DIA-Based Quantitative Proteomics in the Flower Buds of Two Malus sieversii (Ledeb.) M. Roem Subtypes at Different Overwintering Stages.

Malus sieversii is considered the ancestor of the modern cultivated apple, with a high value for apple tolerance breeding. Despite studies on the temperature adaptability of M. sieversii carried out at a physiological response and the genome level, information on the proteome changes of M. sieversii during dormancy is limited, especially about the M. sieversii subtypes. In this study, a DIA-based approach was employed to screen and identify differential proteins involved in three overwintering periods of flower buds in two M. sieversii subtypes (Malus sieversii f. luteolus, GL; Malus sieversii f. aromaticus, HC) with different overwintering adaptabilities. The proteomic analysis revealed that the number of the down-regulated differential expression proteins (DEPs) was obviously higher than that of the up-regulated DEPs in the HC vs. GL groups, especially at the dormancy stage and dormancy-release stage. Through functional classification of those DEPs, the majority of the DEPs in the HC vs. GL groups were associated with protein processing in the endoplasmic reticulum, oxidative phosphorylation, starch and sucrose metabolism and ribosomes. Through WGCNA analysis, tricarboxylic acid cycle and pyruvate metabolism were highly correlated with the overwintering stages; oxidative phosphorylation and starch and sucrose metabolism were highly correlated with the Malus sieversii subtypes. This result suggests that the down-regulation of DEPs, which are predominantly enriched in these pathways, could potentially contribute to the lower cold tolerance observed in HC during overwintering stage.

Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice.

Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge-associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell-type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution.

Long noncoding RNAs AC026904.1 is essential for TGF-ß-induced migration and epithelial-mesenchymal transition through functioning as an enhancer of Slug in lung cancer cells.

Long noncoding RNA (lncRNA) AC026904.1 has been confirmed to be necessary for breast cancer metastasis. This work aims to investigate the effects of lncRNA AC026904.1 on lung cancer metastasis. We found that lncRNA AC026904.1 displayed a higher level in metastatic lung cancer tissues than adjacent tissues and nonmetastatic lung cancer tissues, and lung cancer cells treated with TGF-ß. The expression of AC026904.1 was increased by the non-canonical TGF-ß signaling. Additionally, AC026904.1 acts as an enhancer of the key metastatic factor Slug in the nucleus. This AC026904.1/Slug axis is necessary for TGF-ß-mediated migration and epithelial-mesenchymal transition in lung cancer cells. This work firstly uncovers that AC026904.1 increases Slug expression at transcriptional level and subsequently plays critical effects in lung cancer metastasis, providing novel evidences that AC026904.1 holds great potential to be used as a marker for metastatic lung cancer.

Detection of sulfadimethoxine using optical images of liquid crystals.

A label-free method for sulfadimethoxine (SDM) detection using an aptamer-based liquid crystal biosensor is developed. The sensor probe is fabricated by immobilizing amine-functionalized aptamers onto the glass slide decorating mixed self-assembled layers of triethoxysilylbutyraldehyde (TEA) and N,N-dimethyl-n-octadecyl-3-aminopropyltrimethoxysilylchloride (DMOAP). Liquid crystals (LCs) are supported on the surface and serve as response elements, which assume the homeotropic alignment and cause a dark optical appearance under crossed polarizers. In the presence of SDM, the formation of SDM-aptamer compounds induces a notable change in the topographical structure of the surface, which disturbs the original homeotropic orientation of LCs and results in a bright optical appearance. A detection limit of 10 µg L-1 is obtained, which is far lower than the maximum residue limit (100 µg L-1 in China). This facile method shows good specificity for SDM detection and may have great potential for detecting other small molecules.

Preparation of DNA-functionalized surfaces for simultaneous homeotropic orientation of liquid crystals and optical recognition of analytes: application to the determination of progesterone.

