Detection of Cadmium in Human Biospecimens by a Cadmium-Selective Whole-Cell Biosensor Based on Deoxyviolacein.

Cadmium poses a severe health risk, impacting various bodily systems. Monitoring human exposure is vital. Urine and blood cadmium serve as critical biomarkers. However, current urine and blood cadmium detection methods are expensive and complex. Being cost-effective, user-friendly, and efficient, visual biosensing offers a promising complement to existing techniques. Therefore, we constructed a cadmium whole-cell biosensor using CadR10 and deoxyviolacein pigment in this study. We assessed the sensor for time-dose response, specific response to cadmium, sensitivity response to cadmium, and stability response to cadmium. The results showed that (1) the sensor had a preferred signal-to-noise ratio when the incubation time was 4 h; (2) the sensor showed excellent specificity for cadmium compared to the group 12 metals and lead; (3) the sensor was responsive to cadmium down to 1.53 nM under experimental conditions and had good linearity over a wide range from 1.53 nM to 100 µM with good linearity (R2 = 0.979); and (4) the sensor had good stability. Based on the excellent results of the performance tests, we developed a cost-effective, high-throughput method for detecting urinary and blood cadmium. Specifically, this was realized by adding the blood or urine samples into the culture system in a particular proportion. Then, the whole-cell biosensor was subjected to culture, n-butanol extraction, and microplate reading. The results showed that (1) at 20% urine addition ratio, the sensor had an excellent curvilinear relationship (R2 = 0.986) in the range of 3.05 nM to 100 µM, and the detection limit could reach 3.05 nM. (2) At a 10% blood addition ratio, the sensor had an excellent nonlinear relationship (R2 = 0.978) in the range of 0.097-50 µM, and the detection limit reached 0.195 µM. Overall, we developed a sensitive and wide-range method based on a whole-cell biosensor for the detection of cadmium in blood and urine, which has the advantages of being cost-effective, ease of operation, fast response, and low dependence on instrumentation and has the potential to be applied in the monitoring of cadmium exposure in humans as a complementary to the mainstream detection techniques.

Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

HuaChanSu suppresses the growth of hepatocellular carcinoma cells by interfering with pentose phosphate pathway through down-regulation of G6PD enzyme activity and expression.

HuaChanSu is active water extracts from the skin of Bufo bufo gargarizans Cantor. It has been already used to treat clinical cancers including HCC (Hepatocellular carcinoma, HCC), however, the molecular mechanisms under HuaChanSu's anti-cancer effects remain unclear. PPP (Pentose phosphate pathway, PPP), the major source of ribose and NADPH (Nicotinamide adenine dinucleotide phosphate, NADPH), is always over-activated and particularly critical for tumor cells growth. In this study, firstly, we illustrate that HuaChanSu restrains the growth of human hepatoma cells. More importantly, we demonstrate that the expression of G6PD (Glucose-6-phosphate dehydrogenase, G6PD), the first rate-limiting enzyme of the PPP, is restrained in human hepatoma cells after treatment with HuaChanSu. Additionally, our results show that G6PD enzyme activity and dimer formation are inhibited by HuaChanSu. Furthermore, we find that HuaChanSu could inhibit NADPH production and nucleotide level. In addition, we identify that expression of PLK1 (Polo-like kinase 1, PLK1) is also reduced in response to HuaChanSu, and knockdown of PLK1 restrains enzyme activity and dimer formation of G6PD, but has no effect on G6PD protein level. Subsequently, we demonstrate that inhibition of G6PD could restrain the proliferation of tumor cells and enhance the inhibitory effect of HuaChanSu on cell proliferation of human hepatoma cells. In conclusion, for the first time, our study reveals that HuaChanSu interferes with PPP via suppression of G6PD expression and enzyme activity to restrain growth of tumor cells, and these results provide a novel insight for the anti-hepatoma mechanisms of HuaChanSu and promote the innovation of the research model of TCM. Moreover, the development of drugs targeting abnormal tumor metabolism is currently a hot topic, our works provide theoretical support for further drug development from HuaChanSu, meanwhile, the revelation of the new molecular mechanism also provides a new perspective for the study of the pathogenesis of liver cancer. Short abstract: HuaChanSu suppresses expression of G6PD, the first rate-limiting enzyme of the PPP, restrains G6PD enzyme activity and dimer formation via inhibition of PLK1, knockdown of G6PD could impair the growth of human hepatoma cells and increase the blocking effect of HuaChanSu on cell proliferation of cancer cells. In addition, HuaChanSu restrains NADPH production and nucleotide level, implying the suppression of PPP flux. Our study suggests that HuaChanSu interferes with PPP via G6PD inhibition to exert anti-hepatoma effects.

