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Abstract Background Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. Methods High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. Results PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. Conclusions PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer.

Abstract Current research indicate that inflammation is linked to the development of overactive bladder (OAB). The aim of this study was to examine the correlation between OAB and the systemic immunity-inflammation index (SII) in the USA. We analyzed data from 31,881 participants in the National Health and Nutrition Examination Survey 2005–2018. SII, calculated as platelet count × neutrophil count/lymphocyte count, was categorized into quartiles. OAB was defined by the presence of urge urinary incontinence and nocturia. Weighted logistic regression models were used to examine the independent relationship between SII and OAB, adjusting for demographic factors, kidney function, and diabetes status. The results showed that each tenfold increase in log-transformed SII was associated with an 18% higher odds of OAB (OR 1.18, 95% CI 1.08–1.28) in the fully adjusted model. Compared to the lowest SII quartile, the highest quartile had a 28% increased OAB risk (OR 1.28, 95% CI 1.12–1.47). The positive association between SII and OAB risk was consistently observed across subgroups stratified by age, sex, race, marital status, education, and poverty level. Our study reveals a positive correlation between SII levels and OAB, indicating that higher SII levels are associated with an increased likelihood of developing OAB.

Abstract Background Long noncoding RNAs (lncRNAs) are RNA transcripts over 200 nucleotides in length that do not code for proteins. Initially considered a genomic mystery, an increasing number of lncRNAs have been shown to have vital roles in physiological and pathological conditions by regulating gene expression through diverse mechanisms depending on their subcellular localization. Dysregulated angiogenesis is responsible for various vascular oculopathies, including diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and corneal neovascularization. While anti-VEGF treatment is available, it is not curative, and long-term outcomes are suboptimal, and some patients are unresponsive. Results and summary To better understand these diseases, researchers have investigated the role of lncRNAs in regulating angiogenesis and models of vascular oculopathies. This review summarizes recent research on lncRNAs in ocular angiogenesis, including the pro-angiogenic lncRNAs ANRIL, HOTAIR, HOTTIP, H19, IPW, MALAT1, MIAT, NEAT1, and TUG1, the anti-angiogenic lncRNAs MEG3 and PKNY, and the human/primate specific lncRNAs lncEGFL7OS, discussing their functions and mechanisms of action in vascular oculopathies.

Abstract Objective This study aimed to investigate the relationship between drinking status and kidney stones occurrence among United States (US) adults who consume alcohol. Methods We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES 2007–2018). Questionnaires yielded information on alcohol consumption and kidney health. Drinking status was categorized into four groups—former, mild, moderate, and heavy—based on alcohol consumption patterns. The aim was to explore the relationship between drinking status and the prevalence of kidney stones occurrence. For this analysis, we examined a group of individuals diagnosed with kidney stones. With survey weights applied, the total weight of the group was 185,690,415. Results We used logistic regression to measure the relationship between drinking status and the likelihood of developing kidney stones. In a fully adjusted model, former drinkers were less likely to have previously experienced kidney stones (OR 0.762, 95% CI 0.595–0.977, P

Objective: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. Methods: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone

Abstract Background Numerous studies have shown that the dietary inflammatory index (DII) is associated with adverse health effects. However, the relationship between DII and prostate cancer (PCa) remains controversial. Although alcohol is included in DII as a dietary factor, the various adverse health effects of alcohol consumption are not only related to inflammation. On the other hand, it has been a long-standing debate whether alcohol consumption is linked to the risk of PCa. Therefore, to clarify whether drinking affects the relationship between DII and PCa, we evaluated the correlation between DII and prostate-specific antigen (PSA) based on the National Health and Nutrition Examination Survey (NHANES) database. Methods We used data from the NHANES spanning from 2005 to 2010 to analyze the relationship between PCa and DII. Out of the 31,034 NHANES participants, we enrolled 4,120 individuals in our study, utilizing dietary intake data from a twenty-four-hour period to determine DII scores. Demographic data, physical and laboratory test results were collected to compare between low PSA and high PSA groups, and to calculate the odds ratio between both groups, we employed a logistic regression analysis. Results In this cross-sectional investigation of PCa, drinkers and non-drinkers had different relationships between DII and PSA levels (OR: 1.2, 95% Cl: 1-1.44 vs. OR: 0.98, 95% Cl: 0.9–1.07), and DII and abstaining from alcohol were effective in reducing the incidence of PSA (p-value for significant interaction = 0.037). Conclusion The results of our study suggest that drinking may influence the relationship between DII and PSA levels. DII is likely to be a reliable indicator for estimating PSA levels among non-drinkers, who may limit their intake of pro-inflammatory ingredients to lower the incidence and death of PCa.

Investigating the mathematical and geometric principles embedded in ancient classic architecture is a significant tradition in the history of architectural development. Drawing inspiration from the modular design and creative ideology based on the geometric proportions of squareness and roundness in ancient Chinese architecture, we propose a new mode of squareness and roundness composition based on scale proportion specifically for the design of multi-story buildings. Taking Yingxian Wooden Pagoda as the case study, we not only re-evaluate the modular system and proportional rules followed in the design of the entire pagoda, but also reveal the technical approaches and geometric rules for effectively controlling the form of multi-story buildings. In particular, the mode of squareness and roundness composition based on scale proportion, utilizing a modular grid combined with squareness and roundness drawings as decision-making tools, can control the scale and proportion of buildings across different design dimensions and organically coordinate the design of multi-story buildings’ plans and elevations. Thus, it can achieve an effective balance of multi-story architectural forms. This study has potential applications in the creation of traditional multi-story buildings and heritage restoration projects, and offers valuable insights for future research on ancient multi-story buildings.

