Tomato sucrose transporter SlSUT4 participates in flowering regulation by modulating gibberellin biosynthesis.

The functions of sucrose transporters (SUTs) differ among family members. The physiological function of SUT1 has been studied intensively, while that of SUT4 in various plant species including tomato (Solanum lycopersicum) is less well-understood. In this study, we characterized the function of tomato SlSUT4 in the regulation of flowering using a combination of molecular and physiological analyses. SlSUT4 displayed transport activity for sucrose when expressed in yeast (Saccharomyces cerevisiae), and it localized at both the plasma membrane and tonoplast. SlSUT4 interacted with SlSUT1, causing partial internalization of the latter, the main phloem loader of sucrose in tomato. Silencing of SlSUT4 promoted SlSUT1 localization to the plasma membrane, contributing to increased sucrose export and thus increased sucrose level in the shoot apex, which promoted flowering. Both silencing of SlSUT4 and spraying with sucrose suppressed gibberellin biosynthesis through repression of ent-kaurene oxidase and gibberellin 20-oxidase-1 (2 genes encoding key enzymes in gibberellin biosynthesis) expression by SlMYB76, which directly bound to their promoters. Silencing of SlMYB76 promoted gibberellin biosynthesis. Our results suggest that SlSUT4 is a functional SUT in tomato; downregulation of SlSUT4 expression enhances sucrose transport to the shoot apex, which promotes flowering by inhibiting gibberellin biosynthesis.

Apigenin Enhanced Antitumor Effect of Cisplatin in Lung Cancer via Inhibition of Cancer Stem Cells.

Cancer stem cell theory has been proposed to explain tumor heterogeneity and the carcinogenesis process. Highly tumorigenic lung cancer stem cells develop resistance to cisplatin (CDDP), a common chemotherapy drug. Herein, we attempted to clarify whether apigenin (API) can improve the antitumor efficiency of CDDP in lung cancer using cancer stem cells. Lung cancer stem cells were identified as CD 133 positive cancer cells in non-small cell lung cancer (NSCLC) A549, H1299 cells and CDDP-resistant NSCLC A549R cells. The cytotoxic effect of API was measured in CDDP-treated A549, H1299, and A549R cells. API repressed CD 133 positive cells and enhanced the antitumor effect of CDDP in A549, H1299, and A549R cells. The synergistic antitumor effect of API and CDDP was blocked by addition of the p53 inhibitor Pifithrin-α, and siRNA targeting the p53 gene in A549R cells. Furthermore, API eliminates CDDP-induced CSC via p53, since A549R cells lacking p53 and Pifithrin-α addition derepressed the decrease in CD 133 positive cells after API treatment in CDDP-treated A549 and A549R cells. The findings indicate that API might eliminate cancer stem cells and enhance the antitumor effects of CDDP in NSCLC via p53.

Regulation of human cardiac Kv1.5 channels by extracellular acidification.

Human Kv1.5 channels (hKv1.5) conduct the ultra-rapid delayed rectifier potassium current (I Kur), which plays an important role in action potential repolarization of atrial myocytes. The present study was undertaken to examine the effects of acidic pH on hKv1.5 wild-type (WT) and its pore mutant channels heterologously expressed in Chinese hamster ovary (CHO) cells using site-directed mutagenesis combined with whole-cell patch-clamp technique. Both extracellular and intracellular acidifications equally and reversely reduced the amplitude of hKv1.5 currents. The extracellular acidification significantly shifted the voltage dependence of current activation to more depolarized potentials and accelerated deactivation kinetics of the current. The ancillary ß subunits Kvß1.3 and Kvß1.2, known to modify the pharmacological sensitivities of hKv1.5, enhanced the extracellular proton-induced inhibitory effect on hKv1.5 current. In addition, several mutants (T462C, T479A, T480A, and I508A) exhibited significantly higher sensitivity to acidic pH-induced inhibition compared with WT channel, whereas the inhibitory effect of acidic pH was markedly reduced in H463G mutant. These observations indicate that (1) extracellular acidification modifies hKv1.5 gating and activity, (2) ß subunits and several residues (T462, T479, T480, and I508) play critical roles in determining the sensitivity of the channel to acidic exposure, and (3) H463 may be a critical sensor for the channel inhibition by extracellular protons.

