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Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

To improve the driving comfort of combine harvesters, driver seat low-frequency vibration and related driver ride-comfort problems were investigated on a Chinese CFFL-850 crawler-type full-feed combine harvester based on ISO2631. Driver vibration and driving seat transmission characteristics were measured under the following conditions: no-load idling, driving on the road, driving in the field, and simulated harvesting. The root mean square values composite vibration under four conditions were 3.63 m/s2, 2.35 m/s2, 3.34 m/s2, and 2.67 m/s2, respectively. For the same condition, the maximum root mean square scores of vibration component on driver whole-body occurred in the seat support surface (test point 1) and vertical direction (Z direction), which were 3.56 m/s2, 2.05 m/s2, 3.15 m/s2, and 2.43 m/s2, respectively. The test point 2 to test point 1 vertical-transfer function curve trends were nearly identical. Nearly all of the transfer coefficients were greater than 1 in the range of 1-50 Hz, therefore, the seat vibration attenuation performance was poor. Based on the analysis results, the driver seat structure was altered and a verification test was performed. The test results indicated that after an X-damping mechanism was installed, vibration acceleration, on the surface of the seat support under the road-driving conditions, decreased from 2.35 m/s2 to 1.68 m/s2. Under the simulated harvesting condition, the vibration acceleration decreased from 2.56 m/s2 to 1.46 m/s2. Nearly all of the seat vertical transfer coefficients were less than 1 within the frequency range of 1-80 Hz, therefore the dynamic comfort of the seat was ameliorated after structural improvement.

The oil-film-lubricated mechanical face seal described here is a hydrodynamically lubricated, noncontacting, mechanical face seal with zero leakage. On the basis of systematic theoretical analyses, research on design methods, and experimental investigations, many field applications have been made. The experimental investigations include test rig development; long-time high-speed running tests; frequent start-up and shut-down tests; measurements of the seal leakage, face temperature, and characteristics of the self-circulating screw pump; observation, measurement, and solution of interface wear, and so on. Until now, this new seal design has been successfully applied in more than 40 high-speed turbocompressors in the oil refinery and petrochemical industries, achieving zero leakage and long operation. These seals are all designed with different face spiral-groove patterns, structure arrangements, and supporting systems. Presented at the 59th Annual Meeting in Toronto, Ontario, Canada May 17-20, 2004 Review led by Jim Netzel

Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18X per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from EPAS1, a transcription factor involved in response to hypoxia. One SNP at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent ( L -Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L -arginine ( L -Arg) using the homogenization/emulsification method. The L -Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L -Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L -Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L -Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy. Graphical Abstract

Background Cancer subtype classification is helpful for personalized cancer treatment. Although, some approaches have been developed to classifying caner subtype based on high dimensional gene expression data, it is difficult to obtain satisfactory classification results. Meanwhile, some cancers have been well studied and classified to some subtypes, which are adopt by most researchers. Hence, this priori knowledge is significant for further identifying new meaningful subtypes. Results In this paper, we present a combined parallel random forest and autoencoder approach for cancer subtype identification based on high dimensional gene expression data, ForestSubtype. ForestSubtype first adopts the parallel RF and the priori knowledge of cancer subtype to train a module and extract significant candidate features. Second, ForestSubtype uses a random forest as the base module and ten parallel random forests to compute each feature weight and rank them separately. Then, the intersection of the features with the larger weights output by the ten parallel random forests is taken as our subsequent candidate features. Third, ForestSubtype uses an autoencoder to condenses the selected features into a two-dimensional data. Fourth, ForestSubtype utilizes k-means++ to obtain new cancer subtype identification results. In this paper, the breast cancer gene expression data obtained from The Cancer Genome Atlas are used for training and validation, and an independent breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium is used for testing. Additionally, we use two other cancer datasets for validating the generalizability of ForestSubtype. ForestSubtype outperforms the other two methods in terms of the distribution of clusters, internal and external metric results. The open-source code is available at https://github.com/lffyd/ForestSubtype . Conclusions Our work shows that the combination of high-dimensional gene expression data and parallel random forests and autoencoder, guided by a priori knowledge, can identify new subtypes more effectively than existing methods of cancer subtype classification.