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1.
Carl van Walraven 《CMAJ》2013,185(16):E755-E762
Background:
Changes in the long-term survival of people admitted to hospital is unknown. This study examined trends in 1-year survival of patients admitted to hospital adjusted for improved survival in the general population.Methods:
One-year survival after admission to hospital was determined for all adults admitted to hospital in Ontario in 1994, 1999, 2004, or 2009 by linking to vital statistics datasets. Annual survival in the general population was determined from life tables for Ontario.Results:
Between 1994 and 2009, hospital use decreased (from 8.8% to 6.3% of the general adult population per year), whereas crude 1-year mortality among people with hospital admissions increased (from 9.2% to 11.6%). During this time, patients in hospital became significantly older (median age increased from 51 to 58 yr) and sicker (the proportion with a Charlson comorbidity index score of 0 decreased from 68.2% to 60.0%), and were more acutely ill on admission (elective admissions decreased from 47.4% to 42.0%; proportion brought to hospital by ambulance increased from 16.1% to 24.8%). Compared with 1994, the adjusted odds ratio (OR) for death at 1 year in 2009 was 0.78 (95% confidence interval [CI] 0.77–0.79). However, 1-year risk of death in the general population decreased by 24% during the same time. After adjusting for improved survival in the general population, risk of death at 1 year for people admitted to hospital remained significantly lower in 2009 than in 1994 (adjusted relative excess risk 0.81, 95% CI 0.80–0.82).Interpretation:
After accounting for both the increased burden of patient sickness and improved survival in the general population, 1-year survival for people admitted to hospital increased significantly from 1994 to 2009. The reasons for this improvement cannot be determined from these data. Hospitals have a special place in most health care systems. Hospital staff care for the people with the most serious illnesses and the most vulnerable. They are frequently the location of many life-defining moments — including birth, surgery, acute medical illness and death — of many people and their families. Hospitals serve as a focus in the training of most physicians. In addition, they consume a considerable proportion of health care expenditures worldwide. 1 Given the prominence of hospitals in health care systems, measuring outcomes related to hospital care is important. In particular, the measurement of trends for outcomes of hospital care can help us to infer whether the care provided to hospital patients is improving. Previous such studies have focused on survival trends for specific diseases or patients who received treatment in specific departments. 2 – 12 None of these studies have adjusted for survival trends in the general population, the adjustment for which is important to determine whether changes in survival of patients in hospital merely reflect changes in the overall population. In this study, whether or not patient outcomes have changed over time was determined by examining trends in 1-year survival in all patients admitted to hospital, adjusting for improved survival in the general population. 相似文献2.
3.
4.
5.
Ellen J. Tisdale Fouad Azizi Cristina R. Artalejo 《The Journal of biological chemistry》2009,284(9):5876-5884
Rab2 requires glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and atypical
protein kinase Cι (aPKCι) for retrograde vesicle formation from
vesicular tubular clusters that sort secretory cargo from recycling proteins
returned to the endoplasmic reticulum. However, the precise role of GAPDH and
aPKCι in the early secretory pathway is unclear. GAPDH was the first
glycolytic enzyme reported to co-purify with microtubules (MTs). Similarly,
aPKC associates directly with MTs. To learn whether Rab2 also binds directly
to MTs, a MT binding assay was performed. Purified Rab2 was found in a
MT-enriched pellet only when both GAPDH and aPKCι were present, and
Rab2-MT binding could be prevented by a recombinant fragment made to the Rab2
amino terminus (residues 2-70), which directly interacts with GAPDH and
aPKCι. Because GAPDH binds to the carboxyl terminus of α-tubulin,
we characterized the distribution of tyrosinated/detyrosinated α-tubulin
that is recruited by Rab2 in a quantitative membrane binding assay.
Rab2-treated membranes contained predominantly tyrosinated α-tubulin;
however, aPKCι was the limiting and essential factor.
Tyrosination/detyrosination influences MT motor protein binding; therefore, we
determined whether Rab2 stimulated kinesin or dynein membrane binding.
Although kinesin was not detected on membranes incubated with Rab2, dynein was
recruited in a dose-dependent manner, and binding was aPKCι-dependent.
