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Secreted common fungal extracellular membrane (CFEM) domain proteins have been implicated in multiple biological functions in fungi. However, it is still largely unknown whether the ferric iron (Fe 3+ ), as an important trace element, was involved with the biological function of CFEM proteins. In this study, a new CFEM protein CgCsa, with high expression levels at the early inoculation stage on peppers by Colletotrichum gloeosporioides was investigated. Deletion of the targeted gene CgCsa revealed multiple biological roles in hyphal growth restriction, highly reduced conidial yield, delayed conidial germination, abnormal appressorium with elongated bud tubes, and significantly reduced virulence of C. gloeosporioides. Moreover, in CgCsa mutants, the expression levels of four cell wall synthesis-related genes were downregulated, and cell membrane permeability and electrical conductivity were increased. Compared to the wild-type, the CgCsa mutants downregulated expressions of iron transport-related genes, in addition, its three-dimensional structure was capable binding with iron. Increase in the Fe 3+ concentration in the culture medium partially recovered the functions of ΔCgCsa mutant. This is probably the first report to show the association between CgCsa and iron homeostasis in C. gloeosporioides. The results suggest an alternative pathway for controlling plant fungal diseases by deplete their trace elements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ferroptosis is an iron-dependent cell death that was discovered recently. For beneficial microbes to establish mutualistic relationships with hosts, precisely controlled cell death in plant cells is necessary. However, whether ferroptosis is involved in the endophyte‒plant system is poorly understood. Here, we reported that endophytic Streptomyces hygroscopicus OsiSh-2, which established a sophisticated and beneficial interaction with host rice plants, caused ferroptotic cell death in rice characterized by ferroptosis- and immune-related markers. Treatments with ferroptosis inhibitors and inducers, different doses of OsiSh-2, and the siderophore synthesis-deficient mutant ΔcchH revealed that only moderate ferroptosis induced by endophytes is essential for the establishment of an optimal symbiont to enhance plant growth. Additionally, ferroptosis involved in a defence-primed state in rice, which contributed to improved resistance against rice blast disease. Overall, our study provides new insights into the mechanisms of endophyte‒plant interactions mediated by ferroptosis and suggests new directions for crop yield promotion., (© 2024. The Author(s).)

Safety-critical systems, such as the railway signal system, are subject to potentially high costs from failures, including loss of life and property damage. The use of new technology, including communication-based train control (CBTC) systems with software and computers, has changed the types of accidents that occur. Software-related issues and dysfunctional interactions between system components controlled by the software are increasingly the cause of incidents. Developing a "safe" safety-critical system requires accurate and complete safety requirements, which are the foundation of system development. Traditional hazard analysis techniques are insufficient for identifying the causes of accidents in modern railway signaling systems. Systems-Theoretic Process Analysis (STPA) is a powerful new hazard analysis method designed to address these limitations. Building upon this foundation, a hierarchical approach to safety requirement development has been further developed. This approach combines STPA analysis with a hierarchical modeling approach to establish traceability links from safety requirements to specific architectures, refine and allocate system-level safety requirements to relevant subsystems, and abstract safety requirements at higher hierarchical levels to enable easy changes to lower-level implementations. This paper employs the aforementioned methodology within the context of the CBTC system, thereby enhancing risk management and hazard analysis, enabling early insights, and facilitating the generation of safety requirements of CBTC System., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zuxi Chen reports financial support was provided by Fujian Province Department of Science and Technology. Xiaoyong Wang reports financial support was provided by Shanghai Province Department of Science and Technology. Meng Mei reports financial support was provided by 10.13039/501100002855Ministry of Science and Technology of the People's Republic of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Hepatocellular carcinoma is one of the leading causes of cancer-related mortality globally. The emergence of immunotherapy has been shown to be a promising therapeutic approach for hepatocellular carcinoma in recent years. It has been well known that T cell plays a key role in current immunotherapy. However, sustained exposure to antigenic stimulation within the tumor microenvironment may lead to T cell exhaustion, which may cause treatment ineffectiveness. Therefore, reversing T cell exhaustion has been an important issue for the clinical application of immunotherapy, and a comprehensive understanding of the intricacies surrounding T cell exhaustion and its underlying mechanisms is imperative for devising strategies to overcome the T cell exhaustion during treatment. In this review, we summarized the reported drivers of T cell exhaustion in hepatocellular carcinoma and delineate potential ways to reverse it. Additionally, we discussed the interplay among metabolic plasticity, epigenetic regulation, and transcriptional factors in exhausted T cells in hepatocellular carcinoma, and their implication for future clinical applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The global industrialization and modernization have witnessed a rapid progress made in agricultural production, along with the issue of soil heavy metal (HM) pollution, which has posed severe threats to soil quality, crop yield, and human health. Phytoremediation, as an alternative to physical and chemical methods, offers a more cost-effective, eco-friendly, and aesthetically appealing means for in-situ remediation. Despite its advantages, traditional phytoremediation faces challenges, including variable soil physicochemical properties, the bioavailability of HMs, and the slow growth and limited biomass of plants used for remediation. This study presents a critical overview of the predominant plant-based HM remediation strategies. It expounds upon the mechanisms of plant absorption, translocation, accumulation, and detoxification of HMs. Moreover, the advancements and practical applications of phyto-combined remediation strategies, such as the addition of exogenous substances, genetic modification of plants, enhancement by rhizosphere microorganisms, and intensification of agricultural technologies, are synthesized. In addition, this paper also emphasizes the economic and practical feasibility of some strategies, proposing solutions to extant challenges in traditional phytoremediation. It advocates for the development of cost-effective, minimally polluting, and biocompatible exogenous substances, along with the careful selection and application of hyperaccumulating plants. We further delineate specific future research avenues, such as refining genetic engineering techniques to avoid adverse impacts on plant growth and the ecosystem, and tailoring phyto-combined strategies to diverse soil types and HM pollutants. These proposed directions aim to enhance the practical application of phytoremediation and its integration into a broader remediation framework, thereby addressing the urgent need for sustainable soil decontamination and protection of ecological and human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Soil arsenic (As) phytoremediation has long faced the challenge of efficiently absorbing As by plant accumulators while maintaining their health and fast growth. Even at low doses, arsenic is highly toxic to plants. Therefore, plant growth-promoting microorganisms that can mediate As accumulation in plants are of great interest. In this study, the endophyte Enterobacter sp. YG-14 (YG-14) was found to have soil mobilization activity. By constructing a siderophore synthesis gene deletion mutant (ΔentD) of YG-14, the endophyte was confirmed to effectively mobilize Fe-As complexes in mining soil by secreting enterobactin, releasing bioavailable Fe and As to the rhizosphere. YG-14 also enhances As accumulation in host plants via extracellular polymer adsorption and specific phosphatase transfer protein (PitA) absorption. The root accumulation of As was positively correlated with YG-14 root colonization. In addition, YG-14 promoted plant growth and alleviated oxidative damage in R. pseudoacacia L. under arsenic stress. This is the first study, from phenotype, physiology, and molecular perspectives, to determine the role of endophyte in promoting As phytostabilization and maintaining the growth of the host plant. This demonstrated the feasibility of using endophytes with high siderophore production to assist host plants in As phytoremediation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Addressing the environmental contamination from heavy metals and organic pollutants remains a critical challenge. This study explored the resilience and removal potential of Pleurotus ostreatus GEMB-PO1 for copper. P. ostreatus GEMB-PO1 showed significant tolerance, withstanding copper concentrations up to 2 mM. Its copper removal efficiency ranged from 64.56 % at 0.5 mM to 22.90 % at 8 mM. Transcriptomic insights into its response to copper revealed a marked upregulation in xenobiotic degradation-related enzymes, such as laccase and type II peroxidases. Building on these findings, a co-remediation system using P. ostreatus GEMB-PO1 was developed to remove both copper and organic pollutants. While this approach significantly enhanced the degradation efficiency of organic contaminants, it concurrently exhibited a diminished efficacy in copper removal within the composite system. This study underscores the potential of P. ostreatus GEMB-PO1 in environmental remediation. Nevertheless, further investigation is required to optimize the simultaneous removal of organic pollutants and copper., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background:  Various high-energy tasks in the construction industry can lead to craniocerebral injuries. Construction industry-associated penetrating craniocerebral injuries due to metal foreign bodies have unique characteristics. However, no norms exist for removing metal foreign bodies and preventing secondary trauma. This study aimed to explore the characteristics and treatment of construction industry-associated penetrating craniocerebral injuries due to metal foreign bodies., Methods:  Data of patients who suffered from penetrating injuries due to metal foreign bodies and were treated in the Zhongshan People's Hospital from 2001 to 2021 were collected based on the causes of injuries to explore disease characteristics and therapeutic effects., Results:  A total of six patients with penetrating craniocerebral injuries due to metal foreign bodies, who underwent surgeries, were included in the study. Five patients recovered well after the surgery, and one patient died. In four patients, intracranial infection complicated the course after surgery, and two patients had delayed intracranial hematoma., Conclusion:  Patients with construction industry-associated penetrating craniocerebral injuries due to metal foreign bodies are prone to coma and intracranial vascular injuries. Early surgical removal and prevention of intracranial infection are key to achieving good therapeutic effects., Competing Interests: None declared., (Thieme. All rights reserved.)