Lenalidomide use in multiple myeloma (Review).

Lenalidomide is a second-generation new immunomodulatory medication used to treat multiple myeloma (MM). Its mechanism of action involves affecting the expression of vascular endothelial growth factor, interleukin-6, cytochrome c, caspase-8, as well as other factors including immunological modulation and the direct killing of cells, among others, rendering it a fundamental medication, useful for the treatment of MM. Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM. When autologous-hematopoietic stem cell transplantation (ASCT) cannot be utilized to treat newly diagnosed individuals with MM (NDMM), monotherapy maintenance following lenalidomide and dexamethasone may be employed. Following ASCT, single-agent maintenance with lenalidomide can be performed as an additional treatment. The combination of bortezomib and lenalidomide has been demonstrated to be associated with favorable response rates, tolerable toxicity, and therapeutic benefits although caution is warranted to prevent the onset of peripheral neuropathy with its use. A new-generation oral drug with an excellent safety profile, ixazomib, is more practical and therapeutically applicable in relapsed refractory MM. However, the frequent occurrence of cardiovascular events, hematocrit, and infections with it require flexible adjustment in its clinical application. Carfilzomib produces a rapid and profound response in patients with NDMM eligible for transplantation, but its cardiovascular side effects need to be closely monitored. The primary aim of the present review was to examine the pharmacological properties and pharmacokinetics of lenalidomide, as well as the efficacy and safety of lenalidomide-based treatments with reference to data from clinical trials and real-world studies.

SHED-exos promote saliva secretion by suppressing p-ERK1/2-mediated apoptosis in glandular cells.

OBJECTIVES: Confirm that stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-exos) can limit inflammation-triggered epithelial cell apoptosis and explore the molecular mechanism. METHODS: SHED-exos were injected into the submandibular glands (SMGs) of non-obese diabetic (NOD) mice, an animal model of Sjögren's syndrome (SS). Cell death was evaluated by western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining. RESULTS: SHED-exos treatment promoted the saliva flow rates of NOD mice, accompanied by decreased cleaved caspase-3 levels and apoptotic cell numbers in SMGs. SHED-exos inhibited autophagy, pyroptosis, NETosis, ferroptosis, necroptosis and oxeiptosis marker expression in SS-damaged glands. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis of exosomal miRNAs suggested that the rat sarcoma virus (RAS)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway might play an important role. In vivo, the expression of Kirsten RAS, Harvey RAS, MEK1/2 and p-ERK1/2 was upregulated in SMGs, and this change was blocked by SHED-exos treatment. In vitro, SHED-exos suppressed p-ERK1/2 activation and increased cleaved caspase-3 and apoptotic cell numbers, which were induced by IFN-γ. CONCLUSION: SHED-exos suppress epithelial cell death, which is responsible for promoting salivary secretion. SHED-exos inhibited inflammation-triggered epithelial cell apoptosis by suppressing p-ERK1/2 activation, which is involved in these effects.

Multiple myeloma presenting with amyloid arthropathy as the first manifestation: Two case reports.

