Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis.
A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and other relevant data were collected by questionnaire after cancer diagnosis, using a referent period of ‘2 years before diagnosis' to capture pre-diagnosis information. Molecular analyses of microsatellite instability (MSI) status and BRAF V600E mutation status were performed in tumour tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major prognostic factors.
Compared with never smokers, all-cause mortality (overall survival, OS) was higher for current (HR: 1.78; 95% CI: 1.04–3.06), but not for former (HR: 1.06; 95% CI: 0.71–1.59) smokers. The associations of cigarette smoking with the study outcomes were higher among patients with ⩾40 pack-years of smoking (OS: HR: 1.72; 95% CI: 1.03–2.85; disease-free survival (DFS: HR: 1.99; 95% CI: 1.25–3.19), those who smoked ⩾30 cigarettes per day (DFS: HR: 1.80; 95% CI: 1.22–2.67), and those with microsatellite stable (MSS) or MSI-low tumours (OS: HR: 1.38; 95% CI: 1.04–1.82 and DFS: HR: 1.32; 95% CI: 1.01–1.72). Potential heterogeneity was noted for sex (DFS HR: 1.68 for men and 1.01 for women: P for heterogeneity=0.04), and age at diagnosis (OS: HR: 1.11 for patients aged <60 and 1.69 for patients aged ⩾60: P for heterogeneity=0.03).
Pre-diagnosis cigarette smoking is associated with worsened prognosis among patients with CRC.
colorectal cancer; smoking; cancer survival; interaction; MSI; BRAF
Utilizing epitaxial Co2Fe1-xMnxAl full-Heusler alloy
films on GaAs (001), we address the controversy over the analysis for the split
hysteresis loop which is commonly found in systems consisting of both uniaxial and
fourfold anisotropies. Quantitative comparisons are carried out on the values of the
twofold and fourfold anisotropy fields obtained with ferromagnetic resonance and
vibrating sample magnetometer measurements. The most suitable model for describing
the split hysteresis loop is identified. In combination with the component resolved
magnetization measurements, these results provide compelling evidences that the
switching is caused by the domain wall nucleation and movements with the switching
fields centered at the point where the energy landscape shows equal minima for
magnetization orienting near the easy axis and the field supported hard axis.
Incidence; medical staff; thyroid neoplasms
Optical clocks have been the focus of science and technology research areas due to their capability to provide highest frequency accuracy and stability to date. Their superior frequency performance promises significant advances in the fields of fundamental research as well as practical applications including satellite-based navigation and ranging. In traditional optical clocks, ultrastable optical cavities, laser cooling and particle (atoms or a single ion) trapping techniques are employed to guarantee high stability and accuracy. However, on the other hand, they make optical clocks an entire optical tableful of equipment, and cannot work continuously for a long time; as a result, they restrict optical clocks used as very convenient and compact time-keeping clocks. In this article, we proposed, and experimentally demonstrated, a novel scheme of optical frequency standard based on comb-directly-excited atomic two-photon transitions. By taking advantage of the natural properties of the comb and two-photon transitions, this frequency standard achieves a simplified structure, high robustness as well as decent frequency stability, which promise widespread applications in various scenarios.
This study aimed to assess the efficacy of a rural community-based integrated
intervention for early prevention and management of chronic obstructive pulmonary
disease (COPD) in China. This 18-year cluster-randomized controlled trial
encompassing 15 villages included 1008 patients (454 men and 40 women in the
intervention group [mean age, 54 ± 10 years]; 482 men and 32 women in the control
group [mean age, 53 ± 10 years]) with confirmed COPD or at risk for COPD. Villages
were randomly assigned to the intervention or the control group, and study
participants residing within the villages received treatment accordingly.
Intervention group patients took part in a program that included systematic health
education, smoking cessation counseling, and education on management of COPD. Control
group patients received usual care. The groups were compared after 18 years regarding
the incidence of COPD, decline in lung function, and mortality of COPD. COPD
incidence was lower in the intervention group than in the control group (10%
vs 16%, <0.05). A decline in lung function was also
significantly delayed in the intervention group compared to the control group of COPD
and high-risk patients. The intervention group showed significant improvement in
smoking cessation compared with the control group, and smokers in the intervention
group had lower smoking indices than in the control group (350 vs
450, <0.05). The intervention group also had a significantly lower cumulative
COPD-related death rate than the control group (37% vs 47%,
<0.05). A rural community-based integrated intervention is effective in reducing
the incidence of COPD among those at risk, delaying a decline in lung function in
COPD patients and those at risk, and reducing mortality of COPD.
