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Objective: To compare the effects of Pilates exercise (PE) with other forms of exercise on pain and disability in individuals with chronic non-specific low back pain (CNSLBP) and to inform clinical practice and future research. Study design: Systematic review with meta-analysis conducted and reported in line the Preferred Reporting Items for Systematic review and Meta-analysis. Literature search: Six electronic databases were searched from inception to April 2021. Study selection criteria: Randomised controlled trials (RCTs) comparing the effect of PE with other forms of exercise for adults with CNSLBP on pain and disability. Data synthesis: Two reviewers assessed the risk of bias of the trials, guided by the Cochrane RoB2 tool. Available data were extracted for meta-analysis with subgroup analysis. Pilates exercise was compared to general exercise (GE), direction-specific exercise (DSE) and spinal stabilisation exercise (SSE). Certainty of evidence was interpreted following the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Eleven RCTs were included. A low certainty of evidence supported PE was more effective than GE in pain reduction [Effect size (ES) 0.44]. Moreover, very low levels of certainty were revealed for effectiveness of PE compared with DSE for pain reduction (ES 0.65) and equivalence of PE and SSE for pain and disability. Conclusions: This review found no strong evidence for using one type of exercise intervention over another when managing patients with CNSLBP. Existing evidence does not allow this review to draw definitive recommendations. In the absence of a superior exercise form clinicians should work collaboratively with the patient, using the individual's goals and preferences to guide exercise selection. Further appropriately designed research is warranted to explore this topic further.

BackgroundRecent research has shown that the G protein-coupled receptor 110 (GPR110) is an oncogene. The evidence mainly based on high expression of GPR110 in numerous cancer types; and knockdown GPR110 can reduced the cell migration, invasion, and proliferation. GPR110 is, however, mostly expressed in the liver of healthy individuals. The function of GPR110 in liver has not been revealed. Interestingly, expression level of hepatic GPR110 is dramatically decreased in obese subjects. Here, we examined whether GPR110 has a role in liver metabolism.MethodsWe used recombinant adeno-associated virus-mediated gene delivery system and antisense oligonucleotide to manipulate the hepatic GPR110 expression level in diet-induced obese mice to investigate the role of GPR110 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver.ResultsThe expression of GPR110 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (SCD1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of GPR110 by RNA-sequencing analysis. Treatment with the liver-specific SCD1 inhibitor MK8245 and specific shRNAs against SCD1 in primary hepatocytes improved the hepatic steatosis of GPR110-overexpressing mice and lipid profile of hepatocytes, respectively.ConclusionsThese results indicate GPR110 regulates hepatic lipid metabolism through controlling the expression of SCD1. Down-regulation of GPR110 expression can potentially serve as a protective mechanism to stop the over-accumulation of fat in the liver in obese subjects. Overall, our findings not only reveal a new mechanism regulation the progression of NALFD, but also proposed a novel therapeutic approach to combat NAFLD by targeting GPR110.FundingsThis work was supported in part by National Natural Science Foundation of China 81870586 (CMW), 82270941 and 81974117 (JS), Area of Excellence AoE/M-707/18 (AX and CMW), and General Research Fund 15101520 (CMW).HighlightsGPR110 regulates hepatic lipid metabolism.High level of hepatic GPR110 aggravates the progression of NAFLD by inducing SCD1 expression.Reduction in hepatic GPR110 is required to alleviate the progression of NAFLD.Targeting hepatic GPR110 improves hepatic steatosis.

[EN] It has been not easy to recruit postgraduate students from graduates of health professionals programmes in Hong Kong. Recent studies show that Course-based undergraduate research experiences (CURE) not only promote students’ acquisition of research abilities and collaboration skills, but also changes in their career choices and attitude. In this study, we attempted to offer CUREs to students of Medical Laboratory Science programme in our institute as extra-curricular activities to arouse their interest in scientific investigations. They participated to learn research methods, laboratory techniques and get hands-on research experience. The outcomes were evaluated with the CUREs Survey developed by Prof. David Lopatto of Grinnell College and focus group discussion. Results of CUREs survey reveal students obtaining positive gains from the CUREs programme with the relevant learning experience. Similar to previous studies, CUREs participants develop content knowledge, confidence, skills in research and confirm their interest in pursuing science-research related educational or career paths., This study is supported by the Hong Kong Polytechnique University Teaching Development Grants 2019-22 (SS-HTI).

Background: The proportion of the global community aged 60 years and older is rapidly increasing and hearing loss is very prevalent in this group. However, there is limited awareness of the benefit...