BACKGROUND: Multiple myeloma (MM) can be accompanied by amyloidosis, which occurs in a small number of patients and is characterized by deposition of light chains in the joints, leading to multiple myeloma-associated amyloid arthropathy (MAA). As a rare complication of MM, clinical manifestations of MAA are often similar to those of rheumatoid arthritis, and the two are easily confused. CASE SUMMARY: In recent years, our center treated two patients of MM with amyloid arthropathy as the first manifestation, both of whom presented with polyarthritis. After treatment for MM, both patients achieved complete remission. However, subsequently, the two patients underwent hip arthroplasty for femoral neck fractures. Congo red staining and immunofluorescence of the joint tissues confirmed MAA after surgery. Eventually, one of the patients died of MM recurrence, while the other survived. CONCLUSION: MAA should be regarded as an initial symptom of MM and should be taken seriously.

Targeted pharmacokinetics and bioinformatics screening strategy reveals JAK2 as the main target for Xin-Ji-Er-Kang in treatment of MIR injury.

BACKGROUND AND PURPOSE: Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury. EXPERIMENTAL APPROACH: Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro. RESULTS: Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2. CONCLUSION: XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.

Olmesartan Improves Hepatic Sinusoidal Remodeling in Mice with Carbon Tetrachloride-Induced Liver Fibrosis.

Aim: In mice with liver fibrosis produced by carbon tetrachloride (CCl4), the effects of olmesartan on intrahepatic angiogenesis and sinusoidal remodeling will be evaluated. Methods: By injecting CCl4 into the peritoneal cavity, we established a mouse model of liver fibrosis. Using Sirius red and Masson trichrome staining, the extent of liver fibrosis in the animals was determined. Using immunohistochemical labeling and western blotting, the level of α-smooth muscle actin (α-SMA) expression, a characteristic of hepatic stellate cell activation, was assessed. Electron microscopy was used to determine the effect of olmesartan on hepatic sinusoidal capillarization, and immunohistochemical labeling was used to determine the expression levels of endothelial and basement membrane proteins in mouse liver tissues. Platelet-derived growth factor (PDGF), IL-10, vascular endothelial growth factor (VEGF), and angiotensin II levels in mouse serum were measured by Luminex multifactor analysis and ELISA. Olmesartan's effect on the angiotensin II type 1 receptor (AT1R) and the VEGF receptor (VEGFR) was evaluated using western blotting. Results: Olmesartan reduced CCl4-induced inflammatory cell infiltration and collagen deposition to alleviate liver fibrosis. α-SMA expression was decreased, and HSC activation was inhibited in mouse liver tissues by olmesartan treatment. In addition, hepatic sinusoidal capillarization was improved under the action of olmesartan. The expression of collagen IV, fibronectin, CD31, and von Willebrand factor (VWF) in the olmesartan group was also markedly downregulated. In fibrotic mice, olmesartan medication decreased the levels of PDGF, VEGF, and angiotensin II, but it increased the level of IL-10. Moreover, olmesartan reduced the expression of VEGFR-1, VEGFR-2, and AT1R relative to CCl4-induced liver fibrosis. Conclusions: In mice with CCl4-induced fibrosis, olmesartan lowers angiogenesis and improves hepatic sinusoidal remodeling, according to our findings. By acting on the angiotensin II-AT1R-VEGF axis, this is achieved.

Mitochondrial genomes of Sternochetus species (Coleoptera: Curculionidae) and the phylogenetic implications.

