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Abstract Droplet‐based bioprinting has shown remarkable potential in tissue engineering and regenerative medicine. However, it requires bioinks with low viscosities, which makes it challenging to create complex 3D structures and spatially pattern them with different materials. This study introduces a novel approach to bioprinting sophisticated volumetric objects by merging droplet‐based bioprinting and cryobioprinting techniques. By leveraging the benefits of cryopreservation, we fabricated, for the first time, intricate, self‐supporting cell‐free or cell‐laden structures with single or multiple materials in a simple droplet‐based bioprinting process that is facilitated by depositing the droplets onto a cryoplate followed by crosslinking during revival. The feasibility of this approach is demonstrated by bioprinting several cell types, with cell viability increasing to 80%–90% after up to 2 or 3 weeks of culture. Furthermore, the applicational capabilities of this approach are showcased by bioprinting an endothelialized breast cancer model. The results indicate that merging droplet and cryogenic bioprinting complements current droplet‐based bioprinting techniques and opens new avenues for the fabrication of volumetric objects with enhanced complexity and functionality, presenting exciting potential for biomedical applications.

Summary: Foodborne illness caused by consuming foods contaminated by pathogens remains threating to the public health. Despite considerable efforts of using renewable source materials, it is highly demanding to fabricate food packaging with multiple properties including eco-friendliness, bactericidal effect and biocompatibility. Here, sodium lignosulfonate (SL) and ZnO nanoparticles (ZnO NPs) were used as functional filler and structure components, respectively, on the cellulose nanofibers (CNFs)-based films, which endows the produced membrane (CNF/SL-ZnO) the UV-light blocking, antioxidant, and antimicrobial characteristics. Due to the interconnected polymeric structure, the prepared CNF/SL-ZnO films possessed considerable mechanical properties, thermal stability, and good moisture barrier capability. Moreover, the tested samples exhibited an improved shelf life in food packaging. Furthermore, metagenome analysis revealed superior biodegradability of obtained films with negligible side effect on the soil microenvironment. Therefore, the biocompatible, degradable, and antibacterial CNF/SL-ZnO film holds enormous potential for sustainable uses including food packaging.

Symbiotic microorganisms in reef-building corals, including algae, bacteria, archaea, fungi, and viruses, play critical roles in the adaptation of coral hosts to adverse environmental conditions. However, their adaptation and functional relationships in nutrient-rich environments have yet to be fully explored. This study investigated Duncanopsammia peltata and the surrounding seawater and sediments from protected and non-protected areas in the summer and winter in Dongshan Bay. High-throughput sequencing was used to characterize community changes, co-occurrence patterns, and factors influencing symbiotic coral microorganisms (zooxanthellae, bacteria, and archaea) in different environments. The results showed that nutrient enrichment in the protected and non-protected areas was the greatest in December, followed by the non-protected area in August. In contrast, the August protected area had the lowest nutrient enrichment. Significant differences were found in the composition of the bacterial and archaeal communities in seawater and sediments from different regions. Among the coral symbiotic microorganisms, the main dominant species of zooxanthellae is the C1 subspecies (42.22–56.35%). The dominant phyla of bacteria were Proteobacteria, Cyanobacteria, Firmicutes, and Bacteroidota. Only in the August protected area did a large number (41.98%) of SAR324_cladeMarine_group_B exist. The August protected and non-protected areas and December protected and non-protected areas contained beneficial bacteria as biomarkers. They were Nisaea, Spiroplasma, Endozoicomonas, and Bacillus. No pathogenic bacteria appeared in the protected area in August. The dominant phylum in Archaea was Crenarchaeota. These symbiotic coral microorganisms’ relative abundances and compositions vary with environmental changes. The enrichment of dissolved inorganic nitrogen in environmental media is a key factor affecting the composition of coral microbial communities. Co-occurrence analysis showed that nutrient enrichment under anthropogenic disturbances enhanced the interactions between coral symbiotic microorganisms. These findings improve our understanding of the adaptations of coral holobionts to various nutritional environments.

Abstract Three‐dimensional (3D) printing is an emerging technique that has shown promising success in engineering human tissues in recent years. Further development of vat‐photopolymerization printing modalities has significantly enhanced the complexity level for 3D printing of various functional structures and components. Similarly, the development of microfluidic chip systems is an emerging research sector with promising medical applications. This work demonstrates the coupling of a digital light processing (DLP) printing procedure with a microfluidic chip system to produce size‐tunable, 3D‐printable porosities with narrow pore size distributions within a gelatin methacryloyl (GelMA) hydrogel matrix. It is found that the generation of size‐tunable gas bubbles trapped within an aqueous GelMA hydrogel‐precursor can be controlled with high precision. Furthermore, the porosities are printed in two‐dimensional (2D) as well as in 3D using the DLP printer. In addition, the cytocompatibility of the printed porous scaffolds is investigated using fibroblasts, where high cell viabilities as well as cell proliferation, spreading, and migration are confirmed. It is anticipated that the strategy is widely applicable in a range of application areas such as tissue engineering and regenerative medicine, among others.

Coral reefs are typically found in nutrient-limited waters, which may restrict the growth and expansion of corals. Nevertheless, corals are mixotrophs that may adjust to the variation in the availability of energy sources by switching their major nutritional mode between autotrophy (i.e., synthesizing their own food by symbionts) and heterotrophy (i.e., consuming external food sources). Such trophic plasticity may, however, be subject to symbiont genus and environmental conditions. Using a widespread coral species (Pocillopora damicornis), we examine how symbiont genus (Cladocopium vs. Durusdinium) affects the physiological traits (biomass, symbiont density, C:N ratio and chlorophyll content) of corals and their trophic strategy across seasons (summer and winter) based on stable isotope markers (δ13C and δ15N). We found that corals dominated by Cladocopium (PdC) had a lower symbiont density, but higher autotrophic capacity (higher cellular chlorophyll content and higher δ13C) than those by Durusdinium (PdD). Across seasons, the trophic strategy of PdC was flexible that the autotrophic capacity was reduced by 37.1 % from summer to winter, whereas the trophic strategy of PdD remained relatively unchanged. PdC had a greater heterotrophic capacity in winter, while PdD in summer. Our findings suggest that symbiont genus can determine the trophic flexibility of corals and drive trophic niche differentiation between conspecific corals. By adaptively changing trophic strategy, intraspecific competition of corals for energy sources can be reduced, possibly allowing them to persist in oligotrophic waters and adapt to the future oceanic climate.