These combined results suggest a mechanism by which Rab2 controls MT and motor
recruitment to vesicular tubular clusters.The small GTPase Rab2 is essential for membrane trafficking in the early
secretory pathway and associates with vesicular tubular
clusters
(VTCs)2 located
between the endoplasmic reticulum (ER) and the cis-Golgi compartment
(1,
2). VTCs are pleomorphic
structures that sort anterograde-directed cargo from recycling proteins and
trafficking machinery retrieved to the ER
(3-6).
Rab2 bound to a VTC microdomain stimulates recruitment of soluble factors that
results in the release of vesicles containing the recycling protein p53/p58
(7). In that regard, we have
previously reported that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and
atypical PKC ι (aPKCι) are Rab2 effectors that interact directly
with the Rab2 amino terminus and with each other
(8,
9). Their interaction requires
Src-dependent tyrosine phosphorylation of GAPDH and aPKCι
(10). Moreover, GAPDH is a
substrate for aPKCι (11).
GAPDH catalytic activity is not required for ER to Golgi transport indicating
that GAPDH provides a specific function essential for membrane trafficking
from VTCs independent of glycolytic function
(9). Indeed, phospho-GAPDH
influences MT dynamics in the early secretory pathway
(11).GAPDH was the first glycolytic enzyme reported to co-purify with
microtubules (MTs) (12) and
subsequently was shown to interact with the carboxyl terminus of
α-tubulin (13). The
binding of GAPDH to MTs promotes formation of cross-linked parallel MT arrays
or bundles (14,
15). GAPDH has also been
reported to possess membrane fusogenic activity, which is inhibited by tubulin
(16). Similarly, aPKC
associates directly with tubulin and promotes MT stability and MT remodeling
at specific intracellular sites
(17-21).
It may not be coincidental that these two Rab2 effectors influence MT dynamics
because recent studies indicate that the cytoskeleton plays a central role in
the organization and operation of the secretory pathway
(22).MTs are dynamic structures that grow or shrink by the addition or loss of
α- and β-tubulin heterodimers from the ends of protofilaments
(23). Their assembly and
stability is regulated by a variety of proteins traditionally referred to as
microtubule-associated proteins (MAPs). In addition to the multiple
α/β isoforms that are present in eukaryotes, MTs undergo an
assortment of post-translational modifications, including acetylation,
glycylation, glutamylation, phosphorylation, palmitoylation, and
detyrosination, which further contribute to their biochemical heterogeneity
(24,
25). It has been proposed that
these tubulin modifications regulate intracellular events by facilitating
interaction with MAPs and with other specific effector proteins
(24). For example, the
reversible addition of tyrosine to the carboxyl terminus of α-tubulin
regulates MT interaction with plus-end tracking proteins (+TIPs) containing
the cytoskeleton-associated protein glycine-rich (CAP-Gly) motif and with
dynein-dynactin
(27-29).
Additionally, MT motility and cargo transport rely on the cooperation of the
motor proteins kinesin and dynein
(30). Kinesin is a plus-end
directed MT motor, whereas cytoplasmic dynein is a minus-end MT-based motor,
and therefore the motors transport vesicular cargo toward the opposite end of
a MT track (31).Although MT assembly does not appear to be directly regulated by small
GTPases, Rab proteins provide a molecular link for vesicle movement along MTs
to the appropriate target (22,
32-34).
In this study, the potential interaction of Rab2 with MTs and motor proteins
was characterized. We found that Rab2 does not bind directly to preassembled
MTs but does associate when both GAPDH and aPKCι are present and bound to
MTs. Moreover, the MTs predominantly contained tyrosinated α-tubulin
(Tyr-tubulin) suggesting that a dynamic pool of MTs that differentially binds
MAPs/effector proteins/motors associates with VTCs in response to Rab2. To
that end, we determined that Rab2-promoted dynein/dynactin binding to
membranes and that the recruitment required aPKCι. 相似文献
6.