The objective is to develop and validate a combined model for noninvasive preoperative differentiating tumor deposits (TDs) from lymph node metastasis (LNM) in patients with rectal cancer (RC). A total of 204 patients were enrolled and randomly divided into 2 sets (training and validation set) at a ratio of 8:2. Radiomics features of tumor and peritumor fat were extracted by using Pyradiomics software from the axial T2-weighted imaging of MRI. Rad-score based on extracted Radiomics features were calculated by combination of feature selection and the machine learning method. Factors (Rad-score, laboratory test factor, clinical factor, traditional characters of tumor on MRI) with statistical significance were integrated to build a combined model. The combined model was visualized by a nomogram, and its distinguish ability, diagnostic accuracy, and clinical utility were evaluated by the receiver operating characteristic curve (ROC) analysis, calibration curve, and clinical decision curve, respectively. Carbohydrate antigen (CA) 19-9, MRI reported node stage (MRI-N stage), tumor volume (cm3), and Rad-score were all included in the combined model (odds ratio = 3.881 for Rad-score, 2.859 for CA19-9, 0.411 for MRI-N stage, and 1.055 for tumor volume). The distinguish ability of the combined model in the training and validation cohorts was area under the summary receiver operating characteristic curve (AUC) = 0.863, 95% confidence interval (CI): 0.8-0.911 and 0.815, 95% CI: 0.663-0.919, respectively. And the combined model outperformed the clinical model in both training and validation cohorts (AUC = 0.863 vs 0.749, 0.815 vs 0.627, P = .0022, .0302), outperformed the Rad-score model only in training cohorts (AUC = 0.863 vs 0.819, P = .0283). The combined model had highest net benefit and showed good diagnostic accuracy. The combined model incorporating Rad-score and clinical factors could provide a preoperative differentiation of TD from LNM and guide clinicians in making individualized treatment strategy for patients with RC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Endophytes play an important role in shaping plant growth and immunity. However, the mechanisms for endophyte-induced disease resistance in host plants remain unclear. Here, we screened and isolated the immunity inducer ShAM1 from the endophyte Streptomyces hygroscopicus OsiSh-2, which strongly antagonizes the pathogen Magnaporthe oryzae. Recombinant ShAM1 can trigger rice immune responses and induce hypersensitive responses in various plant species. After infection with M. oryzae, blast resistance was dramatically improved in ShAM1-inoculated rice. In addition, the enhanced disease resistance by ShAM1 was found to occur through a priming strategy and was mainly regulated through the jasmonic acid-ethylene (JA/ET)-dependent signaling pathway. ShAM1 was identified as a novel α-mannosidase, and its induction of immunity is dependent on its enzyme activity. When we incubated ShAM1 with isolated rice cell walls, the release of oligosaccharides was observed. Notably, extracts from the ShAM1-digested cell wall can enhance the disease resistance of the host rice. These results indicated that ShAM1 triggered immune defense against pathogens by damage-associated molecular pattern (DAMP)-related mechanisms. Our work provides a representative example of endophyte-mediated modulation of disease resistance in host plants. The effects of ShAM1 indicate the promise of using active components from endophytes as plant defense elicitors for the management of plant disease. IMPORTANCE The specific biological niche inside host plants allows endophytes to regulate plant disease resistance effectively. However, there have been few reports on the role of active metabolites from endophytes in inducing host disease resistance. In this study, we demonstrated that an identified α-mannosidase protein, ShAM1, secreted by the endophyte S. hygroscopicus OsiSh-2 could activate typical plant immunity responses and induce a timely and cost-efficient priming defense against the pathogen M. oryzae in rice. Importantly, we revealed that ShAM1 enhanced plant disease resistance through its hydrolytic enzyme (HE) activity to digest the rice cell wall and release damage-associated molecular patterns. Taken together, these findings provide an example of the interaction mode of endophyte-plant symbionts and suggest that HEs derived from endophytes can be used as environmentally friendly and safe prevention agent for plant disease control., Competing Interests: The authors declare no conflict of interest.

Camellia oleifera ( C. oleifera ) is a unique edible oil crop in China cultivated in the hilly southern mountains. Although C. oleifera is classified as a drought-tolerant tree species, drought remains the main factor limiting the growth of C. oleifera in summer and autumn. Using endophytes to improve crop drought tolerance is one effective strategy to meet our growing food crop demand. In this study, we showed that endophyte Streptomyces albidoflavus OsiLf-2 could mitigate the negative impact of drought stress on C. oleifera , thus improving seed, oil, and fruit quality. Microbiome analysis revealed that OsiLf-2 treatment significantly affected the microbial community structure in the rhizosphere soil of C. oleifera , decreasing both the diversity and abundance of the soil microbe. Likewise, transcriptome and metabolome analyses found that OsiLf-2 protected plant cells from drought stress by reducing root cell water loss and synthesizing osmoregulatory substances, polysaccharides, and sugar alcohols in roots. Moreover, we observed that OsiLf-2 could induce the host to resist drought stress by increasing its peroxidase activity and synthesizing antioxidants such as cysteine. A multi-omics joint analysis of microbiomes, transcriptomes, and metabolomes revealed OsiLf-2 assists C. oleifera in resisting drought stress. This study provides theoretical and technical support for future research on endophytes application to enhance the drought resistance, yield, and quality of C. oleifera ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Cui, Wang, Xu, Zhang, Wang, Chen and Zhu.)