Seasonal thermal stratification is a common environmental phenomenon in reservoir water bodies and an important research topic for deep water reservoirs. A thermally stratified reservoir is an ideal system for investigating the interaction between factors affecting the environment and microorganism communities under spatial–temporal variation. However, few studies have focused on the effects of water stratification and mixing periods in microbial communities and nitrogen conversion. Therefore, using metagenomic sequencing and quantitative polymerase chain reaction, we investigated the microbial diversity and function in the Xin'anjiang Reservoir during water stratification and mixing period. Principal component analysis indicated that the bacterial communities were mostly affected by water stratification, mainly at 10-m depths, whereas the archaea community was influenced by the entire water profile. The predominant archaeal phyla changed from Candidatus_Woesearchaeota and Euryarchaeota to Thaumarchaeota with the increasing water depth during water stratification. The stratified variations of the dominant archaeal phyla strongly reflected the seasonal changes and vertical gradient in water temperature, dissolved oxygen, and pH. Linear regression analysis indicated that variations in microbial composition altered the overall functional attributes of the communities, especially in the archaeal community. Regarding nitrogen metabolism across the whole reservoir, the number of nitrification and denitrification genes dropped in the same direction as the river flow in spring and summer, while the opposite trend was observed in autumn and winter. The functional genes of the water profiles in the transitional and lacustrine zones varied considerably except in winter. Additionally, the copies of nitrification-related genes were more during the stratification stage than during the mixing stage, whereas copies of denitrification-related genes showed the opposite trend. Overall, this study provides unique insights regarding the effects of seasonal stratification on the distribution and function of microorganisms in large-deep reservoirs, which should be considered when establishing guidelines for reservoirs management.

ABSTRACTThe establishment, maintenance and dynamic regulation of three-dimensional (3D) chromatin structures provide an important means for partitioning of genome into functionally distinctive domains, which helps to define specialized gene expression programs associated with developmental stages and cell types. Increasing evidence supports critical roles for intrinsically disordered regions (IDRs) harbored within transcription factors (TFs) and chromatin-modulatory proteins in inducing phase separation, a phenomenon of forming membrane-less condensates through partitioning of biomolecules. Such a process is also critically involved in the establishment of high-order chromatin structures and looping. IDR- and phase separation-driven 3D genome (re)organization often goes wrong in disease such as cancer. This review discusses about recent advances in understanding how phase separation of intrinsically disordered proteins (IDPs) modulates chromatin looping and gene expression.

Bisphenol AF (BPAF) is an emerging endocrine-disrupting chemical (EDC) prevalent in the environment as one of the main substitutes for bisphenol A. Sex-specific effects of EDCs have been commonly reported and closely linked to sexually dimorphic patterns of hormone metabolism and related gene expression during different exposure windows, but our understanding of these mechanisms is still limited. Here, following 28-day exposure of adult zebrafish to an environmentally relevant concentration of BPAF at 10 μg/L, the global transcriptional networks applying RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) were respectively investigated in the male and female fish liver, connecting the sex-dependent toxicity of the long-term exposure of BPAF to molecular responses. As a result, more differentially expressed genes (DEGs) were detected in males (811) than in females (195), and spermatogenesis was the most enriched Gene Ontology (GO) functional classification in males, while circadian regulation of gene expression was the most enriched GO term in females. The expression levels of selected DEGs were routinely verified using qRT-PCR, which showed consistent alterations with the transcriptional changes in RNA-seq data. The causal network analysis by IPA suggested that the adverse outcomes of BPAF in males including liver damage, apoptosis, inflammation of organ, and liver carcinoma, associated with the regulation of several key DEGs detected in RNA-seq, could be linked to the activation of upstream regulatory molecules ifnα, yap1, and ptger2; while, the inhibition of upstream regulators hif1α, ifng, and igf1, leading to the down-regulated expression of several key DEGs, might be involved in BPAF’s effects in females. Furthermore, BPAF exposure altered hepatic histological structure and inhibited antioxidant capability in both male and female livers. Overall, this study revealed different regulation networks involved in the sex-dependent effects of BPAF on the fish liver, and these detected DEGs upon BPAF exposure might be used as potential biomarkers for further assessing sex-specific hepatotoxicity following environmental EDC exposure.

Summary: Lineage plasticity, especially transdifferentiation between neural/neuroendocrine (NE) and non-NE lineage, has been observed in multiple cancer types and linked to increased tumor aggressiveness. However, existing NE/non-NE subtype classifications in various cancer types were established through ad hoc approaches in different studies, making it difficult to align findings across cancer types and extend investigations to new datasets. To address this issue, we developed a generalized strategy to generate quantitative NE scores and a web application to facilitate its implementation. We applied this method to nine datasets covering seven cancer types, including two neural cancers, two neuroendocrine cancers, and three non-NE cancers. Our analysis revealed significant NE inter-tumoral heterogeneity and identified strong associations between NE scores and molecular, histological, and clinical features, including prognosis in different cancer types. These results support the translational utility of NE scores. Overall, our work demonstrated a broadly applicable strategy for determining the NE properties of tumors.

Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. In this study, we created a wide variety of engineered therapeutic cells (ThC) loaded in micropore-forming gelatin methacryloyl (GelMA) hydrogel (CellDex) capsules that can be cultured in vitro prior to their transplantation in surgically debulked solid tumors. We show that both allogeneic and autologous engineered cells, such as stem cells (SCs), macrophages, NK cells, and T cells, proliferate within CellDex capsules and migrate out of the gel in vitro and in vivo. Furthermore, tumor cell specific therapeutic proteins and oncolytic viruses released from CellDex capsules retain and prolong their anti-tumor effects. In vivo, ThCs in pre-manufactured Celldex capsules persist long-term and track tumor cells. Moreover, chimeric antigen receptor (CAR) T cell bearing CellDex (T-CellDex) and human SC releasing therapeutic proteins (hSC-CellDex) capsules show therapeutic efficacy in metastatic and primary brain tumor resection models that mimic standard of care of tumor resection in patients. Overall, this unique approach of pre-manufactured micropore-forming CellDex capsules offers an effective off-the-shelf clinically viable strategy to treat solid tumors locally.