Chronic obstructive pulmonary disease; Randomized controlled trial; Integrated intervention; Rural area; Lung function; Smoking cessation
In this study, water-soluble silicon quantum dots have quasi-blue emission at 390 nm by being capped with 1-vinylimidazole in resese micelles. As-obtained silicon quantum dots have a diameter of 2~5 nm and high crystallinity. The quasi-blue emission of the silicon quantum dots is likely attributed to the polarity of the capping ligands. Moreover, the silicon quantum dots are water-soluble and have photoluminescence nanosecond decay time, suggesting their potential application in biological field.
Water-soluble; Quasi-blue emission; Silicon quantum dots
Urological reconstructive surgery is sometimes hampered by a lack of tissue. In some cases, autologous urothelial cells (UCs) are not available for cell expansion and ordinary tissue engineering. In these cases, we wanted to explore whether autologous mesenchymal stem cells (MSCs) from bone marrow could be used to create urological transplants. MSCs from human bone marrow were cultured in vitro with medium conditioned by normal human UCs or by indirect co-culturing in culture well inserts. Changes in gene expression, protein expression and cell morphology were studied after two weeks using western blot, RT-PCR and immune staining. Cells cultured in standard epithelial growth medium served as controls. Bone marrow MSCs changed their phenotype with respect to growth characteristics and cell morphology, as well as gene and protein expression, to a UC lineage in both culture methods, but not in controls. Urothelial differentiation was also accomplished in human bone marrow MSCs seeded on a three-dimensional poly(ε-caprolactone) (PCL)–collagen construct. Human MSCs could easily be harvested by bone marrow aspiration and expanded and differentiated into urothelium. Differentiation could take place on a three-dimensional hybrid PCL-reinforced collagen-based scaffold for creation of a tissue-engineered autologous transplant for urological reconstructive surgery.
human bone marrow stem cells; mesenchymal stem cells; mesenchymal stromal cells; transdifferentiation; urothelial cells; tissue engineering
To determine the predictive factors of visual outcomes in children with open globe injury and to give guidance to reduce the incidence of open globe injury.
One hundred and forty eyes of 137 consecutive open globe injury patients, who were treated at the Eye Center of Second Bethune Hospital affiliated with Jilin University between August 2005 and August 2012, were retrospectively analyzed. Data recorded included demographic characteristics, causes of injury, location and extent of injury, presenting visual acuity, detailed ocular anterior and posterior segment evaluations, details of primary and subsequent surgeries, and postoperative complications and outcomes. The follow-up data included the most recent best-corrected visual acuity, complications, and the duration of follow-up.
Of the 137 patients, there were 116 (84.7%) boys and 21 (15.3%) girls. Their ages ranged between 3 and 17 years old (mean=11.57±4.19 years old). Sixty (43.8%) children had a right eye injury, whereas 74 (54.0%) had a left eye injury. Only three (2.2%) children suffered bilateral eye injury. Living utensils, industrial tools, and fireworks contributed to the most common causes of open globe injury. Eighty-one (59.1%) had sharp force injuries, 23 (16.8%) had blunt injuries, and 33 (24.1%) had missile injuries.
Unfavorable visual outcomes were related to a younger age at presentation, poor presenting visual acuity, injuries caused by blunt or missile objects, posterior wound location, hyphema, vitreous hemorrhage, and surgical intervention of pars plana vitrectomy.
Chronic ethanol consumption can produce learning and memory deficits. Brain-derived
neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism.
In this study, we examined the expression of BDNF, tropomyosin receptor kinase B
(TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of
chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg;
10 males and 10 females) were obtained from Harbin Medical University. A stable
alcoholism model was established through ad libitum feeding, and
anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the
stems of watermelon; developed in our laboratory), at low- and high-doses, was
carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The
morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The
number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the
dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed
using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF,
TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly
localized in the granular cell layer of the DG and in the pyramidal cell layer of the
CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF
and TrkB were decreased in chronic alcoholism, and increased after abstinence. The
CA4 region appeared to show the greatest differences. Changes in p75NTR expression
were the opposite of those of BDNF and TrkB, with the greatest differences observed
in the DG and CA4 regions.