Candida antarctica lipase B (CALB) is one of the most widely used and studied enzymes in the world. In order to achieve the high-level expression of CALB in Pichia, we optimized the codons of CALB gene and α-factor by using a de novo design and synthesis strategy. Through comparative analysis of a series of recombinants with different expression components, we found that the methanol-inducible expression recombinant carrying the codon-optimized α-factor and mature CALB gene (pPIC9KαM-CalBM) has the highest lipase production capacity. After fermentation parameters optimization, the lipase activity and protein content of the recombinant pPIC9KαM-CalBM reached 6,100 U/mL and 3.0 g/L, respectively, in a 5-L fermentor. We believe this strategy could be of special interest due to its capacity to improve the expression level of target gene, and the Pichia transformants carrying the codon-optimized gene had great potential for the industrial-scale production of CALB lipase. 相似文献
7.
8.
Cell death can be divided into the anti-inflammatory process of apoptosis and the
pro-inflammatory process of necrosis. Necrosis, as apoptosis, is a regulated form of cell
death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor-Interacting Protein (RIP)
1/3 are major mediators. We previously showed that absence or inhibition of PARP-1
protects mice from nephritis, however only the male mice. We therefore hypothesized that
there is an inherent difference in the cell death program between the sexes. We show here
that in an immune-mediated nephritis model, female mice show increased apoptosis compared
to male mice. Treatment of the male mice with estrogens induced apoptosis to levels
similar to that in female mice and inhibited necrosis. Although PARP-1 was activated in
both male and female mice, PARP-1 inhibition reduced necrosis only in the male mice. We
also show that deletion of RIP-3 did not have a sex bias. We demonstrate here that male
and female mice are prone to different types of cell death. Our data also suggest that
estrogens and PARP-1 are two of the mediators of the sex-bias in cell death. We therefore
propose that targeting cell death based on sex will lead to tailored and better treatments
for each gender. 相似文献
9.
David Joachim Schiemann Martha Lucía Qui?ones Pinzón Thomas Hankeln 《Memórias do Instituto Oswaldo Cruz》2014,109(3):384-387
Malaria is still a primary health problem in Colombia. The locality of Tierradentro
is situated in the municipality of Montelíbano, Córdoba, in the northwest of
Colombia, and has one of the highest annual parasite index of malaria nationwide.
However, the vectors involved in malaria transmission in this locality have not yet
been identified. In this study, the local anthropophilic Anopheles
composition and natural infectivity with Plasmodium were
investigated. In August 2009, 927 female Anopheles mosquitoes were
collected in eight localities using the human landing catch method and identified
based on their morphology. Cryptic species were determined by restriction fragment
length polymorphism-internal transcribed spacer (ITS)2 molecular analysis. Eight
species [Anopheles nuneztovari s.l. (92.8%), Anopheles
darlingi (5.1%), Anopheles triannulatus s.l. (1.8%),
Anopheles pseudopunctipennis s.l. (0.2%), Anopheles
punctimacula s.l. (0.2%), Anopheles apicimacula (0.1%),
Anopheles albimanus (0.1%) and Anopheles rangeli
(0.1%)] were identified and species identity was confirmed by ITS2
sequencing. This is the first report of An. albimanus, An.
rangeli and An. apicimacula in Tierradentro. Natural
infectivity with Plasmodium was determined by ELISA. None of the
mosquitoes was infectious for Plasmodium. An. nuneztovari s.l. was
the predominant species and is considered the primary malaria vector; An.
darlingi and An. triannulatus s.l. could serve as
secondary vectors. 相似文献
10.
Two new species Dacne (Xenodacne) tangliangi
sp. n. andDacne (Xenodacne) hujiayaoi
sp. n. are described from China. A key to Chinese species and subspecies of genus Dacne Latreille is provided. 相似文献
11.