Epibacteria of seaweeds play an important role for the development of hosts and are influenced by the planktonic surrounding seawater bacteria. However, to date, the knowledges related to both epiphytic and surrounding seawater bacterial communities associated with northern farmed Saccharina japonica are very limited. In this study, using 16S rRNA gene amplicon sequencing, the shifts of epiphytic and surrounding seawater bacterial communities of the northern farmed S. japonica from mature sporophytes, sporelings (3 time points) to juvenile sporophytes (2 time points) were investigated. The dominant genera of epibacterial communities were Alcanivorax (mature sporophytes and 4-week-old sporelings), Bacillus (7-week-old sporelings and 9-week-old sporelings), Halomonas (4-week-old juvenile sporophytes) and Cobetia (9-week-old juvenile sporophytes). Meanwhile, the Chao1 indexes and beta diversity of epibacterial communities were significantly different with the development of S. japonica (p < 0.05). Furthermore, Alcanivorax, Bacillus and Halomonas were both dominant and core genera, indicating that these taxa may be beneficial to the development of S. japonica. The alpha diversity indexes of both epiphytic and surrounding seawater bacterial communities were significantly different for 9-week-old juvenile sporophytes. Therefore, the epibacterial communities were influenced by both development of S. japonica and the surrounding seawater bacterial communities. This study not only extends the understanding of the bacterial communities associated with the northern farmed S. japonica, but also help to make production management by monitoring the variations in both epiphytic and surrounding seawater bacterial communities.

Scientific selection of an ecological restoration approach from among the three common approaches: natural restoration, assisted restoration, and ecological reconstruction is the first step to successful ecological restoration. This study chose the appropriate ecological restoration approach for the study area from the following two perspectives. The threshold effect considers the degree of damage to the muddy coast and makes an estimate of its resilience. The development needs of the coastal zone consider the needs of muddy coasts for ecological protection, safety, and culture and aesthetics; development planning aims to determine the priority of these three needs. This study also assessed common technical measures for ecological restoration of muddy coasts and analyzed the applicability and advantages and disadvantages of each perspective to assist in the selection of specific ecological restoration measures suited to local conditions. The target area for ecological restoration was the muddy coastal area around Yundanmen Island, Sansha Bay, Ningde City, China, which had been degraded by reclamation and aquaculture. Based on conceptual models for selection, ecological restoration approaches for the study area were determined, technical measures were selected, and the plan was developed and implemented. We analyzed the initial effects of ecological restoration on birds, vegetation, and benthic organisms to verify the effectiveness of the chosen ecological restoration approach. This study provides scientific support for rationally planning the ecological restoration of muddy coasts and a reference for the selection of other coastal ecological restoration approaches and technical measures.

Ecological footprint is an operational quantitative method to convert the biological resources consumed by human beings and the wastes discharged into bioproductive land area. Compared to the ecological carrying capacity, the ecological footprint model can evaluate the sustainability of regional development. However, owing to shortcomings in the evaluation of regional sustainable development, the ecological footprint model is unable to reflect the ecological inequity between regions caused by trade, and so it has been revised to a consumptive and productive ecological footprint model. The purpose of this study was to analyze the changing trends of productive and consumptive ecological footprint and deficit by calculating the ecological footprint of Xiamen City, China, from 2010 to 2019. This study also evaluates the sustainability and fairness of this zone's development and determines the patterns of its sustainable development. The results show that the productive ecological surplus of Xiamen increased by nearly 15 times from − 0.0084 in 2010 to 0.1165 in 2019, while the consumption ecological deficit increased by 30 times, from 0.0228 in 2010 to 0.3338 in 2019. Therefore, Xiamen is regionally sustainable but nationally unsustainable as it takes up the resources of other regions of the country. The city should take more responsibility for current national ecological problems. Therefore, within the rational range of its ecological carrying capacity, Xiamen should harness local natural resources, ensure a sufficient supply of local farmland, increase the yield per unit of agricultural products, and ensure consumption of more locally-produced products.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

PurposeTo systematically evaluate the effect of Sodium-glucose cotransporter 2 (SGLT2) inhibitors on adipose tissue in patients with type 2 diabetes.MethodsWe searched PubMed, Cochrane Library, EMBASE, and Web of science databases for literature pertaining to Randomized controlled trials (RCTs) of SGLT2 inhibitors in treating type 2 diabetes patients. The retrieval time was from the date of establishment of the databases to September 1, 2022. Meta-analysis was performed using RevMan5.4 software.ResultsTotally 551 patients were included in 10 articles. Meta-analysis results showed that compared with the control group, the visceral adipose tissue (WMD = -16.29 cm2, 95% CI: -25.07 ~ -7.50, P

We provide insights and innovative ideas for China to achieve green development and promote high-quality economic development by studying the impact of air quality on enterprise productivity. This paper uses data from 2008 to 2016 for A-share companies listed on the Shanghai and Shenzhen stock markets, as well as the levels of particulate matter under 2.5 μm in diameter for 214 major Chinese cities. At the same time, this paper innovatively applies regression discontinuity and the Spatial Durbin Model for empirical testing. Considering the endogeneity, we choose the air flow index as an instrumental variable and the generalized space two-stage least squares method for the endogenous test. Additionally, we use dynamic regression and different spatial weight matrix to conduct robustness tests and reselect data from 2008 to 2012 and 2013 to 2016 as samples. Moreover, we test corporate heterogeneity from three perspectives: pollutant type, firm equity, and an industry’s technological level. The results show that the deterioration of local air quality significantly inhibits firm productivity, while the spatial spillover effects of pollution from surrounding cities also have a significant dampening effect on firm productivity. This negative effect is transmitted through research and development innovation capacity, human capital, and government subsidies. This empirical evidence from listed companies can be used for evaluating air quality management to enhance enterprise productivity, as well as to provide policy recommendations for boosting firm productivity through improved air quality.

Abstract USP7, one of the most abundant ubiquitin-specific proteases (USP), plays multifaceted roles in many cellular events, including oncogenic pathways. Accumulated studies have suggested that USP7, through modulating the MDM2/MDMX-p53 pathway, is a promising target for cancer treatment; however, little is known about the function of USP7 in p53-deficient tumors. Here we report that USP7 regulates the autoregulation of SMAD3, a key regulator of transforming growth factor β (TGFβ) signaling, that represses the cell progression of p53-deficient lung cancer. CRISPR/Cas9-mediated inactivation of USP7 in p53-deficient lung cancer H1299 line resulted in advanced cell proliferation in vitro and in xenograft tumor in vivo. Genome-wide analyses (ChIP-seq and RNA-seq) of USP7 KO H1299 cells reveal a dramatic reduction of SMAD3 autoregulation, including decreased gene expression and blunted function of associated super-enhancer (SE). Furthermore, biochemical assays show that SMAD3 is conjugated by mono-ubiquitin, which negatively regulates the DNA-binding function of SMAD3, in USP7 KO cells. In addition, cell-free and cell-based analyses further demonstrate that the deubiquitinase activity of USP7 mediates the removal of mono-ubiquitin from SMAD3 and facilitates the DNA-binding of SMAD3-SMAD4 dimer at SMAD3 locus, and thus enhance the autoregulation of SMAD3. Collectively, our study identified a novel mechanism by which USP7, through catalyzing the SMAD3 de-monoubiquitination, facilitates the positive autoregulation of SMAD3, and represses the cancer progression of p53-deficient lung cancer.