Chronic alcoholism; Brain-derived neurotrophic factor; Tropomyosin receptor kinase B; p75 Neurotrophin receptor; Immunohistochemistry
The study determined pharmacist support on patients receiving multi-drug therapy for coronary heart disease by evaluating patient self-care ability, quality of life, and drug therapy compliance. In this study, ninety patients were randomly assigned to an experimental group (n=45) and a control group (n=45). The control group received conventional clinical care. The experimental group received clinical care plus pharmacist support that included medication review, patient education, lifestyle management, discharge guidance, and telephone follow-up. Eighty-five patients completed the study. Self-care ability and quality of life were evaluated before hospital discharge. The experimental group understood their condition better than the control group (P<0.05), the differences between the groups in understanding treatment goals, drug regimens, lifestyle modifications, psychogenic disorders, and satisfaction evaluations were more pronounced (P<0.01). At six-month follow-up, the difference between the groups in drug therapy compliance was P<0.01, as was success rate by intention-to-treat (77.8% vs. 48.9%) and per-protocol (81.4% vs. 52.4%). Two adverse drug reactions occurred in the experimental group and three in the control group. Pharmacist support improved self-care ability, quality of life, drug therapy compliance, and treatment success rate in coronary heart disease patients.
Coronary heart disease; pharmacist; quality of life; clinical pharmacy service
Severe refractory asthma is associated with enhanced nitrative stress. To determine the mechanisms for high nitrative stress in human severe asthma, 3-nitrotyrosine (3NT) was compared with Th1 and Th2 cytokine expression. In severe asthma, high 3NT levels were associated with high IFN-γ and low IL-13 expression, both of which have been reported to increase inducible nitric oxide synthase (iNOS) in human airway epithelial cells (HAEC). We found IL-13 and IFN-γ synergistically enhanced iNOS, nitrite and 3NT, corresponding with increased H2O2. Catalase inhibited while superoxide dismutase enhanced 3NT formation, supporting a critical role for H2O2 but not peroxynitrite, in 3NT generation. Dual oxidase-2 (DUOX2), central to H2O2 formation, was also synergistically induced by IL-13 and IFN-γ. The catalysis of nitrite and H2O2 to nitrogen dioxide radical (NO2•) requires an endogenous peroxidase in this epithelial cell system. Thyroid peroxidase (TPO) was identified by microarray analysis ex vivo as a gene distinguishing HAEC of severe asthma from controls. IFN-γ induced TPO in HAEC and siRNA knockdown decreased nitrated tyrosine residues. Ex vivo, DUOX2, TPO and iNOS were higher in severe asthma and correlated with 3NT. Thus a novel iNOS-DUOX2-TPO-NO2• metabolome drives nitrative stress in HAEC and likely in severe asthma.
A charge-density wave (CDW) state has a broken symmetry described by a complex order parameter with an amplitude and a phase. The conventional view, based on clean, weak-coupling systems, is that a finite amplitude and long-range phase coherence set in simultaneously at the CDW transition temperature Tcdw. Here we investigate, using photoemission, X-ray scattering and scanning tunnelling microscopy, the canonical CDW compound 2H-NbSe2 intercalated with Mn and Co, and show that the conventional view is untenable. We find that, either at high temperature or at large intercalation, CDW order becomes short-ranged with a well-defined amplitude, which has impacts on the electronic dispersion, giving rise to an energy gap. The phase transition at Tcdw marks the onset of long-range order with global phase coherence, leading to sharp electronic excitations. Our observations emphasize the importance of phase fluctuations in strongly coupled CDW systems and provide insights into the significance of phase incoherence in ‘pseudogap’ states.
Charge density waves are described by a complex order parameter whose amplitude is expected to vanish at the transition temperature. This study shows that the transition in 2H-NbSe2 is driven by fluctuations of the phase of the order parameter, with a finite amplitude surviving in the disordered state.
Fbxl7, a subunit of the SCF (Skp-Cul1-F-box protein) complex induces mitotic arrest in cells; however, molecular factors that control its cellular abundance remain largely unknown. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18. An FQ motif within Fbxl7 serves as a molecular recognition site for Fbxl18 interaction. Ectopically expressed Fbxl7 induces apoptosis in Hela cells, an effect profoundly accentuated after cellular depletion of Fbxl18 protein or expression of Fbxl7 plasmids encoding mutations at either Lys 109 or within the FQ motif. Ectopic expression of Fbxl18 plasmid-limited apoptosis caused by overexpressed Fbxl7 plasmid. Thus, Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7 that may impact cellular processes involved in cell cycle progression.
Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single-gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%. Vacuolar pH homeostasis, superoxide dismutase activity, and mitochondrial proteostasis were found to be strong determinants of the response to DR. Proteomic analysis of cells deficient in prohibitins revealed induction of a mitochondrial unfolded protein response (mtUPR) which has not previously been described in yeast. Mitochondrial proteotoxic stress in prohibitin mutants was suppressed by DR via reduced cytoplasmic mRNA translation. A similar relationship between prohibitins, the mtUPR, and longevity was also observed in Caenorhabditis elegans. These observations define conserved molecular processes that underlie genotype-dependent effects of DR that may be important modulators of DR in higher organisms.
aging; replicative lifespan; longevity; yeast; dietary restriction; mitochondria; mitochondrial unfolded protein response
Chronological aging of budding yeast cells results in a reduction in subsequent replicative life span through unknown mechanisms. Here we show that dietary restriction during chronological aging delays the reduction in subsequent replicative life span up to at least 23 days of chronological age. We further show that among the viable portion of the control population aged 26 days, individual cells with the lowest mitochondrial membrane potential have the longest subsequent replicative lifespan. These observations demonstrate that dietary restriction modulates a common molecular mechanism linking chronological and replicative aging in yeast and indicate a critical role for mitochondrial function in this process.
chronological lifespan; replicative lifespan; caloric restriction; calorie restriction; dietary restriction; glucose; mitochondria
Laryngeal squamous cell carcinoma (LSCC) is one of the most common carcinomas of the head and neck. Despite advances in diagnosis and treatment, the survival of patients with LSCC has not improved in the past two decades. TIP30, a newly identified tumour suppressor, appears to be involved in multiple processes during tumour development. Here, we investigated the involvement of TIP30 in chemoresistance of LSCC in vitro and in vivo. We showed that TIP30 expression decreased significantly in drug-selected cells (DSCs) of laryngeal carcinoma. Suppressing TIP30 enhanced resistance capability to multiple chemotherapy drugs, cell proliferation and self-renewal in Hep2 cells. Additionally, decreased self-renewal capacity and chemotherapeutic resistance were observed in DSCs overexpressing TIP30. Furthermore, TIP30 negatively regulated tumourigenesis and chemoresistance in LSCC cells subcutaneously transplanted into nude mice. Moreover, decreased TIP30 expression contributed to chemoresistance, self-renewal and proliferation of LSCC cells via nuclearlisation of β-catenin, a cell–cell adhesion and stem cell renewal regulator. Consistently, Kaplan–Meier and Cox proportional hazards regression modelling analyses showed that decreased TIP30 expression independently predicted poor survival in patients with LSCC. Taken together, our results reveal that TIP30 has a crucial role in chemoresistance of LSCC through the AKT/glycogen synthase kinase-3β/β-catenin signalling pathway and may be a promising candidate for improving LSCC chemotherapy.
Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have
been widely used to repair cartilage defects. However, chondrocyte phenotype is
easily lost when chondrocytes are expanded in vitro by a process
defined as “dedifferentiation”. To ensure successful therapy, an effective
pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers
in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA)
has been used in the treatment of arthritis, but its biocompatibility is inferior to
that of other compounds. In this study, we modified GA by incorporating
sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and
evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could
effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote
chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular
matrix. On the other hand, expression of the collagen I gene was effectively
down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C.
Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the
JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the
strongest response was observed with 0.25 µg/mL. This study provides a basis for
further studies on a novel agent in the treatment of articular cartilage defects.
Sulfamonomethoxine sodium; Gallic acid; Pro-chondrogenic agent; Chondrocyte; Rabbit articular cartilage; Dedifferentiation
Three studies were conducted to investigate whether a chelated Cu can replace CuSO4 as a growth promoter in pigs. In Exp. 1, a total of 240 piglets (Large White×Landrace, 7.36±0.10 kg) were randomly allocated to 1 of 3 treatments with 8 replicates and 10 piglets per pen. Treatments included a NRC control (CuSO4, 6 mg/kg), two Cu supplementations from either CuSO4 or Cu(HMTBa)2 at 170 mg/kg. Pigs fed Cu(HMTBa)2 were 6.0% heavier than pigs fed either the NRC control or 170 mg/kg CuSO4 (p = 0.03) at the end of the experiment. During the 42 days of experimental period, pigs fed Cu(HMTBa)2 gained 9.0% more (p = 0.01), tended to eat more feed (p = 0.09), and had better feed efficiency (p = 0.06) than those fed CuSO4. Compared with the 6 mg/kg CuSO4 NRC control, liver Cu was increased 2.7 times with 170 mg/kg CuSO4 supplementation, and was further increased with Cu(HMTBa)2 (4.5 times, p<0.05). In Exp. 2, a total of 616 crossbred piglets (PIC, 5.01±0.25 kg) were randomly allocated to 1 of 4 treatments with 7 replicates and 22 piglets per pen. Treatments included a NRC control (from CuSO4), and three pharmaceutical levels of Cu (150 mg/kg) supplemented either from CuSO4, tri-basic copper chloride (Cu2[OH]3Cl), or Cu(HMTBa)2. Pigs fed CuSO4 or Cu(HMTBa)2 had better feed efficiency (p = 0.01) and tended to gain more (p = 0.08) compared with those fed the NRC control. Pigs fed Cu2(OH)3Cl were intermediate. Pigs fed Cu(HMTBa)2 had the highest liver Cu, which was significantly higher than those fed (Cu2[OH]3Cl) or the negative control (p = 0.01). In Exp. 3, a total of 1,048 pigs (PIC, 32.36±0.29 kg) were allotted to 6 treatments with 8 replicates per treatment and 20 to 22 pigs per pen. The treatments included a NRC control with 4 mg/kg Cu from CuSO4, a positive control with 160 mg/kg Cu from CuSO4, and incremental levels of Cu(HMTBa)2 at 20, 40, 80, and 160 mg/kg. During the overall experimental period of 100 days, no benefit from 160 mg/kg CuSO4 was observed. Pigs fed Cu(HMTBa)2 had increased ADG (linear and quadratic, p≤0.05) and feed efficiency (linear and quadratic, p≤0.05) up to 80 mg/kg and no further improvement was observed at 160 mg/kg for the whole experimental period. Pigs fed 80 mg/kg Cu(HMTBa)2 weighed 1.8 kg more (p = 0.07) and were 2.3 kg heavier in carcass (p<0.01) compared with pigs fed 160 mg/kg CuSO4. In addition, loin depth was increased with increased Cu(HMTBa)2 supplementation with pigs fed 80 mg/kg Cu(HMTBa)2 had the greatest loin depth (p<0.05). In summary, Cu(HMTBa)2 can be used to replace high CuSO4 as a growth promoter in nursery and grower-finisher pigs.
Chelated Trace Mineral; Cu(HMTBa)2; Copper; Growth Promoter; Swine
Somatostatin receptor 1 (SSTR1) was preferentially methylated in Epstein-Barr virus (EBV)-positive gastric cancer using promoter methylation array. We aimed to analyse the epigenetic alteration and biological function of SSTR1 in EBV-associated gastric cancer (EBVaGC).
Promoter methylation was examined by combined bisulphite restriction analysis (COBRA) and pyrosequencing. The biological functions of SSTR1 were evaluated by loss- and gain-of-function assays.