Xiaojing Wang Snezana Levic Michael Anne Gratton Karen Jo Doyle Ebenezer N. Yamoah Anthony E. Pegg 《The Journal of biological chemistry》2009,284(2):930-937
Male gyro (Gy) mice, which have an X chromosomal deletion inactivating the
SpmS and Phex genes, were found to be profoundly hearing
impaired. This defect was due to alteration in polyamine content due to the
absence of spermine synthase, the product of the SpmS gene. It was
reversed by breeding the Gy strain with CAG/SpmS mice, a transgenic line that
ubiquitously expresses spermine synthase under the control of a composite
cytomegalovirus-IE enhancer/chicken β-actin promoter. There was an almost
complete loss of the endocochlear potential in the Gy mice, which parallels
the hearing deficiency, and this was also reversed by the production of
spermine from the spermine synthase transgene. Gy mice showed a striking toxic
response to treatment with the ornithine decarboxylase inhibitor
α-difluoromethylornithine (DFMO). Within 2–3 days of exposure to
DFMO in the drinking water, the Gy mice suffered a catastrophic loss of motor
function resulting in death within 5 days. This effect was due to an inability
to maintain normal balance and was also prevented by the transgenic expression
of spermine synthase. DFMO treatment of control mice or Gy-CAG/SpmS had no
effect on balance. The loss of balance in Gy mice treated with DFMO was due to
inhibition of polyamine synthesis because it was prevented by administration
of putrescine. Our results are consistent with a critical role for polyamines
in regulation of Kir channels that maintain the endocochlear potential and
emphasize the importance of normal spermidine:spermine ratio in the hearing
and balance functions of the inner ear.Polyamines are essential for viability in mammals. Knockouts of the genes
for ornithine decarboxylase and S-adenosylmethionine decarboxylase,
which are enzymes needed for the synthesis of putrescine, spermidine, and
spermine, are lethal at early stages of embryonic development
(1,
2). There is convincing
evidence that the formation of hypusine in eIF5A, which requires spermidine as
a precursor, is essential for eukaryotes
(3). However, the function(s)
of spermine is not so well established. Yeast mutants with inactivated
spermine synthase grow at a normal rate
(4). Mammalian cells in culture
also grow normally in the presence of inhibitors of spermine synthase
(5) or after inactivation of
the spermine synthase gene (SpmS)
(6–8).
Inactivation of both of the genes that were originally described as encoding
spermine synthases in plants leads to profound developmental defects
(9–11),
but recently it was discovered that one of these genes actually encodes a
thermospermine synthase, and it appears that the lack of thermospermine may be
responsible for these defects
(12).In contrast, spermine is clearly required for normal development in
mammals. The rare human Snyder-Robinson syndrome is caused by mutations in
SpmS located in the X chromosome that drastically reduces the amount
of spermine synthase (13,
14). This leads to mental
retardation, hypotonia, cerebellar circuitry dysfunction, facial asymmetry,
thin habitus, osteoporosis, and kyphoscoliosis. Male mice, which have an X
chromosomal deletion that includes SpmS and have no detectable
spermine synthase activity, do survive but are only viable on the B6C3H
background
(15–17).
This mouse strain having an X-linked dominant mutation was isolated from a
female offspring of an irradiated mouse and was termed gyro
(Gy)2 based on a
circling behavior pattern in affected males
(18). Subsequent studies have
shown that the Gy mice have a deletion of part of the X chromosome that
inactivates both Phex, a gene that regulates phosphate metabolism,
and SpmS (16,
19). The lack of SpmS
causes a total absence of spermine
(6,
7,
15,
16). Such Gy mice suffer from
hypophosphatemia, have a greatly reduced size, sterility, and neurological
abnormalities, and have a short life span
(6,
16,
18). All of these changes
except the hypophosphatemia are reversed when spermine synthase activity is
restored (20).The original characterization of Gy mice also reported preliminary
indications that these mice had hearing defects lacking the Preyer reflex
(21,
22). This is of particular
interest in the context of polyamine metabolism because a drug,
α-difluoromethylornithine (DFMO, Eflornithine), that targets ornithine
decarboxylase has been shown to cause occasional hearing loss in some patients
(23–26).