Abstract Integrated renovation projects are important for marine ecological environment protection. Three-dimensional hydrodynamics and water quality models are developed for the Maowei Sea to assess the hydrodynamic environment base on the MIKE3 software with high resolution meshes. The results showed that the flow velocity changed minimally after the project, decreasing by approximately 0.12 m/s in the east of the Maowei Sea area and increasing by approximately 0.01 m/s in the northeast of the Shajing Port. The decrease in tidal prism (~ 2.66 × 106 m3) was attributed to land reclamation, and accounted for just 0.86% of the pre-project level. The water exchange half-life increased by approximately 1 day, implying a slightly reduced water exchange capacity. Siltation occurred mainly in the reclamation and dredging areas, amounting to back-silting of approximately 2 cm/year. Reclamation project is the main factor causing the decrease of tidal volume and weakening the hydrodynamics in Maowei Sea. Adaptive management is necessary for such a comprehensive regulation project. According to the result, we suggest that reclamation works should strictly prohibit and dredging schemes should optimize in the subsequent regulation works.

The benefit of induction chemotherapy before definitive chemoradiotherapy (CRT) for patients with esophageal cancer is still uncertain. The results of this phase II randomized trial show that the addition of induction chemotherapy to CRT does not improve the response rate or survival of patients with unresectable esophageal squamous cell carcinoma.

Despite its prominent therapeutic efficacy, chemotherapy has raised serious concerns due to the severe adverse effects and multidrug resistance evoked, which propels the search for safe and green therapeutic agents. BAMLET (bovine α-lactalbumin made lethal against tumor cell) is a well-known protein-based anticancer agent of selective tumoricidal activity. Here, we prepared oleic acid-modified mesoporous silica nanoparticles (OA-MSNs) conjugated with bovine α-lactalbumin, a lipoprotein complex resembling BAMLET formed on the surface of MSNs (MSN-BAMLET) to load the anticancer drug of docetaxel (DTX). Compared to that of OA-MSNs/DTX, the obtained MSN-BAMLET/DTX with a sustained and pH-responsive drug release behaviors exhibited good biocompatibility and enhanced cytotoxic effect against cancer cells. Moreover, the presence of lipoprotein complex in MSN-BAMLET contributed to the improved dispersion of the composite in solution and the inhibitory effect on the migration of cancer cells. Furthermore, the adsorption profiles of protein corona on the obtained nanoparticles were analyzed. It was found that the marked low amount and abundance of plasma proteins were adsorbed on the α-lactalbumin coated siliceous composite demonstrated its long circulation property. Finally, in vivo study showed that MSN-BAMLET/DTX contributed to the effective cancer ablation and the prolonged survival. Therefore, the constructed MSN-BAMLET of the mesoregular structure and peculiar tumoricidal effect provides a manipulable nanoplatform as drug nanocarrier for therapeutic applications.

How histone modifications crosstalk with DNA methylation to regulate epigenomic patterning and genome stability in mammals remains elusive. Here, the authors show that DNA methyltransferase DNMT1 is a reader for histone H4K20 trimethylation via its BAH1 domain, which leads to optimal maintenance of DNA methylation at repetitive LINE-1 elements.

Abstract Porphyrin iron molecules (hemin) were successfully grafted on the channeled mesoporous silica of SBA-15 (FeIX-SBA-15), in which attached hemin molecules acted as the enzyme mimic for catalyzing oxidation reactions. In the presence of H2O2, the prepared FeIX-SBA-15 composite effectively degraded industrial dye Orange II and catalyzed tetramethylbenzidine hydrochloride (TMB) both in the solution and on the membrane, from which the colorimetric H2O2 detection was achieved. Moreover, the hemin-grafted composites showed high loading content of anticancer drug of doxorubicin hydrochloride (DOX) displaying the sustained releasing behavior as monitored by real-time cell analysis, which resulted in improved inhibitory effect on cancer cells growth compared with that DOX/SBA-15. The hemin-modified mesoporous silica nanocomposite provides an integrated nanoplatform with promising biomedical applications.

Ling Cai et al. used transcriptomic profiling data of healthy lung, patient-derived small cell lung cancer cell lines, xenografts, and primary tumors to examine a link between neuroendocrine (NE) signatures and immune gene expression. Their findings suggest that cell-autonomous immune gene repression is a shared feature between healthy and tumor cells of NE lineage and may influence tumor-immune cell interaction and response to immunotherapy.

The fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.

Background and AimsTo compare the effects of real-time and retrospective flash glucose monitoring (FGM) on daily glycemic control and lifestyle in patients with type 2 diabetes on premix insulin therapy.Methods and ResultsA total of 172 patients using premix insulin, with HbA1c ≥ 7.0% (56 mmol/mol), or the time below the target (TBR) ≥ 4%, or the coefficient of variation (CV) ≥36% during the screening period, were randomly assigned to retrospective FGM (n = 89) or real-time FGM group (n = 83). Another two retrospective or real-time 14-day FGMs were performed respectively, 1 month apart. Both groups received educations and medication adjustment after each FGM. Time in range (3.9~10.0 mmol/l, TIR) increased significantly after 3 months in the real-time FGM group (6.5%) compared with the retrospective FGM group (-1.1%) (p = 0.014). HbA1c decreased in both groups (both p < 0.01). Real-time FGMs increased daily exercise time compared with the retrospective group (p = 0.002).ConclusionsReal-time FGM with visible blood glucose improves daily glycemic control and diabetes self-care behaviors better than retrospective FGM in patients with type 2 diabetes on premix insulin therapy.Clinical Trial Registrationhttps://clinicaltrials.gov/NCT04847219.