The three weevil species, Sternochetus gravis, S. mangiferae, and S. olivieri, have all been reported to be serious pests of mango fruits. Morphology, biology, and various management approaches of these economically important weevils have been well studied. However, no mitochondrial genomes have been reported from the genus Sternochetus. Herein, we assembled mitogenomes of all the three Sternochetus species to reveal their mitogenomic characteristics. A DNA library of 350 bp insert size was constructed and sequenced in Illumina's HiSeq 6000 platform with a pair-end 150 bp sequencing strategy by Novogene. The sequence reads were assembled using GetOrganelle v1.7.1 and the genes were annotated by Geneious Prime 2021.0.3 and MITOS Web Server. Coupled with 61 published mitogenomes from 13 subfamilies of Curculionidae, we reconstructed phylogenetic trees to resolve evolutionary relationships of these closely related species and also examined subfamily-level classification among Curculionidae. All three mitogenomes are double-stranded circular molecules with 22 transfer RNA genes, 13 protein-coding genes (PCGs), 2 ribosomal RNA genes, and 1 noncoding control region as in other insects. Higher interspecific nucleotide divergence (about 10%) of 13 PCGs indicated these three Sternochetus species diverged a long time ago. Phylogenetic analyses using both maximum likelihood and Bayesian inference methods showed that Sternochetus falls into the basal clade of Cryptorhynchini, a tribe in the subfamily Molytinae. The relationship of S. olivieri as a sister species to S. gravis + S. mangiferae was strongly supported. The monophyly of Cryptorhynchini was also well supported whereas Molytinae was suggested to be a polyphyletic group.

Genetic diversity and genetic structure of Puya raimondii (Bromeliaceae) for its conservation in the Peruvian Andes

Resumen Puya raimondii es una especie endémica de los altos Andes de Perú y Bolivia. En el Perú se distribuye desde 8.068501°S, 16.170280°W hasta 16.180580° S, 70.658873° W, entre los 3600 y 4800 m de altitud, viviendo en condiciones climáticas extremas propias de la Puna, donde juega un papel ecológico importante. Pese a la amplia distribución de las poblaciones de P. raimondii en el Perú, aparentemente son bastante uniformes morfológicamente; por lo que surgen las siguientes preguntas: ¿Podrán las actuales herramientas moleculares mostrar diferencias entre las numerosas poblaciones? ¿Son suficientes las áreas de conservación establecidas para P. raimondii ya que albergan la variabilidad existente? Para responder a estas interrogantes, este trabajo tuvo como objetivo evaluar la diversidad genética y estructura genética en una población del norte del país, Pachapaqui (departamento de Ancash), una población del centro, Yanacancha (Junín), y una población del sur, Lampa - sector Choconchaca (Puno), utilizando marcadores microsatélites (SSR) específicos para la especie. Los parámetros de diversidad genética utilizados incluyeron número de alelos (A), alelos exclusivos (RA), heterocigosidad observada (Ho), heterocigosidad esperada (He) e índice de contenido polimórfico (PIC). Los resultados mostraron que el número total de A varió de 2 ‒ 13, los valores de He fueron 0 ‒ 0.723 y Ho 0 ‒ 0.929, con un He promedio de 0.217, indicando una diversidad genética moderada a alta, siendo la población de Lampa-sector Choconchaca, la que presentó mayor diversidad alélica y mayor diversidad genética. La prueba de Hardy-Weinberg mostró que las poblaciones se encuentran en desequilibrio HW, el análisis estadístico indica un 65% de variación genética a nivel poblacional y valores de FST (0.426) y RST (0.650) que indican alta diferenciación genética entre poblaciones, con dos grupos genéticos (K=2) que corresponden a las poblaciones del centro-norte y sur del Perú. Los resultados brindan información útil para establecer estrategias de conservación para P. raimondii, que conduzcan a la creación de una área de conservación adicional para proteger a las poblaciones del sur del Perú.