ABSTRACT Background: This study aimed to explore the prevalence and clinical risk factors in patients diagnosed with incidental prostate cancer (IPC) during certain surgeries (transurethral resection of the prostate [TURP], open prostatectomy [OP], and holmium laser enucleation of the prostate [HoLEP]) after clinically suspected benign prostatic hyperplasia (BPH). Materials and Methods: Literature search of the MEDILINE, Web of Science, Embase, and Cochrane Library databases was performed to identify eligible studies published before June 2021. Multivariate adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) of the prevalence and clinical risk factors of IPC were calculated using random or fixed-effect models. Results: Twenty-three studies were included in the meta-analysis. Amongst the 94.783 patients, IPC was detected in 24.715 (26.1%). Results showed that the chance of IPC detection (10%, 95% CI: 0.07-4.00; P

Oxidative stress is hypothesized to drive the progression of age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cell layer is important for supporting the function of retina and is particularly susceptible to oxidative stress-induced cell death. How RPE cells die in AMD, especially in geographic atrophy (GA), a late stage of dry AMD, is still controversial. The goal of this study is to compare the features and mechanisms of RPE cell death induced by different oxidative stresses, to identify potential universal therapeutic targets for GA. RPE cell death was induced both in vitro and ex vivo by 4-Hydroxynonenal (4-HNE), a major product of lipid peroxidation, sodium iodate (NaIO3) that has been widely used to model RPE cell death in dry AMD, a ferroptosis inducer RAS-selective lethal 3 (RSL3) or a necroptosis inducer shikonin. We found that RPE necroptosis and ferroptosis show common and distinct features. Common features include receptor-interacting protein kinase (RIPK)1/RIPK3 activation and lipid reactive oxygen species (ROS) accumulation, although lipid ROS accumulation is much milder during necroptosis. This supports cross talk between RPE ferroptosis and necroptosis pathways and is consistent with the rescue of RPE necroptosis and ferroptosis by RIPK1 inhibitor Necrostatin-1 (Nec-1) or in Ripk3−/− RPE explants. Distinct feature includes activated mixed lineage kinase domain like pseudokinase (MLKL) that is translocated to the cell membrane during necroptosis, which is not happening in ferroptosis. This is consistent with the failure to rescue RPE ferroptosis by MLKL inhibitor necrosulfonamide (NSA) or in Mlkl−/− RPE explants. Using this framework, we found that 4-HNE and NaIO3 induced RPE cell death likely through necroptosis based on the molecular features and the rescuing effect by multiple inhibitors. Our studies suggest that multiple markers and inhibitors are required to distinguish RPE necroptosis and ferroptosis, and that necroptosis inhibitor Nec-1 could be a potential therapeutic compound for GA since it inhibits RIPK1/RIPK3 activation and lipid ROS accumulation occurred in both necroptosis and ferroptosis pathways.

Paratesticular liposarcoma (PLS) causes scrotal mass changes, rarely in the urinary system. Before surgery, PLS causes scrotal mass changes that are difficult to distinguish from other causes. There has been a report of a giant paratestis liposarcoma resection and refusal to undergo orchiectomy. A 65-year-old man presented with finding the left scrotal mass after 2 years. Physical examination showed that the left scrotal mass was obviously difficult to retract. Pelvic CT showed that the left scrotal mass and flaky fat density shadow accompanied with left inguinal hernia. During surgery, laparoscopic exploration was performed to rule out inguinal hernia, and a scrotal exploration was also performed concurrently. The intraoperative frozen pathology considered lipogenic tumor, and the patient’s wife refused to undergo simultaneous left radical orchiectomy. Later the mass was completely removed, and postoperative pathology confirmed paratestis liposarcoma. During a 15-month routine follow-up, the tumor did not recur locally or metastasize distantly. PLS should be focused on early diagnosis and treatment, preoperative examinations and postoperative pathology should be combined, and highly personalized treatment will be implemented.

Purpose: To investigated the association between serum total testosterone and Gleason score upgrading of low-risk prostate cancer after radical prostatectomy (RP). Materials and Methods: Medline, Web of Science, Embase, and Cochrane Library databases were searched to identify eligible studies published before October 2021. Multivariate adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated using random or fixed effects models. Results: Five studies comprising 1,203 low-risk prostate cancer patients were included. The results showed that low serum total testosterone (

BackgroundPostpartum depression has a crucial impact on the physical and psychological comfort and the work of postnatal women, the growth and development of infants and mental health in adulthood. Finding a safe and effective anti-postnatal depression drug is currently an important research goal in this field.MethodsIn this study, the forced swimming test (FST) and tail suspension test (TST) were used to evaluated the depressive behaviors of mice, and the changes of metabolites and intestinal microflora in mice with postpartum depression were examined through non-target metabolomics and 16S RNA sequencing respectively.ResultsWe found that traditional Chinese medicine compound 919 Syrup could alleviate postpartum depression in mice and inhibit the elevated erucamide level in depressive hippocampus. However, mice treated with antibiotics were not sensitive to the anti-postnatal depression effect of 919 Syrup, and the level of 5-aminovaleric acid betaine (5-AVAB) in their hippocampus was significantly decreased. Transplanting fecal microflora treated with 919 Syrup could effectively improve the depressive behaviors of mice, upregulate the level of gut-derived 5-AVAB in the hippocampus, and downregulate the level of erucamide. Erucamide was significantly negatively correlated with increased Bacteroides in intestine after 919 Syrup treatment or fecal transplantation, and significantly positively correlated with Ruminococcaceae UCG-014 which was increased in feces of mice with postpartum depression. The increase of Bacteroides, Lactobacillus, and Ruminiclostridium in intestine after fecal transplantation had a clearly positive correlation with 5-AVAB.ConclusionIn brief, 919 Syrup may downregulate the ratio of hippocampal metabolites erucamide to 5-AVAB by regulating intestinal flora to alleviate postpartum depression, laying a scientific foundation for future pathological research and development of therapeutic drugs for postpartum depression.