AimTo explore the chronic effects of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM).MethodsThis is a secondary analysis of a real-world study evaluating the efficacy and safety of premixed insulin treatment in patients with T2DM via 3-month intermittent flash glucose monitoring. Male patients aged 18-60 who were using metformin during the 3-month study period were included as the metformin group. The control group included males without metformin therapy by propensity score matching analysis with age as a covariate. Testosterone levels were measured at baseline and after 3-month treatment.ResultsAfter 3-month treatment, the control group had higher levels of total testosterone, free and bioavailable testosterone than those at baseline (P

Abstract Background The production of foam nests is one of the strategies that has evolved to allow some anuran species to protect their eggs and larvae. Despite considerable knowledge of the biochemical components of and construction behavior leading to anuran foam nests, little is known about the molecular basis of foam nest construction. Rhacophorus omeimontis presents an arboreal foam-nesting strategy during the breeding season. To better understand the molecular mechanism of foam nest production, transcriptome sequencing was performed using the oviduct of female R. omeimontis during the period when foam nest production began and the period when foam nest production was finished. Results The transcriptomes of six oviduct samples of R. omeimontis were obtained using Illumina sequencing. A total of 84,917 unigenes were obtained, and 433 genes (270 upregulated and 163 downregulated) were differentially expressed between the two periods. These differentially expressed genes (DEGs) were mainly enriched in extracellular space and extracellular region based on Gene Ontology (GO) enrichment analysis and in the pathways of two-component system, cell adhesion molecules, steroid hormone biosynthesis and neuroactive ligand-receptor interaction based on Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Specifically, genes encoding lectins, surfactant proteins and immunity components were highly expressed when the foam nest construction began, indicating that the constituents of foam nests in R. omeimontis were likely a mixture of surfactant, lectins and immune defense proteins. During the period when foam nest production was finished, genes related to lipid metabolism, steroid hormone and immune defense were highly expressed, indicating their important roles in regulating the process of foam nesting. Conclusions Our study provides a rich list of potential genes involved in the production of foam nests in R. omeimontis. These results provide insights into the molecular mechanisms underlying the process of foam nest construction and will facilitate further studies of R. omeimontis.

Both OFPs and ERECTA (ER) regulate plant response to environmental stresses as well as plant growth and development. Blunt-endeded siliques, the characterized phenotype of the er mutants, was observed in transgenic plants overexpressing Class III OFP genes, including OFP13, OFP15, OFP16 and OFP18. We found here that overexpression of ER restored the blunt-endeded siliques phenotypes observed in 35S:OFP15 or 35S:OFP16 plants, whereas er ofp15 and er ofp16 double mutants showed an overall phenotype similar to er single mutants, but their siliques were not blunt-endeded. By generating and characterizing transgenic plants overexpressing putative MAPK phosphorylation sites mutated OFP15 and OPF18, we found that phosphorylation status in Class III OFPs may affect their function in regulating plant growth and development. RT-PCR analysis showed that the expression levels of OFP15, OFP16 and OFP18 were increased in er mutants. Taken together, these results suggest that functions of Class III OFPs may depend on ER signaling.

Sedimentary microorganisms play crucial roles in maintaining the functional stability of aquatic ecosystems. However, their taxonomic composition and assembly processes are not well known in estuarine–coastal margins because of their complex environment. We investigated microbial communities, co-occurrence relationships, and underlying mechanisms in 33 surface sediment samples collected in the Jiulong River Estuary and the Taiwan Strait to reveal their composition dynamics. The abundance, diversity, and composition of microorganisms demonstrated obvious spatial variables. Methanobacterium and Methanosarcina, as well as Candidatus_Nitrosopumilus and Nitrososphaeraceae were the main methanogenic and ammonia-oxidizing archaea, with an average abundance of more than 5.91% and 4.27%, respectively. Along with a salinity gradient increase, the relative abundance of methanogenic archaea (from 42.9% to 16.6%) contrasted with the trend of ammonia-oxidizing archaea (from 6.04% to 18.7%). The number of methanogenic archaea gradually decreased with increasing geographic distance (p < 0.05), whereas ammonia-oxidizing archaea showed no significant change (p > 0.05). In co-occurrence patterns, closer inter-taxa connections were observed among archaea–archaea and bacteria–bacteria than in archaea–bacteria, which indicated that coexistence within the same kingdom was greater than interaction between different kingdoms in shaping the community structure along the salinity gradient. Furthermore, null model analyses of the microbial community showed that undominated was the most prominent process, explaining over 44.9% of community variation, followed by heterogeneous selection and dispersal limitation, which contributed to 27.7% and 16.3%, respectively. We demonstrated that stochasticity, rather than determinism, regulates community assembly. These results further highlight that intra-kingdom co-occurrence and stochastic processes shape the structure and assembly of microbial communities in estuarine–coastal margins.

Water eutrophication is a global ecological issue, and thermal stratification of water bodies can enable eutrophication. We examined bacterial communities in the stratified water columns and sediments in two different trophic reservoirs along the Wujiang River using quantitative real-time PCR and high-throughput sequencing. Bacterial 16S rRNA gene copies varied from 3.70 × 107 to 5.27 × 108 copies/L in the water column of Hongjiadu (HJD) Reservoir (60 m water depth) with slightly stratified variation; while in Wujiangdu (WJD) Reservoir (70 m water depth), bacterial abundance decreased markedly from the surface to the bottom(1.74 × 109 to 2.38 × 107 copies/L). The vertical distribution patterns of bacteria in both reservoirs resembled those of water Chlorophyll a (Chla) concentrations. The abundance was negatively correlated with water depth (D), total nitrogen (TN), nitrate (NO3–-N), and positively correlated with water temperature (T) and dissolved oxygen (DO) level. In contrast, the alpha diversity of bacteria showed the opposite trend in the vertical water column. Proteobacteria, Actinobacteria, and Bacteroidetes were the predominant phyla in the water column of both reservoirs. Compared to WJD Reservoir, HJD Reservoir displayed marked vertical spatial difference in bacterial community structure during thermal stratification. In particular, Pseudomonas was frequently detected at the bottom of the HJD Reservoir. These results were consistent with predictive metagenomic profiling that revealed different vertical functional variation patterns of the bacterial communities in the two reservoirs. The bacterial community structure of HJD Reservoir was associated with water D, ammonium (NH4+-N), nitrite (NO2–-N), and total phosphorus (TP). The community structure of WJD Reservoir was related to water T, Chla, NO3–-N, and TN. The findings highlighted the important roles played by thermal stratification and nutrients in shaping the water bacterial community structure. Additionally, the absolute abundance of water nitrifiers (AOB gene copies) and denitrifiers (narG, nirS, norB, and nosZ gene copies) displayed significant vertical differences in the water columns of both reservoirs. Gene copies involved in denitrification were significantly higher than those involved in nitrification. Water phosphorus and nitrogen contents were important variables influencing the absolute abundance of ammonia oxidizers and denitrifying bacteria, respectively. Our study revealed that the emergence of thermal stratification was responsible for the vertical stratification of bacteria in water and affected the bacterial community structure together with nutrients.

Abscisic acid (ABA) regulates plant responses to abiotic stresses via regulating the expression of downstream genes, yet the functions of many ABA responsive genes remain unknown. We report here the characterization of MYB71, a R2R3 MYB transcription factor in regulating ABA responses in Arabidopsis. RT-PCR results show that the expression level of MYB71 was increased in response to ABA treatment. Arabidopsis protoplasts transfection results show that MYB71 was specifically localized in nucleus and it activated the Gal4:GUS reporter gene when recruited to the Gal4 promoter by a fused DNA binding domain GD. Roles of MYB71 in regulating plant response to ABA were analyzed by generating Arabidopsis transgenic plants overexpression MYB71 and gene edited mutants of MYB71. The results show that ABA sensitivity was increased in the transgenic plants overexpression MYB71, but decreased in the MYB71 mutants. By using a DEX inducible system, we further identified genes are likely regulated by MYB71, and found that they are enriched in biological process to environmental stimuli including abiotic stresses, suggesting that MYB71 may regulate plant response to abiotic stresses. Taken together, our results suggest that MYB71 is an ABA responsive gene, and MYB71 functions as a transcription activator and it positively regulates ABA response in Arabidopsis.

BackgroundGrade prognostic assessment (GPA) is widely used to evaluate the prognosis of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This study aimed to investigate whether lymph node status (LNS) could be included as one of the GPA variables for NSCLC with BMs.MethodsOverall, 586 patients with NSCLC and BMs were retrospectively analyzed. Overall survival stratified by LNS was analyzed using the Kaplan-Meier method. Multivariate analysis was also performed to identify independent prognostic factors using the Cox proportional hazards progression model. In the updated GPA index, prognostic factors and criteria of GPA score were weighted by effect magnitude relative risk (RR) and statistical significance.ResultsIn NSCLC patients with BMs, those with lymph node involvement had worse overall survival (mOS, 13.4 months vs. 25.9 months, P

Introduction: A certain number of small cell lung cancer (SCLC) patients become long-term survivors after treatment, and they are at high risk to develop a second primary malignancy, including non-small cell lung cancer. However, the optimal management of early-stage second primary non-small cell lung cancer (SPLC) after SCLC remains unknown. This study aims to evaluate the survival benefits of surgery in these patients.Methods: Patients with early-stage SPLC after SCLC were identified from the Surveillance, Epidemiology, and End Results database. Patients were balanced with propensity score matching (PSM). Overall survival (OS) and lung cancer-specific survival (CSS) were compared between non-surgery group and surgery group with the Kaplan–Meier method and Cox multivariate regressions.Results: A total of 228 patients with early-stage SPLC after SCLC were identified. Surgery was associated with significantly improved OS and CSS in the multivariate Cox regression analysis (OS, 5-year survival: 41.2 vs. 11.6%, HR: 0.42, 95% CI: 0.31–0.59, P < 0.01; CSS, 5-year survival: 46.8 vs. 24.3%, HR: 0.53, 95% CI: 0.37–0.75, P < 0.01). However, no statistically significant survival difference was found between sublobar resection and lobectomy (OS, 5-year survival: 41.0 vs. 45.3%, P = 0.73; CSS, 5-year survival: 43.5 vs. 54.1%, P = 0.49). After 1:1 PSM, 162 patients were selected for further analysis, and surgery continued to demonstrate superior survival (OS, 5-year survival: 44.2 vs. 7.2%, HR: 0.48, 95% CI: 0.33–0.70, P < 0.01; CSS, 5-year survival: 48.0 vs. 20.6%, HR: 0.44, 95% CI: 0.42–0.97, P = 0.03).Conclusion: The resection of early-stage SPLC after SCLC led to significantly improved OS and CSS and therefore should be considered whenever possible. Nevertheless, further randomized controlled trials are warranted to investigate the safety and effect of surgery in these patients.

Abstract Background Trichome formation in Arabidopsis is regulated by a MBW complex formed by MYB, bHLH and WD40 transcriptional factors, which can activate GLABRA2 (GL2) and the R3 MYB transcription factor genes. GL2 promotes trichome formation, whereas R3 MYBs are able to block the formation of the MBW complex. It has been reported that the C2H2 transcription factor GIS (GLABROUS INFLORESCENCE STEMS) functions upstream of the MBW activator complex to regulate trichome formation, and that the expression of TCL1 is not regulated by the MBW complex. However, gis and the R3 MYB gene mutant tcl1 (trichomeless 1) have opposite inflorescence trichome phenotypes, but their relationship in regulating trichome formation remained unknown. Results By generating and characterization of the gis tcl1 double mutant, we found that trichome formation in the gis tcl1double and the tcl1 single mutants were largely indistinguishable, but the trichome formation in the 35S:TCL1/gis transgenic plant was similar to that in the gis mutant. By using quantitative RT-PCR analysis, we showed that expression level of GIS was increased in the triple mutant tcl1 try cpc, but the expression level of TCL1 was not affected in the gis mutant. On the other hand, trichome morphology in both gis tcl1 and 35S:TCL1/gis plants was similar to that in the gis mutant. Conclusions In summary, our results indicate that GIS may work downstream of TCL1 to regulate trichome formation, and GIS has a dominant role in controlling trichome morphology.

Summary: Self-renewal and differentiation of adult stem cells are tightly regulated partly through configuration of chromatin structure by chromatin remodelers. Using knockout mice, we here demonstrate that bromodomain PHD finger transcription factor (BPTF), a component of the nucleosome remodeling factor (NURF) chromatin-remodeling complex, is essential for maintaining the population size of hematopoietic stem/progenitor cells (HSPCs), including long-term hematopoietic stem cells (HSCs). Bptf-deficient HSCs are defective in reconstituted hematopoiesis, and hematopoietic-specific knockout of Bptf caused profound defects including bone marrow failure and anemia. Genome-wide transcriptome profiling revealed that BPTF loss caused downregulation of HSC-specific gene-expression programs, which contain several master transcription factors (Meis1, Pbx1, Mn1, and Lmo2) required for HSC maintenance and self-renewal. Furthermore, we show that BPTF potentiates the chromatin accessibility of key HSC “stemness” genes. These results demonstrate an essential requirement of the chromatin remodeler BPTF and NURF for activation of “stemness” gene-expression programs and proper function of adult HSCs. : Wang and colleagues show that a chromatin remodeler, BPTF, sustains appropriate functions of hematopoietic stem/progenitor cells (HSPCs). BPTF loss causes bone marrow failure and anemia. The authors further define a BPTF-dependent gene-expression program in HSPCs, which contains key HSC stemness factors. These results demonstrate an essential requirement of the BPTF-associated chromatin remodelers for HSC functionality and adult hematopoiesis. Keywords: Bptf, hematopoietic stem cells, chromatin remodeler, Meis1, Pbx1, Mn1, DNA accessibility, NURF, AP1 complex

Persisting declination of amphibians around the world has resulted in the public attaching importance to the conservation of their biodiversity. Genetic data can be greatly helpful in conservation planning and management, especially in species that are small in size and hard to observe. It is essential to perform genetic assessments for the conservation of Leptobrachium leishanense, an endangered toad and receiving secondary protection on the list of state-protected wildlife in China. However, current molecular markers with low reliability and efficiency hinder studies. Here, we sampled 120 adult toes from the population in the Leishan Mountain, 23 of which were used to develop tetranucleotide microsatellite markers based on one reference L. leishanense genome. After primer optimization, stability detection, and polymorphism detection, we obtained 12 satisfactory microsatellite loci. Then, we used these loci to evaluate the genetic diversity and population dynamics of the 120 individuals. Our results show that there is a low degree of inbreeding in the population, and it has a high genetic diversity. Recently, the population has not experienced population bottlenecks, and the estimated effective population size was 424.3. Accordingly, stabilizing genetic diversity will be key to population sustainability. Recovering its habitat and avoiding intentional human use will be useful for conservation of this species.

Somatic copy number alterations (SCNA) can confound gene co-expression analysis in cancers. Here the authors develop a method to remove the effects of SCNA in co-expression analysis, improving the analysis of network rewiring in cancer, and provide a database with adjusted data from TCGA.

Abstract In spinal degenerative disease, an injectable liquid hydrogel can fill in defect entirely, lessen the danger of implant relocation and following loss of disc height, minimizing the operative trauma. Here, we propose an injectable in-situ chemically cross-linked hydrogel by a two-component reaction of liquid silk fibroin with liquid polyurethane at physiological temperature conditions. Confined compression tests and fatigue tests were reported to assess physical properties of the hydrogel. Impact of different diameter on the biomechanical behaviours was tested to evaluate the clinical potentiality of the hydrogel for replacing nucleus pulposus. Degradation behaviours in different solutions and animal experiments were also investigated to examine the tissue biocompatibility of the hydrogel. The hydrogel modulus was affected by the hydrogel geometrical (diameter) parameters. SF/PU composite hydrogel can survive a million cycles, unconstrained fatigue resistance. More importantly, in vivo biocompatibility using New Zealand white rabbits, showed good biocompatibility over a three-month period in culture. Particularly, they showed the significant clinical merit of providing stronger axial compressive stiffness on confined compression test. Based on the outcomes of the present research, the SF/PU composite hydrogel may provide significant advantages for use in future clinical application in replacing nucleus pulposus field.

Palbociclib has been shown to be a highly effective therapy in hormone receptor positive metastatic breast cancer when used in combination with letrozole or fulvestrant. Grade 3/4 neutropenia is a common side effect although febrile neutropenia is relatively uncommon. Insufficient data exist to describe the hematological safety of palbociclib in African American women (AAW) known to have a high incidence of benign ethnic neutropenia (BEN). PALOMA 1, 2 and 3, the initial phase II/III studies that led to the U.S. Food and Drug Administration (FDA) approval of palbociclib in metastatic breast cancer, only included participants with baseline absolute neutrophil count (ANC) of 1500/mm3 or higher. African American women (AAW) were underrepresented in the PALOMA trials and this may be partially explained by strict requirements for minimal ANC ≥1500/mm3. The ANC of 1500/mm3 for initiation of treatment in those with BEN has been previously challenged. In this study, we propose to lower the ANC cutoff for enrollment to 1000/mm3. PALINA (NCT02692755) is a phase II, single arm, multicenter clinical trial that will enroll 35 patients. The primary endpoint is to assess the proportion of patients who complete therapy without the development of febrile neutropenia or treatment discontinuation due to neutropenia. The secondary endpoints include number of patients who required dose delays or dose reductions in palbociclib attributed to neutropenia, rate of grade 3/4 neutropenia, clinical benefit rate at 24 weeks, the association between metabolite and exosomal signature with disease response and the association between baseline ANC prior to cancer diagnosis and the Duffy Null polymorphism (SNP rs2814778) with hematological safety. PALINA will provide important information about the hematologic safety of palbociclib in AAW with advanced breast cancer. Keywords: Palbociclib, Letrozole, Fulvestrant, African-American

Summary: Inborn errors of metabolism (IEMs) link metabolic defects to human phenotypes. Modern genomics has accelerated IEM discovery, but assessing the impact of genomic variants is still challenging. Here, we integrate genomics and metabolomics to identify a cause of lactic acidosis and epilepsy. The proband is a compound heterozygote for variants in LIPT1, which encodes the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. Metabolomics reveals abnormalities in lipids, amino acids, and 2-hydroxyglutarate consistent with loss of multiple 2KDHs. Homozygous knockin of a LIPT1 mutation reduces 2KDH lipoylation in utero and results in embryonic demise. In patient fibroblasts, defective 2KDH lipoylation and function are corrected by wild-type, but not mutant, LIPT1 alleles. Isotope tracing reveals that LIPT1 supports lipogenesis and balances oxidative and reductive glutamine metabolism. Altogether, the data extend the role of LIPT1 in metabolic regulation and demonstrate how integrating genomics and metabolomics can uncover broader aspects of IEM pathophysiology. : Ni et al. investigate human LIPT1 deficiency, which results in developmental delay, epilepsy, and broad metabolic abnormalities, including lactic acidosis, L- and D-2-hydroxyglutaric aciduria, defective lipogenesis, and an altered balance between oxidative and reductive glutamine metabolism. Keywords: inborn errors of metabolism, metabolomics, genomics, lactic acidosis, epilepsy,developmental delay, 2-ketoacid dehydrogenase, lipoylation, lipogenesis, fatty acid oxidation