The soil moisture active/passive (SMAP) mission represents a significant advance in measuring soil moisture from satellites. However, its large spatial-temporal data gaps limit the use of its values in near-real-time (NRT) applications. Considering this, the study uses NRT operational metadata (precipitation and skin temperature), together with some surface parameterization information, to feed into a random forest model to retrieve the missing values of the SMAP L3 soil moisture product. This practice was tested in filling the missing points for both SMAP descending (6:00 AM) and ascending orbits (6:00 PM) in a crop-dominated area from 2015 to 2019. The trained models with optimized hyper-parameters show the goodness of fit (R 2 ≥ 0.86), and their resulting gap-filled estimates were compared against a range of competing products with in situ and triple collocation validation. This gap-filling scheme driven by low-latency data sources is first attempted to enhance NRT spatiotemporal support for SMAP L3 soil moisture., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

In recent years, due to the intensification of human activities, water ecological problems are gradually increasing. As the third largest freshwater lake in China, Lake Taihu is an important drinking water source for several densely populated cities in China. The prominent water ecological problem in this area is mainly Cyanobacteria Bloom. Cyanobacterial blooms have been erupting which have affected local residents' drinking water and caused losses to the national economy. Based on the interpretation results of MODIS data in the Lake Taihu region from 2004 to 2014, this paper analyzes the main driving factors of cyanobacterial bloom are phosphorus and potassium through the correlation analysis of nitrogen, phosphorus, potassium and cyanobacteria area, normalizes nutrient, and identifies that the water level of Lake Taihu is the influencing factor of cyanobacterial bloom. A Lake Taihu cyanobacteria bloom hazard function is constructed to quantitatively assess the losses (economic losses) caused by cyanobacterial blooms from 2001 to 2012, supporting for cyanobacteria control management in Lake Taihu., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The West Liaohe Plain (WLP) is a typical crop-pastoral ecotone of the semiarid area in Northwestern, China. Land use/cover change (LUCC) of the WLP might endanger this ecosystem, triggering long-lasting environmental concerns. LUCC data for China (1980-2020) and hydrometeorological data were analyzed to reveal factors contributing to change and explore sustainable development opportunities. The results show that characteristics of the main land-use types in the WLP have changed significantly, especially cultivated land area, which increased by 15.2% and 6.79% during the periods 1980-1995 and 2000-2020, respectively. Response relationships were observed due to natural (precipitation, temperature, and runoff) and anthropogenic (economy) factors and LUCC. Between 2000 and 2020, the impact of anthropogenic factors on cultivated land was stronger than on grassland at the class and landscape level, using the landscape indices which were selected, including percent of landscape (PLAND), number of patches (NP), largest patch index (LPI), and Shannon's evenness index (SHEI). Expansion of cultivated land from 1990 to 1995 was not only related to anthropogenic factors but also to hydrological & climatic factors. The results of this study have the potential to influence sustainable land resource development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Endophytes can benefit the growth and stress resistance of host plants by secreting bioactive components. Thiamine is an essential vitamin involved in many metabolic pathways and can only be synthesized by microbes and plants. In this study, we found that thiamine could inhibit the development of the phytopathogen Magnaporthe oryzae and decrease the rice blast index under field conditions. In the thiamine biosynthesis pathway, the key enzyme ShTHIC of an endophyte Streptomyces hygroscopicus OsiSh-2 and OsTHIC of rice ( Oryza sativa ) were highly homologous. Gene overexpression or knockout approaches revealed that both THIC contributed to thiamine synthesis and resistance to M. oryzae . Furthermore, S. hygroscopicus OsiSh-2 colonization led to a decrease in the thiamine synthesis level of rice but still maintained thiamine homeostasis in rice. However, inoculation with the ShTHIC knockout strain Δ THIC reduced the thiamine content in rice, although the thiamine synthesis level of rice was increased. After infection with M. oryzae , blast resistance was dramatically improved in OsiSh-2-inoculated rice but decreased in Δ THIC -inoculated rice compared with non-inoculated rice. This result demonstrated that ShTHIC could regulate thiamine biosynthesis and consequently assist blast resistance in the OsiSh-2-rice symbiont. Our results revealed a novel blast-resistance mechanism mediated by a key thiamine biosynthetic enzyme from an endophyte OsiSh-2.

Graph convolutional network (GCN) outputs powerful representation by considering the structure information of the data to conduct representation learning, but its robustness is sensitive to the quality of both the feature matrix and the initial graph. In this article, we propose a novel multigraph fusion method to produce a high-quality graph and a low-dimensional space of original high-dimensional data for the GCN model. Specifically, the proposed method first extracts the common information and the complementary information among multiple local graphs to obtain a unified local graph, which is then fused with the global graph of the data to obtain the initial graph for the GCN model. As a result, the proposed method conducts the graph fusion process twice to simultaneously learn the low-dimensional space and the intrinsic graph structure of the data in a unified framework. Experimental results on real datasets demonstrated that our method outperformed the comparison methods in terms of classification tasks.

The functional connectomic profile is one of the non-invasive imaging biomarkers in the computer-assisted diagnostic system for many neuro-diseases. However, the diagnostic power of functional connectivity is challenged by mixed frequency-specific neuronal oscillations in the brain, which makes the single Functional Connectivity Network (FCN) often underpowered to capture the disease-related functional patterns. To address this challenge, we propose a novel functional connectivity analysis framework to conduct joint feature learning and personalized disease diagnosis, in a semi-supervised manner, aiming at focusing on putative multi-band functional connectivity biomarkers from functional neuroimaging data. Specifically, we first decompose the Blood Oxygenation Level Dependent (BOLD) signals into multiple frequency bands by the discrete wavelet transform, and then cast the alignment of all fully-connected FCNs derived from multiple frequency bands into a parameter-free multi-band fusion model. The proposed fusion model fuses all fully-connected FCNs to obtain a sparsely-connected FCN (sparse FCN for short) for each individual subject, as well as lets each sparse FCN be close to its neighbored sparse FCNs and be far away from its furthest sparse FCNs. Furthermore, we employ the l 1 -SVM to conduct joint brain region selection and disease diagnosis. Finally, we evaluate the effectiveness of our proposed framework on various neuro-diseases, i.e., Fronto-Temporal Dementia (FTD), Obsessive-Compulsive Disorder (OCD), and Alzheimer's Disease (AD), and the experimental results demonstrate that our framework shows more reasonable results, compared to state-of-the-art methods, in terms of classification performance and the selected brain regions. The source code can be visited by the url https://github.com/reynard-hu/mbbna.