The work describes a simplified method for the preparation of liquid crystal (LC) bioassay using DNA-based capture molecules and having lower detection limits. The capture DNA probes of the stem-loop structure were immobilized on the surface of a glass slide. A homeotropic orientation of LC molecules can be obtained with the proper surface coverage of capture DNA probes. In the presence of analytes (specifically shown here for the progesterone as a model analyte), the molecular binding between capture DNA probes and progesterone opens the loop of the capture DNA probes. The opened sequence is then amenable to hybridization with a reporter DNA probe that is immobilized on gold nanoparticles. This changes the surface microstructure, disrupts the orientation of LC molecules, and results in an enhanced optical response, expressed as the average grey value of the images. This new kind of surface treatment for simultaneous recognition of target molecules and homeotropic anchoring of LCs reduces the number of preparation steps and makes the process of LC bioassay easier. This method has a detection limit as low as 0.1 pmol·L-1 of progesterone. Graphical abstract Schematic presentation of the liquid crystal-based DNA assay. DMOAP: Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride; TEA: Triethoxsilylbutyraldehyde; 5CB: 4-cyano-4'-pentylbiphenyl; P4: progesterone.

Comparative proteomic analysis reveals the roots response to low root-zone temperature in Malus baccata.

Soil temperature is known to affect plant growth and productivity. In this study we found that low root-zone temperature (LRT) inhibited the growth of apple (Malus baccata Borkh.) seedlings. To elucidate the molecular mechanism of LRT response, we performed comparative proteome analysis of the apple roots under LRT for 6 days. Total proteins of roots were extracted and separated by two-dimensional gel electrophoresis (2-DE) and 29 differentially accumulated proteins were successfully identified by MALDI-TOF/TOF mass spectrometry. They were involved in protein transport/processing/degradation (21%), glycometabolism (20%), response to stress (14%), oxidoreductase activity (14%), protein binding (7%), RNA metabolism (7%), amino acid biosynthesis (3%) and others (14%). The results revealed that LRT inhibited glycometabolism and RNA metabolism. The up-regulated proteins which were associated with oxidoreductase activity, protein metabolism and defense response, might be involved in protection mechanisms against LRT stress in the apple seedlings. Subsequently, 8 proteins were selected for the mRNA quantification analysis, and we found 6 of them were consistently regulated between protein and mRNA levels. In addition, the enzyme activities in ascorbate-glutathione (AsA-GSH) cycle were determined, and APX activity was increased and GR activity was decreased under LRT, in consistent with the protein levels. This study provides new insights into the molecular mechanisms of M. baccata in responding to LRT.

Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.

A distant downstream enhancer directs essential expression of Tbx18 in urogenital tissues.

The vertebrate T-box transcription factor gene Tbx18 performs a vital role in development of multiple organ systems. Tbx18 insufficiency manifests as recessive phenotypes in the upper urinary system, cardiac venous pole, inner ear, and axial skeleton; homozygous null mutant animals die perinatally. Here, we report a new regulatory mutation of Tbx18, a reciprocal translocation breaking 78kbp downstream of the gene. 12Gso homozygotes present urinary and vertebral defects very similar to those associated with Tbx18-null mutations, but 12Gso is clearly not a global null allele since homozygotes survive into adulthood. We show that 12Gso down-regulates Tbx18 expression in a manner that is both spatially- and temporally-specific; combined with other data, the mutation points particularly to the presence of an essential urogenital enhancer located near the translocation breakpoint site. In support of this hypothesis, we identify a distal enhancer element, ECR1, which is active in developing urogenital and other tissues; we propose that disruption of this element leads to premature loss of Tbx18 function in 12Gso mutant mice. These data reveal a long-range regulatory architecture extending far downstream of Tbx18, identify a novel and likely essential urogenital enhancer, and introduce a new tool for dissecting postnatal phenotypes associated with dysregulation of Tbx18.

A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye.