Abstract Background Complete resection of locally advanced sigmoid colon cancer (LASCC) is sometimes difficult. Patients with LASCC have a dismal prognosis and poor quality of life, which has encouraged the evaluation of alternative multimodality treatments. This prospective study aimed to assess the feasibility and efficacy of neoadjuvant chemoradiotherapy (neoCRT) followed by surgery as treatment of selected patients with unresectable LASCC. Methods We studied the patients with unresectable LASCC who received neoCRT followed by surgery between October 2010 and December 2012. The neoadjuvant regimen consisted of external-beam radiotherapy to 50 Gy and capecitabine-based chemotherapy every 3 weeks. Surgery was scheduled 6–8 weeks after radiotherapy. Results Twenty-one patients were included in this study. The median follow-up was 42 months (range, 17–57 months). All patients completed neoCRT and surgery. Resection with microscopically negative margins (R0 resection) was achieved in 20 patients (95.2%). Pathologic complete response was observed in 8 patients (38.1%). Multivisceral resection was necessary in only 7 patients (33.3%). Two patients (9.5%) experienced grade 2 postoperative complications. No patients died within 30 days after surgery. For 18 patients with pathologic M0 (ypM0) disease, the cumulative probability of 3-year local recurrence-free survival, disease-free survival and overall survival was 100.0%, 88.9% and 100.0%, respectively. For all 21 patients, the cumulative probability of 3-year overall survival was 95.2% and bladder function was well preserved. Conclusion For patients with unresectable LASCC, preoperative chemoradiotherapy and surgery can be performed safely and may result in an increased survival rate.

AIM: To assess the visual function prognosis after vitrectomy for patients with proliferative diabetic retinopathy(PDR)at stage Ⅵ and the impacting factors and to evaluate visual function using multifocal electroretinogram(mfERG). METHODS: One hundred and thirteen cases(130 eyes)with PDR at stage VI treated with standard vitreoretinal surgery were retrospectively analyzed. According to the OCT examination before surgeries and ocular fundus during surgeries, the reviewed cases were divided into two groups: patients with traction retinal detachment and maculopathy(99 cases with 113 eyes)and without maculopathy(14 cases with 17 eyes). Eyes underwent OCT and mfERG examination. Visual acuity preoperative and postoperative, mfERGP1 wave amplitudes, morphology features of macular,complications and prognoses were analyzed. RESULTS: The rate of improved visual acuity postoperatively was 63.1%(82/130). The vision was 0.05 or better in 19 eyes(14.6%)preoperatively, and in 61 eyes(46.9%)postoperatively, in which the vision of 56 eyes were >0.1. In patients without maculopathy, the rate of visual improvements were 88.2% and there were 94.1% with the vision >0.1, which were both better than patients with significant maculopathy group(59.3% and 35.4%), and the differences were significant(PPPCONCLUSION: The visual function of eyes with PDR at stage VI is improved after vitrectomy. The amplitude densities of P1 wave in the 6 rings increase markedly after vitrectomy, and they turn to be better with time. The improvement of visual function in severe PDR without maculopathy group is better than that in severe PDR with maculopathy group after vitrectomy.

It is known that high quality proton beams can be produced in the radiation pressure acceleration (RPA) by using a circularly polarized ultraintense super-Gaussian laser. However, a transverse mismatching phenomenon between the laser intensity profile and the particle spatial distribution appears in the later stage of RPA, which leads to a decompression of proton beam and broadening of the energy spectrum. To weaken this effect, a new scheme with an additional plasma channel located behind a thin hydrogen foil is proposed. It is found that a good local matching can be maintained when the laser pulse propagates in the channel, which contributes to a stable RPA for a longer time. Two-dimensional particle-in-cell simulations show that the proton beam has a peak energy of 2.0 GeV and energy spread of 13.8% at t=300 fs. With further acceleration until t=500 fs, a better quality beam with about 40% increase in peak energy and 26.2% improvement in energy conversion efficiency for high-energy protons (≥1.5 GeV) can be obtained finally. Meanwhile, the energy spread drops from 100% to 28.5%. This work may provide a more promising way to generate the high quality proton beam.

The construction of gene regulatory networks (GRNs) is an essential component of biomedical research to determine disease mechanisms and identify treatment targets. Gaussian graphical models (GGMs) have been widely used for constructing GRNs by inferring conditional dependence among a set of gene expressions. In practice, GRNs obtained by the analysis of a single data set may not be reliable due to sample limitations. Therefore, it is important to integrate multiple data sets from comparable studies to improve the construction of a GRN. In this article, we introduce an equivalent measure of partial correlation coefficients in GGMs and then extend the method to construct a GRN by combining the equivalent measures from different sources. Furthermore, we develop a method for multiple data sets with a natural missing mechanism to accommodate the differences among different platforms in multiple sources of data. Simulation results show that this integrative analysis outperforms the standard methods and can detect hub genes in the true network. The proposed integrative method was applied to 12 lung adenocarcinoma data sets collected from different studies. The constructed network is consistent with the current biological knowledge and reveals new insights about lung adenocarcinoma.

The identifier system of current internet is based on IP address and characterized by binding the identity and location, so it can't adapt well to multi-demands of future internet, such as scalability, mobility and safety. The various international mainstream identifier systems of future internet architecture were classified firstly, which were summed up along the two development routes, one was incremental route, and another was clean-slate route. Then the challenges of design solution should be meet were analyzed. In addition, with the development trend of the internet architecture, some advices of evolution and development of the identifier system were proposed.

Ribosome biogenesis requires an enormous commitment of energy and resources in growing cells. In budding yeast, the transcriptional coactivator Ifh1p is an essential regulator of ribosomal protein (RP) gene transcription. Here, we report that Ifh1p is dynamically acetylated and phosphorylated as a function of the growth state of cells. Ifh1p is acetylated at numerous sites in its N-terminal region by Gcn5p and deacetylated by NAD+-dependent deacetylases of the sirtuin family. Acetylation of Ifh1p is responsive to intracellular acetyl-CoA levels and serves to regulate the stability of Ifh1p. The phosphorylation of Ifh1p is mediated by protein kinase A and is dependent on TORC1 signaling. Thus, multiple nutrient-sensing mechanisms converge on Ifh1p. However, instead of modulating overall rates of RP gene transcription or cell growth, the nutrient-responsive phosphorylation of Ifh1p plays a more prominent role in the regulation of cellular replicative lifespan.