Robinia pseudoacacia L., a pioneer woody legume grown in mining areas, has been recognized as a remarkable accumulator of various heavy metals. Compared with other hazardous heavy metals (HMs), it is of low capacity in accumulating Cd, which, as a result, may hinder the phytoremediation efficiency. To enhance R. pseudoacacia's uptake efficiency of Cd, the individual effects of various rhizobia and arbuscular mycorrhizal fungi have been reported, however, the combined influence of endophytes and biochar receives little attention. In the current study, a Cd-adsorbing endophyte Enterobacter sp. YG-14 was inoculated to R. pseudoacacia, and its extraordinary effect on increasing R. pseudoacacia's Cd uptake was found, which was ascribed to the reinforced root Cd chelation by the strain through secreting siderophores/LMWOAs. Further, P-enriched sludge biochar was applied along with YG-14 to form a combined biochar-endophyte-accumulator system, in which biomineralization were reinforced (i.e. CdCO 3 and Cd 2 P 2 O 7 were generated), as the total and acid-soluble Cd in rhizosphere were reduced by 61.75% and 69.01% respectively, and soil's bacterial diversity was further improved with diversified N 2 -fixing microbial biomarkers. Multiple synergistic effects (E > 0) were also found, with the optimum performance on plant growth parameters (increased by 39.61%-561.91%) in comparison to the control group. Moreover, the system exhibited a preferable Cd phytostabilization capacity with the highest increase (81.42%) in Cd accumulation and a significant reduction (72.73%) in Cd root-to-shoot translocation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Plants fine-tune the growth-defense trade-off to survive when facing pathogens. Meanwhile, plant-associated microbes, such as the endophytes inside plant tissues, can benefit plant growth and stress resilience. However, the mechanisms for the beneficial microbes to increase stress resistance with little yield penalty in host plants remain poorly understood. In the present study, we report that endophytic Streptomyces hygroscopicus OsiSh-2 can form a sophisticated interaction with host rice, maintaining cellular homeostasis under pathogen-infection stress, and optimize plant growth and disease resistance in rice. Four-year field trials consistently showed that OsiSh-2 could boost host resistance to rice blast pathogen Magnaporthe oryzae while still maintaining a high yield. The integration of the proteomic, physiological, and transcriptional profiling analysis revealed that OsiSh-2 induced rice defense priming and controlled the expression of energy-consuming defense-related proteins, thus increasing the defense capability with the minimized costs of plant immunity. Meanwhile, OsiSh-2 improved the chloroplast development and optimally maintained the expression of proteins related to plant growth under pathogen stress, thus promoting the crop yield. Our results provided a representative example of an endophyte-mediated modulation of disease resistance and fitness in the host plant. The multilayer effects of OsiSh-2 implicate a promising future of using endophytic actinobacteria for disease control and crop yield promotion. IMPORTANCE Under disease stress, activation of defense response in plants often comes with the cost of a reduction in growth and yield, which is referred as the growth-defense trade-off. The microorganisms which can be recruited by plants to mitigate the growth-defense trade-off are of great value in crop breeding. Here, we reported a rice endophytic actinomycetes Streptomyces hygroscopicus OsiSh-2, which can improve host performances on resistance to rice blast while still sustaining high yield in the 4-year field trials. The proteomic, physiological, and transcriptional profiling data offer insights into the molecular basis underlying the balancing between defense and growth in OsiSh-2-rice symbiont. The findings provide an example for the endophyte-mediated modulation of growth-defense trade-offs in plants and indicated the promising application of endophytic actinobacterial strains in agriculture to breed "microbe-optimized crops."

There is a critical need to develop in vitro culture systems appropriate for the expansion of adipose tissue, in order to gain new insights into metabolic diseases and to assist in the restoration of tissue defects. Conventional two- or three-dimensional (2D or 3D) in vitro models of adipocytes require a combination of supplements to induce adipocyte maturation that greatly increases the cost of large-scale industrial production. In the present study, a microporous, perforated bacterial cellulose (BC)-assisted culture system was developed that promoted the adhesion, proliferation, and adipogenic differentiation of preadipocytes. Additionally, the system maintained the cells as mature unilocular adipocytes ex vivo in normal cell culture medium in long-term culture. All cells were derived from isolated adipose tissue without the use of expensive enzymes for tissue digestion. In contrast to culture in hard tissue culture plates, preadipocytes in the soft 3D environments formed multidimensional interlaced cell contacts, undergoing significant spontaneous lipid accumulation and could be cultured for up to threemonths in maintenance medium. More importantly, the cultured adipose tissue-derived cell bank created here was able to produce injury repair activators that promoted the proliferation of fibroblasts with little fibrosis and the functional differentiation of myoblasts, displaying the potential for use in adipose reconstruction. Thus, the present study demonstrates the potential of a mechanically flexible BC scaffold to generate volume tunable adipose constructs and provides a low-cost and user-friendly strategy for large-scale industrial production of adipose tissue., (© 2021 IOP Publishing Ltd.)

Unsupervised feature selection (UFS) is a popular technique of reducing the dimensions of high-dimensional data. Previous UFS methods were often designed with the assumption that the whole information in the data set is observed. However, incomplete data sets that contain unobserved information can be often found in real applications, especially in industry. Thus, these existing UFS methods have a limitation on conducting feature selection on incomplete data. On the other hand, most existing UFS methods did not consider the sample importance for feature selection, i.e., different samples have various importance. As a result, the constructed UFS models easily suffer from the influence of outliers. This article investigates a new UFS method for conducting UFS on incomplete data sets to investigate the abovementioned issues. Specifically, the proposed method deals with unobserved information by using an indicator matrix to filter it out the process of feature selection and reduces the influence of outliers by employing the half-quadratic minimization technique to automatically assigning outliers with small or even zero weights and important samples with large weights. This article further designs an alternative optimization strategy to optimize the proposed objective function as well as theoretically and experimentally prove the convergence of the proposed optimization strategy. Experimental results on both real and synthetic incomplete data sets verified the effectiveness of the proposed method compared with previous methods, in terms of clustering performance on the low-dimensional space of the high-dimensional data.

The limited availability of nutrient Fe severely impairs the health of almost all organisms. Endophytic actinobacteria can benefit the host plant in different ways. We previously inferred that the rice (Oryza) endophytic Streptomyces hygroscopicus OsiSh-2 possesses a highly efficient Fe-acquisition system. In this work, we first evaluated the effects of OsiSh-2 on the Fe-deficiency resilience of the host rice. The results demonstrated that the inoculation of OsiSh-2 considerably increased the plant biomass, Fe concentration and translocation factor, and chlorophyll content, and net leaf photosynthetic rate under Fe limiting condition. The expression of genes involved with Fe 3+ -reduction-related strategy in rice was up-regulated, while that involved with Fe 3+ -chelation-related strategy was down-regulated by OsiSh-2 treatment. Meanwhile, the OsiSh-2-rice symbiont showed enhancement of Fe 3+ -chelate reductase activity, total siderophore production, and acidification trend in the rhizosphere under Fe deficiency compared to plants without this endophyte. In conclusion, endophytic OsiSh-2 could protect plants against Fe-deficient stress by a sophisticated interaction with the host, including modulating Fe chelation, solubilization, reduction and translocation, ultimately leading to enhanced fitness of plant., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: Identification and characterization of a novel bacterial carbohydrate esterase (PaCes7) with application potential for lignocellulose and pesticide degradation., Results: PaCes7 was identified from the lignocellulolytic bacterium, Pantoea ananatis Sd-1 as a new carbohydrate esterase. Recombinant PaCes7 heterologously expressed in Escherichia coli showed a clear preference for esters with short-chain fatty acids and exhibited maximum activity towards α-naphthol acetate at 37 °C and pH 7.5. Purified PaCes7 exhibited its catalytic activity under mesophilic conditions and retained more than 40% activity below 30 °C. It displayed a relatively wide pH stability from pH 6-11. Furthermore, the enzyme was strongly resistant to Mg 2+ , Pb 2+ , and Co 2+ and activated by K + and Ca 2+ . Both P. ananatis Sd-1 and PaCes7 could degrade the pesticide carbaryl. Additionally, PaCes7 was shown to work in combination with cellulase and/or xylanase in rice straw degradation., Conclusions: The data suggest that PaCes7 possesses promising biotechnological potential.

Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo . Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis., Competing Interests: The authors are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and/or shareholders of Merck & Co., Inc., Kenilworth, NJ, USA. P.S.K. is a current employee and/or shareholder of Jnana Therapeutics. P.C. is a current employee and/or shareholder of PRA Health Sciences. Y.Z. is a current employee and/or shareholder of HistoBridge, LLC. Y.H. and T.E.A. are current employees of FDA. T-Q.C. is a current employee and/or shareholder of Calico Life Sciences. J.C. is a current employee and/or shareholder of AstraZeneca. L-J.M. is a current employee and/or shareholder of Johnson and Johnson. M.H. is a current employee and/or shareholder of Maze Therapeutics. K.K.J. is a current employee and/or shareholder of Shrὄdinger, Inc. I.K.S and S.P. are current employees and/or shareholders of Kallyope, Inc., (© 2020 Elsevier Inc.)