Gain-of-function KCNH2 mutations in patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST segment elevation on electrocardiograms (ECGs) that predisposes patients to sudden cardiac death as a result of polymorphic ventricular tachyarrhythmia or ventricular fibrillation (VF). In BrS patients, except for SCN5A, mutations in other responsible genes are poorly elucidated. METHODS AND RESULTS: We identified 4 KCNH2 mutations, T152I, R164C, W927G, and R1135H, in 236 consecutive probands with BrS or Brugada-like ECG. Three of these mutation carriers showed QTc intervals shorter than 360 milliseconds and 1 experienced VF. We performed patch-clamp analyses on I(Kr) reconstituted with the KCNH2 mutations in Chinese hamster ovary cells and compared the phenotypes of the patients with different genotypes. Three mutations, R164C, W927G, and R1135H, increased I(Kr) densities. Three mutations, T152I, R164C, and W927G, caused a negative shift in voltage-dependent activation curves. Only the R1135H mutant channel prolonged the deactivation time constants. We also identified 20 SCN5A and 5 CACNA1C mutation carriers in our cohort. Comparison of probands' phenotypes with 3 different genotypes revealed that KCNH2 mutation carriers showed shorter QTc intervals and SCN5A mutation carriers had longer QRS durations. CONCLUSIONS: All KCNH2 mutations that we identified in probands with BrS exerted gain-of-function effects on I(Kr) channels, which may partially explain the ECG findings in our patients.

How can the rule of law under the WTO framework ensure sustainable fishery governance through fishery subsidies? A study from the perspective of special and differential treatment.

Background: Considering the declining situation of sustainability in global marine fisheries, World Trade Organization (WTO) members successfully concluded the Agreement on Fisheries Subsidies(AFS) after 21 years of negotiations in 2022. As an the integral part of these negotiations, special and differential treatment (SDT) provisions provide developing countries with special rights and developed countries with the possibility to treat developing countries more favorably than other WTO members. Objective: This study analyzed the role of SDT for fisheries subsidies in ensuring sustainable fishery governance by the rule of law, as well as the reflection of SDT under the AFS, to explore whether SDT can support sustainable fishery governance under the WTO framework. Methods: This study is primarily based on official data and critical legal studies and used normative analysis and historical analysis to expose the essence of the SDT issue in the AFS as a political game in the legal form. Results: The practical challenges in the implementation of SDT may affect the compliance willingness of member states. To overcome the obstacles, such as ambiguity and inefficiency, that impede the legalization process of sustainable global marine fishery governance, it is necessary to emphasize the value of SDT for the common interests of the WTO members in marine fisheries legislation. This will benefit the developing countries, especially the small island developing states, in the short term; and the common interests of developed and developing countries in the long term. Policy implications: SDT facilitated the consensus between the developing and developed countries on issues such as illegal, unreported, and unregulated fishing subsidies and overfishing subsidies. However, current SDT practices have deviated from the original intention of the fairness and democratic approach of global marine fisheries governance, which should take into consideration the specific situation of developing countries.

Quantitative evaluation of endobronchial ultrasound elastography in the diagnosis of benign and malignant mediastinal and hilar lymph nodes.