IntroductionUrban cultural heritage sites bear the cultural functions of a city, hold spiritual and cultural value, can recall emotional memories, and serve the cultural leisure activities of the residents. Urban cultural heritage sites can help citizens perceive a sense of belonging and a feeling of relaxation, but whether and to what extent cultural heritage sites affect mental health remains unknown.MethodsBased on attention restoration theory, multiple research methods are adopted in this study to examine the impact of cultural heritage on human restorative mechanisms. Five representative cultural heritage sites from the cultural heritage-rich city of Xi'an are selected as the research object. In addition, a questionnaire survey and physiological experiments are conducted. Perceived restorative scale, skin conductance response, heart rate variability, and eye movement data while viewing photographs of the cases are collected from the participants.ResultsResults show that cultural heritage sites have psychophysiological restorative effects, which are especially significant in the fascination dimension. Moreover, historical buildings can promote the restorative effects of cultural heritage sites.DiscussionThis finding may lead to new conservation and innovation planning strategies considering the mental health effects of cultural heritage.

Abstract With the development of modern tokamak devices, the magnetic interference problem has become increasingly serious. On considering the International Thermonuclear Experimental Reactor (ITER), for example, the stray magnetic field around the tokamak device will be over 200 mT. To ensure the reliable operation of the electrical and electronic equipment installed around the tokamak, the magnetic immunity test becomes a mandatory requirement. Generally, a set of coils is employed to realize the required test field. Since the coil power loss and conductor mass are proportional to the dimension and intensity of the test field, optimization design is of great significance. This paper presents the multi‐objective optimization design of a large‐scale high‐intensity homogeneous magnetic field coil system. The analytical model of the multi‐coil system is proposed, and the constrained multi‐objective optimization model is established based on the non‐dominated sorting genetic algorithm. Taking the ITER test coil as an example, the optimization design is performed and the Pareto‐front is figured out. The designed four‐coil system enables the magnetic field immunity tests for equipment within 1 m side‐length at a highest test level of 275 mT with a magnetic field inhomogeneity of 1.05. The validity of the proposed model is verified by the finite element analysis and experimental tests.

The genus Rhododendron is known for its preference for acidic soils, although some genotypes can tolerate a more neutral or alkaline pH. In this study, a greenhouse experiment was set up for 140 days to examine different parameters to assess pH stress in the progeny of R. fortunei and the cross combination R. ‘Pink Purple Dream’ x ‘Belami’. Additional cultivars ‘Gomer Waterer’ and ‘Cunningham’s White’ were included in the greenhouse test. The plants were divided into two groups. One group was planted in a substrate with a neutral pH (treatment, pH 6.3) and the other group of plants was planted in an acidic pH substrate (control, pH 4.5). Tolerance to pH stress was evaluated for the individual genotypes on both substrates 140 days after the start of the experiment. The following parameters were analyzed: shoot length, root development, chlorophyll fluorescence (Fv/Fm), leaf color and weight (fresh and dry). In intolerant genotypes, all parameters except for number of shoots were negatively affected by pH stress; especially, the development of roots was negatively impacted by the neutral pH, resulting in above-ground symptoms of pH stress, including decreased height and lower fresh and dry weight. The results show variation in pH tolerance within the genotypes tested and point to the potential for the selection of Rhododendron genotypes with improved tolerance to neutral pH.

Purpose: This study aimed to explore the prevalence and predictors of incidental prostate cancer (IPC) after transurethral resection of the prostate (TURP) with negative results on transperineal magnetic resonance imaging (MRI)/transrectal ultrasonography (TRUS) fusion prostate biopsy or TRUS-guided prostate biopsy. Materials and Methods: Data of 253 patients who underwent TURP with a preliminary diagnosis of benign prostatic hyperplasia (BPH) were evaluated. The prevalence of IPC was calculated. Univariate and multivariate logistic regression analyses were conducted to explore independent predictive factors of IPC. Results: A total of 253 patients were included. IPC was diagnosed in 12 patients (4.7%). The mean age of the patients and the mean prostate volume were 69.8±7.07 years and 89.3±49.29 mL, respectively. The prevalence of IPC was higher in the TRUS guided prostate biopsy group than in the transperineal MRI/TRUS fusion prostate biopsy group (11 of 203 [5.4%] vs. 1 of 50 [2.0%], p=0.47), but the difference was not statistically significant. Our results indicated that older age (≥70 y) (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.02–1.27; p=0.025) and smaller prostate volume (OR, 0.97; 95% CI, 0.938–0.998; p=0.039) were associated with an increased incidence of IPC after TURP. Conclusions: Our findings indicate that the prevalence of IPC may be higher among patients who undergo transrectal prostate biopsy before TURP than among those who undergo transperineal MRI/TRUS fusion prostate biopsy. Older age and smaller prostate volume were independent predictors of increasing the risk for IPC after TURP.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