The molecular links between extracellular signals and the regulation of localized protein synthesis in plant cells are poorly understood. Here, we show that in Arabidopsis thaliana, the extracellular peptide RALF1 and its receptor, the FERONIA receptor kinase, promote root hair (RH) tip growth by modulating protein synthesis. We found that RALF1 promotes FERONIA-mediated phosphorylation of eIF4E1, a eukaryotic translation initiation factor that plays a crucial role in the control of mRNA translation rate. Phosphorylated eIF4E1 increases mRNA affinity and modulates mRNA translation and, thus, protein synthesis. The mRNAs targeted by the RALF1-FERONIA-eIF4E1 module include ROP2 and RSL4, which are important regulators of RH cell polarity and growth. RALF1 and FERONIA are expressed in a polar manner in RHs, which facilitate eIF4E1 polar localization and thus may control local ROP2 translation. Moreover, we demonstrated that high-level accumulation of RSL4 exerts negative-feedback regulation of RALF1 expression by directly binding the RALF1 gene promoter, determining the final RH size. Our study reveals that the link between RALF1-FERONIA signaling and protein synthesis constitutes a novel component regulating cell expansion in these polar growing cells., (Copyright © 2019 The Author. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate. The family of P21-activated kinases (PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis. In this work, we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth. PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer. Our small molecule screening identified a relatively specific PAK1-targeted inhibitor, CP734. Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity. Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways. Little toxicity of CP734 was observed in murine models. Combined with gemcitabine or 5-fluorouracil, CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells. All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer., Competing Interests: The authors disclose no potential conflicts of interest., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The conversion of light energy into chemical energy in leaves is very important for plant growth and development. During this process, chlorophylls and their derivatives are indispensable as their fundamental role in the energy absorption and transduction activities. Chlorophyll variation mutants are important materials for studying chlorophyll metabolism, chloroplast biogenesis, photosynthesis and related physiological processes. Here, a chlorophyll-reduced mutant (crm1) was isolated from ethyl methanesulfonate (EMS) mutagenized Brassica napus. Compared to wild type, crm1 showed yellow leaves, reduced chlorophyll content, fewer thylakoid stacks and retarded growth. Quantitative mass spectrometry analysis with Tandem Mass Tag (TMT) isobaric labeling showed that totally 4575 proteins were identified from the chloroplast of Brassica napus leaves, and 466 of which displayed differential accumulations between wild type and crm1. The differential abundance proteins were found to be involved in chlorophyll metabolism, photosynthesis, phagosome and proteasome. Our results suggest that the decreased abundance of chlorophyll biosynthetic enzymes, proteins involved in photosynthesis might account for the reduced chlorophyll content, impaired thylakoid structure, and reduction of plant productivity. The increased abundance of proteins involved in phagosome and proteasome pathways might allow plants to adapt the proteome to environmental conditions to ensure growth and survival due to chlorophyll reduction. BIOLOGICAL SIGNIFICANCE: Photosynthesis, which consists of light and dark reactions, is fundamental to biomass production. Chloroplast is regarded as the main site for photosynthesis. During photosynthesis, the pigment chlorophyll is essential for light harvesting and energy transfer. This work provides new insights into protein expression patterns, and enables the identification of many attractive candidates for investigation of chlorophyll biosynthesis, chloroplast structure and photosynthesis in Brassica napus. These findings may be applied to improve the photosynthetic efficiency by genetic engineering in crops., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2019. Published by Elsevier B.V.)

Microbial antagonists and their bioactive metabolites provide one of the best alternatives to chemical pesticides to control crop disease for sustainable agriculture and global food security. The rice endophyte Streptomyces hygroscopicus OsiSh-2, with remarkable antagonistic activity towards the rice blast fungus Magnaporthe oryzae, was reported in our previous study. The present study deciphered the possible direct interaction mode of OsiSh-2 against M. oryzae. An in vitro antibiotic assay for OsiSh-2 culture filtrate revealed strong suppression of mycelial growth, conidial germination and appressorial formation of M. oryzae. Meanwhile, severe morphological and internal abnormalities in M. oryzae hyphae were observed under a scanning electron microscope and transmission electron microscope. Foliar treatment of rice seedlings by OsiSh-2 culture filtrate in the greenhouse and in the field showed 23.5% and 28.3% disease reduction, respectively. Correspondingly, OsiSh-2 culture filtrate could induce disorganized chitin deposition in the cell wall and lowered ergosterol content in the cell membrane of M. oryzae. Additionally, cell wall integrity pathway activation, large cell electrolytes release, reactive oxygen species accumulation and tricarboxylic acid cycle-related enzyme activity changes were found in M. oryzae. All these results suggested that the direct antagonistic activity of OsiSh-2 against M. oryzae may be attributed to damaging the integrity of the cell wall and membrane and disrupting mitochondrial function in the pathogen., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for chronic kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, that was shown to have beneficial effects in preclinical models. In this study we investigated the effects of MK-8722 in a progressive rat model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We found that MK-8722 administration in a therapeutic paradigm is profoundly renoprotective, as demonstrated by a reduction in proteinuria (63% decrease in MK-8722 10 mg/kg per day compared with vehicle group) and a significant improvement in glomerular filtration rate (779 and 430 μ l/min per gram kidney weight in MK-8722 10 mg/kg per day and vehicle group, respectively), as well as improvements in kidney fibrosis. We provide evidence that the therapeutic effects of MK-8722 may be mediated by modulation of renal mitochondrial quality control as well by attenuating fibrotic and lipotoxic mechanisms in kidney cells. MK-8722 (10 mg/kg per day compared with vehicle group) achieved modest blood pressure reduction (10 mmHg lower for mean blood pressure) and significant metabolic improvements (decreased plasma glucose, triglyceride, and body weight) that could contribute to renoprotection. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach. SIGNIFICANCE STATEMENT: We demonstrate in the present study that the pharmacological activation of AMPK using a small-molecule agent provided renoprotection and improved systemic and cellular metabolism. We further indicate that modulation of renal mitochondrial quality control probably contributed to renoprotection and was distinct from the effects of enalapril. Our findings suggest that improving renal mitochondrial biogenesis and function and attenuating fibrosis and lipotoxicity by targeting key metabolic nodes could be a potential therapeutic approach in management of CKD that could complement the current standard of care., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Injuries to the skin are common in daily life, and a certain type or size of defect is not easily restored using conventional dressings or naturally. The repair of these defects requires restoration of function in regenerated tissues. In this study, a tissue engineered skin was designed and fabricated using a bio-3D printing system. Polycaprolactone and bacterial cellulose comprised the scaffold, due to their excellent biocompatibility and multifunctionality. Adipose-derived mesenchymal stem cells (Ad-MSCs) were seeded onto the scaffold to functionalize it as an artificial skin. The finished artificial skin had mechanical properties similar to that of natural skin, and its fibrous structure providing a unique micro-environment that could regulate the paracrine function of the Ad-MSCs. This effect could be greatly increased by changes in the characteristics of the biomaterials. The artificial skin exhibited high biological activity, strong induction of cell recruitment, migration, growth and up-regulation of gene expression of relevant factors, resulting in excellent wound healing characteristics. This study clarified novel design aspects of cell-material interactions in which the topographical characteristics of materials can be further developed to establish cell signaling or communication networks that take advantage of the paracrine actions of Ad-MSCs to promote specific tissue regeneration or repair characteristics.