OBJECTIVE: To compare the diagnostic value of different quantitative methods of endobronchial ultrasound elastography in benign and malignant mediastinal and hilar lymph nodes. METHODS: This retrospective study included patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal and hilar lymph node enlargement in our hospital between January 2019 and August 2022. We compared different quantitative elastography parameters [red area ratio (RAR, lymph node red area/lymph node area), green area ratio (GAR, lymph node green area/lymph node area), blue area ratio (SAR, lymph node blue area/lymph node area), mixed area ratio (MAR, lymph node green area/lymph node area), blue-green lymph node area/lymph node area), strain rate ratio (SR), strain rate in the target lymph node (LPA), ratio of blue area to total lymph node area outside the center of the target lymph node (PAR), and average grey value (MGV)], in order to find the best quantitative evaluation method. RESULTS: A total of 244 patients (346 lymph nodes) were included in this study. All quantitative elastography parameters were statistically significant for the differentiation of benign and malignant lesions except the average grey value of the target lymph nodes. The area under the receiver operating characteristic curve of SAR was 0.872 (95% confidence interval: 0.83-0.91), the cutoff value was 0.409, and the sensitivity, specificity, positive and negative predictive values were 85.4%, 78.0%, 80.4%, and 83.4%, respectively. CONCLUSION: Compared with other types of quantitative analysis, SAR has a higher predictive significance for benign and malignant lymph nodes.

Risk factors for acute exacerbation of interstitial lung disease during chemotherapy for lung cancer: a systematic review and meta-analysis.

Purpose: The aim of this study was to investigate the risk factors for acute exacerbation (AE) of interstitial lung disease caused by chemotherapy for lung cancer. Methods: We searched PubMed, Embase, and The Cochrane Library databases from the establishment of each database to April 2023. Eligible studies were included, and the data on risk factors related to AE caused by chemotherapy in interstitial lung disease were extracted. Results: A total of 878 articles were retrieved and 21 met the inclusion criteria. The studies included 1,275 patients with lung cancer combined with interstitial lung disease. The results of the meta-analysis showed four significant risk factors for AE of interstitial lung disease, namely age < 70 years (odds ratio [OR]: 1.98, 95% confidence interval [CI]: 1.05-3.72), forced vital capacity (FVC) (MD=-9.33, 95% CI: -13.7-4.97), usually interstitial pneumonia (UIP) pattern on computed tomography (CT) (OR: 2.11, 95% CI: 1.43-3.11), and serum surfactant protein D (SP-D) (SMD: 0.35, 95% CI: 0.03-0.67). Conclusion: When patients with lung cancer complicated with interstitial lung disease are aged < 70 years, have a UIP pattern on CT, have lower FVC values, and have higher serum levels of SP-D, chemotherapy should be carried out with care.

Quantitative analysis of endobronchial elastography combined with serum tumour markers of lung cancer in the diagnosis of benign and malignant mediastinal and hilar lymph nodes.

Purpose: In malignant tumours, elastography and serum tumour markers have shown high diagnostic efficacy. Therefore, we aimed to quantitatively analyse the results of endobronchial elastography combined with serum tumour markers of lung cancer to accurately distinguish benign and malignant mediastinal and hilar lymph nodes. Methods: Data of patients who underwent endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal lymph node enlargement in our hospital between January 2018 and August 2022 were retrospectively collected. The characteristics of quantitative elastography and serum tumour markers were evaluated. Results: We enrolled 197 patients (273 lymph nodes). In the differential diagnosis of benign and malignant mediastinal and hilar lymph nodes, the stiffness area ratio (SAR), strain ratio (SR), and strain rate in lymph nodes were significant, among which SAR had the highest diagnostic value (cut-off value, 0.409). The combination of the four tumour markers had a high diagnostic value (AUC, 0.886). Three types of quantitative elastography indices combined with serum tumour markers for lung cancer showed a higher diagnostic value (AUC, 0.930; sensitivity, 83.5%; specificity, 89.3%; positive predictive value, 88.1%; negative predictive value, 85%) (p < 0.05). In the differential diagnosis of pathological types of lung cancer, different quantitative elastography indicators and serum tumour markers for lung cancer have different diagnostic significance for the differential diagnosis of lung cancer pathological types. Conclusion: The quantitative analysis of endobronchial ultrasound elastography combined with tumour markers can improve the diagnosis rate of benign and malignant mediastinal and hilar lymph nodes, help guide the puncture of false negative lymph nodes, and reduce the misdiagnosis rate.