CREB-H is a key liver-enriched transcription factor governing lipid metabolism. Additional targets of CREB-H remain to be identified and characterized. Here, we identified a novel fasting- and CREB-H-induced (FACI) protein that inhibits intestinal lipid absorption and alleviates diet-induced obesity in mice.FACI was identified by reanalysis of existing transcriptomic data. FaciFACI expression was enriched in liver and intestine. FACI is a phospholipid-binding protein that localizes to plasma membrane and recycling endosomes. Hepatic transcription of Faci was regulated by not only CREB-H, but also nutrient-responsive transcription factors sterol regulatory element-binding protein 1 (SREBP1), hepatocyte nuclear factor 4α (HNF4α), peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), and CREB, as well as fasting-related cyclic adenosine monophosphate (cAMP) signaling. Genetic knockout of Faci in mice showed an increase in intestinal fat absorption. In accordance with this, Faci deficiency aggravated high-fat diet-induced obesity, hyperlipidemia, steatosis, and other obesity-related metabolic dysfunction in mice.FACI is a novel CREB-H-induced protein. Genetic disruption of Faci in mice showed its inhibitory effect on fat absorption and obesity. Our findings shed light on a new target of CREB-H implicated in lipid homeostasis.

Purpose: Cortical auditory evoked potential (CAEP) procedures are a useful way of estimating behavioural thresholds without active participant cooperation. They are becoming more common in ...

This review gives an overview of the roles of histone acetylation and methylation in obesity and related metabolic diseases. Nutrition can change gene expression via epigenetics such as DNA methylation and post-translational modifications of histones. A growing number of both experimental and clinical studies suggested that histone modifications are very sensitive to changes in nutritional availability and potentially impact the development and progression of metabolic disorders. Recent advances in proteomic studies provided evidence linking histone modifications to over-nutrition and metabolic dysregulation. In this review, we will summarize the recent findings on two classical histone modifications, i.e., acetylation and methylation and the related findings from clinical studies and potential applications. The involvement of histone modifications in the progression of metabolic diseases is now widely appreciated. Over the recent years, mass spectrometry-based proteomics approaches discovered and mapped different kind of histone modifications linking obesity and metabolic diseases. The list of these modifications is evergrowing; however, their functions and roles in obesity are not well understood. Same as for the most well studied histone modifications, namely acetylation and methylation. Although much has been learnt from these two modifications, their contributions in regulation of metabolism are still largely unknown. It will be necessary to carry out more studies to further dissect the importance of the availability of substrates and activities of the enzymes for histone acetylation and methylation in the metabolic tissues.

Background Pin2/ TRF 1‐interacting protein, PinX1, was previously identified as a tumor suppressor. Here, we discovered a novel transcript variant of mP inX1 (mouse PinX1), mP inX1t (mouse PinX1t), in embryonic stem cells ( ESC s). The aims of this investigation were (1) to detect the presence of mP inX1 and mP inX1t in ESC s and their differentiation derivatives; (2) to investigate the role of mP inX1 and mP inX1t on regulating the characteristics of undifferentiated ESC s and the cardiac differentiation of ESC s; (3) to elucidate the molecular mechanisms of how mP inX1 and mP inX1t regulate the cardiac differentiation of ESCs. Methods and Results By 5′ rapid amplification of cDNA ends, 3′ rapid amplification of cDNA ends, and polysome fractionation followed by reverse transcription–polymerase chain reaction, mP inX1t transcript was confirmed to be an intact mRNA that is actively translated. Western blot confirmed the existence of mP inX1t protein. Overexpression or knockdown of mP inX1 (both decreased mP inX1t expression) both decreased while overexpression of mP inX1t increased the cardiac differentiation of ESC s. Although both mP inX1 and mP inX1t proteins were found to bind to cardiac transcription factor mRNA s, only mP inX1t protein but not mP inX1 protein was found to bind to nucleoporin 133 protein, a nuclear pore complex component. In addition, mP inX1t‐containing cells were found to have a higher cytosol‐to‐nucleus ratio of cardiac transcription factor mRNA s when compared with that in the control cells. Our data suggested that mP inX1t may positively regulate cardiac differentiation by enhancing export of cardiac transcription factor mRNA s through interacting with nucleoporin 133. Conclusions We discovered a novel transcript variant of mP inX1, the mP inX1t, which positively regulates the cardiac differentiation of ESC s.