Pax6 encodes a transcription factor with key roles in the development of the pancreas, central nervous system, and eye. Gene expression is orchestrated by several alternative promoters and enhancer elements that are distributed over several hundred kilobases. Here, we describe a reciprocal translocation, called 1Gso, which disrupts the integrity of transcripts arising from the 5'-most promoter, P0, and separates downstream promoters from enhancers active in pancreas and eye. Despite this fact, 1Gso animals exhibit none of the dominant Pax6 phenotypes, and the translocation complements recessive brain and craniofacial phenotypes. However, 1Gso fails to complement Pax6 recessive effects in lacrimal gland, conjunctiva, lens, and pancreas. The 1Gso animals also express a corneal phenotype that is related to but distinct from that expressed by Pax6 null mutants, and an abnormal density and organization of retinal ganglion cell axons; these phenotypes may be related to a modest upregulation of Pax6 expression from downstream promoters that we observed during development. Our investigation maps the activities of Pax6 alternative promoters including a novel one in developing tissues, confirms the phenotypic consequences of upstream enhancer disruption, and limits the likely effects of the P0 transcript null mutation to recessive abnormalities in the pancreas and specific structures of the eye.

[Metoprolol attenuates pressure overload-induced myocardial hypertrophy through modulating Dryk1A-ASF-CaMKIIδ signaling pathways].

OBJECTIVE: Previous study showed that the signaling pathway of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A)-alternative splicing factor (ASF)- alternative splicing of Ca(2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is related to myocardial hypertrophy. The aim of present study was to determine the effect and related mechamism of metoprolol on pressure overload induced myocardial hypertrophy. METHODS: Pressure overload-induced hypertension was induced by coarctation of suprarenal abdominal aorta in rats. Rats were randomly divided into sham-operated control, hypertension and hypertension plus metoprolol (30 mg×kg(-1)×d(-1)) groups (n = 10 each). Blood pressure, the left ventricular weight to body weight ratio and cardiomyocytes area were measured, the protein expression of Dyrk1A and ASF were determined by Western blot and mRNA expression of alternative splicing of CaMKIIδ was detected by RT-PCR. RESULTS: Four weeks after coarctation, cardiac hypertrophy was evidenced in rats of hypertensive group, and the protein expression of Dyrk1A was significantly upregulated, while the expression of ASF was significantly downregulated, the mRNA expression of CaMKIIδ A and B were significantly upregulated and mRNA expression of CaMKIIδ C was significantly downregulated compared to those in sham-operated control rats (all P < 0.05). Treatment with metoprolol effectively attenuated cardiac hypertrophy and reversed pressure overload induced changes on Dyrk1A and ASF, and alternative splicing of CaMKIIδ (all P < 0.05). CONCLUSION: Metoprolol attenuates pressure overload-induced cardiac hypertrophy possibly through modulating Dryk1A-ASF-CaMKIIδ signaling pathways.

Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.

Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1E61A confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1E61A, thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.

Median arcuate ligament syndrome with retroperitoneal haemorrhage: A case report.

BACKGROUND: Median arcuate ligament syndrome (MALS) is relatively rare and is due to extraluminal compression of the coeliac artery by the median arcuate ligament of the diaphragm. Here, we report a case of MALS found in a patient with abdominal pain and retroperitoneal haemorrhage for education and dissemination. CASE SUMMARY: This article describes a 46-year-old female patient who was admitted to our hospital with abdominal pain as her chief complaint. She had experienced no obvious symptoms but had retroperitoneal bleeding during the course of the disease. Contrast-enhanced computed tomography (CT) and noninvasive CT angiography (CTA) led to an initial misdiagnosis of pancreaticoduodenal artery aneurysm (PDAA) causing retroperitoneal hemorrhage. After intraoperative exploration and detailed analysis of enhanced CT and CTA images, a final diagnosis of MALS was made. The cause of the haemorrhage was bleeding from a branch of the gastroduodenal artery, not rupture of a PDAA. The prognosis of MALS combined with PDAA treated by laparoscopy and interventional therapy is still acceptable. The patient was temporarily treated by gastroduodenal suture haemostasis and was referred for further treatment. CONCLUSION: MALS is very rare and usually has postprandial abdominal pain, upper abdominal murmur, and weight loss. It is diagnosed by imaging or due to complications. When a patient has abdominal bleeding or PDAA, we should consider whether the patient has celiac trunk stenosis (MALS or other etiology). When abdominal bleeding is combined with an aneurysm, we generally think of aneurysm rupture and hemorrhage first, but it may also be collateral artery rupture and hemorrhage.

BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16.