Abstract Puya raimondii is an endemic species from the high Andes of Peru and Bolivia. In Peru it is distributed from 8.068501°S, 16.170280°W to 16.180580°S, 70.658873°W, between 3600 and 4800 m, living in extreme climatic conditions typical of the Puna, where it plays an important ecological role. Despite the wide distribution of P. raimondii populations in Peru, they appear to be fairly uniform morphologically. The following questions arise: Will the current molecular tools be able to show differences between the numerous populations? Are the conservation areas established for P. raimondii sufficient since they harbor the existing variability? To answer these questions, this work aimed to evaluate the genetic diversity and genetic structure in a northern population, Pachapaqui (Ancash department), a central population, Yanacancha (Junin), and a southern population, Lampa - Choconchaca sector (Puno), using microsatellite markers (SSR) specific for the species. The genetic diversity parameters used included number of alleles (A), exclusive alleles (RA), observed heterozygosity (Ho), expected heterozygosity (He), and polymorphic content index (PIC). The results showed that the total number of A varied from 2 - 13, the He values were 0 ‒ 0.723 and Ho 0 ‒ 0.929, with an average He of 0.217, indicating a moderate to high genetic diversity, being the population of Lampa-Choconchaca sector, the one that presented the greatest allelic diversity and the greatest genetic diversity. The Hardy-Weinberg test showed that the populations are in HW disequilibrium, the statistical analysis indicates 65% of the genetic variation at the population level and values of FST (0.426) and RST (0.650) that indicate high genetic differentiation among populations, with two genetic groups (K=2) that correspond to the populations of northern-central and southern Peru. The results provide useful information to establish conservation strategies for P. raimondii, which lead to the creation of an additional conservation area to protect the populations in southern Peru.

Plastome-based phylogeny improves community phylogenetics of subtropical forests in China.

Phylogenetic trees have been extensively used in community ecology. However, how the phylogeny construction affects ecological inferences is poorly understood. In this study, we constructed three different types of phylogenetic trees (a synthetic-tree generated using V.PhyloMaker, a barcode-tree generated using rbcL+matK+trnH-psbA, and a plastome-tree generated from plastid genomes) that represented an increasing level of phylogenetic resolution among 580 woody plant species from six forest dynamic plots in subtropical evergreen broadleaved forests of China. We then evaluated the performance of each phylogeny in estimations of community phylogenetic structure, turnover and phylogenetic signal in functional traits. As expected, the plastome-tree was most resolved and most supported for relationships among species. For local phylogenetic structure, the three trees showed consistent results with Faith's PD and MPD; however, only the synthetic-tree produced significant clustering patterns using MNTD for some plots. For phylogenetic turnover, contrasting results between the molecular trees and the synthetic-tree occurred only with nearest neighbor distance. The barcode-tree agreed more with the plastome-tree than the synthetic-tree for both phylogenetic structure and turnover. For functional traits, both the barcode-tree and plastome-tree detected phylogenetic signal in maximum height, but only the plastome-tree detected signal in leaf width. This is the first study that uses plastid genomes in large-scale community phylogenetics. Our results highlight the improvement of plastome-trees over barcode-trees and synthetic-trees for the analyses studied here. Our results also point to the possibility of type I and II errors in estimation of phylogenetic structure and turnover and detection of phylogenetic signal when using synthetic-trees.

Plastid phylogenomics and biogeographic analysis support a trans-Tethyan origin and rapid early radiation of Cornales in the Mid-Cretaceous.