Both tendon injuries and tendinopathies, particularly rotator cuff tears, increase with tendon aging. Tendon stem cells play important roles in promoting tendon growth, maintenance, and repair. Aged tendons show a decline in regenerative potential coupled with a loss of stem cell function. Recent studies draw attention to aging primarily a disorder of stem cells. The micro-environment (“niche”) where stem cells resided in vivo provides signals that direct them to metabolize, self-renew, differentiate, or remain quiescent. These signals include receptors and secreted soluble factors for cell-cell communication, extracellular matrix, oxidative stress, and vascularity. Both intrinsic cellular deficits and aged niche, coupled with age-associated systemic changes of hormonal and metabolic signals can inhibit or alter the functions of tendon stem cells, resulting in reduced fitness of these primitive cells and hence more frequent injuries and poor outcomes of tendon repair. This review aims to summarize the biological changes of aged tendons. The biological changes of tendon stem cells in aging are reviewed after a systematic search of the PubMed. Relevant factors of stem cell aging including cell-intrinsic factors, changes of microenvironment, and age-associated systemic changes of hormonal and metabolic signals are examined, with findings related to tendon stem cells highlighted when literature is available. Future research directions on the aging mechanisms of tendon stem cells are discussed. Better understanding of the molecular mechanisms underlying the functional decline of aged tendon stem cells would provide insight for the rational design of rejuvenating therapies.

Objectives To facilitate early diagnosis of infants with hearing loss, a universal newborn hearing screening program (UNHS) has been implemented in Hong Kong's public hospitals for over a decade. However, there have been no known studies investigating parent attitudes to, and satisfaction with, UNHS since its launch in Hong Kong. The present study aimed to investigate knowledge of UNHS as well as infant hearing development, and attitudes and satisfaction with UNHS, in Hong Kong mothers with newborns. The study was designed to help evaluate and improve an established UNHS public hospital program, based on the perspectives of service users. Methods A researcher-developed questionnaire was administered to 102 mothers whose newborn had received UNHS in the postnatal wards of a large public hospital in Hong Kong. The questionnaire considered parental knowledge of UNHS and infant hearing development, attitudes and satisfaction toward public hospital UNHS. In the knowledge dimension, parents' preferred time and location for pre-test information delivery, interpretation of screening results, and knowledge of hearing developmental milestones were surveyed. In addition, maternal attitudes to and satisfaction with UNHS screening services, the potential impact of UNHS on parent emotions and parent-baby bonding, attitudes toward informed consent, and willingness to comply with diagnostic assessment referral were also be surveyed. Results Mean participant scores on knowledge of infant hearing development were relatively low (M = 2.59/6.0, SD = 0.90). Many mothers also underestimated the potential ongoing risks of hearing impairment in babies. Around 80% of mothers thought an infant could not have hearing impairment after passing the screening. In addition, one-third of mothers thought a baby could not later develop hearing impairment in infancy or childhood. In terms of attitudes and satisfaction, participants gave somewhat negative ratings for questions regarding receiving sufficient information about the screening (M = 2.90/5.0, SD = 1.27), screening procedure (M = 2.20/5.0, SD = 1.08), and sufficiency of information about results (M = 2.87/5.0, SD = 1.14). Nonetheless, participants gave positive ratings concerning whether screening could lead to early diagnosis (M = 4.61/5.0, SD = 0.57) and over 95% of mothers supported UNHS despite potential for false positive results. Mothers reported a high willingness to bring their baby to follow-up assessments if required (M = 4.53/5.0, SD = 0.56). Participants gave positive ratings for their level of satisfaction with the time and location of first UNHS information provision (M = 4.34/5.0, SD = 0.80) and the way permission was asked for screening the baby (M = 4.04/5.0, SD = 0.97) but alternative procedures were also recommended. Most recommendations focused on providing more information about the test and a more detailed explanation of screening results. Conclusions The survey results highlighted the need to provide more information to parents about infant hearing development to support home monitoring for signs of hearing loss after UNHS, as well as more detailed explanation and information regarding hearing screening and the implications of results to parents. Regardless of location, surveys of this type may provide valuable support for UNHS program quality assurance.