Promoter hypermethylation of SSTR1 was detected in EBV-positive gastric cancer cell lines (AGS-EBV) with SSTR1 transcriptional silence, but not in EBV-negative gastric cancer cell lines with SSTR1 expression. Expression level of SSTR1 was restored in AGS-EBV by exposure to demethylating agent. Moreover, methylation level of SSTR1 was significantly higher in EBV-positive primary gastric cancers compared with EBV-negative gastric cancers (P=0.004). Knock-down of SSTR1 in gastric cancer cell lines (AGS and BGC823) increased cell proliferation and colony formation ability, and promoted G1 to S-phase transition, enhanced cell migration and invasive ability. In contrast, ectopic expression of SSTR1 in gastric cancer cell lines (MKN28 and MGC803) significantly suppressed cell growth in culture conditions and reduced tumour size in nude mice. The tumour suppressive effect of SSTR1 was associated with upregulation of cyclin-dependent kinase inhibitors (p16, p15, p27 and p21); downregulation of oncogenes (MYC and MDM2), key cell proliferation and pro-survival regulators (PI3KR1, AKT, BCL-XL and MET); and inhibition of the migration/invasion-related genes (integrins, MMP1 (matrix metallopeptidase 1), PLAUR (plasminogen activator urokinase receptor) and IL8 (interleukin 8)).
Somatostatin receptor 1 is a novel methylated gene driven by EBV infection in gastric cancer cells and acts as a potential tumour suppressor.
Epstein-Barr virus; gastric cancer; somatostatin receptor 1; tumour suppressor gene; epigenetic alteration
The high-precision distribution of optical pulse trains via fibre links has had a considerable impact in many fields. In most published work, the accuracy is still fundamentally limited by unavoidable noise sources, such as thermal and shot noise from conventional photodiodes and thermal noise from mixers. Here, we demonstrate a new high-precision timing distribution system that uses a highly precise phase detector to obviously reduce the effect of these limitations. Instead of using photodiodes and microwave mixers, we use several fibre Sagnac-loop-based optical-microwave phase detectors (OM-PDs) to achieve optical-electrical conversion and phase measurements, thereby suppressing the sources of noise and achieving ultra-high accuracy. The results of a distribution experiment using a 10-km fibre link indicate that our system exhibits a residual instability of 2.0 × 10−15 at1 s and8.8 × 10−19 at 40,000 s and an integrated timing jitter as low as 3.8 fs in a bandwidth of 1 Hz to 100 kHz. This low instability and timing jitter make it possible for our system to be used in the distribution of optical-clock signals or in applications that require extremely accurate frequency/time synchronisation.
There is growing evidence that stochastic events play an important role in determining individual longevity. Studies in model organisms have demonstrated that genetically identical populations maintained under apparently equivalent environmental conditions display individual variation in lifespan that can be modeled by the Gompertz-Makeham law of mortality. Here we report that within genetically identical haploid and diploid wild type populations, shorter-lived cells tend to arrest in a budded state, while cells that arrest in an unbudded state are significantly longer-lived. This relationship is particularly notable in diploid BY4743 cells, where mother cells that arrest in a budded state have a shorter mean lifespan (25.6 vs. 35.6) and larger coefficient of variance with respect to individual lifespan (0.42 vs. 0.32) than cells that arrest in an unbudded state. Mutations that cause genomic instability tend to shorten lifespan and increase the proportion of the population that arrest in a budded state. These observations suggest that randomly occurring damage may contribute to stochasticity during replicative aging by causing a subset of the population to terminally arrest prematurely in the S or G2 phase of the cell cycle.