The Cornales is a relatively small but morphologically diverse order in the basal position of the Asterids clade. Previous study hypothesized that the order might have undergone ancient rapid radiation during the Cretaceous when major angiosperm lineages were established. We conducted the phylogenomic analysis of Cornales using 81 plastid genome sequences with 67 newly generated in this study to test the hypothesis. This sampling represents all the families and 31 out of 48 genera in the order. Phylogenetic analyses were conducted using different datasets to examine the effects of different coding positions and character coding methods. We further conducted divergence time, diversification rate, and biogeographic analyses to understand the early evolutionary history of Cornales in space and time. Our phylogenetic analyses of four datasets (the amino acid characters, the 1st and 2nd codon positions of protein coding genes, nucleotide characters with degenerated coding method, and noncoding regions) resulted in a robust phylogeny congruent with results of previous studies, showing (((Cornaceae-Alangiaceae)-(Curtisiaceae-Grubbiaceae))-(((Nyssaceae-Davidiaceae)-Mastixiaceae)-((Hydrostachyaceae-(Hydrangeaceae-Loasaceae)))). Phylogenetic relationships within families were also well resolved. Conflicts in the placement of Hydrostachyaceae were found from analyses of two datasets, the nucleotide characters of all codon position and the 3rd codon positions, where the family was united with Loasaceae, but not strongly supported. Results from divergence time analyses suggested a mid-Cretaceous origin of Cornales followed by rapid early diversification into major clades/families within 10 million years. The early diversification of Cornales may have been facilitated by divergence in habitat and morphology following geographic dispersals. The ancestral distribution of the order was inferred as a widespread range covering Asia, Europe, North America, and Africa when including fossils in the analyses, suggesting an origin of the order likely along the Tethys Seaway where the areas were connected in the mid-Cretaceous. Inferred geographic origins of each family differed to some extent between analyses including fossils vs excluding fossils. In the analysis with extant and fossil species, the origins of the African Hydrostachyaceae and Grubbiaceae-Curtisiaceae clade were inferred to have involved two independent events, an intercontinental dispersal from the northern hemisphere to Africa and an intercontinental vicariance between the northern hemisphere and Africa, respectively. Other families were inferred to have evolved in the northern hemisphere with subsequent intercontinental dispersal(s) to other areas including to Central and South America, during their subsequent diversification. Net diversification rate analysis based on treePL dated phylogeny using MEDUSA detected a nearly 5-fold decrease in the African endemic Curtisiaceae-Grubbiaceae (CuG) clade and an increase of rate in the Hydrangeaceae-Loasaceae (HL) clade. Within HL, a decrease in the Fendlera-Jamesia clade and an increase in the Philadelphus clade were also detected. The findings are also consistent with the level of present species diversity in these lineages. Our study demonstrated the value of plastid genome in phylogenomic study, but posed an old challenge of biogeographic study with fossil data and raised caution for the synonymous substitution sites of plastid genome in phylogenomics studies.

[Curcumin Increases the Chemosensitivity of Multiple Myeloma to Bortezomib by Inhibiting the Notch1 Signaling Pathway].

OBJECTIVE: To evaluated the effect of curcumin on the bortezomib-resistant myeloma cells and the expression of Notch1 signaling pathway, in order to further explore its potential mechanism. METHODS: Curcumin, bortezomib, and curcumin combined bortezomib were added into RPMI 8266, U266, 5 nmol/L bortezomib-resistant RPMI 8266 (RPMI 8226-V5R), 5 nmol/L bortezomib-resistant U 266 (U266-V5R) and CD138+ plasma cells respectively. The cell proliferation was measured by MTT assay. the apoptotic rate was determined by flow cytometry, and the Western blot was used to detect the expression of apoptosis-related proteins. Then, the expression of Notch1 in cells was inhibited by notch1 inhibitor DAPT and RNA interference, the above-motioned experiments should be repeated. RESULTS: Compared with single drug-treated groups, the treatment with 2 drugs could further inhibit cell proliferation, induce apoptosis and enhance the inhibition effect on notch1 signaling pathway (P<0.05), while the inhibiting Notch1 signaling pathway could reduce cell proliferation and increase the expression of cleaved caspase-3. CONCLUSION: Curcumin can increase chemosensitivity of myeloma cells to bortezomib, this effect may be related to the inhibition of Notch1.

Ancient Polyploidy and Genome Evolution in Palms.