Background and purpose Raloxifene can induce both endothelium-dependent and -independent relaxation in different arteries. However, the underlying mechanisms by which raloxifene triggers endothelium-independent relaxation are still incompletely understood. The purpose of present study was to examine the roles of NOSs and Ca2+ channels in the relaxant response to raloxifene in the rat isolated, endothelium-denuded aorta. Experimental approach Changes in isometric tension, cGMP, nitrite, inducible NOS protein expression and distribution in response to raloxifene in endothelium-denuded aortic rings were studied by organ baths, radioimmunoassay, Griess reaction, western blot and immunohistochemistry respectively. Key results Raloxifene reduced the contraction to CaCl2 in a Ca2+ -free, high K+ -containing solution in intact aortic rings. Raloxifene also acutely relaxed the aorta primarily through an endothelium-independent mechanism involving NO, mostly from inducible NOS (iNOS) in vascular smooth muscle layers. This effect of raloxifene involved the generation of cGMP and nitrite. Also, it was genomic in nature, as it was inhibited by a classical oestrogen receptor antagonist and inhibitors of RNA and protein synthesis. Raloxifene-induced stimulation of iNOS gene expression was partly mediated through activation of the NF-κB pathway. Raloxifene was more potent than 17β-estradiol or tamoxifen at relaxing endothelium-denuded aortic rings by stimulation of iNOS. Conclusions and implications Raloxifene-mediated vasorelaxation in rat aorta is independent of a functional endothelium and is mediated by oestrogen receptors and NF-κB. This effect is mainly mediated through an enhanced production of NO, cGMP and nitrite, via the induction of iNOS and inhibition of calcium influx through Ca2+ channels in rat aortic smooth muscle.

Growing evidence supports that dysregulation of adipose tissue-derived factors contributes to the pathogenesis of diabetes and its complications. Since our global gene profiling analysis has identified lipocalin-14 (LCN14)—a secretory protein with lipid-binding properties—as a potential adipokine highly expressed in white adipose tissue (WAT), this study aims to explore the metabolic roles of LCN14 in obese mice, and to investigate the functional mechanisms involved. Immunoassays and western blotting were performed to determine the circulating level and tissue distribution of LCN14, respectively. Recombinant adeno-associated virus (rAAV)-mediated gene delivery was used to overexpress LCN14 in diet-induced obese (DIO) mice and the effects on glucose and lipid metabolism were examined. LCN14 is expressed predominantly in WAT. Both circulating levels of LCN14 and its expression in adipose tissues are repressed in DIO and genetically inherited diabetic (db/db) mice. Overexpression of LCN14 by rAAV-mediated gene delivery in DIO mice significantly increased insulin sensitivity in major metabolic tissues and ameliorated hyperglycaemia by inhibiting hepatic gluconeogenesis. The reduced hepatic glucose production is attributed to the suppressive effects of LCN14 on the expression of gluconeogenic genes and on glycerol efflux in adipocytes, possibly by reducing the expression of aquaporin-7. Reduced LCN14 expression is involved in the pathogenesis of obesity-related metabolic dysregulation. LCN14 exerts its beneficial effects on glucose homeostasis and insulin sensitivity via its actions in both adipocytes and hepatocytes.

Aims: Angiotensin-converting enzyme 2 (ACE2)–angiotensin (1-7) [Ang (1-7)]-Mas constitutes the vasoprotective axis and is demonstrated to antagonize the vascular pathophysiological effects of the classical renin–angiotensin system. We sought to study the hypothesis that upregulation of ACE2-Ang (1-7) signaling protects endothelial function through reducing oxidative stress that would result in beneficial outcome in diabetes. Results: Ex vivo treatment with Ang (1-7) enhanced endothelium-dependent relaxation (EDR) in renal arteries from diabetic patients. Both Ang (1-7) infusion via osmotic pump (500 ng/kg/min) for 2 weeks and exogenous ACE2 overexpression mediated by adenoviral ACE2 via tail vein injection (109 pfu/mouse) rescued the impaired EDR and flow-mediated dilatation (FMD) in db/db mice. Diminazene aceturate treatment (15 mg/kg/day) activated ACE2, increased the circulating Ang (1-7) level, and augmented EDR and FMD in db/db mouse arteries. In addition, activation of the ACE2-Ang (1-7) axis reduced reactive oxygen species (ROS) overproduction determined by dihydroethidium staining, CM-H2DCFDA fluorescence imaging, and chemiluminescence assay in db/db mouse aortas and also in high-glucose-treated endothelial cells. Pharmacological benefits of ACE2-Ang (1-7) upregulation on endothelial function were confirmed in ACE2 knockout (ACE2 KO) mice both ex vivo and in vitro. Innovation: We elucidate that the ACE2-Ang (1-7)-Mas axis serves as an important signal pathway in endothelial cell protection in diabetic mice, especially in diabetic human arteries. Conclusion: Endogenous ACE2-Ang (1-7) activation or ACE2 overexpression preserves endothelial function in diabetic mice through increasing nitric oxide bioavailability and inhibiting oxidative stress, suggesting the therapeutic potential of ACE2-Ang(1-7) axis activation against diabetic vasculopathy. Antioxid. Redox Signal. 23, 880–892.