replicative lifespan; longevity; yeast; senescence; DNA damage; sir2; cell cycle arrest
Proper control of apoptotic signaling is important for maintenance of testicular homeostasis after ionizing radiation (IR). Herein, we challenged the hypothesis that ghrelin, a pleiotropic modulator, is potentially involved in IR-induced germ cell injury. Lower body exposure to 2 Gy of IR induced a notable increase of ghrelin expression in the nuclear of differentiating spermatogonia at defined stages, with an impairment in the Leydig cells (LCs)-expressing ghrelin. Unexpectedly, inhibition of the ghrelin pathway by intraperitoneal injection of a specific GHS-R1α antagonist enhanced spermatogonia elimination by apoptosis during the early recovery following IR, and thereafter resulted in impaired male fertility, suggesting that the anti-apoptotic effects of evoked ghrelin, although transient along testicular IR injury, have a profound influence on the post-injury recovery. In addition, inhibition of ghrelin signaling resulted in a significant increase in the intratesticular testosterone (T) level at the end of 21 days after IR, which should stimulate the spermatogenic recovery from surviving spermatogonia to a certain extent during the late stage. We further demonstrated that the upregulation and nuclear trafficking of ghrelin, elaborately regulated by IR-elicited antioxidant system in spermatogonia, may act through a p53-dependent mechanism. The elicitation of ghrelin expression by IR stress, the regulation of ghrelin expression by IR-induced oxidative stress and the interaction between p53 and ghrelin signaling during IR injury were confirmed in cultured spermatogonia. Hence, our results represent the first evidence in support of a radioprotective role of ghrelin in the differentiating spermatogonia. The acutely, delicate regulation of local-produced ghrelin appears to be a fine-tune mechanism modulating the balance between testicular homeostasis and early IR injury.
ionizing radiation; ghrelin; spermatogonia; oxidative stress; p53
Oplopantriol-A (OPT) is a natural polyyne from Oplopanax horridus. We show here that OPT preferentially kills cancer cells and inhibits tumor growth. We demonstrate that OPT-induced cancer cell death is mediated by excessive endoplasmic reticulum (ER) stress. Decreasing the level of ER stress either by inactivating components of the unfolded protein response (UPR) pathway or by expression of ER chaperone protein glucose-regulated protein 78 (GRP78) decreases OPT-induced cell death. We show that OPT induces the accumulation of ubiquitinated proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part, through interfering with the ubiquitin/proteasome pathway. In support of this, inhibition of protein synthesis significantly decreased the accumulation of ubiquitinated proteins, which is correlated with significantly decreased OPT-induced ER stress and cell death. Finally, we show that OPT treatment significantly induced the expression of BH3-only proteins, Noxa and Bim. Knockdown of both Noxa and Bim significantly blocked OPT-induced cell death. Taken together, our results suggest that OPT is a potential new anticancer agent that induces cancer cell death through inducing ER stress and BH3 proteins Noxa and Bim.
ER stress; Oplopantriol-A; unfolded protein response; noxa; bim
Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) after curative resection. Therefore, it is critical to understand the mechanisms underlying tumor metastasis in HCC. We have previously shown that elevated expression of myeloid differentiation factor 88 (MyD88) may promote tumor growth and metastasis in HCC. In this study, we reported that enhanced expression of MyD88 promoted epithelial–mesenchymal transition (EMT) properties and tumor-initiating capabilities in HCC cells. MyD88 was found to be able to interact with p85, a regulatory subunit of phosphoinositide 3-kinase (PI3-K), independent of TLR/IL-1R-mediated response and caused PI3-K/v-akt murine thymoma viral oncogene homolog (Akt) activation, which resulted in subsequent phosphorylation of glycogen synthase kinase-3β and stabilization of Snail, a critical EMT mediator. Consistently, we observed a significant correlation between MyD88 expression and p-Akt levels in a cohort of HCC patients, and found that the combination of these two parameters have better prognostic value for HCC patients. Taken together, these results suggest that elevated MyD88 may facilitate HCC metastasis by promoting EMT properties and tumor-initiating capabilities via PI3–K/Akt pathway.
tumor metastasis; myeloid differentiation factor 88; epithelial–mesenchymal transition
While environmental stress likely plays a significant role in promoting aging, the relationship remains poorly understood. In order to characterize this interaction in a more comprehensive manner, we examined the stress response profiles for 46 long-lived yeast mutant strains across four different stress conditions (oxidative, ER, DNA damage, and thermal), grouping genes based on their associated stress response profiles. Unexpectedly, cells lacking the mitochondrial AAA protease gene AFG3 clustered strongly with long-lived strains lacking cytosolic ribosomal proteins of the large subunit. Similar to these ribosomal protein mutants, afg3Δ cells show reduced cytoplasmic mRNA translation, enhanced resistance to tunicamycin that is independent of the ER unfolded protein response, and Sir2-independent but Gcn4-dependent life span extension. These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging.
aging; stress response; translation; mitochondria; ER stress; replicative lifespan; longevity; yeast; epistasis; phenotype mapping