An endophytic bacterium YG-3 with high cadmium (Cd) resistance was isolated from poplar grown in a composite mine tailing. It was identified as Burkholderia cenocepacia based on genomic, physiological and biochemical analyses. The Cd removal rate by YG-3 could reach about 60.0% in Cd aqueous solution with high concentrations of both 100 and 500 mg L-1. Meanwhile, various absorption and adsorption strategies were found in the two different Cd concentrations. The global resistance mechanisms of YG-3 were investigated in several levels, i.e., physiological observation, such as scanning electron microscopy and transmission electron microscopy; biochemical detection for active compound production and infrared spectroscopy; label-free quantitative proteomic profile analysis. The results indicated that YG-3 possesses a complex mechanism to adapt to Cd stress: (1) binding of Cd to prevent it from entering the cell by the cell wall components, as well as secreted siderophores and exopolysaccharides; (2) intracellular sequestration of Cd by metalloproteins; (3) excretion of Cd from the cell by efflux pumps; (4) alleviation of Cd toxicity by antioxidants. Our results demonstrate that endophyte YG-3 is well adjusted to largely remove Cd and has potential to cooperate with its host to improve phytoremediation efficiency in heavy metal-contaminated sites.

Crude glycerol is largely generated as the main by-product of the biodiesel industry and is unprofitable for industrial application without costly purification. The direct bioconversion of crude glycerol into 1,3-propanediol (1,3-PDO) by microorganisms is a promising alternative for effective and economic utilization. In this study, Klebsiella pneumoniae 2e was newly isolated for the conversion of crude glycerol into 1,3-PDO. Batch fermentation analysis confirmed that crude glycerol and its main impurities had slight impacts on the growth, key enzyme activity, and 1,3-PDO production of K. pneumoniae 2e. The 1,3-PDO yield from crude glycerol by K. pneumoniae 2e reached 0.64 mol 1,3-PDO/mol glycerol, which was higher than that by most reported 1,3-PDO-producing Klebsiella strains. Genomic profiling revealed that K. pneumoniae 2e possesses 30 genes involved in glycerol anaerobic metabolism and 1,3-PDO biosynthesis. Quantitative real-time PCR analysis of these genes showed that the majority of the genes encoding the key enzymes for glycerol metabolism and 1,3-PDO biosynthesis were significantly upregulated during culture in crude glycerol relative to that in pure glycerol. Further comparative genomic analysis revealed a novel glycerol uptake facilitator protein in K. pneumoniae 2e and a higher number of stress response proteins than in other Klebsiella strains. This work confirms the adaptability of a newly isolated 1,3-PDO-producing strain, K. pneumoniae 2e, to crude glycerol and provides insights into the molecular mechanisms involved in its crude glycerol tolerance, which is valuable for industrial 1,3-PDO production from crude glycerol. IMPORTANCE The rapid development of the biodiesel industry has led to tremendous crude glycerol generation. Due to the presence of complex impurities, crude glycerol has low value for industry without costly purification. Obtaining novel microorganisms capable of direct and efficient bioconversion of crude glycerol to value-added products has great economic potential for industrial application. In this work, we characterized a newly isolated strain, Klebsiella pneumoniae 2e, with the capacity to efficiently produce 1,3-propanediol (1,3-PDO) from crude glycerol and demonstrated its adaptation to crude glycerol. Our work provides insights into the molecular mechanisms of K. pneumoniae 2e adaptation to crude glycerol and the expression patterns of its genes involved in 1,3-PDO biosynthesis, which will contribute to the development of industrial 1,3-PDO production from crude glycerol., (Copyright © 2019 American Society for Microbiology.)

Heavy metal pollution in lakes is becoming increasingly of interest to researchers. Because heavy metals have high mobility and do not degrade, they migrate easily between different environmental mediums through processes such as suspended solids deposition, sediment resuspension, and diffusion, among others. These processes are particularly pronounced in shallow lakes since the hydrodynamism is higher in bodies of water with minimal depth. Lake Ulansuhai-a typical shallow lake in the Hetao irrigation district in Inner Mongolia-also experiences intense sandstorm activity, which compounds the suspended solids exchange intensity between water and sediment, strengthening the migration of heavy metals in the lake system. This study examines the fate and transport of two heavy metals-Zn and Pb-within this lake, using a field experiment to determine the flux of sediment re-suspension and deposition and a laboratory experiment to modify the QWASI model for shallow bodies of water. The aquivalence and mass balance approaches were used to develop this modified QWASI model. The margins of error between the modeled and the measured average concentrations of Zn and Pb in water were 5.0%-30.6% and 5.8%-29.5%, respectively, and in sediment were 0.3%-4.9% and 0.9-5.5%, respectively. These results suggest that the modified QWASI model developed here could indeed be used to more accurately represent the fate and transport of Zn and Pb during the icefree period of a shallow lake., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rice blast caused by Magnaporthe oryzae severely impacts global rice yield stability. The rice endophyte Streptomyces sporocinereus OsiSh-2, with strong antagonistic activity towards M. oryzae, has been reported in our previous study. To decipher the model of the antagonistic action of OsiSh-2 towards M. oryzae, we compared the iron-capturing abilities of these two strains. The cultivation of OsiSh-2 and a M. oryzae strain under iron-rich and iron-starved conditions showed that M. oryzae depended more on iron supplementation for growth and development than did OsiSh-2. Genomic analysis of the S. sporocinereus and M. oryzae species strains revealed that they might possess different iron acquisition strategies. The actinobacterium OsiSh-2 is likely to favor siderophore utilization compared to the fungus M. oryzae. In addition, protein annotations found that OsiSh-2 contains the highest number of the siderophore biosynthetic gene clusters among the 13 endophytic actinomycete strains and 13 antifungal actinomycete strains that we compared, indicating the prominent siderophore production potential of OsiSh-2. Additionally, we verified that OsiSh-2 could excrete considerably more siderophores than Guy11 under iron-restricted conditions and displayed greater Fe 3+ -reducing activity during iron-supplemental conditions. Measurements of the iron mobilization between the antagonistic OsiSh-2 and Guy11 showed that the iron concentration is higher around OsiSh-2 than around Guy11. In addition, adding iron near OsiSh-2 could decrease the antagonism of OsiSh-2 towards Guy11. Our study revealed that the antagonistic capacity displayed by OsiSh-2 towards M. oryzae was related to the competition for iron. The highly efficient iron acquisition system of OsiSh-2 may offer valuable insight for the biocontrol of rice blast.

Purpose To evaluate the biodistribution, metabolism, and pharmacokinetics of a new type I collagen-targeted magnetic resonance (MR) probe, CM-101, and to assess its ability to help quantify liver fibrosis in animal models. Materials and Methods Biodistribution, pharmacokinetics, and stability of CM-101 in rats were measured with mass spectrometry. Bile duct-ligated (BDL) and sham-treated rats were imaged 19 days after the procedure by using a 1.5-T clinical MR imaging unit. Mice were treated with carbon tetrachloride (CCl 4 ) or with vehicle two times a week for 10 weeks and were imaged with a 7.0-T preclinical MR imaging unit at baseline and 1 week after the last CCl 4 treatment. Animals were imaged before and after injection of 10 µmol/kg CM-101. Change in contrast-to-noise ratio (ΔCNR) between liver and muscle tissue after CM-101 injection was used to quantify liver fibrosis. Liver tissue was analyzed for Sirius Red staining and hydroxyproline content. The institutional subcommittee for research animal care approved all in vivo procedures. Results CM-101 demonstrated rapid blood clearance (half-life = 6.8 minutes ± 2.4) and predominately renal elimination in rats. Biodistribution showed low tissue gadolinium levels at 24 hours (<3.9% injected dose [ID]/g ± 0.6) and 10-fold lower levels at 14 days (<0.33% ID/g ± 12) after CM-101 injection with negligible accumulation in bone (0.07% ID/g ± 0.02 and 0.010% ID/g ± 0.004 at 1 and 14 days, respectively). ΔCNR was significantly (P < .001) higher in BDL rats (13.6 ± 3.2) than in sham-treated rats (5.7 ± 4.2) and in the CCl 4 -treated mice (18.3 ± 6.5) compared with baseline values (5.2 ± 1.0). Conclusion CM-101 demonstrated fast blood clearance and whole-body elimination, negligible accumulation of gadolinium in bone or tissue, and robust detection of fibrosis in rat BDL and mouse CCl 4 models of liver fibrosis. © RSNA, 2017 Online supplemental material is available for this article.