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic db/db mice (db/db SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic db/m+ mice. The exosomal proteins, rather than RNAs, mostly account for db/db SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in db/db SExos. Silence or overexpression of arginase 1 confirmed its essential role in db/db SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of blood-borne substances that monitor vascular homeostasis.

Peroxiredoxins (Prxs), scavenge cellular peroxides by forming recyclable disulfides but under high oxidative stress, hyperoxidation of their active-site Cys residue results in loss of their peroxidase activity. Saccharomyces cerevisiae deficient in human Prx (hPrx) orthologue TSA1 show growth defects under oxidative stress. They can be complemented with hPRXI but not by hPRXII, but it is not clear how the disulfide and hyperoxidation states of the hPrx vary in yeast under oxidative stress. To understand this, we used oxidative-stress sensitive tsa1tsa2Δ yeast strain to express hPRXI or hPRXII. We found that hPrxI in yeast exists as a mixture of disulfide-linked dimer and reduced monomer but becomes hyperoxidized upon elevated oxidative stress as analyzed under denaturing conditions (SDS-PAGE). In contrast, hPrxII was present predominantly as the disulfide in unstressed cells and readily converted to its hyperoxidized, peroxidase-inactive form even with mild oxidative stress. Interestingly, we found that plant extracts containing polyphenol antioxidants provided further protection against the growth defects of the tsa1tsa2Δ strain expressing hPrx and preserved the peroxidase-active forms of the Prxs. The extracts also helped to protect against hyperoxidation of hPrxs in HeLa cells. Based on these findings we can conclude that resistance to oxidative stress of yeast cells expressing individual hPrxs requires the hPrx to be maintained in a redox state that permits redox cycling and peroxidase activity. Peroxidase activity decreases as the hPrx becomes hyperoxidized and the limited protection by hPrxII compared with hPrxI can be explained by its greater sensitivity to hyperoxidation.

Adipocyte differentiation is closely associated with obesity and obesity-induced metabolic disorders. Epidemiological studies have demonstrated the association of obesity with environmental pollutants, such as polybrominated diphenyl ethers (PBDEs), common flame retardants in various consumer products. However, their obesogenic effects and mechanism are underexplored. We employed non-targeted metabolomics studies based on liquid chromatography-high resolution mass spectrometry to determine how 2,2′,4,4′-tetra-brominated biphenyl ether (BDE 47), one of the main congeners of PBDEs detected in human tissue, promotes adipocyte differentiation of mouse preadipocyte 3 T3-L1 cells. The promoting effects of BDE 47 exposure (5 or 10 μM) on adipocyte differentiation were confirmed by enhancing lipid accumulation and expression levels of biomarkers of adipogenesis. For the first time, we demonstrated that BDE 47 upregulated purine metabolism and altered glutathione metabolism to promote oxidative stress and uric acid production in adipocytes. BDE 47 also elevated mitochondrial respiration and glycolysis in adipocytes to induce more ATP to combat oxidative stress. Antioxidant treatments, including the suppression of xanthine oxidase, inhibited the effects of BDE 47 on inducing oxidative stress and lipid accumulation. BDE 47 may be a potential environmental obesogen by providing a permissive oxidative environment to induce adipocyte differentiation.

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells. The aggravated steatosis in

Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT.

Summary A Bayesian approach is presented for nonparametric estimation of an additive regression model with autocorrelated errors. Each of the potentially non-linear components is modelled as a regression spline using many knots, while the errors are modelled by a high order stationary autoregressive process parameterized in terms of its autocorrelations. The distribution of significant knots and partial autocorrelations is accounted for using subset selection. Our approach also allows the selection of a suitable transformation of the dependent variable. All aspects of the model are estimated simultaneously by using the Markov chain Monte Carlo method. It is shown empirically that the approach proposed works well on several simulated and real examples.

