This study was carried out to characterize three aldehydes of health concern (formaldehyde, acetaldehyde, and acrolein) at a central Beijing site in the summer and early fall of 2008 (from June to October). Aldehydes in polluted atmospheres come from both primary and secondary sources, which limits the control strategies for these reactive compounds. Measurements were made before, during, and after the Beijing Olympics to examine whether the dramatic air pollution control measures implemented during the Olympics had an impact on concentrations of the three aldehydes and their underlying primary and secondary sources. Average concentrations of formaldehyde, acetaldehyde and acrolein were 29.3±15.1 μg/m3, 27.1±15.7 μg/m3 and 2.3±1.0 μg/m3, respectively, for the entire period of measurements, all being at the high end of concentration ranges measured in cities around the world in photochemical smog seasons. Formaldehyde and acrolein increased during the pollution control period compared to the pre-Olympic Games, followed the changing pattern of temperature, and were significantly correlated with ozone and with a secondary formation factor identified by principal component analysis (PCA). In contrast, acetaldehyde had a reduction in mean concentration during the Olympic air pollution control period compared to the pre-Olympic period and was significantly correlated with several pollutants emitted from local emission sources (e.g., NO2, CO, and PM2.5). Acetaldehyde was also more strongly associated with primary emission sources including vegetative burning and oil combustion factors identified through the PCA. All three aldehydes were lower during the post-Olympic sampling period compared to the before and during Olympic periods, likely due to seasonal and regional effects. Our findings point to the complexity of source control strategies for secondary pollutants.
aldehydes; air pollution; acrolein; pollutant sources; principal component analysis; Olympics
Recently, variations in a component of high-density lipoprotein (HDL), namely apolipoprotein M (apoM), were found to be associated with chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the association between apoM and COPD severity. Factors associated with apoM, COPD, or coronary artery disease (CAD) were also assessed.
A total of 110 COPD patients and 110 age- and sex-matched non-COPD controls were included. Among them, thirty COPD patients and seven non-COPD controls had CAD. ApoM and pentraxin-3 levels were measured by ELISA. Additionally, the levels of high-sensitivity C-reactive protein (hs-CRP), cholesterol, and triglyceride were assessed using an automatic biochemical analyzer.
Serum apoM levels increased gradually with COPD severity, with the most prominent apoM elevation observed in very severe COPD cases. In addition, ApoM was correlated with percent-predicted forced expiratory volume in one second (% predicted FEV1) (r = −0.38, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (r = 0.23, P < 0.017), and hs-CRP (r = 0.24, P = 0.01) in COPD patients. Furthermore, apoM was shown to be a risk factor for COPD onset (OR = 1.095, 95 % CI = 1.034–1.160, P = 0.002), but not associated with CAD in COPD patients.
Serum apoM was elevated in COPD patients and increased gradually with COPD severity. However, there was no association between apoM and CAD development in COPD patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-016-0228-1) contains supplementary material, which is available to authorized users.
Apolipoprotein M; Chronic obstructive pulmonary disease; Forced expiratory volume in one second, % predicted FEV1; Cardiovascular disease
Pain is common in men undergoing rigid cystoscopy. Even with the application of a lubricant containing 2 % lidocaine, about 76 % of men suffer from mild to severe pain when undergoing rigid cystoscopy. The most painful part of the procedure for men is when the cystoscope passes through the membranous urethra. Song et al. (Neurourol Urodyn 29:592–5, 2010) did autopsies on males and found that the dorsal nerve of the penis (DNP), the terminal branch of the pudendal nerve, innervates the membranous urethra in 53.3 % of specimens. In addition, the urethral mucosa has branches of innervated DNP. Dorsal penile nerve block (DPNB) is usually used for circumcision in children, and it has been shown to provide effective analgesia for penile surgeries. In this study, we hypothesized that DPNB could reduce the overall pain level in men during rigid cystoscopy.
The trial is a prospective, randomized, double-blind, placebo-controlled, single-center trial to evaluate the effectiveness and safety of DPNB in analgesia for men undergoing rigid cystoscopy. Participants will be enrolled and randomly allocated into one of three groups according to the different analgesia regimens: 1) tetracaine gel group (DPNB with saline), 2) DPNB group (DPNB with ropivacaine plus plain lubricant), 3) combination group (DPNB with ropivacaine plus tetracaine gel). The primary outcome of this study is the visual analog scale (VAS, 0–10) for pain at cystoscopic inspection of the external sphincter. VAS scores evaluated at other time points serve as secondary outcomes. Vital signs are secondary outcomes that address the discomfort and pain during the procedure. Furthermore, the incidence of adverse events as secondary outcomes will also be recorded for evaluation of the safety of DPNB in rigid cystoscopy. Clinical assessments will be evaluated prior to DPNB, at administration of the lubricant gel, at cystoscopic inspection of the penile and bulbar urethra, external sphincter, prostate, and bladder, as well as at withdrawal of the cystoscope.
This research will determine the effectiveness and safety of DPNB in men undergoing rigid cystoscopy. The results of this trial may have important implications for exploring the role of DPNB in analgesia for cystoscopy in men.
ClinicalTrials.gov identifier NCT02502487 (6 Jul 2015).
Analgesia; Dorsal penile nerve block; Rigid cystoscopy; Men
Phosphoinositide-dependent protein kinase-1 (PDK-1), which functions downstream of phosphoinositide 3-kinase (AGE-1) and activates protein kinases of the AGC family, plays critical roles in regulating biology processes, such as metabolism, growth, development and survival. In the free-living nematode Caenorhabditis elegans, PDK-1 is a key component of the insulin-like signalling pathway, regulating the entry into and exit from dauer (arrested development). Although it is proposed that similar molecular mechanisms control the transition from the free-living to the parasitic stages of nematodes, nothing is known about PDK-1 in Haemonchus contortus, a socioeconomically important gastric nematode of ruminants.
Here, we isolated and characterized the pdk-1 gene (Hc-pdk-1) and its inferred product (Hc-PDK-1) from H. contortus. Using in vitro and in vivo methods, we then studied the transcriptional profiles of Hc-pdk-1 and anatomical gene expression patterns of Hc-PDK-1 in different developmental stages of C. elegans.
In silico analysis of Hc-PDK-1 displayed conserved functional domains, such as protein kinase and pleckstrin homology (PH) domains and two predicted phosphorylation sites (Thr226/Tyr229), which are crucial for the phosphorylation of downstream signalling. The Hc-pdk-1 gene is transcribed in all of the main developmental stages of H. contortus, with its highest transcription in the infective third-stage larvae (iL3) compared with other stages. Transgene constructs, in which respective promoters were fused to the coding sequence for green fluorescent protein (GFP), were used to transform C. elegans, and to localize and compare the expression of Hc-pdk-1 and Ce-pdk-1. The expression of GFP under the control of the Hc-pdk-1 promoter was localized to the intestine, and head and tail neurons, contrasting somewhat the profile for the C. elegans ortholog, which is expressed in pharynx, intestine and head and tail neurons.
This is the first characterization of pdk-1/PDK-1 from a trichostrongyloid nematode. Taken together, the findings from this study provide a first glimpse of the involvement of Hc-pdk-1 in the insulin-like signalling pathway in H. contortus.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1351-6) contains supplementary material, which is available to authorized users.
Haemonchus contortus; Transgenesis; Development; pdk-1 gene
In the present study, we reconstructed the insulin/insulin-like growth factor 1 signalling (IIS) pathway for Haemonchus contortus, which is one of the most important eukaryotic pathogens of livestock worldwide and is related to the free-living nematode Caenorhabditis elegans.
We curated full-length open-reading frames from assembled transcripts, defined the complement of genes that encode proteins involved in this pathway and then investigated the transcription profiles of these genes for all key developmental stages of H. contortus.
The core components of the IIS pathway are similar to their respective homologs in C. elegans. However, there is considerable variation in the numbers of isoforms between H. contortus and C. elegans and an absence of AKT-2 and DDL-2 homologs from H. contortus. Interestingly, DAF-16 has a single isoform in H. contortus compared with 12 in C. elegans, suggesting novel functional roles in the parasitic nematode. Some IIS proteins, such as DAF-18 and SGK-1, vary in their functional domains, indicating distinct roles from their homologs in C. elegans.
This study paves the way for the further characterization of key signalling pathways in other socioeconomically important parasites and should help understand the complex mechanisms involved in developmental processes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1341-8) contains supplementary material, which is available to authorized users.
Nematode; Haemonchus contortus; Insulin-like signalling pathway
Wound healing occupies a remarkable place in everyday pathology and remains a challenging clinical problem. In our previous study, we prepared a silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNPs) nanofiber via electrospinning and revealed that it could promote wound healing; however, the healing mechanism remained unknown. Therefore, we aimed to clarify the mechanism underlying the accelerated healing effect of the PVA/COS-AgNPs nanofiber. The TGFβ1/Smad signaling pathway is actively involved in wound healing. Considering the key role of this signaling pathway in wound healing, our preliminary study showed that the TGFβ1 level was significantly increased during the early stage of wound healing. Thus, in this study, hematoxylin–eosin, Masson’s trichrome, immunofluorescent staining, hydroxyproline content, quantitative real-time polymerase chain reaction, and Western blot analyses were used to analyze the wound healing in a rat model treated with gauze, the PVA/COS-AgNPs nanofiber, and the nanofiber plus SB431542 (an inhibitor of TGFβ1 receptor kinase). The results showed that the PVA/COS-AgNPs nanofiber promoted wound healing and upregulated the expression levels of cytokines associated with the TGFβ1/Smad signaling pathway such as TGFβ1, TGFβRI, TGFβRII, collagen I, collagen III, pSmad2, and pSmad3. Inhibiting this pathway with SB431542 resulted in prevention of the PVA/COS-AgNPs nanofiber-associated salutary effects on the early stage of wound healing and relative cytokines expression. In conclusion, the wound healing effect of the PVA/COS-AgNPs nanofiber involves activation of the TGFβ1/Smad signaling pathway.
wound healing; electrospinning; nanofiber; silver nanoparticles; TGFβ1; Smad proteins
Caucasian populations have a higher prevalence of cardiovascular disease (CVD) when compared with their Chinese counterparts and CVD is associated with autonomic function. It is unknown whether autonomic function during exercise recovery differs between Caucasians and Chinese. The present study investigated autonomic recovery following an acute bout of treadmill exercise in healthy Caucasians and Chinese. Sixty-two participants (30 Caucasian and 32 Chinese, 50% male) performed an acute bout of treadmill exercise at 70% of heart rate reserve. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were obtained during 5-min epochs at pre-exercise, 30-min, and 60-min post-exercise. HRV was assessed using frequency [natural logarithm of high (LnHF) and low frequency (LnLF) powers, normalized high (nHF) and low frequency (nLF) powers, and LF/HF ratio] and time domains [Root mean square of successive differences (RMSSD), natural logarithm of RMSSD (LnRMSSD) and R–R interval (RRI)]. Spontaneous BRS included both up-up and down-down sequences. At pre-exercise, no group differences were observed for any HR, HRV and BRS parameters. During exercise recovery, significant race-by-time interactions were observed for LnHF, nHF, nLF, LF/HF, LnRMSSD, RRI, HR, and BRS (up-up). The declines in LnHF, nHF, RMSSD, RRI and BRS (up-up) and the increases in LF/HF, nLF and HR were blunted in Chinese when compared to Caucasians from pre-exercise to 30-min to 60-min post-exercise. Chinese exhibited delayed autonomic recovery following an acute bout of treadmill exercise. This delayed autonomic recovery may result from greater sympathetic dominance and extended vagal withdrawal in Chinese.
Trial Registration: Chinese Clinical Trial Register ChiCTR-IPR-15006684
Orai1, a specific nonvoltage‐gated Ca2+ channel, has been found to be one of key molecules involved in store‐operated Ca2+ entry (SOCE). Orai1 may associate with other proteins to form a signaling complex, which is essential for regulating a variety of physiological functions. In this study, we studied the possible interaction between Orai1 and large conductance Ca2+‐activated potassium channel (BKC
a). Using RNA interference technique, we demonstrated that the SOCE and its associated membrane hyperpolarization were markedly suppressed after knockdown of Orai1 with a specific Orai1 siRNA in rat mesenteric artery smooth muscle. Moreover, isometric tension measurements showed that agonist‐induced vasocontraction was increased after Orai1 was knocked down or the tissue was incubated with BKC
a blocker iberiotoxin. Coimmunoprecipitation data revealed that BKC
a and Orai1 could reciprocally pull down each other. In situ proximity ligation assay further demonstrated that Orai1 and BKC
a are in close proximity. Taken together, these results indicate that Orai1 physically associates with BKC
a to form a signaling complex in the rat mesenteric artery smooth muscle. Ca2+ influx via Orai1 stimulates BKC
a, leading to membrane hyperpolarization. This hyperpolarizing effect of Orai1‐BKC
a coupling could contribute to reduce agonist‐induced membrane depolarization, therefore preventing excessive contraction of the rat mesenteric artery smooth muscle in response to contractile agonists.
BKCa; mesenteric artery; Orai1; store‐operated Ca2+ entry; vascular smooth muscle cells
DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation.
DNA mismatch repair; Infertility; Assisted reproductive technology
Terahertz (THz) radiation can revolutionize modern science and technology. To this date, it remains big challenges to develop intense, coherent and tunable THz radiation sources that can cover the whole THz frequency region either by means of only electronics (both vacuum electronics and semiconductor electronics) or of only photonics (lasers, for example, quantum cascade laser). Here we present a mechanism which can overcome these difficulties in THz radiation generation. Due to the natural periodicity of 2π of both the circular cylindrical graphene structure and cyclotron electron beam (CEB), the surface plasmon polaritions (SPPs) dispersion can cross the light line of dielectric, making transformation of SPPs into radiation immediately possible. The dual natural periodicity also brings significant excellences to the excitation and the transformation. The fundamental and hybrid SPPs modes can be excited and transformed into radiation. The excited SPPs propagate along the cyclotron trajectory together with the beam and gain energy from the beam continuously. The radiation density is enhanced over 300 times, up to 105 W/cm2. The radiation frequency can be widely tuned by adjusting the beam energy or chemical potential. This mechanism opens a way for developing desired THz radiation sources to cover the whole THz frequency regime.
Moving images are often essential in medical education, to learn new procedures and advanced skills, but, in the past, high-quality movie transmission was technically much more challenging than transmitting still pictures because of technological limitations and cost.
Materials and Methods:
We established a new system, taking advantage of two advanced technologies, the digital video transport system (DVTS) and the research and education network (REN), which enabled satisfactory telemedicine on a routine basis.
Between 2003 and 2013, we organized 360 programs connecting 221 hospitals or facilities in 34 countries in Asia and beyond. The two main areas were endoscopy and surgery, with 113 (31%) and 106 (29%) events, respectively. Teleconferences made up 76% of the total events, with the remaining 24% being live demonstrations. Multiple connections were more popular (63%) than one-to-one connections (37%). With continuous technological development, new high-definition H.323 and Vidyo® (Hackensack, NJ) systems were used in 47% and 39% of events in 2011 and 2012, respectively. The evaluation by questionnaires was favorable on image and sound quality as well as programs.
Remote medical education with moving images was well accepted in Asia with changing needs and developing technologies.
telemedicine; remote education; Internet; research and education network; digital video transport system
Chemokine receptor CXCR3 has been proved to play an important role in tumorigenesis and tumor progression in many malignancies, but its precise efficacy on gastric cancer (GC) has not been evaluated yet. The present study was aimed to explore the correlation of chemokine receptor CXCR3 with tumor-infiltrating lymphocytes (TILs) and prognosis in advanced gastric cancer (GC). Expression of CXCR3 and CD4+, CD8+ TILs was conducted in 192 advanced GC specimens and 48 corresponding paracancerous tissues by immunohistochemical (IHC) analysis. CXCR3 expression in GC tissues was significantly higher than that in paracancerous tissues (P<0.001) and CD8+, CD4+ TILs infiltration increased with high CXCR3 expression (P=0.032 and P<0.001, respectively). Our study showed significantly lower CXCR3 expression in patients with greater tumor invasion depth and lymph node metastasis compared with patients with lesser tumor invasion depth and without lymph node metastasis (P=0.002 and P=0.001, respectively). Univariate analysis indicated that patients with high CXCR3 expression and high CD8+ TILs infiltration had longer overall survival (OS) (log-rank test, P<0.001 and P=0.002, respectively). Univariate and multivariate analyses indicated that CXCR3 expression was an independent prognostic factor for OS (P=0.002). The present study suggested that CXCR3 expression was upregulated in advanced GC and was associated with increased CD4+, CD8+ TILs infiltration and improved OS. Therefore, CXCR3 overexpression is implicated as a favorable prognostic biomarker in human advanced GC.
Gastric cancer; CXCR3; CD8; CD4; prognosis; biomarker
There are still disagreements on which is a better approach to choose to establish percutaneous tract for percutaneous nephrolitotomy (PCNL), between supracostal and infracostal approaches. The aim of this study is to investigate the safety, efficacy and practicability of minimally invasive PCNL (MPCNL) with the aid of a patented system either through supracostal or through infracostal access.
A retrospective study was carried out for 83 patients with renal or upper ureteral stones. Under the guidance of B ultrasound or C-arm, these patients were treated by MPCNL through either 12th rib infracostal (Group 1, 43 cases) or supracostal (Group 2, 40 cases) access approach. These 2 groups were compared for total number of percutaneous tracts, average time in establishing a given percutaneous tract, the number of percutaneous tract used for each case, the average stone clearance time, the clearance rate of all stones by one surgery, and the amount of bleeding using a single percutaneous tract.
There was a significantly smaller total number of percutaneous tracts needed, a smaller number of cases that needed two percutaneous tracts to clear stones completely, a shorter average time in establishing a percutaneous tract, and a smaller average amount of bleeding in infracostal access group. At the same time, there were a significantly larger number of cases in which stones were cleared completely using a single percutaneous tract and a higher renal stone clearance rate by one surgery.
There were several advantages of infracostal access. These included accuracy in establishing a percutaneous tract, safety, quickness, convenience and flexibility in moving the patented sheath, and higher renal and upper ureteral stone clearance rate by one surgery.
Patented system; Percutaneous nephrolithotomy; Percutaneous tract access
Introduction: This study was to investigate whether there was statistical difference between the bilateral temporomandibular joint (TMJ) in patients with unilateral TMJ pain or joint sounds, using cone beam computed tomography (CBCT). Methods: TMJ CBCT images of 123 cases were used to preliminarily determine the indicators suitable for the measuring method. TMJ CBCT image reconstruction was performed and 19 indicators were measured. Thirty-six cases without TMJ complaint served as controls. The comparison of bilateral TMJs was analyzed by paired t-test to find out the indicators without statistical significance. Twenty-nine patients with unilateral TMJ pain or joint sounds who underwent CBCT at the hospital were enrolled for the comparative study. The measured values were analyzed by paired t-test to determine the indicators with statistical difference. Results: In the control group, only radius value of bilateral TMJ was different statistically (P < 0.05). In the TMJ complaint group, the vertical 60° joint space of the bilateral TMJ was statistically different (P < 0.05) and the rest of the measured values showed no statistical difference. Conclusions: In the patients with unilateral TMJ pain or joint sounds, the vertical 60° joint space of the symptomatic side was significantly increased comparing with the asymptomatic side.
Temporomandibular joint; unilateral TMJ pain; TMJ sounds; cone beam computed tomography
Bone tissue engineering shows good prospects for mandibular reconstruction. In recent studies, prefabricated tissue-engineered bone (PTEB) by recombinant human bone morphogenetic proteins (rhBMPs) applied in vivo has found to be an effective alternative for autologous bone grafts. However, the optimal time to transfer PTEB for mandibular reconstruction is still not elucidated. Thus, here in an animal experiment of rhesus monkey, the suitable transferring time for PTEB to reconstruct mandibular defects was evaluated by 99mTc-MDP SPECT/CT, and its value in monitoring orthotopic rhBMP-2 implants for mandibular reconstruction was also evaluated. The result of SPECT/CT showed higher 99mTc-MDP uptake, indicating osteoinductivity, in rhBMP-2 incorporated demineralized freeze-dried bone allograft (DFDBA) and coralline hydroxyapatite (CHA) implants than those without BMP stimulation. 99mTc-MDP uptake of rhBMP-2 implant peaked at 8 weeks following implantation while CT showed the density of these implants increased after 13 weeks’ prefabrication. Histology confirmed that mandibular defects were repaired successfully with PTEB or orthotopically rhBMP-2 incorporated CHA implants, in accordance with SPECT/CT findings. Collectively, data shows 99mTc-MDP SPECT/CT is a sensitive and noninvasive tool to monitor osteoinductivity and bone regeneration of PTEB and orthotopic implants. The PTEB achieved peak osteoinductivity and bone density at 8 to 13 weeks following ectopic implantation, which would serve as a recommendable time frame for its transfer to mandibular reconstruction.
Iron plaque is a strong adsorbent on rice roots, acting as a barrier to prevent metal uptake by rice. However, the role of root iron plaque microbes in governing metal redox cycling and metal bioavailability is unknown. In this study, the microbial community structure on the iron plaque of rice roots from an arsenic-contaminated paddy soil was explored using high-throughput next-generation sequencing. The microbial composition and diversity of the root iron plaque were significantly different from those of the bulk and rhizosphere soils. Using the aoxB gene as an identifying marker, we determined that the arsenite-oxidizing microbiota on the iron plaque was dominated by Acidovorax and Hydrogenophaga-affiliated bacteria. More importantly, the abundance of arsenite-oxidizing bacteria (AsOB) on the root iron plaque was significantly negatively correlated with the arsenic concentration in the rice root, straw and grain, indicating that the microbes on the iron plaque, particularly the AsOB, were actively catalyzing arsenic transformation and greatly influencing metal uptake by rice. This exploratory research represents a preliminary examination of the microbial community structure of the root iron plaque formed under arsenic pollution and emphasizes the importance of the root iron plaque environment in arsenic biogeochemical cycling compared with the soil-rhizosphere biotope.
Endocrine disrupting chemicals (EDCs) are chemicals that have the capacity to interfere with normal endocrine systems. Two EDCs, bisphenol A (BPA) and triclosan (TCS), are mass-produced and widespread. They both have estrogenic properties and similar chemical structures and pharmacokinetic features and have been detected in human fluids and tissues. Clinical evidence has suggested a positive association between BPA exposure and implantation failure in IVF patients. Studies in mouse models have suggested that preimplantation exposure to BPA and TCS can lead to implantation failure. This paper reviews the relationship between preimplantation exposure to BPA and TCS and implantation failure and discusses the remaining problems and possible solutions.
Our previous study indicates microRNA-506 (miR-506) is downregulated in hepatocellular carcinoma (HCC). In the current study, we investigate the effects of miR-506 on proliferation, migration and invasion in HCC. We report that enforced expression of miR-506 inhibits proliferation, migration and invasion in vitro, and suppresses tumor growth in vivo. Conversely, suppression of miR-506 exhibits promoting effects on proliferation, migration and invasion in vitro, and on tumor growth in vivo. In addition, miR-506 binds to the 3’UTR of F-spondin 1(SPON1), and enforced expression of miR-506 decreases accumulation of SPON1. Moreover, enforced expression of SPON1 and suppression of SPON1 alleviates effects of miR-506 mimics and inhibitors on proliferation, migration and invasion in vitro, respectively. In conclusion, microRNA-506 regulates proliferation, migration and invasion in HCC by targeting SPON1.
microRNA-506; proliferation; migration and invasion; hepatocellular carcinoma; SPON1
Keap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/− (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.
Keap1; Nrf2; the redox cycle; the cell cycle; hepatocyte proliferation
Infective L3s (iL3s) of parasitic nematodes share common behavioural, morphological and developmental characteristics with the developmentally arrested (dauer) larvae of the free-living nematode Caenorhabditis elegans. It is proposed that similar molecular mechanisms regulate entry into or exit from the dauer stage in C. elegans, and the transition from free-living to parasitic forms of parasitic nematodes. In C elegans, one of the key factors regulating the dauer transition is the insulin-like receptor (designated Ce-DAF-2) encoded by the gene Ce-daf-2. However, nothing is known about DAF-2 homologues in most parasitic nematodes. Here, using a PCR-based approach, we identified and characterised a gene (Hc-daf-2) and its inferred product (Hc-DAF-2) in Haemonchus contortus (a socioeconomically important parasitic nematode of ruminants). The sequence of Hc-DAF-2 displays significant sequence homology to insulin receptors (IR) in both vertebrates and invertebrates, and contains conserved structural domains. A sequence encoding an important proteolytic motif (RKRR) identified in the predicted peptide sequence of Hc-DAF-2 is consistent with that of the human IR, suggesting that it is involved in the formation of the IR complex. The Hc-daf-2 gene was transcribed in all life stages of H. contortus, with a significant up-regulation in the iL3 compared with other stages. To compare patterns of expression between Hc-daf-2 and Ce-daf-2, reporter constructs fusing the Ce-daf-2 or Hc-daf-2 promoter to sequence encoding GFP were microinjected into the N2 strain of C. elegans, and transgenic lines were established and examined. Both genes showed similar patterns of expression in amphidial (head) neurons, which relate to sensation and signal transduction. Further study by heterologous genetic complementation in a daf-2-deficient strain of C. elegans (CB1370) showed partial rescue of function by Hc-daf-2. Taken together, these findings provide a first insight into the roles of Hc-daf-2/Hc-DAF-2 in the biology and development of H. contortus, particularly in the transition to parasitism.
Parasitic nematode; Haemonchus contortus; daf-2; Development; Transgenesis
A series of 4-bicyclic heteroaryl
inhibitors of the serotonin transporter (SERT), norepinephrine transporter
(NET), and dopamine transporter (DAT) was discovered. The synthesis
and structure–activity relationship (SAR) of these triple reuptake
inhibitors (TRIs) will be discussed. Compound 10i (AMR-2),
a very potent inhibitor of SERT, NET, and DAT, showed efficacy in
the rat forced-swim and mouse tail suspension models with minimum
effective doses of 0.3 and 1 mg/kg (po), respectively.
At efficacious doses in these assays, 10i exhibited substantial
occupancy levels at the three transporters in both rat and mouse brain.
The study of the metabolism of 10i revealed the formation
of a significant active metabolite, compound 13.
Triple reuptake inhibitor; TRI; serotonin reuptake
inhibitor; dopamine reuptake inhibitor; norepinephrine
reuptake inhibitor; depression; antidepressant
The microbial communities in acid mine drainage have been extensively studied to reveal their roles in acid generation and adaption to this environment. Lacking, however, are integrated community- and organism-wide comparative gene transcriptional analyses that could reveal the response and adaptation mechanisms of these extraordinary microorganisms to different environmental conditions. In this study, comparative metagenomics and metatranscriptomics were performed on microbial assemblages collected from four geochemically distinct acid mine drainage (AMD) sites. Taxonomic analysis uncovered unexpectedly high microbial biodiversity of these extremely acidophilic communities, and the abundant taxa of Acidithiobacillus, Leptospirillum and Acidiphilium exhibited high transcriptional activities. Community-wide comparative analyses clearly showed that the AMD microorganisms adapted to the different environmental conditions via regulating the expression of genes involved in multiple in situ functional activities, including low-pH adaptation, carbon, nitrogen and phosphate assimilation, energy generation, environmental stress resistance, and other functions. Organism-wide comparative analyses of the active taxa revealed environment-dependent gene transcriptional profiles, especially the distinct strategies used by Acidithiobacillus ferrivorans and Leptospirillum ferrodiazotrophum in nutrients assimilation and energy generation for survival under different conditions. Overall, these findings demonstrate that the gene transcriptional profiles of AMD microorganisms are closely related to the site physiochemical characteristics, providing clues into the microbial response and adaptation mechanisms in the oligotrophic, extremely acidic environments.
Ischemia reperfusion (I/R) injury is a major cause of myocardial damage. Hydrogen sulfide (H2S), a gaseous signal molecule, has drawn considerable attention for its role in various pathophysiological processes. Multiple lines of evidence reveal the protective effects of H2S in various models of cardiac injury, however, the exact mechanism underlying this protective effect of H2S against myocardial I/R injury is not fully understood. The present study was designed to investigate whether H2S preconditioning attenuates myocardial I/R injury in rats and whether the observed protection is associated with reduced endo/sarcoplasmic reticulum (ER/SR) stress. We found that H2S preconditioning significantly reduced myocardial infarct size, preserved left ventricular function, and inhibited I/R-induced cardiomyocyte apoptosis in vivo. Furthermore, H2S preconditioning significantly attenuated I/R-induced ER/SR stress responses, including the increased expression of glucose-regulated protein 78, C/EBP homologous protein, and activate transcription factor in myocardium. Additionally, we demonstrate that H2S preconditioning attenuates ER/SR stress and inhibits cardiomyocyte apoptosis in an in vitro model of hypoxia/reoxygenation in rat H9c2 cardiac myocytes. In conclusion, these results suggest that H2S-attenuated ER/SR stress plays an important role in its protective effects against I/R-induced myocardial injury.
Ischemia/reperfusion; hydrogen sulfide; endo/sarcoplasmic reticulum stress; myocardial protection
Root samples of ‘Sanhu’ red tangerine trees infected with and without Candidatus Liberibacter asiaticus (CLas) were collected at 50 days post inoculation and subjected to RNA-sequencing and isobaric tags for relative and absolute quantification (iTRAQ) to profile the differentially expressed genes (DEGs) and proteins (DEPs), respectively. Quantitative real-time PCR was subsequently used to confirm the expression of 16 selected DEGs. Results showed that a total of 3956 genes and 78 proteins were differentially regulated by HLB-infection. Among the most highly up-regulated DEPs were sperm specific protein 411, copper ion binding protein, germin-like proteins, subtilisin-like proteins and serine carboxypeptidase-like 40 proteins whose transcript levels were concomitantly up-regulated as shown by RNA-seq data. Comparison between our results and those of the previously reported showed that known HLB-modulated biological pathways including cell-wall modification, protease-involved protein degradation, carbohydrate metabolism, hormone synthesis and signaling, transcription activities, and stress responses were similarly regulated by HLB infection but different or root-specific changes did exist. The root unique changes included the down-regulation in genes of ubiquitin-dependent protein degradation pathway, secondary metabolism, cytochrome P450s, UDP-glucosyl transferases and pentatricopeptide repeat containing proteins. Notably, nutrient absorption was impaired by HLB-infection as the expression of the genes involved in Fe, Zn, N and P adsorption and transportation were significantly changed. HLB-infection induced some cellular defense responses but simultaneously reduced the biosynthesis of the three major classes of secondary metabolites, many of which are known to have anti-pathogen activities. Genes involved in callose deposition were up-regulated whereas those involved in callose degradation were also up-regulated, indicating that the sieve tube elements in roots were hanging on the balance of life and death at this stage. In addition, signs of carbohydrate starvation were already eminent in roots at this stage. Other interesting genes and pathways that were changed by HLB-infection were also discussed based on our findings.
The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway plays critical roles in skeletal development. The impact and underlying mechanisms of its dysregulation in bone homeostasis is poorly defined. The best known and characterized mTOR signaling dysregulation in human disease is called Tuberous Sclerosis Complex (TSC). TSC is an autosomal dominant neurocutaneous syndrome with a high frequency (>66%) of osseous manifestations such as sclerotic lesions in the craniofacial region. TSC is caused by mutations of TSC1 or TSC2, the heterodimer protein inhibitor of mTORC1 signaling. The underlying mechanism of bone lesions in TSC is unclear. We generated a TSC mouse model with TSC1 deletion in neural crest derived (NCD) cells, which recapitulated the sclerotic craniofacial bone lesion in TSC patients. We demonstrated that TSC1 null NCD osteoblasts overpopulated the NCD bones and the resultant increased bone formation is responsible for the sclerotic bone phenotype. Mechanistically, osteoblast number increase is due to the hyperproliferation of osteoprogenitor cells at an early postnatal stage. Noteworthy, administration of rapamycin, an mTORC1 inhibitor at early postnatal stage can completely rescue the excess bone acquisition, but late treatment cannot. Altogether, our data suggested that enhanced mTORC1 signaling in NCD cells can enlarge the osteoprogenitor pool and lead to the excess bone acquisition, which is likely the underlying mechanism of sclerotic bone lesion observed in TSC patients.
mice; craniofacial; osteoblast; tuberous sclerosis; Tsc1; neural crest; mTOR