Objective: To identify and characterize a novel bacterial pyranose 2-oxidase (P2Ox) and investigate its potential use in lignin degradation applications., Results: A new bacterial P2Ox (PaP2Ox) enzyme was identified in the lignocellulolytic bacterium Pantoea ananatis Sd-1. The PaP2Ox open reading frame was cloned, and the encoded protein was heterologously expressed in an Escherichia coli expression system. Unlike another reported bacterial P2Ox enzyme, the purified PaP2Ox exhibits a homotetrameric spatial conformation that is similar to fungal P2Oxs, with each subunit having a molecular mass of 65 kDa. The recombinant PaP2Ox exhibits maximum activity at 50 °C and pH 6.5 with D-glucose as its preferred substrate. In addition, this enzyme was shown to work in combination with bacterial laccase in lignin degradation., Conclusions: The bacterial enzyme PaP2Ox has potential use in ligninolytic systems and shows promising value in industrial biotechnological applications.

Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by ∼30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold)., (© 2017 by the American Diabetes Association.)

Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK-0429, a compound that was originally developed as an αvβ3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK-0429 is an equipotent pan-inhibitor of multiple av integrins. MK-0429 dose-dependently inhibited podocyte motility and also suppressed TGF-β-induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK-0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy., (© 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db / db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Insulin resistance and diabetes can develop spontaneously with obesity and aging in rhesus monkeys, highly similar to the natural history of obesity, insulin resistance, and progression to type 2 diabetes in humans. The current studies in obese rhesus were undertaken to assess hepatic and adipose contributions to systemic insulin resistance-currently, a gap in our knowledge-and to benchmark the responses to pioglitazone (PIO). A two-step hyperinsulinemic-euglycemic clamp, with tracer-based glucose flux estimates, was used to measure insulin resistance, and in an intervention study was repeated following 6 wk of PIO treatment (3 mg/kg). Compared with lean healthy rhesus, obese rhesus has a 60% reduction of glucose utilization during a high insulin infusion and markedly impaired suppression of lipolysis, which was evident at both low and high insulin infusion. However, obese dysmetabolic rhesus manifests only mild hepatic insulin resistance. Six-week PIO treatment significantly improved skeletal muscle and adipose insulin resistance (by ~50%). These studies strengthen the concept that insulin resistance in obese rhesus closely resembles human insulin resistance and indicate the value of obese rhesus for appraising new insulin-sensitizing therapeutics., (Copyright © 2017 the American Physiological Society.)

Background: Biocontrol is a promising strategy in the control of rice blast disease. In the present study, we isolated and characterized a novel antagonist to the pathogen Magnaporthe oryzae from rice endophytic actinomycetes., Results: Out of 482 endophytic actinomycetes isolated from rice blast infected and healthy rice, Streptomyces endus OsiSh-2 exhibited remarkable in vitro antagonistic activity. Scanning electron microscopy observations of M. oryzae treated by OsiSh-2 revealed significant morphological alterations in hyphae. In 2-year field tests, the spraying of OsiSh-2 spore solution (10 7  spores mL -1 ) is capable of reducing rice blast disease severity by 59.64%. In addition, a fermentation broth of OsiSh-2 and its cell-free filtrates could inhibit the growth of M. oryzae, suggesting the presence of active enzymes and secondary metabolites. OsiSh-2 tested positive for polyketide synthase-I and nonribosomal peptide synthetase genes and can produce cellulase, protease, gelatinase, siderophore, indole-3-acetic acid and 1-amino-cyclopropane-1-carboxylate deaminase. A preliminary separation indicated that the methanol extract of OsiSh-2 could suppress the growth of pathogens. The major active component was identified as nigericin., Conclusion: Endophytic S. endus OsiSh-2 has potential as a biocontrol agent against rice blast in agriculture. © 2016 Society of Chemical Industry., (© 2016 Society of Chemical Industry.)

The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na + /K + /2Cl - cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups-control, high-salt diet alone; ROMKi B 3 mg·kg - 1 ·d - 1 ; ROMKi B 10 mg·kg - 1 ·d - 1 ; and hydrochlorothiazide 25 mg·kg - 1 ·d - 1 -were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was superior to hydrochlorothiazide at reducing blood pressure. Furthermore, ROMKi B provided beneficial effects on both the plasma lipid profile and bone mineral density. Chronic ROMK inhibition not only prevented but also reversed the development of hypertension and end-organ damage in Dahl salt-sensitive rats. Our findings suggest a potential utility of ROMKi B as a novel antihypertensive agent, particularly for the treatment of the salt-sensitive hypertension patient population., (© 2016 American Heart Association, Inc.)

Background: Lignocellulolytic bacteria have revealed to be a promising source for biofuel production, yet the underlying mechanisms are still worth exploring. Our previous study inferred that the highly efficient lignocellulose degradation by bacterium Pantoea ananatis Sd-1 might involve Fenton chemistry (Fe 2+  + H 2 O 2  + H +  → Fe 3+  + OH· + H 2 O), similar to that of white-rot and brown-rot fungi. The aim of this work is to investigate the existence of this Fenton-based oxidation mechanism in the rice straw degradation process of P. ananatis Sd-1., Results: After 3 days incubation of unpretreated rice straw with P. ananatis Sd-1, the percentage in weight reduction of rice straw as well as its cellulose, hemicellulose, and lignin components reached 46.7, 43.1, 42.9, and 37.9 %, respectively. The addition of different hydroxyl radical scavengers resulted in a significant decline ( P  < 0.001) in rice straw degradation. Pyrolysis gas chromatography-mass spectrometry and Fourier transform infrared spectroscopy analysis revealed the consistency of chemical changes of rice straw components that exists between P. ananatis Sd-1 and Fenton reagent treatment. In addition to the increased total iron ion concentration throughout the rice straw decomposition process, the Fe 3+ -reducing capacity of P. ananatis Sd-1 was induced by rice straw and predominantly contributed by aromatic compounds metabolites. The transcript levels of the glucose-methanol-choline oxidoreductase gene related to hydrogen peroxide production were significantly up-regulated (at least P  < 0.01) in rice straw cultures. Higher activities of GMC oxidoreductase and less hydrogen peroxide concentration in rice straw cultures relative to glucose cultures may be responsible for increasing rice straw degradation, which includes Fenton-like reactions., Conclusions: Our results confirmed the Fenton chemistry-assisted degradation model in P. ananatis Sd-1. We are among the first to show that a Fenton-based oxidation mechanism exists in a bacteria degradation system, which provides a new perspective for how natural plant biomass is decomposed by bacteria. This degradative system may offer an alternative approach to the fungi system for lignocellulosic biofuels production.