Background and Objectives. Oxidative stress can initiate endothelial dysfunction and atherosclerosis. This study evaluated whether tetramethylpyrazine (TMP), the predominant active ingredient in Rhizoma Ligustici Wallichii (chuanxiong), prevents endothelial dysfunction in a rat model of oxidative stress.Methods. Isolated rat aortic rings were pretreated with various drugs before the induction of endothelial dysfunction by hydrogen peroxide (H2O2). Changes in isometric tension were then measured in acetylcholine- (ACh-) relaxed rings. Endothelial nitric oxide synthase (eNOS) expression was evaluated in the rings by Western blotting, and superoxide anion (O2∙-) content was assessed in primary rat aortic endothelial cells by dihydroethidium- (DHE-) mediated fluorescence microscopy.Results. ACh-induced endothelium-dependent relaxation (EDR) was disrupted by H2O2in endothelium-intact aortic rings. H2O2-impaired relaxation was ameliorated by acute pretreatment with low concentrations of TMP, as well as by pretreatment with catalase and the NADPH oxidase inhibitors, apocynin and diphenyleneiodonium (DPI). TMP, apocynin, and DPI also reducedO2∙-accumulation in endothelial cells,but TMP failed to alter eNOS expression in aortic rings incubated with H2O2.Conclusions. TMP safeguards against oxidative stress-induced endothelial dysfunction, suggesting that the agent might find therapeutic utility in the management of vascular diseases. However, TMP’s role in inhibiting NADPH oxidase and its vascular-protective mechanism of action requires further investigation.

Activating transcription factor 4 (ATF4) is a master regulator of genes involved in unfolded protein response (UPR) and its translation is regulated through reinitiation at upstream open reading frames. Here, we demonstrate internal ribosome entry site (IRES)-mediated translation of an alternatively spliced variant of human ATF4. This variant that contains four upstream open reading frames in the 5′ leader region was expressed in leukocytes and other tissues. mRNA and protein expression of this variant was activated in the UPR. Its translation was neither inhibited by steric hindrance nor affected by eIF4G1 inactivation, indicating a cap-independent and IRES-dependent mechanism not mediated by ribosome scanning-reinitiation. The IRES activity mapped to a highly structured region that partially overlaps with the third and fourth open reading frames was unlikely attributed to cryptic promoter or splicing, but was activated by PERK-induced eIF2α phosphorylation. Taken together, our findings reveal a new mechanism for translational regulation of ATF4 in mammalian UPR.

Most unwanted RNA transcripts in the nucleus of eukaryotic cells, such as splicing-defective pre-mRNAs and spliced-out introns, are rapidly degraded by the nuclear exosome. In budding yeast, a number of these unwanted RNA transcripts, including spliced-out introns, are first recognized by the nuclear exosome cofactor Trf4/5p-Air1/2p-Mtr4p polyadenylation (TRAMP) complex before subsequent nuclear-exosome-mediated degradation. However, it remains unclear when spliced-out introns are recognized by TRAMP, and whether TRAMP may have any potential roles in pre-mRNA splicing. Here, we demonstrated that TRAMP is cotranscriptionally recruited to nascent RNA transcripts, with particular enrichment at intronic sequences. Deletion of TRAMP components led to further accumulation of unspliced pre-mRNAs even in a yeast strain defective in nuclear exosome activity, suggesting a novel stimulatory role of TRAMP in splicing. We also uncovered new genetic and physical interactions between TRAMP and several splicing factors, and further showed that TRAMP is required for optimal recruitment of the splicing factor Msl5p. Our study provided the first evidence that TRAMP facilitates pre-mRNA splicing, and we interpreted this as a fail-safe mechanism to ensure the cotranscriptional recruitment of TRAMP before or during splicing to prepare for the subsequent targeting of spliced-out introns to rapid degradation by the nuclear exosome., link_to_OA_fulltext

Wireless sensor networks based on the IEEE 802.15.4 standard is able to carry out short-distance transmissions in low-rate and low-power wireless personal area networks. To access the channel, it uses the slotted carrier sense multiple access with collision avoidance (CSMA/CA) in the contention access period (CAP) under superframe structure with beacon frame broadcast to bound the duration of superframe. However, the beacon frame is transmitted periodically without CSMA/CA so that it could be collided continuously. This type of collision causes node lost synchronization and unable to join a network because the beacon frame cannot be normally received. This paper proposes a simple time shift scheme based on IEEE 802.15.4 to keep original superframe structure and distribute transmission of beacon frame over active period to avoid beacon frame collisions. We use a simple function to allocate beacon frame transmission in the active period. The simulation results show that the proposed scheme significantly reduces the beacon collision and lost synchronization rate, and it also improves the throughput.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension.