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1.
Neurotox Res ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691187

RESUMO

Correlation between the level of high-sensitivity C-reactive protein (hs-CRP) and the incidence of intracranial arterial stenosis (ICAS) is unclear. We aim to investigate the relationship between hs-CRP levels and ICAS. A total of 1458 patients aged ≥ 40 years were enrolled in this study. All the participants had a magnetic resonance angiography (MRA) examination for the evaluation of ICAS. Participants were classified into four groups according to stroke and ICAS. Multivariable logistic regression models were used to assess the relationship of hs-CRP levels and ICAS status. A total of 432 (29.63%) subjects had ICAS. The levels of hs-CRP in stroke group were significantly higher than those in non-stroke group (p < 0.001). Patients with ICAS tend to have higher hs-CRP levels (p < 0.001). In multivariate analysis, the fourth hs-CRP quartile had the strongest association with ICAS in both stroke group and non-stroke group (OR 2.512, 95% CI 1.651-3.853, p < 0.001 for stroke group, and OR 2.534, 95% CI 1.435-4.595, p = 0.002 for non-stroke group) among the four quartiles of hs-CRP levels. Our study suggests that elevated serum hs-CRP levels are associated with higher risk of ICAS, in both stroke patients and non-stroke participants.

2.
FASEB J ; 33(11): 13051-13061, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31589480

RESUMO

Polycystic kidney disease (PKD) is characterized by the expansion of fluid-filled cysts in the kidney, which impair the function of kidney and eventually leads to end-stage renal failure. It has been previously demonstrated that transgenic overexpression of prothymosin α (ProT) induces the development of PKD; however, the underlying mechanisms remain unclear. In this study, we used a mouse PKD model that sustains kidney-specific low-expression of Pkd1 to illustrate that aberrant up-regulation of ProT occurs in cyst-lining epithelial cells, and we further developed an in vitro cystogenesis model to demonstrate that the suppression of ProT is sufficient to reduce cyst formation. Next, we found that the expression of ProT was accompanied with prominent augmentation of protein acetylation in PKD, which results in the activation of downstream signal transducer and activator of transcription (STAT) 3. The pathologic role of STAT3 in PKD has been previously reported. We determined that this molecular mechanism of protein acetylation is involved with the interaction between ProT and STAT3; consequently, it causes the deprivation of histone deacetylase 3 from the indicated protein. Conclusively, these results elucidate the significant role of ProT, including protein acetylation and STAT3 activation in PKD, which represent potential for ameliorating the disease progression of PKD.-Chen, Y.-C., Su, Y.-C., Shieh, G.-S., Su, B.-H., Su, W.-C., Huang, P.-H., Jiang, S.-T., Shiau, A.-L., Wu, C.-L. Prothymosin α promotes STAT3 acetylation to induce cystogenesis in Pkd1-deficient mice.

3.
Cell Death Dis ; 10(9): 662, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506423

RESUMO

Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1ß, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.

4.
Nat Commun ; 10(1): 4233, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530812

RESUMO

We present a high-quality de novo genome assembly (rheMacS) of the Chinese rhesus macaque (Macaca mulatta) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), rheMacS increases sequence contiguity 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). We improve gene annotation by generating more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to ape genomes. Many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a subset that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. The rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.

5.
Cell ; 178(6): 1509-1525.e19, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491389

RESUMO

Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.

6.
Nat Commun ; 10(1): 3733, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427575

RESUMO

Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.

7.
BMC Vet Res ; 15(1): 304, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438945

RESUMO

BACKGROUND: Brucellosis is a worldwide zoonotic infectious disease that is transmitted in various ways and causes great harm to humans and animals. The brucellosis pathogen is Brucella, which mainly resides in macrophage cells and survives and replicates in host cells. However, the mechanisms underlying Brucella survival in macrophage cells have not been thoroughly elucidated to date. Peroxiredoxin 6 (Prdx6) is a bifunctional protein that shows not only GSH peroxidase activity but also phospholipase A2 activity and plays important roles in combating oxidative damage and regulating apoptosis. RESULTS: Recombinant mouse (Mus musculus) Prdx6 (MmPrdx6) was expressed and purified, and monoclonal antibodies against MmPrdx6 were prepared. Using the Brucella suis S2 strain to infect RAW264.7 murine macrophages, the level of intracellular Prdx6 expression first decreased and later increased following infection. Overexpressing Prdx6 in macrophages resulted in an increase in B. suis S2 strain levels in RAW264.7 cells, while knocking down Prdx6 reduced the S2 levels in cells. CONCLUSIONS: Host Prdx6 can increase the intracellular survival of B. suis S2 strain and plays a role in Brucella infection.

8.
Biomed Res Int ; 2019: 7165406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467907

RESUMO

Early detection and treatment are critical in the management of osteoarthritis (OA). OA is closely associated with angiogenesis and the inhibition of angiogenesis presents a novel therapeutic approach to reduce inflammation and pain in OA. Recent reports suggest that circulating microRNAs (miRNAs) have great potential as biomarkers for the diagnosis and prognosis in OA. In this study, we aimed to explore the clinical significance of miR-210 in synovial fluid samples from 10 healthy volunteers and 20 early-stage OA and 20 late-stage OA patients. miR-210 expression was assessed by real-time RT-PCR. VEGF protein levels were examined by ELISA. The results show that miR-210 is significantly upregulated in early-stage OA and late-stage OA patients compared with healthy individuals. Higher levels of VEGF are also found in OA compared with the control. Moreover, miR-210 levels are positively correlated with VEGF levels, suggesting that miR-210 might contribute to OA development through promoting VEGF expression and angiogenesis. In conclusion, upregulation of miR-210 in synovial fluid may occur in the early stage of OA and can be a useful biomarker for early diagnosis of OA.

9.
Cell Metab ; 30(2): 290-302.e5, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31204281

RESUMO

CD8+ T cell expansions and functions rely on glycolysis, but the mechanisms underlying CD8+ T cell glycolytic metabolism remain elusive. Here, we show that acylglycerol kinase (AGK) is required for the establishment and maintenance of CD8+ T cell metabolic and functional fitness. AGK deficiency dampens CD8+ T cell antitumor functions in vivo and perturbs CD8+ T cell proliferation in vitro. Activation of phosphatidylinositol-3-OH kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, which mediates elevated CD8+ T cell glycolysis, is tightly dependent on AGK kinase activity. Mechanistically, T cell antigen receptor (TCR)- and CD28-stimulated recruitment of PTEN to the plasma membrane facilitates AGK-PTEN interaction and AGK-triggered PTEN phosphorylation, thereby restricting PTEN phosphatase activity in CD8+ T cells. Collectively, these results demonstrate that AGK maintains CD8+ T cell metabolic and functional state by restraining PTEN activity and highlight a critical role for AGK in CD8+ T cell metabolic programming and effector function.

10.
J Virol ; 93(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31189711

RESUMO

Autophagy maintains cellular homeostasis by degrading organelles, proteins, and lipids in lysosomes. Autophagy is involved in the innate and adaptive immune responses to a variety of pathogens. Some viruses can hijack host autophagy to enhance their replication. However, the role of autophagy in porcine reproductive and respiratory syndrome virus (PRRSV) infection is unclear. Here, we show that N-Myc downstream-regulated gene 1 (NDRG1) deficiency induced autophagy, which facilitated PRRSV replication by regulating lipid metabolism. NDRG1 mRNA is expressed ubiquitously in most porcine tissues and most strongly in white adipose tissue. PRRSV infection downregulated the expression of NDRG1 mRNA and protein, while NDRG1 deficiency contributed to PRRSV RNA replication and progeny virus assembly. NDRG1 deficiency reduced the number of intracellular lipid droplets (LDs), but the expression levels of key genes in lipogenesis and lipolysis were not altered. Our results also show that NDRG1 deficiency promoted autophagy and increased the subsequent yields of hydrolyzed free fatty acids (FFAs). The reduced LD numbers, increased FFA levels, and enhanced PRRSV replication were abrogated in the presence of an autophagy inhibitor. Overall, our findings suggest that NDRG1 plays a negative role in PRRSV replication by suppressing autophagy and LD degradation.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-positive-stranded RNA virus, causes acute respiratory distress in piglets and reproductive failure in sows. It has led to tremendous economic losses in the swine industry worldwide since it was first documented in the late 1980s. Vaccination is currently the major strategy used to control the disease. However, conventional vaccines and other strategies do not provide satisfactory or sustainable prevention. Therefore, safe and effective strategies to control PRRSV are urgently required. The significance of our research is that we demonstrate a previously unreported relationship between PRRSV, NDRG1, and lipophagy in the context of viral infection. Furthermore, our data point to a new role for NDRG1 in autophagy and lipid metabolism. Thus, NDRG1 and lipophagy will have significant implications for understanding PRRSV pathogenesis for developing new therapeutics.

11.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(2): 164-170, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-31106533

RESUMO

OBJECTIVE: To explore the effect and mechanism of human adipose-derived mesenchymal stem cells (hADMSCs) on phenotypic polarization of microglia. METHODS: BV-2 microglia of C57/BL6 mice were co-cultured with hADMSCs+lipopolysaccharide (LPS), or cultured with LPS alone. Cell morphology was observed under an inverted microscope. The effect of hADMSCs on microglial proliferation was evaluated by CCK-8 assay. The impact of hADMSCs on microglia M1/M2 phenotype markers were detected using quantitative real-time PCR (RT-qPCR). The affect of hADMSCs on the proteins expression levels of Toll-like receptor 4 (TLR4)-TIR domain containing adaptor protein inducing interferon ß (TRIF) signaling pathway in BV-2 microglia was detected by using Western blot analysis. RESULTS: As compared with the LPS treatment, hADMSCs treatment had no obvious effect on microglia morphology, whereas showed significant inhibition on microglial proliferation activity (P<0.05). Simultaneously, hADMSCs treatment reduced expression of microglia M1 phenotype markers (P<0.05), and increased microglia M1 phenotype markers in gene levels (P<0.05). At the same time, protein expression levels of TRIF, TLR4, phosphorylated interferon regulatory factor 3 (P-IRF3) and interferon regulatory factor 3 (IRF3) in BV-2 microglia were decreased after hADMSCs treatment. CONCLUSION: hADMSCs can blockade the LPS-induced pro-inflammatory microglia M1 phenotype, whereas induces protective microglial M2 phenotype, which may be related to inhibition of the TLR4-TRIF signaling pathway.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Polaridade Celular , Células-Tronco Mesenquimais/citologia , Microglia/citologia , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo , Tecido Adiposo/citologia , Animais , Células Cultivadas , Humanos , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
12.
Enzyme Microb Technol ; 127: 22-31, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31088613

RESUMO

The recombinant rAgaZC-1 was a family GH50 ß-agarase from Vibrio sp. ZC-1 (CICC 24670). In this paper, the mutant D622G (i.e., mutate the aspartic acid at position 622 to glycine) had better thermo-stability than rAgaZC-1, showing 1.5℃ higher T5010 (the temperature at which the half-time is 10 min) and 4-folds of half-time at 41℃, while they had almost same optimum temperature (38.5℃), optimum pH (pH6.0) and catalytic efficiency. Thermal deactivation kinetical analysis showed that D622G had higher activation energy for deactivation, enthalpy and Gibbs free energy than rAgaZC-1, indicating that more energy is required by D622G for deactivation. Substrate can protect agarase against thermal inactivation, especially D622G. Hence the yield of agarose hydrolysis catalyzed by D622G was higher than that by rAgaZC-1. The models of D622G and rAgaZC-1 predicted by homology modeling were compared to find that it is the improved distribution of surface electrostatic potential, great symmetric positive potential and more hydrophobic interactions of D622G that enhance the thermo-stability.


Assuntos
Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Temperatura Alta , Mutagênese , Vibrio/enzimologia , Estabilidade Enzimática , Glicosídeo Hidrolases/química , Concentração de Íons de Hidrogênio , Hidrólise , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Conformação Proteica , Estabilidade Proteica , Sefarose/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-31144626

RESUMO

Low-dimensional discriminative representations enhance machine learning methods in both performance and complexity. This has motivated supervised dimensionality reduction (DR), which transforms high-dimensional data into a discriminative subspace. Most DR methods require data to be i.i.d. However, in some domains, data naturally appear in sequences, where the observations are temporally correlated. We propose a DR method, namely, latent temporal linear discriminant analysis (LT-LDA), to learn low-dimensional temporal representations. We construct the separability among sequence classes by lifting the holistic temporal structures, which are established based on temporal alignments and may change in different subspaces. We jointly learn the subspace and the associated latent alignments by optimizing an objective that favors easily separable temporal structures. We show that this objective is connected to the inference of alignments and thus allows for an iterative solution. We provide both theoretical insight and empirical evaluations on several real-world sequence datasets to show the applicability of our method.

14.
Zool Res ; 40(3): 236-238, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31011135

RESUMO

Why humans have large brains with higher cognitive abilities is a question long asked by scientists. However, much remains unknown, especially the underlying genetic mechanisms. With the use of a transgenic monkey model, we showed that human-specific sequence changes of a key brain development gene (primary microcephaly1, MCPH1) could result in detectable molecular and cognitive changes resembling human neoteny, a notable characteristic developed during human evolution.