ABSTRACT Background: Periodontal disease is reportedly associated with the risk of various systemic diseases, including pancreatic and lung cancers. However, its association with prostate cancer remains inconclusive. Herein, we explored the association of periodontal disease with the risk of prostate cancer through a meta-analysis. Materials and Methods: MEDLINE, Embase, Web of Sciences and Cochrane Library databases were searched for eligible publications up to April 2020. Multivariate adjusted risk estimates with corresponding 95% confidence intervals (CIs) were extracted and calculated using random- or fixed-effect models. Results: Nine cohort studies involving 3.353 prostate cancer cases with 440.911 participants were identified and included in the meta-analysis. We found that periodontal disease significantly increased the risk of prostate cancer by 1.40-fold (hazard ratio [HR]=1.40, 95% CI: 1.16-1.70; P=0.001; I2=76.1%) compared with normal condition. Interestingly, the risk of developing prostate cancer was not significant in patients treated with periodontal therapy (HR=1.22, 95% CI: 0.86-1.73; P=0.272; I2=65.2%). The results of subgroup analyses were also consistent and significant when stratified by study design and follow-up period, whereas conflicting results were observed in periodontal disease ascertainment stratification. These findings were robust as indicated by sensitivity analyses. Conclusions: Periodontal disease was associated with the increased risk of prostate cancer, whereas no significant association was observed in patients treated with periodontal therapy. Hence, the awareness and importance for maintaining oral health should be improved, and the underlying mechanisms linking periodontal disease and prostate cancer should be fully explored in future research.

With rapid urbanization, contradictions between rapid economic development and a lack of spiritual culture become increasingly complicated. Accessibility is a useful spatial quantitative index to evaluate the spiritual and cultural construction of the city. Amongst various accessibility methods, the two-step floating catchment area (2SFCA) method is suitable for evaluating cultural urban land use (CULU) based on its advantage of flexibility and rationality. This study selects Xi'an as the representative ancient city. Based on comparing accessibility results between different travel modes (walk, bus, subway, and total), and analyzing through statistics, Z-score, and comparison of classification, comparison of a particular area, we obtain the characteristics of CULU accessibility in Xi'an. Firstly, for different travel modes, the distribution of CULU accessibility value in Xi'an is imbalanced, and the accessibility value of bus and subway is closely related to public transport resources. Secondly, CULU in Xi'an has apparent features of being dense in the center, sparse in the suburbs, and lack edge, which correspond to the development of the city. Finally, about 60% accessibility value is contributed by historical CULU, which reflects the typical characteristics of Xi'an as an ancient city with rich historical resources. This study profoundly analyses the attributes of CULU in Xi'an and provides essential data for decision-makers. Furthermore, it gives a significant exploration for building a CULU evaluation system in the future.

This study used a structural equation modeling approach to investigate the relationships among L2 writing anxiety, L2 writing self-efficacy, L2 writing self-regulated strategies and L2 writing engagement, and possible mediators that regulate the effect of individual factors. A questionnaire was administered to 340 Chinese high school students from different parts of the country. The results of the study suggested a negative relationship between L2 writing anxiety and L2 writing self-efficacy, and a direct effect of both on L2 writing engagement. While a higher level of L2 writing self-efficacy indicated a lower level of L2 writing anxiety and more students’ L2 writing engagement, L2 writing efficacy had a much stronger direct effect on L2 writing engagement than L2 writing anxiety. In addition, L2 writing self-regulated strategies were found to play a mediating role between L2 writing self-efficacy and L2 writing engagement, but not between L2 writing anxiety and L2 writing engagement. This study helps to understand the interplay of individual factors related to L2 writing and sheds light on promoting English writing abilities of Chinese high school students.

IntroductionThe response mechanism of Rhododendron simsii and its endophytic microorganism to heat stress is still unclear.MethodsThe light incubator was used to set the temperature gradients, and the control (CK) was (day/night: 14/10 h) 25/22°C, the moderate-heat-stress (MHS) was 35/30°C and the high-heat-stress (HHS) was 40/35°C.ResultsCompared with CK, MHS significantly increased the contents of malondialdehyde, hydrogen peroxide, proline, and soluble sugar, as well as the activities of catalase and peroxidase in leaf, while HHS increased the activities of ascorbate peroxidase, and decreased chlorophyll content. Compared with CK, MHS reduced soil available nitrogen (N) content. Both heat stress changed the endophytic microbial community structure in roots. MHS enriched Pezicula and Paracoccus, while HHS significantly enriched Acidothermus and Haliangium. The abundance of Pezicula positively correlated with the contents of chlorophyll a and proline in leaf, and negatively correlated with soil ammonium N content. The abundance of Pezicula and Haliangium positively correlated with soluble sugar and malondialdehyde contents, respectively.ConclusionsOur results suggest that root endophytic microorganisms play an important role in helping Rhododendron resisting heat stress, mainly by regulating soil N content and plant physiological characteristics.

The relationship between Rhododendron simsii and its soil microbial community under heat stress was not clear. In this study, the effects of heat stress on the physiological characteristics, soil physicochemical properties and soil microbial community structure of R. simsii were investigated. The experimental control (CK) was set as day/night (14/10 h) 25/20°C and experimental treatments were set as light heat stress (LHS) 35/30°C and high heat stress (HHS) 40/35°C. Our results showed that, compared with CK, LHS treatment significantly increased malondialdehyde, hydrogen peroxide, proline and soluble sugar contents, as well as catalase and peroxidase activities, while HHS treatment significantly increased ascorbate peroxidase activity and decreased chlorophyll content. Compared with CK, LHS treatment significantly reduced soil ammonium-nitrogen and nitrate-nitrogen content, while HHS significantly increased soil ammonium-nitrogen content. Compared with CK, both treatments changed the soil microbial community structure. For bacterial community, LHS and HHS treatment resulting in the significant enrichment of Burkholderia-Caballeronia-Paraburkholderia and Occallatibacte, respectively. For fungal community, LHS treatment resulting in the significant enrichment of Candida, Mortierella and Boothiomyces. The redundancy analysis showed that plant physiological characteristics, soil ammonium-nitrogen content were significantly correlated with the soil microbial community. Therefore, heat stress altered the soil microbial community structure, and affected the availability of soil available nitrogen, which in turn affected the physiological characteristics of R. simsii. We suggest that soil microbial community may play an important role in plant resistance to heat stress, and its mechanism deserves further study.

Retinal pigment epithelial (RPE) cells form a monolayer between the neuroretina and choroid. It has multiple important functions, including acting as outer blood-retina barrier, maintaining the function of neuroretina and photoreceptors, participating in the visual cycle and regulating retinal immune response. Due to high oxidative stress environment, RPE cells are vulnerable to dysfunction, cellular senescence, and cell death, which underlies RPE aging and age-related diseases, including age-related macular degeneration (AMD). Mitochondria are the powerhouse of cells and a major source of cellular reactive oxygen species (ROS) that contribute to mitochondrial DNA damage, cell death, senescence, and age-related diseases. Mitochondria also undergo dynamic changes including fission/fusion, biogenesis and mitophagy for quality control in response to stresses. The role of mitochondria, especially mitochondrial dynamics, in RPE aging and age-related diseases, is still unclear. In this review, we summarize the current understanding of mitochondrial function, biogenesis and especially dynamics such as morphological changes and mitophagy in RPE aging and age-related RPE diseases, as well as in the biological processes of RPE cellular senescence and cell death. We also discuss the current preclinical and clinical research efforts to prevent or treat RPE degeneration by restoring mitochondrial function and dynamics.

Abstract Background Drought stress is the most harmful one among other abiotic stresses with negative impacts on crop growth and development. Drought-hardening is a feasible and widely used method in tobacco seedlings cultivation. It has gained extensive interests due to its role in improving drought tolerance. This research aimed to investigate the role of drought-hardening and to unravel the multiple mechanisms underlying tobacco drought tolerance and adaptation. Results This study was designed in which various drought-hardening treatments (CK (no drought-hardening), T1 (drought-hardening for 24 h), T2 (drought-hardening for 48 h), and T3 (drought-hardening for 72 h)) were applied to two tobacco varieties namely HongHuaDaJinYuan (H) and Yun Yan-100 (Y). The findings presented a complete framework of drought-hardening effect at physiological, biochemical, and gene expression levels of the two tobacco varieties under drought stress. The results showed that T2 and T3 significantly reduced the growth of the two varieties under drought stress. Similarly, among the various drought-hardening treatments, T3 improved both the enzymatic (POD, CAT, APX) and non-enzymatic (AsA) defense systems along with the elevated levels of proline and soluble sugar to mitigate the negative effects of oxidative damage and bringing osmoregulation in tobacco plants. Finally, the various drought-hardening treatments (T1, T2, and T3) showed differential regulation of genes expressed in the two varieties, while, particularly T3 drought-hardening treatment-induced drought tolerance via the expression of various stress-responsive genes by triggering the biosynthesis pathways of proline (P5CS1), polyamines (ADC2), ABA-dependent (SnRK2, AREB1), and independent pathways (DREB2B), and antioxidant defense-related genes (CAT, APX1, GR2) in response to drought stress. Conclusions Drought-hardening made significant contributions to drought tolerance and adaptation in two tobacco variety seedlings by reducing its growth and, on the other hand, by activating various defense mechanisms at biochemical and molecular levels. The findings of the study pointed out that drought-hardening is a fruitful strategy for conferring drought tolerance and adaptations in tobacco. It will be served as a useful method in the future to understand the drought tolerance and adaptation mechanisms of other plant species. Graphical abstract Drought-hardening improved drought tolerance and adaptation of the two tobacco varieties. T1 indicates drought-hardening for 24 h, T2 indicates drought-hardening for 48 h, T3 indicates drought-hardening for 72 h

Abstract Background Transurethral resection of the prostate (TURP) is the first choice for the treatment of benign prostatic hyperplasia. However, Transurethral split of prostate (TUSP) also seems to have clear clinical efficacy and clinical promotion value. To better clarify the potential and limitations of this treatment of prostate hyperplasia. This study objectively evaluated the clinical efficacy and safety of TUSP. Methods The Pubmed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Database for Chinese Technical Periodicals (VIP), Wanfang (Wanfang data), and SinoMed databases were searched for relevant studies. We then used Revman Manager 5.3 to perform a meta-analysis of all randomized controlled trials that evaluated the efficacy and safety of TUSP versus the classic surgical procedures commonly used in the clinic. Results A total of 7 studies involving 592 patients were included. The combined data showed that TUSP can shorten the operation time [MD: -33.68; 95% CI: − 38.45 to − 28.91; P

Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1.

ABSTRACT Purpose Several studies have demonstrated the strong correlation between the levels of preoperative serum total cholesterol (TC) and the survival of patients with surgically treated renal cell carcinoma (RCC). However, this association remains controversial. We performed a meta-analysis of published reports to evaluate the prognostic significance of the preoperative serum TC levels for patients with surgically treated RCC. Material and Methods The databases from MEDLINE (via PubMed), Embase, Web of Science and Cochrane Library were systematically searched to identify the eligible studies published before August 2019. Multivariate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated through inverse variance by using random-effects models. Results Nine cohort studies comprising 15.609 patients were identified. Low preoperative serum TC levels were associated with poor cancer-specific survival (CSS; HR=0.98, 95% CI: 0.97-0.99; P=0.005; I2=74.2%) and progression-free survival (PFS; HR=0.69, 95% CI: 0.49-0.98; P=0.036; I2=80%) in patients with surgically treated RCC. However, no significant association was observed between low preoperative serum TC levels and shorter overall survival (HR=0.93, 95% CI: 0.87-1.00; P=0.057; I2=86.2%). Sensitivity analyses validated the reliability and rationality of the results. Conclusions Preoperative serum TC level is an independent poor prognostic factor for patients with surgically treated RCC, with lower levels associated with worse CSS and PFS. Hence, this parameter may provide additional guidance in the selection of therapeutic strategies to improve prognosis, considering that cholesterol is a broadly applied routine marker in clinical practice.

Ecological security patterns are employed to characterize the health and integrity of an ecosystem. It is essential to achieve sustainable and high-quality development of cities and urban agglomerations and to enhance human well-being. Considering the Guanzhong Plain urban agglomeration as an example, this paper proposes a technical framework for the delineation of ecological security patterns at the urban agglomeration scale with the objective of protecting and restoring mountains-rivers-forests-farmlands-lakes-grasslands. The ecological sources were indicated by the importance-sensitivity ecological assessment method. Ecological corridors were identified by a minimum resistance model, and the ecological security pattern was derived. Twenty-three important ecological source sites were identified within the urban agglomeration, mainly located in the southern part of the Guanzhong Plain urban agglomeration, with an area of 9122.36 km2, accounting for 8.52% of the study area. The ecological sensitivity of the mountainous areas was relatively high, with ecological corridors showing a denser distribution in the south. The results of the study suggest that green infrastructure in the northern region should be strengthened, that the ecological functions of ecologically sensitive areas should be protected and enhanced, and that the connectivity of ecological corridors should be strengthened. The results provide guidance for the optimization of regional ecological security patterns for and the joint prevention and control of environmental pollution in the Guanzhong Plain.

In this paper, we focus on the redesign of the output layer for the weighted regularized extreme learning machine (WRELM). For multi-classification problems, the conventional method of the output layer setting, named “one-hot method”, is as follows: Let the class of samples be r; then, the output layer node number is r and the ideal output of s-th class is denoted by the s-th unit vector in Rr (1≤s≤r). Here, in this article, we propose a “binarymethod” to optimize the output layer structure: Let 2p−1

The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently. Ilicicolin A (Ili-A), an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501, shows antiproliferative activity in human PCa cells, but its mechanism of action against Castration-resistant prostate cancer is not known. Herein, RNA-sequencing showed the EZH2 pathway to be involved in PCa proliferation. Ili-A at low doses reduced the protein level of EZH2, leading to transcriptional change. Interestingly, Ili-A suppressed the binding of EZH2 to promoter regions in AR/serine/threonine polo-like kinase-1/aurora kinase A. Moreover, Ili-A could enhance the anticancer activity of enzalutamide in CRPC cancer models. These data suggest that Ili-A could be used in combination with enzalutamide to treat CRPC.

The Large-scale Superconductor Test Facility (LSTF) is an important part of comprehensive research facilities in support of China Fusion Engineering Test Reactor (CFETR). In order to protect the superconducting magnets from being damaged in quench accident, the Quench Protection System (QPS) should be designed to commutate the energy stored in the coils. The snubber circuit is used to reduce the reverse recovery current and voltage of thyristor in QPS, and it can impact the reliability and stability of the QPS. In general, the studies of snubber circuit are focused on the DC turn-off process of thyristor used in HVDC, which has small turn-off current. However, the turn-off current can reach to 100 kA in the QPS of LSTF. In this paper, a thyristor reverse recovery model is described, and the key parameters of reverse recovery current are obtained from the testing experiment. Based on the transient analysis of snubber circuit, a systematic approach is used to minimizing the resistance and capacitance of snubber circuit of QPS working condition is proposed. By the MATLAB simulation and comparison, minimum parameters of snubber circuit were obtained, and proved that the approach can improve the reliability and stability of system, while reduce the cost of QPS.

Rhododendron species are typical calcifuges that do not grow well in calcareous soils characterized by alkaline pH and high concentrations of Ca2+. In this study, we investigated the effects of three pH levels and a Ca2+ treatment on the in vitro germination and seedling growth of three Rhododendron species: R. chihsinianum, R. fortunei, and R. vernicosum. Alkaline pH had no significant effect on germination parameters (gMAX, mean germination time and germination uniformity) but significantly increased abnormal leaf development (AL) and mortality in all three species. Adding extra Ca2+ reduced the mean germination time for R. vernicosum. The negative influence of alkaline pH on seedlings was already visible on the second day of treatment as measured by chlorophyll fluorescence imaging parameters (Fv/Fm and ΦPSII) on R. fortunei. Extra Ca2+ alleviated the negative effect of alkaline pH and increased Fv/Fm 41 days after seed germination in R. fortunei and R. chihsinianum and reduced mortality for all three species. In conclusion, alkaline pH mainly influenced seedling development and growth but not the germination process itself. Chlorophyll fluorescence imaging can be an efficient way to perform high-throughput in vitro screening of Rhododendron seedlings for alkalinity tolerance.

Herein, A4 typing paper was used as a novel source to manufacture FeNi3 and NiCx coated carbon skeleton via facile routes. The product was examined for its ability to absorb electromagnetic emission which can be a health hazard. The impact of precursor concentration on the final electromagnetic wave absorption of samples was evaluated; the composite prepared under suitable concentration possesses outstanding multiband absorption ability of −34.64 dB and −26.7 dB at 2.32 GHz and 17.2 GHz, respectively, together with an ultra-wide effective absorption bandwidth of 9.58 GHz at only 3.9 mm. The strong dipole polarization and broad frequency range of preferable impedance matching, along with the coupling of other auxiliary mechanisms, are responsible for this excellent property. The as-prepared absorber has great potency for multiband absorption of electromagnetic waves.