Mung bean nuclease is a single stranded specific DNA and RNA endonuclease purified from mung bean sprouts. It yields 5'-phosphate terminated mono- and oligonucleotides. The activity level of this nuclease can act as a marker to monitor the developmental process of mung bean sprouts. In order to facilitate the activity and physiological analysis of this nuclease, we have developed a biosensing assay system based on the mung bean nuclease-induced single-stranded DNA scission and the affinity difference of graphene oxide for single-stranded DNA containing different numbers of bases. This end-point measurement method can detect mung bean nuclease in a range of 2×10(-4) to 4×10(-2) with a detection limit of 1×10(-4) unit/mL. In addition, we demonstrate the utility of the assay for screening chemical antibiotics and metal ions, resulting in the identification of several inhibitors of this enzyme in vitro. Furthermore, we firstly report that inhibiting mung bean nuclease by gentamycin sulfate and kanamycin in vivo can suppress mung bean sprouts growth. In summary, this method provides an alternative tool for the biochemical analysis for mung bean nuclease and indicates the feasibility of high-throughput screening specific inhibitors of this nuclease in vitro and in vivo., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Bariatric surgery induces weight loss and improvement of insulin resistance; one aspect of both is an amelioration of hepatic steatosis. This study was undertaken to assess the changes in the hepatic lipidome after duodenal-jejunal bypass (DJB) surgery., Methods: A DJB surgical model was developed and characterized in diet-induced obese mice. In comparison with sham-operated mice, an unbiased lipidomic profiling of hepatic lipids was performed together with measurements of gene expression within key pathways of hepatic lipid metabolism., Results: In the liver of DJB mice, a dramatic reduction (by 77%) in hepatic triacylglycerols was observed. Global lipidomic profiling identified marked decreases of triacylglycerols comprised of medium length fatty acids and with low double bond content. Specific diacylglycerol species were also among the most dramatic decreases in hepatic lipids, whereas lysophosphatidic acids and phosphatidic acids were increased. Expression of fatty acid transporter and lipogenic genes was down-regulated., Conclusions: From in-depth analysis of hepatic lipid composition, specific lipid intermediates were identified that are preferentially changed following DJB surgery. These changes were most likely due to DJB-induced weight loss, and only further studies will be able to distinguish weight loss-dependent from weight loss-independent changes., (© 2016 The Obesity Society.)

There can be marked variations in soil hydraulic properties in a soil vertical profile from the soil surface to the base of the root zone. Many existing two-layer soil moisture (TLSM) models cannot well describe typical stratified soil profiles. A modified TLSM model is presented in this study. The modified model results and those from two existing models are compared with field observations. The modified TLSM model had the best agreement with the field observations. In both the surface layer and the root zone layer, the root mean square errors of soil moisture estimated by the modified model were smaller than those for the other models. The parameters in the modified TLSM model are relatively easy to determine. The modified TLSM model offers clear advantages over current TLSM models., (© 2016, National Ground Water Association.)

As a waste-management endonuclease, DNase I has been suggested to be one of the deoxyribonucleases responsible for DNA fragmentation during apoptosis. We report here an alternative fluorescence method for DNase I assay with high accuracy and sensitivity by applying a DNA/GO (graphene oxide) probe. The method with a detection limit of 1 U mL(-1) was then applied to investigate the effects of external factors including antibiotics and heavy metal ions on DNase I. The results demonstrated that gentamicin sulfate was a strong inhibitor with an IC50 value of 0.57 ± 0.12 mM. The investigated heavy metal ions showed an inhibitory effect on DNase I activity in a concentration dependent manner with IC50 values of 0.04 μg/mL (Hg(2+)), 0.10 μg/mL (Pb(2+)), 1.35 μg/mL (Cd(2+)), 1.20 μg/mL (As(2+)), and 1.80 μg/mL (Cu(2+)). Finally, the new method was applied to detect DNase levels in complicated tumor tissue and cell samples and the results showed that DNase levels increased in tumor tissues compared with that of adjacent tissue. From the above results, we conclude that the method can be widely used for high - throughput assay of DNase I in biological samples as well as drug screening in vitro. Graphical Abstract The schematic of real-time monitoring of DNase I using GO - quenched hairpin probe as the substrate. The process of nucleotide digestion catalyzed by DNase I produces short fragments of hairpin probe and accordingly causes a significant increase in fluorescence. At first, GO can absorb the hairpin probes and quenched their fluorescence. When there is DNase I, the DNase can cleave the double strands of DNA. Fluorescence is restored due to the significantly weaker binding ability of small DNA fragments to GO compared with long DNA fragments. So, we can detect the increase in fluorescence to study the activity of DNase.

Background: Exploring microorganisms especially bacteria associated with the degradation of lignocellulosic biomass shows great potentials in biofuels production. The rice endophytic bacterium Pantoea ananatis Sd-1 with strong lignocellulose degradation capacity has been reported in our previous study. However, a comprehensive analysis of its corresponding degradative system has not yet been conducted. The aim of this work is to identify and characterize the lignocellulolytic enzymes of the bacterium to understand its mechanism of lignocellulose degradation and facilitate its application in sustainable energy production., Results: The genomic analysis revealed that there are 154 genes encoding putative carbohydrate-active enzymes (CAZy) in P. ananatis Sd-1. This number is higher than that of compared cellulolytic and ligninolytic bacteria as well as other eight P. ananatis strains. The CAZy in P. ananatis Sd-1 contains a complete repertoire of enzymes required for cellulose and hemicellulose degradation. In addition, P. ananatis Sd-1 also possesses plenty of genes encoding potential ligninolytic relevant enzymes, such as multicopper oxidase, catalase/hydroperoxidase, glutathione S-transferase, and quinone oxidoreductase. Quantitative real-time PCR analysis of parts of genes encoding lignocellulolytic enzymes revealed that they were significantly up-regulated (at least P < 0.05) in presence of rice straw. Further identification of secretome of P. ananatis Sd-1 by nano liquid chromatography-tandem mass spectrometry confirmed that considerable amounts of proteins involved in lignocellulose degradation were only detected in rice straw cultures. Rice straw saccharification levels by the secretome of P. ananatis Sd-1 reached 129.11 ± 2.7 mg/gds. Correspondingly, the assay of several lignocellulolytic enzymes including endoglucanase, exoglucanase, β-glucosidase, xylanase-like, lignin peroxidase-like, and laccase-like activities showed that these enzymes were more active in rice straw relative to glucose substrates. The high enzymes activities were not attributed to bacterial cell densities but to the difference of secreted protein contents., Conclusion: Our results indicate that P. ananatis Sd-1 can produce considerable lignocellulolytic enzymes including cellulases, hemicellulases, and ligninolytic relevant enzymes. The high activities of those enzymes could be efficiently induced by lignocellulosic biomass. This identified degradative system is valuable for the lignocellulosic bioenergy industry.

Objectives: Isolation and identification of a novel laccase (namely Lac4) with various industrial applications potentials from an endophytical bacterium., Results: Endophyte Sd-1 cultured in rice straw showed intra- and extra-cellular laccase activities. Genomic analysis of Sd-1 identified four putative laccases, Lac1 to Lac4. However, only Lac4 contains the complete signature sequence of laccase and shares at most 64 % sequence identity with other characterized bacterial multi-copper oxidases. Recombinant Lac4 can oxidize non-phenolic and phenolic compounds under acidic conditions and at 30-50 °C; Km values of Lac4 for ABTS at pH 2.5 and for guaiacol at pH 4.5 were 1 ± 0.15 and 6.1 ± 1.7 mM, respectively. The activity of Lac4 was stimulated by 0.8 mM Cu(2+) and 5 mM Fe(2+). In addition, Lac4 could decolorize various synthetic dyes and exhibit the degradation rate of 38 % for lignin., Conclusions: The data suggest that Lac4 possesses promising biotechnological potentials.