The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.

Cascaded Convolutional Neural Network-Based Hyperspectral Image Resolution Enhancement via an Auxiliary Panchromatic Image.

Owing to the limits of incident energy and hardware system, hyperspectral (HS) images always suffer from low spatial resolution, compared with multispectral (MS) or panchromatic (PAN) images. Therefore, image fusion has emerged as a useful technology that is able to combine the characteristics of high spectral and spatial resolutions of HS and PAN/MS images. In this paper, a novel HS and PAN image fusion method based on convolutional neural network (CNN) is proposed. The proposed method incorporates the ideas of both hyper-sharpening and MS pan-sharpening techniques, thereby employing a two-stage cascaded CNN to reconstruct the anticipated high-resolution HS image. Technically, the proposed CNN architecture consists of two sub-networks, the detail injection sub-network and unmixing sub-network. The former aims at producing a latent high-resolution MS image, whereas the latter estimates the desired high-resolution abundance maps by exploring the spatial and spectral information of both HS and MS images. Moreover, two model-training fashions are presented in this paper for the sake of effectively training our network. Experiments on simulated and real remote sensing data demonstrate that the proposed method can improve the spatial resolution and spectral fidelity of HS image, and achieve better performance than some state-of-the-art HS pan-sharpening algorithms.

Specific protein 1 inhibitor mithramycin A protects cardiomyocytes from myocardial infarction via interacting with PARP.

Specific protein 1 (SP1) might act as a critical transcription regulator in myocardial infarction (MI), but little evidence about its function in regulating cardiac apoptosis, a major cause of MI development, has been revealed. This study tried to investigate the role of SP1 in MI and its interaction with poly-ADP-ribose polymerase (PARP)-1 by using SP1 inhibitor, mithramycin A (mithA). Primary mouse cardiomyocytes and commercial mouse cardiomyocytes were subjected to mithA treatment under hypoxia conditions, while cell viability, Nix promoter activity, and its expression were detected correspondingly. PARP overexpression and knockdown were conducted, respectively, in mithA-treated and SP1-overexpressing cells. Co-immunoprecipitation was used to verify the interaction between PARP and SP1. For in vivo experiments, mithA administration was performed after the injections of adenovirus for PARP overexpression, and then, MI introduction was carried out. Infarct size and lactate dehydrogenase level were measured to assess MI injury. SP1 inhibitor mithA attenuated hypoxia-induced decrease of cell viability and Nix transcriptional activation, which could be inhibited by PARP overexpression. Knockdown of PARP prevented SP1-induced transcription of Nix and cell viability change, and PARP showed direct interaction with SP1. Furthermore, mithA administration reduced MI injuries, while PARP overexpression could suppress the improvement. The cardioprotective role of SP1 inhibitor mithA was demonstrated here expanding the role of SP1 in MI development involving hypoxia-induced cardiac apoptosis. Moreover, PARP acted as a transcriptional coactivator in Nix transcription involving its interaction with SP1.

Arginine methylation of ribose-5-phosphate isomerase A senses glucose to promote human colorectal cancer cell survival.

Cancer cells remodel their metabolic network to adapt to variable nutrient availability. Pentose phosphate pathway (PPP) plays protective and biosynthetic roles by oxidizing glucose to generate reducing power and ribose. How cancer cells modulate PPP activity in response to glucose supply remains unclear. Here we show that ribose-5-phosphate isomerase A (RPIA), an enzyme in PPP, directly interacts with co-activator associated arginine methyltransferase 1 (CARM1) and is methylated at arginine 42 (R42). R42 methylation up-regulates the catalytic activity of RPIA. Furthermore, glucose deprivation strengthens the binding of CARM1 with RPIA to induce R42 hypermethylation. Insufficient glucose supply links to RPIA hypermethylation at R42, which increases oxidative PPP flux. RPIA methylation supports ROS clearance by enhancing NADPH production and fuels nucleic acid synthesis by increasing ribose supply. Importantly, RPIA methylation at R42 significantly potentiates colorectal cancer cell survival under glucose starvation. Collectively, RPIA methylation connects glucose availability to nucleotide synthesis and redox homeostasis.