Review study on governance and international law for coastal and marine ecosystems in response to climate change: Social science perspective.

As a common concern of humankind, the governance of coastal and marine ecosystems is increasingly coming to the fore of the international community as part of the joint response to climate change. Since the signing of the Declaration of the United Nations Conference on the Human Environment and the United Nations Convention on the Law of the Sea several decades ago, the international community has been exploring how international law can be improved in this respect. At present, the governance and international law of coastal and marine ecosystems in response to climate change are studied from theoretical and methodological perspectives. Extensive empirical studies help pinpoint specific issues related to each topic and provide valuable empirical references for both developed and developing countries. Based on social science publications, the authors use technical means to visualize research related to this topic, and conduct comprehensive reviews of these papers. They reveal that research based on these topics started late and is characterized by fragmentation. The research potential related to mentioned topic has yet to be explored extensively.

Comparison of Dexmedetomidine Versus Propofol in Mechanically Ventilated Patients With Sepsis: A Meta-Analysis of Randomized Controlled Trials.

Purpose: The aim of the present study was to evaluate the effects of dexmedetomidine compared with propofol in mechanically ventilated patients with sepsis. Methods: We searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials comparing the effects of dexmedetomidine versus propofol in septic patients requiring mechanical ventilation from inception to December 2021. The primary outcome was 28/30-day mortality and secondary outcomes were ventilator-free days and the length of ICU stay. Pooled relative risk (RR), mean deviation (MD), along with 95% confidence intervals (CI) were used to express outcomes by the software of Review Manager 5.3. Results: Seven studies with a total of 1,212 patients were eligible for meta-analysis. The results primarily showed that dexmedetomidine had no significant effects on the 28/30-day mortality (RR = 1.04 [0.85-1.26], p = 0.70, I2 = 3%). As for secondary outcomes, the administration of dexmedetomidine was not associated with longer-ventilator-free days (MD = 0.50 [-2.15, 3.15], p = 0.71, I2 = 24%) compared with propofol. However, our results revealed dexmedetomidine could shorten the length of ICU stay (MD = -0.76 [-1.34, -0.18], p = 0.01, I2 = 33%). Conclusion: Administration of dexmedetomidine for sedation in septic patients who required mechanical ventilation had no effect on 28/30-day mortality and ventilator-free days, but it could shorten the length of ICU stay.

Smart Responsive Azo-Copolymer with Photoliquefaction for Switchable Adhesive Application.

The development and utilization of switchable adhesives are considered to be an essential target to solve the problems of their separation and recycling in some specific service environments, such as the preparation or repair process of electronic devices. Intelligent materials with controllable phase transition are utilized to fabricate switchable adhesives because of the significantly diverse adhesion strengths in different phase states. Photoresponsive azobenzene and its derivatives usually possess different melting temperatures (Tm) or/and glass transition temperatures (Tg) of the cis-trans isomers, which are beneficial to making the photoinduced solid-liquid phase transition for switchable adhesive application possible. Here, a novel three-component azo-copolymer (PNIM-Azo) with fast and reversible photoinduced solid-liquid phase transition has been designed and synthesized. PNIM-Azo possesses reversible bonding/debonding processes, resulting from the different adhesion strengths between trans-configuration PNIM-Azo in the solid state and cis-configuration in the liquid state. Moreover, by incorporating commercialized 2-methoxyethyl acrylate and N-isopropylacrylamide with O and N heteroatoms into the copolymer, the trans-configuration PNIM-Azo possesses the highest adhesion strength (∼11 MPa between two glass substrates) among all of the reported azobenzene-based switchable adhesives, which could be attributed to the increase in the entanglement effect because of the H-bond in the polymer chains formed by introducing heteroatoms. Our synthesized PNIM-Azo copolymer provides an alternative for designing and developing switchable adhesives with high adhesion strength for some electronic production processes.

The roles of synovial hyperplasia, angiogenesis and osteoclastogenesis in the protective effect of apigenin on collagen-induced arthritis.

