述,为GPC3用于治疗HCC提供证据和新方向。

Genome-wide association study of berryrelated traits in grape[Vitis vinifera L.]based on genotyping-by-sequencing markers

Deciphering the genetic control of grape berry traits is crucial for optimizing yield,fruit quality,and consumer acceptability.In this study,an association panel of 179 grape genotypes comprising a mixture of ancient cultivars,landraces,and modern varieties collected worldwide were genotyped with genotyping-by-sequencing using a genome-wide association approach based on 32,311 single-nucleotide polymorphism(SNP)markers.Genome-wide efficient mixed-model association was selected as the optimal statistical model based on the results of known control loci of grape berry color traits.Many of the associated SNPs identified in this study were in accordance with the previous QTL analyses using biparental mapping.The grape skin color locus was found to be associated with a mybA transcription factor on chromosome 2.Two strong and distinct association signals associated with berry development periods were found on chromosome 16.Most candidate genes of the interval were highlighted as receptor-like protein kinase.For berry weight,significant association loci were identified on chromosome 18,as previously known,and on chromosome 19 and chromosome 17,as newly mapped.Berry flesh texture was newly located on chromosome 16;candidate genes in the interval were related to calcium.Berry flavor was determined on chromosome 5.Genomic regions were further investigated to reveal candidate genes.In this work,we identified interesting genetic determinants of grape berry-related traits.The identification of the markers closely associated with these berry traits may be useful for grape molecular breeding.

GRACE-based estimates of water discharge over the Yellow River basin

As critical component of hydrologic cycle, basin discharge is a key issue for understanding the hydrological and climatologic related to water and energy cycles. Combining GRACE gravity field models with ET from GLDAS models and precipitation from GPCP, discharge of the Yellow River basin are estimated from the water balance equation. While comparing the results with discharge from GLDAS model and in situ measurements, the results reveal that discharge from Mosaic and CLM GLDAS model can partially represent the river discharge and the discharge estimation from water balance equation could reflect the discharge from precipitation over the Yellow River basin.

Comparison of prognostic factors in different age groups and prognostic significance of neutrophil-lymphocyte ratio in patients with gastric cancer

BACKGROUND Gastric cancer(GC)is one of the most common malignant tumors in the world.Although in recent years tremendous progress has been made in its early detection,the postoperative overall survival(OS)of GC patients remains extremely low.A number of studies have shown that age,to varying degrees,affects the prognosis of patients with GC.Therefore,this study retrospectively analyzed the clinical and pathologic data of patients with GC to explore the differences in the clinical characteristics and prognostic factors in different age groups.AIM To explore the difference in clinicopathological characteristics and prognostic factors in GC patients in different age groups.METHODS In this retrospective study,we analyzed 1037 GC patients admitted to Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 2010 to January 2013.The patients were divided into two groups based on age:Younger group(less than 70 years old)and older group(no less than 70 years old).In the younger group,we subdivided the patients in two subgroups by a cutoff value of 45 years.The clinical features and prognostic factors were analyzed in both groups.Subsequently,we retrieved studies that evaluated the predictive role of neutrophil-lymphocyte ratio(NLR)by searching two medical databases,PubMed and EMBASE,to conduct a meta-analysis.Random-effects model was used to pool the data.RESULTS In the retrospective study,the mean OS time of the younger group(64.7 mo)was significantly longer than that of the older group(48.1 mo)(P<0.001).Among patients under 70 years of age,hospitalization time,tumor–node–metastasis(TNM)stage,vascular invasion,and preoperative low pre-albumin were independently associated with OS(P<0.005).In patients aged 70 years and above,TNM stage,esophageal invasion,histological type,and preoperative NLR were independent factors for OS(P<0.05).The OS of these older patients was also significantly shorter(P<0.05).In the meta-analysis,19 retrieved studies included a total of 8312 patients,among whom 3558 had elevated NLR values.The results showed that high NLR value was a risk factor for the prognosis of GC(P<0.01).CONCLUSION The OS of elderly patients is significantly worse than that of younger patients.There are significant differences in clinicopathological characteristics and prognostic factors between younger and older patients.NLR is a convenient,inexpensive,and reproducible marker that can be used as an important predictor of the prognosis of GC.

Monoterpenoid Indole Alkaloids from Inadequately Dried Leaves of Alstonia scholaris

Six new indole alkaloids,named alstoniascholarines L–Q(1–6),together with nineteen known analogues were isolated from the inadequately dried leaves of Alstonia scholaris.Their structures were elucidated on the basis of extensive analysis of spectroscopic data and by comparison of their physical and spectroscopic data with the literature values.In addition,the new alkaloids were tested for their cytotoxic and neurite outgrowth-promoting activities.