Mechanisms of genome evolution are fundamental to our understanding of adaptation and the generation and maintenance of biodiversity, yet genome dynamics are still poorly characterized in many clades. Strong correlations between variation in genomic attributes and species diversity across the plant tree of life suggest that polyploidy or other mechanisms of genome size change confer selective advantages due to the introduction of genomic novelty. Palms (order Arecales, family Arecaceae) are diverse, widespread, and dominant in tropical ecosystems, yet little is known about genome evolution in this ecologically and economically important clade. Here, we take a phylogenetic comparative approach to investigate palm genome dynamics using genomic and transcriptomic data in combination with a recent, densely sampled, phylogenetic tree. We find conclusive evidence of a paleopolyploid event shared by the ancestor of palms but not with the sister clade, Dasypogonales. We find evidence of incremental chromosome number change in the palms as opposed to one of recurrent polyploidy. We find strong phylogenetic signal in chromosome number, but no signal in genome size, and further no correlation between the two when correcting for phylogenetic relationships. Palms thus add to a growing number of diverse, ecologically successful clades with evidence of whole-genome duplication, sister to a species-poor clade with no evidence of such an event. Disentangling the causes of genome size variation in palms moves us closer to understanding the genomic conditions facilitating adaptive radiation and ecological dominance in an evolutionarily successful, emblematic tropical clade.

Homeologue-specific expression divergence in the recently formed tetraploid Capsella bursa-pastoris (Brassicaceae).

Following allopolyploid formation, extensive genome evolution occurs, with the eventual loss of many homeologous gene copies. Although this process of diploidization has occurred many times independently, the evolutionary forces determining the probability and rate of gene loss remain poorly understood. Here, we conduct genome and transcriptome sequencing in a broad sample of Chinese accessions of Capsella bursa-pastoris, a recently formed allotetraploid. Our whole genome data reveal three groups of these accessions: an Eastern group from low-altitude regions, a Western group from high-altitude regions, and a much more differentiated Northwestern group. Population differentiation in total expression was limited among closely related populations; by contrast, the relative expression of the two homeologous copies closely mirrors the genome-wide SNP divergence. Consistent with this, we observe a negative correlation between expression changes in the two homeologues. However, genes showing population genomic evidence for adaptive evolution do not show an enrichment for expression divergence between homeologues, providing no clear evidence for adaptive shifts in relative gene expression. Overall, these patterns suggest that neutral drift may contribute to the population differentiation in the expression of the homeologues, and drive eventual gene loss over longer periods of time.

Water-oil Janus emulsions: microfluidic synthesis and morphology design.

In this work we developed a facile method to prepare water-oil Janus emulsions in situ with tunable morphologies by using a double-bore capillary microfluidic device. In addition, by combining the theory model and our liquids' properties, we propose a method to design the morphology of water-oil Janus emulsions. To systematically research Janus morphologies we combined the theory model and the fluids' properties. Under the model guidance, we carefully selected the liquids system where only the interfacial tension between the water phase and the continuous phase changed while keeping the other two interfacial tensions unchanged. Thus we could adjust the Janus morphology by changing the surfactant mass fraction in the continuous phase. In addition, with the double-bore capillary, we prepared water-oil Janus emulsions with a large flow ratio range. By adjusting the flow ratio and the surfactant mass fraction, we successfully prepared Janus emulsions with gradual morphology changes, which would be meaningful in fields that have a high demand for morphology designing of amphiphilic Janus particles.

The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the antiproliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA.

Metadherin contributes to the pathogenesis of chronic lymphocytic leukemia partially through Wnt/ß-catenin pathway.

Metadherin (MTDH) is involved in aberrant proliferation, migration, and chemoresistance of tumor cells. It has been demonstrated that it can promote tumor growth by modulation multiple oncogenic signaling pathways. However, MTDH expression, significance, and related mechanism in chronic lymphocytic leukemia (CLL) are still unclear. The objective of this study was to investigate the expression of MTDH in CLL and the involvement of Wnt/ß-catenin signaling pathway in MTDH effects. Overexpression of MTDH mRNAs was seen in CLL samples. MTDH expression was associated with Rai stage classification of CLL, and altered levels of ß2-MG and lactate dehydrogenase in serum samples from patients. Overexpression of MTDH protein was seen in 87 % of CLL samples. Specific siRNAs inhibited MEC-1 cell growth and enhanced cell apoptosis (P < 0.05). Inhibition of MTDH expression resulted in decreased expression levels of lymphoid enhancer-binding factor 1 (LEF-1), and its downstream target genes c-myc and cyclin D1. And there was a strong correlation between MTDH and LEF-1 protein expression in 14 patients with CLL. The results demonstrate that MTDH is specifically expressed in B cell of CLL and exert a preservative role through activation of Wnt signaling pathway. Our findings indicated that MTDH may be a potential therapeutic target of CLL.