Age-related macular degeneration (AMD) is a major cause of irreversible blindness among the elderly population. Dysfunction and degeneration of the retinal pigment epithelial (RPE) layer in the retina underscore the pathogenesis of both dry and wet AMD. Advanced age, cigarette smoke and genetic factors have been found to be the prominent risk factors for AMD, which point to an important role for oxidative stress and aging in AMD pathogenesis. However, the mechanisms whereby oxidative stress and aging lead to RPE cell degeneration are still unclear. As cell senescence and cell death are the major outcomes from oxidative stress and aging, here we review the mechanisms of RPE cell senescence and different kinds of cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, with an aim to clarify how RPE cell degeneration could occur in response to AMD-related stresses, including H2O2, 4-Hydroxynonenal (4-HNE), N-retinylidene-N-retinyl-ethanolamine (A2E), Alu RNA and amyloid β (Aβ). Besides those, sodium iodate (NaIO3) induced RPE cell degeneration is also discussed in this review. Although NaIO3 itself is not related to AMD, this line of study would help understand the mechanism of RPE degeneration.

Abstract Background The aim of the project is to retrospectively study the changes in bacterial pathogens in acute neonatal bacterial conjunctivitis from 2002 to 2016 in Southern China. The results may provide the guidance for drug choice for acute neonatal bacterial conjunctivitis. Methods Secretion specimens for bacterial culture were taken from 485 cases with clinically diagnosed acute bacterial neonatal conjunctivitis. Bacterial pathogens were detected by Gram staining and subsequent bacterial culture. Results From the analysis of the bacterial pathogens in 485 cases of acute neonatal conjunctivitis patients from 2002 to 2016 in Southern China, there is an overall trend of decreasing detection of Gram-positive bacteria and increasing detection of Gram-negative bacteria from the conjunctival sac secretions. Gram-positive bacteria in the bacteria-positive samples dropped year by year from 82.6% in 2002 to 72.4% in 2016. Accordingly, the ratio of Gram-negative bacteria increased from 17.4% in 2002 to 27.6% in 2016. Of note, despite the overall trend, there was a significant increase in detection of Gram-positive bacteria and decrease in detection of Gram-negative bacteria from 2011 to 2012. Among the Gram-positive bacteria, there is a trend of increasing percentage of the opportunistic pathogens (an ~60% increase in Staphylococcus epidermidis and Staphylococcus saprophytic) and decreasing percentage of Staphylococcus aureus (~30% decrease) and hemolytic streptococcus (~20% decrease) in the last 15 years. The main Gram-negative bacterium is Neisseria gonorrhoeae. Overall, there is a change in the pattern of bacterial species in acute neonatal bacterial conjunctivitis in Southern China in the last 15 years. Conclusion Our study provides a trend analysis of the bacterial pathogens in the conjunctival sac secretions of the acute neonatal bacterial conjunctivitis patients in Southern China in recent years. This data could provide useful information regarding the treatment options for neonatal bacterial conjunctivitis.

Abstract Glaucoma is a major cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP), which causes optic nerve damage and retinal ganglion cell death, is the primary risk factor for blindness in glaucoma patients. IOP is controlled by the balance between aqueous humor secretion from the ciliary body (CB) and its drainage through the trabecular meshwork (TM). How microRNAs (miRs) regulate IOP and glaucoma in vivo is largely unknown. Here we show that miR-143 and miR-145 expression is enriched in the smooth muscle and trabecular meshwork in the eye. Targeted deletion of miR-143/145 in mice results in significantly reduced IOP, consistent with an ~2-fold increase in outflow facilities. However, aqueous humor production in the same mice appears to be normal based on a microbeads-induced glaucoma model. Mechanistically, we found that miR-143/145 regulates actin dynamics and the contractility of TM cells, consistent with its regulation of actin-related protein complex (ARPC) subunit 2, 3, and 5, as well as myosin light chain kinase (MLCK) in these cells. Our data establish miR-143/145 as important regulators of IOP, which may have important therapeutic implications in glaucoma.

In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 expression. MAX protein was identified as a lncEGFL7OS-interacting protein that functions to regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer. CRISPR-mediated targeting of EGLF7/miR-126/lncEGFL7OS locus inhibits angiogenesis, inciting therapeutic potential of targeting this locus. Our study establishes lncEGFL7OS as a human/primate-specific EC-restricted lncRNA critical for human angiogenesis.

Rhododendrons are typically known to be calcifuges that cannot grow well in lime soils. Data on lime tolerance of different taxa in Rhododendron are scarce. Habitats of naturally distributed specimens of genus Rhododendron were compiled as Chinese text-based locations from the Chinese Virtual Herbarium. The locations were then geocoded into latitude/longitude pairs and subsequently connected to soil characteristics including pH and CaCO3 from the Harmonized World Soil Database (HWSD). Using the upper quartile values of pH > 7.2 and CaCO3 > 2% weight in topsoil as threshold, we predicted the lime tolerant taxa. A dataset of 31,146 Rhododendron specimens including the information on taxonomy, GPS locations and soil parameters for both top- and subsoil was built. The majority of the specimens were distributed in soils with moderately acidic pH and without presence of CaCO3. 76 taxa with potential lime tolerance were predicted out of 525 taxa. The large scale data analysis based on combined data of geocoded herbarium specimens and HWSD allows identification of valuable Rhododendron species, subspecies or botanical varieties with potential tolerance to lime soils with higher pH. The predicted tolerant taxa are valuable resources for an in-depth evaluation of lime tolerance or for further use in horticulture and breeding.