Apigenin (API) is a plant flavone that is known to exert a protective effect in rheumatoid arthritis (RA), which is a chronic autoimmune disease. However, the molecular mechanism for API's protective effect against RA is still unclear. Here, a collagen-induced arthritis (CIA) mouse model was used to assess the protective effect of API on RA. Histomorphological studies, immunohistochemistry, RT-PCR, and western blot were conducted to elucidate the roles of synovial hyperplasia, angiogenesis, and osteoclastogenesis in the protective effect of API on RA. Fibroblast-like synoviocytes (FLSs) were isolated to measure the effect of API on FLS proliferation and apoptosis. API exhibited a significant protective effect in CIA mice in a dose- and time-dependent manner. An increase in apoptosis and decrease in proliferation were observed after the API treatment in FLSs, suggesting that API might inhibit synovial hyperplasia. Moreover, CIA angiogenesis was repressed by API via down-regulation of VEGF and VEGFR. Furthermore, API regulated the osteoclastogenesis-associated RANKL/RANK/OPG system in CIA mice. Therefore, API inhibits CIA by repressing synovial hyperplasia, angiogenesis, and osteoclastogenesis. This suggested that API might be a putative low toxicity candidate drug for RA treatment.

Serum albumin attenuates the open-channel blocking effects of propofol on the human Kv1.5 channel.

The intravenous anesthetic propofol modulates various ion channel functions. It is generally accepted that approximately 98% of propofol binds to blood constituents and that the free (unbound) drug preferentially affects target proteins including ion channels. However, modulatory effects of propofol on ion channels have not been previously explored in the presence of serum albumin. This study was designed to investigate the effects of serum albumin on the blocking action of propofol on the human Kv1.5 (hKv1.5) current. Whole-cell patch-clamp method was used to record the hKv1.5 channel current, heterologously expressed in Chinese hamster ovary cells, in the absence and presence of bovine serum albumin (BSA). Propofol induced a time-dependent decline of the hKv1.5 current during depolarizing steps and slowed the time course of tail current decay upon repolarization, supporting that propofol acts as an open-channel blocker. This blocking effect was reversible and concentration-dependent with an IC50 of 62.9±3.1µM (n = 6). Bath application of 1% BSA markedly reduced the blocking potency of propofol on hKv1.5 current (IC50 of 1116.0±491.4µM; n = 6). However, in the presence of BSA, the propofol-induced inhibition of hKv1.5 current was also accompanied by a gradual decline of activated current during depolarization and deceleration of deactivating tail current upon repolarization. The presence of BSA greatly attenuated the blocking potency of propofol on hKv1.5 channel without affecting the mode of action of propofol on the channel. Serum albumin thus appears to bind to propofol and thereby reducing effective concentrations of the drug for inhibition of hKv1.5 channel.

Putative binding sites for arachidonic acid on the human cardiac Kv 1.5 channel.

BACKGROUND AND PURPOSE: In human heart, the Kv 1.5 channel contributes to repolarization of atrial action potentials. This study examined the electrophysiological and molecular mechanisms underlying arachidonic acid (AA)-induced inhibition of the human Kv 1.5 (hKv 1.5) channel. EXPERIMENTAL APPROACH: Site-directed mutagenesis was conducted to mutate amino acids that reside within the pore domain of the hKv 1.5 channel. Whole-cell patch-clamp method was used to record membrane currents through wild type and mutant hKv 1.5 channels heterologously expressed in CHO cells. Computer docking simulation was conducted to predict the putative binding site(s) of AA in an open-state model of the Kv 1.5 channel. KEY RESULTS: The hKv 1.5 current was minimally affected at the onset of depolarization but was progressively reduced during depolarization by the presence of AA, suggesting that AA acts as an open-channel blocker. AA itself affected the channel at extracellular sites independently of its metabolites and signalling pathways. The blocking effect of AA was attenuated at pH 8.0 but not at pH 6.4. The blocking action of AA developed rather rapidly by co-expression of Kv ß1.3. The AA-induced block was significantly attenuated in H463C, T480A, R487V, I502A, I508A, V512A and V516A, but not in T462C, A501V and L510A mutants of the hKv 1.5 channel. Docking simulation predicted that H463, T480, R487, I508, V512 and V516 are potentially accessible for interaction with AA. CONCLUSIONS AND IMPLICATIONS: AA itself interacts with multiple amino acids located in the pore domain of the hKv 1.5 channel. These findings may provide useful information for future development of selective blockers of hKv 1.5 channels.