Germline translocations in mice: unique tools for analyzing gene function and long-distance regulatory mechanisms.

Translocations have provided invaluable tools for identifying both cancer-linked genes and loci associated with heritable human diseases, but heritable human translocations are rare and few mouse models exist. Here we report progress on analysis of a collection of heritable translocations generated by treatment of mice with specific chemicals or radiation during late spermatogenic stages. The translocation mutants exhibit a range of visible phenotypes reflecting the disruption of coding sequences or the separation of genes from essential regulatory elements. The breakpoints of both radiation-induced and chemically induced mutations in these mice are remarkably clean, with very short deletions, duplications, or inversions in some cases, and ligation mediated by microhomology, suggesting nonhomologous end joining as the major path of repair. These mutations provide new tools for the discovery of novel genes and regulatory elements linked to human developmental disorders and new clues to the molecular basis of human genetic disease.

COX-2 rs5275 and rs689466 polymorphism and risk of lung cancer: A PRISMA-compliant meta-analysis.

BACKGROUND: Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the synthesis of prostaglandin, which plays an important role in the inflammation response. The overexpression of COX-2 in lung cancer has been found in several studies, suggesting that COX-2 contributes to carcinogenesis. There are many previous case-control studies focused on the association between COX-2 polymorphism and lung cancer risk, however, the conclusion remained controversial. OBJECTIVES: We performed this meta-analysis to evaluate the association between COX-2 rs5275 and rs689466 polymorphism and susceptibility to lung cancer. METHODS: A systematic literature research was conducted on PubMed, Embase, Cochrane Library, OVID, Web of Science, and Google Scholar up to November 30, 2017. The quality of studies was assessed by Newcastle-Ottawa scale. We combined odds ratios (ORs) and 95% confidence intervals (CIs) in 5 different genetic models for evaluation under a fixed-effect model or random-effect model. Subgroup analysis was performed according to source of control, ethnicity, pathological types, and smoking status. Sensitivity analysis and publication bias were also conducted. RESULTS: Eventually, 14 eligible studies were included in our meta-analysis. We found rs5275 gene polymorphism decreased the risk of lung cancer under heterozygote model (OR: 0.91, 95% CI: 0.84-0.98, P = .02). COX-2 rs689466 gene polymorphism was also related to a significantly reduced risk under allele (OR: 0.88, 95% CI: 0.82-0.95, P = .001), homozygote (OR: 0.81, 95% CI: 0.68-0.95, P = .01), heterozygote (OR: 0.81, 95% CI: 0.72-0.91, P < .001), and dominant model (OR: 0.81, 95% CI: 0.72-0.91, P < .001), except for recessive model. Subgroup analysis suggested a similar association in Asians, but not in Caucasians. Polymorphism of rs5275 was strongly associated with a reduced risk of lung adenocarcinoma according to stratified analysis by pathological types. Egger test identified no significant publication bias. CONCLUSIONS: Our meta-analysis demonstrated that COX-2 rs5275 and rs689466 polymorphism significantly decrease the risk of lung cancer in Asians but not in Caucasians, indicating COX-2 could serve as a potential diagnostic marker for lung cancer.

Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth.

It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.

The expression of Troponin T1 gene is induced by ketamine in adult mouse brain.

The glutamatergic system has been implicated in neuropsychiatric disorders, such as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have paradoxical effects of neuroprotection and neurotoxicity. We investigated gene expression in brain tissue of adult mice treated with ketamine to characterize the expression profiles and to identify the affected metabolic pathways. Adult male mice were treated by a single intraperitoneal (i.p.) injection of either s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were differentially expressed in ketamine-treated mouse brains compared with control mice using oligonucleotide microarray analysis, and the expression of Troponin T1 (Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced Tnnt1 expression was confirmed and characterized using RNA in situ hybridization techniques in paraffin embedded brain tissue sections. Tnnt1 expression was induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to interact directly with FoxO1, which is involved in multiple peripheral metabolic pathways and central energy homeostasis. Our findings suggest that the induction of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the genes involved in the metabolic syndromes observed in neuropsychiatric disorders.