Background/Aims: MET can act as an oncogene and its signaling server has essential roles in regulating tumorigenesis. Polymorphisms in MET have been reported to be associated with poor prognosis in human cancer, but an association with the risk of human non-small-cell lung cancer (NSCLC) has not been found so far. In this study rs41281081 and rs76322625, located in the 3'UTR of MET, were selected to evaluate their relationship with the risk of NSCLC among the Chinese population. Methods: A questionnaire, SNaPshot genotype assay, real time PCR assay, cell transfection and the dual luciferase reporter assay were used. Single-nucleotide polymorphisms (SNPs) of rs41281081 and rs76322625 in the 3' untranslated region (UTR) of MET was involved as a risk factor in the occurrence of NSCLC. Results: SNP rs41281081 could be regulated by miR-335 and rs76322625 could be regulated by miR-1026 to cause an up-regulation of MET in patients with NSCLC. Furthermore, the carriers of the GA and AA genotypes in rs41281081, and the CU and UU genotypes in rs76322625 presented with poor cell differentiation and large tumor size, as well as a high probability of metastasis. Conclusion: Our findings have shown that the SNPs rs41281081 and rs76322625 in MET 3ʹUTR, through disruption of the regulatory role of miR-335 and miR-1026 in MET expression, may act as promoting factors in the pathogenesis of NSCLC.

Intelligent bionic leg (IBL) is an advanced prosthesis which can maximum functionally simulate and approach the motion trajectory of human leg. Knee joint is the most important bone of human leg and its bionic design has great significance to prosthesis performance. The structural components of IBL are introduced and virtual prototype is given. The advantages of 4-bar knee joint are analyzed and are adopted in IBL design. The kinematics model of 4-bar knee joint is established. The objective function, constraint condition, parameters selection and setting of genetic algorithm are discussed in detail. Based on genetic algorithm, the optimization design of IBL knee joint is done. The optimization results indicate that the 4-bar mechanism can achieve better anthropomorphic characteristics of human knee joint.

Microphthalmia is characterized by abnormally small eyes and usually retinal dysplasia, accounting for up to 11% of the blindness in children. Right now there is no effective treatment for the disease, and the underlying mechanisms, especially how retinal dysplasia develops from microphthalmia and whether it depends on the signals from lens ectoderm are still unclear. Mutations in genes of the TGF-β superfamily have been noted in patients with microphthalmia. Using conditional knockout mice, here we address the question that whether ocular surface ectoderm-derived Smad4 modulates retinal development. We found that loss of Smad4 specifically on surface lens ectoderm leads to microphthalmia and dysplasia of retina. Retinal dysplasia in the knockout mice is caused by the delayed or failed differentiation and apoptosis of retinal cells. Microarray analyses revealed that members of Hedgehog and Wnt signaling pathways are affected in the knockout retinas, suggesting that ocular surface ectoderm-derived Smad4 can regulate Hedgehog and Wnt signaling in the retina. Our studies suggest that defective of ocular surface ectoderm may affect retinal development.

The recent Zika virus (ZIKV) outbreak in the Americas surprised all of us because of its rapid spread and association with neurologic disorders including fetal microcephaly, brain and ocular anomalies, and Guillain–Barré syndrome. In response to this global health crisis, unprecedented and world-wide efforts are taking place to study the ZIKV-related human diseases. Much has been learned about this virus in the areas of epidemiology, genetic diversity, protein structures, and clinical manifestations, such as consequences of ZIKV infection on fetal brain development. However, progress on understanding the molecular mechanism underlying ZIKV-associated neurologic disorders remains elusive. To date, we still lack a good understanding of; (1) what virologic factors are involved in the ZIKV-associated human diseases; (2) which ZIKV protein(s) contributes to the enhanced viral pathogenicity; and (3) how do the newly adapted and pandemic ZIKV strains alter their interactions with the host cells leading to neurologic defects? The goal of this review is to explore the molecular insights into the ZIKV–host interactions with an emphasis on host cell receptor usage for viral entry, cell innate immunity to ZIKV, and the ability of ZIKV to subvert antiviral responses and to cause cytopathic effects. We hope this literature review will inspire additional molecular studies focusing on ZIKV–host Interactions.

Artemisinin (ART) dimers show potent anti-proliferative activities against breast cancer cells. To facilitate their clinical development, novel pH-responsive artemisinin dimers were synthesized for liposomal nanoparticle formulations. A new ART dimer was designed to become increasingly water-soluble as pH declines. The new artemisinin dimer piperazine derivatives (ADPs) remained tightly associated with liposomal nanoparticles (NPs) at neutral pH but were efficiently released at acidic pH's that are known to exist within solid tumors and organelles such as endosomes and lysosomes. ADPs incorporated into nanoparticles down regulated the anti-apoptotic protein, survivin, and cyclin D1 when incubated at low concentrations with breast cancer cell lines. We demonstrate for the first time, for any ART derivative, that ADP NPs can down regulate the oncogenic protein HER2, and its counterpart, HER3 in a HER2+ cell line. We also show that the wild type epidermal growth factor receptor (EGFR or HER1) declines in a triple negative breast cancer (TNBC) cell line in response to ADP NPs. The declines in these proteins are achieved at concentrations of NP109 at or below 1 µM. Furthermore, the new artemisinin derivatives showed improved cell-proliferation inhibition effects compared to known dimer derivatives.