Assuntos
Encéfalo/crescimento & desenvolvimento , Haplorrinos/genética , Haplorrinos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Animais Geneticamente Modificados , Evolução Biológica , Humanos
15.
Mol Biol Evol ; 36(6): 1302-1315, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840083

RESUMO

We present a method that jointly analyzes the polymorphism and divergence sites in genomic sequences of multiple species to identify the genes under natural selection and pinpoint the occurrence time of selection to a specific lineage of the species phylogeny. This method integrates population genetics models using a Bayesian Poisson random field framework and combines information over all gene loci to boost the power for detecting selection. The method provides posterior distributions of the fitness effects of each gene along with parameters associated with the evolutionary history, including the species divergence time and effective population size of external species. The results of simulations demonstrate that our method achieves a high power to identify genes under positive selection for a wide range of selection intensity and provides reasonably accurate estimates of the population genetic parameters. The proposed method is applied to genomic sequences of humans, chimpanzees, gorillas, and orangutans and identifies a list of lineage-specific targets of positive selection. The positively selected genes in the human lineage are enriched in pathways of gene expression regulation, immune system and metabolism, etc. Our analysis provides insights into natural evolution in the coding regions of humans and great apes and thus serves as a basis for further molecular and functional studies.


Assuntos
Evolução Biológica , Modelos Genéticos , Seleção Genética , Animais , Teorema de Bayes , Simulação por Computador , Genoma , Hominidae/genética , Humanos , Polimorfismo Genético
16.
Cell Mol Immunol ; 16(9): 757-769, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30705387

RESUMO

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.

17.
EMBO J ; 38(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770344

RESUMO

T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

18.
Nat Cell Biol ; 21(5): 662-663, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30783264

RESUMO

In the version of this Article originally published, the labels for Rictor and mTOR in the whole cell lysate (WCL) blots were swapped in Fig. 3b and the mTOR blot was placed upside down. Unprocessed blots of mTOR were also missing from Supplementary Fig. 9. The corrected Figs are shown below. In addition, control blots for the mTOR antibody (Cell Signalling Technology #2972) were also missing. These are now provided below, as Fig. 9, and show that the lower band is likely non-specific.

19.
Cereb Cortex ; 29(2): 838-851, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535007

RESUMO

The von Economo neurons (VENs) are specialized large bipolar projection neurons with restricted distribution in the human brain, and they are far more abundant in humans than in non-human primates. However, VEN functions remain elusive due to the difficulty of isolating VENs and dissecting their connections in the brain. Here, we combined laser-capture-microdissection with RNA sequencing to describe the transcriptomic profile of VENs from human anterior cingulate cortex (ACC). Using pyramidal neurons as reference cells, we identified 344 genes with VEN-associated expression differences, including 215 higher and 129 lower expression genes. Functional enrichment and protein-protein interaction network analyses showed that these genes with VEN-associated expression differences are involved in VEN morphogenesis and functions, such as dendrite branching and axon myelination, and many of them are associated with human social-emotional disorders. With the use of in situ hybridization and immunohistochemistry assays, we validated four novel VEN markers (VAT1L, CHST8, LYPD1, and SULF2). Collectively, we generated a full-spectrum expression profile of VENs from human ACC, greatly enlarging the pool of genes with VEN-associated expression differences that can help researchers to understand the role of VENs in normal and disordered human brains.

20.
Genome Biol Evol ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517636

RESUMO

Yak is one of the largest native mammalian species at the Himalayas, the highest plateau area in the world with an average elevation of more than 4,000 meters above the sea level. Yak is well adapted to high altitude environment with a set of physiological features for a more efficient blood flow for oxygen delivery under hypobaric hypoxia. Yet, the genetic mechanism underlying its adaptation remains elusive. We conducted a cross-tissue, cross-altitude and cross-species study to characterize the transcriptomic landscape of domestic yaks. The generated multi-tissue transcriptomic data greatly improved the current yak genome annotation by identifying tens of thousands novel transcripts. We found that among the eight tested tissues (lung, heart, kidney, liver, spleen, muscle, testis and brain), lung and heart are two key organs showing adaptive transcriptional changes and more than 90% of the cross-altitude differentially expressed genes (DEGs) in lung display a non-linear regulation. Pathways related to cell survival and proliferation are enriched, including PI3K-Akt, HIF-1, focal adhesion and ECM-receptor interaction. These findings, in combination with the comprehensive transcriptome dataset, are valuable to understanding the genetic mechanism of hypoxic adaptation in yak.

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