Research on the fundamental principles of China's marine invasive species prevention legislation.

China's coastal area is severely damaged by marine invasive species. Traditional tort theory resolves issues relevant to property damage or personal injuries, through which plaintiffs cannot cope with the ecological damage caused by marine invasive species. Several defects exist within the current legal regimes, such as imperfect management systems, insufficient unified technical standards, and unsound legal responsibility systems. It is necessary to pass legislation to prevent the ecological damage caused by marine invasive species. This investigation probes the fundamental principles needed for the administration and legislation of an improved legal framework to combat the problem of invasive species within China's coastal waters.

Allozyme variation and population genetic structure of Betula alnoides from Guangxi, China.

Allozyme variation and population genetic structure of Betula alnoides Buch Ham. ex D. Don in 11 natural populations from Guangxi Zhuang Autonomous Region, China, were investigated by starch gel electrophoresis. Variation at 15 loci from 10 enzyme systems was analyzed. Allozyme analysis revealed a high level of genetic variation in this species, with percentage of polymorphic loci (P(p)), the average number of alleles per locus (A(p)), and the expected heterozygosity (H(ep)) being 55.2%, 2.0, and 0.204, respectively, which exceeds the average level among out-crossing wind-pollinated woody species at the population level. At the species level, P(s), A(s), and H(es) were 60.0%, 2.67, and 0.206, respectively. The observed heterozygosity (H(op)) was higher than H(ep), indicating the existence of natural selection against homozygotes. The negative fixation index (F = -0.216) implied a significant excess of heterozygosity at the population level Among-population differentiation (F(ST)) accounted for 4.0% of the total variation. No significant correlation was detected between the genetic distance and geographic distance among populations. Extensive gene flow was inferred, based on the allozyme data (N(m) = 6.000 from F(ST), N(m) = 5.605 from the "private allele" method). The results demonstrated that the fragmentation status of B. alnoides had no remarkable effects on the population genetic structure of this species. Some populations are recommended for both in situ genetic conservation and germplasm collection for breeding programs.

Moderate-density molecular maps of Eucalyptus urophylla S. T. Blake and E. tereticornis Smith genomes based on RAPD markers.

Moderate-density molecular maps were constructed for the genomes of Eucalyptus urophylla S. T. Blake and E. tereticornis Smith using RAPD markers and an interspecific cross between the two species. One hundred and eighty-three primers were employed to generate 245 and 264 parent-specific markers in E. urophylla and E. tereticornis, respectively, as well as 49 parent-shared markers. The normally segregating markers, including 208 (84.9%) specific to maternal E. urophylla, 175 (66.3%) to paternal E. tereticornis, and 48 shared by both parents, were used for framework map construction for each parental species. For maternal E. urophylla, the linkage map consisted of 23 linkage groups, 160 framework markers, and 60 accessory markers, defining a total map distance of 1504.6cM and an average interval of 11.0 +/- 8.07 cM. For paternal E. tereticornis, the linkage map contained 23 linkage groups, 126 framework markers, and 92 accessory markers, defining a total map distance of 1035.7 cM and an average interval of 10.1 +/- 7.23 cM. Genome length was estimated at 1585.7 and 1507.5 cM for E. urophylla and E. tereticornis, respectively, indicating map coverage of 94.9 and 68.7% of the corresponding genomes. Construction of such maps will be valuable for quantitative trait loci (QTLs) detection, marker-assisted selection (MAS), comparative mapping, and whole genome based fingerprint characterization in Eucalyptus breeding programs.