Comparative evolutionary diversity and phylogenetic structure across multiple forest dynamics plots: a mega-phylogeny approach.

Forest dynamics plots, which now span longitudes, latitudes, and habitat types across the globe, offer unparalleled insights into the ecological and evolutionary processes that determine how species are assembled into communities. Understanding phylogenetic relationships among species in a community has become an important component of assessing assembly processes. However, the application of evolutionary information to questions in community ecology has been limited in large part by the lack of accurate estimates of phylogenetic relationships among individual species found within communities, and is particularly limiting in comparisons between communities. Therefore, streamlining and maximizing the information content of these community phylogenies is a priority. To test the viability and advantage of a multi-community phylogeny, we constructed a multi-plot mega-phylogeny of 1347 species of trees across 15 forest dynamics plots in the ForestGEO network using DNA barcode sequence data (rbcL, matK, and psbA-trnH) and compared community phylogenies for each individual plot with respect to support for topology and branch lengths, which affect evolutionary inference of community processes. The levels of taxonomic differentiation across the phylogeny were examined by quantifying the frequency of resolved nodes throughout. In addition, three phylogenetic distance (PD) metrics that are commonly used to infer assembly processes were estimated for each plot [PD, Mean Phylogenetic Distance (MPD), and Mean Nearest Taxon Distance (MNTD)]. Lastly, we examine the partitioning of phylogenetic diversity among community plots through quantification of inter-community MPD and MNTD. Overall, evolutionary relationships were highly resolved across the DNA barcode-based mega-phylogeny, and phylogenetic resolution for each community plot was improved when estimated within the context of the mega-phylogeny. Likewise, when compared with phylogenies for individual plots, estimates of phylogenetic diversity in the mega-phylogeny were more consistent, thereby removing a potential source of bias at the plot-level, and demonstrating the value of assessing phylogenetic relationships simultaneously within a mega-phylogeny. An unexpected result of the comparisons among plots based on the mega-phylogeny was that the communities in the ForestGEO plots in general appear to be assemblages of more closely related species than expected by chance, and that differentiation among communities is very low, suggesting deep floristic connections among communities and new avenues for future analyses in community ecology.

Metadherin interference inhibits proliferation and enhances chemo-sensitivity to doxorubicin in diffuse large B cell lymphoma.

Metadherin (MTDH) is highly expressed in many tumors and is involved in the proliferation, metastasis and drug resistance of tumor cells by regulating multiple signaling pathways. Our previous studies demonstrated that MTDH is overexpressed in diffuse large B cell lymphoma (DLBCL) and involved in apoptosis resistance, in part, via Wnt signaling. Here, we investigated the role of MTDH in the chemo-sensitivity of DLBCL. The study was performed in the DLBCL cell line LY8 to investigate the relationship between MTDH expression and doxorubicin (DOX) sensitivity in DLBCL. A MTDH interference model was developed in LY8 cells by transfected with lentivirus which is carrying MTDH interference sequence. Western blot was used to detect the protein expression. A CCK-8 assay was used to evaluate cell proliferation. The results showed that DOX treatment had no effect on the intracellular MTDH expression of LY8 cells. The proliferation of LY8 cells was inhibited after MTDH interference. MTDH interference increased the DOX sensitivity in the LY8 cell lines. The results suggested that MTDH is a potential therapeutic target in DLBCL, and it cooperates with DOX in treatment of DLBCL.