Although DFMO was ineffective for cancer treatment, it is an extremely
promising agent for cancer chemoprevention
(27,
28). When combined with
sulindac, DFMO treatment produced a substantial reduction in the recurrence of
colorectal adenomas in a large clinical trial
(27). DFMO is a major drug for
the treatment of African sleeping sickness caused by Trypanosoma
brucei (29,
30). It is also used as a
topically applied cream for treatment of unwanted facial hair in women
(31,
32). DFMO is generally well
tolerated even at high doses, but reversible hearing loss has been reported in
multiple clinical trials (25,
33), and a rarer irreversible
defect has also been reported
(34). These side effects are
not observed at lower doses of DFMO
(26,
27).Ototoxicity has been demonstrated to occur in experimental animals treated
with DFMO including rats (35),
guinea pigs (36), gerbils
(37), and mice
(38). Using
immunohistochemistry, a high level of ornithine decarboxylase was observed in
the inner ear of the rat, with the highest in the organ of Corti and lateral
wall followed by the cochlear nerve
(39). Measurements of
polyamines in the relevant structures are very difficult due to the small
amount of tissue available, but as expected, DFMO treatment reduced polyamine
levels and ornithine decarboxylase activity in the inner ear of the guinea pig
(36). A plausible explanation
for the importance of polyamines in auditory physiology is based on their well
documented role as regulators of potassium channels
(38). The inward rectification
of Kir channels is caused by blockage of the outward current by polyamines
(40–42).
Studies of the cloned mouse cochlear lateral wall-specific Kir4.1 channel
showed that inward rectification was reduced and that there was a marked
reduction in endocochlear potential (EP). It was proposed that DFMO treatment
increases the outward Kir4.1 current, resulting in a drop in EP
(38).In the experiments reported here, we have studied in more detail the role
of polyamines in auditory physiology using Gy mice and crosses of these mice
with transgenic CAG/SpmS mice
(43). These mice express
spermine synthase under the control of a composite cytomegalovirus-IE
enhancer/chicken β-actin promoter, which was designed to provide
ubiquitous expression
(44–46).
Assays of the spermine synthase activity in CAG/SpmS line 8 confirmed that
there was a high level of expression of the transgene in many different organs
and that this level was maintained for at least 1 year
(43). Our studies confirm that
Gy mice are totally deaf and that this condition is reversed by the expression
of the SpmS gene. These changes are due to a virtually complete loss
of the EP in the Gy mice. We have also examined the effect of DFMO on the Gy
mice. Unexpectedly, it was found that these mice show a rapid and profound
toxicity to this drug, leading to death within a few days. Within 5 days of
exposure to DFMO in the drinking water, the DFMO-treated mice suffered a
catastrophic loss of balance due to inner ear effects. This toxicity was also
prevented by the transgenic expression of spermine synthase in the Gy
background. 相似文献
12.
Black, Latinx, and Indigenous people have contracted the SARS-CoV-2 virus and died of COVID-19 at higher rates than White people. Individuals rated public transit, taxis, and ride-hailing as the modes of transportation putting them at greatest risk of COVID-19 infection. Cycling may thus be an attractive alternative for commuting. Amid the increase in bikeshare usage during the early months of the pandemic, bikeshare companies made changes to membership requirements to increase accessibility, targeting especially essential workers. Essential workers in the United States are disproportionately Black and Latinx, underpaid, and reliant on public transit to commute to work. We document changes made by bikeshare companies, including benefits to various groups of essential workers, and we discuss such changes in the context of longstanding racial disparities in bikeshare access. While well intended, the arbitrary delineation in eligibility for such benefits by class of essential workers unwittingly curtailed access for many who may have benefited most. Given that equity in bikeshare is an important tool to improve access to safe transportation, critical changes in the distribution, accessibility, and usability of bikeshare networks is essential. Bikeshare companies, city planners, and policy makers should collaborate with community-based bike advocates to implement changes, as vocalized by those most in need of alternative forms of transportation. 相似文献
13.
Rosanna Pescini Gobert Monique van den Eijnden Cedric Szyndralewiez Catherine Jorand-Lebrun Dominique Swinnen Linfeng Chen Corine Gillieron Fiona Pixley Pierre Juillard Patrick Gerber Caroline Johnson-L��ger Serge Halazy Montserrat Camps Agnes Bombrun Margaret Shipp Pierre-Alain Vitte Vittoria Ardissone Chiara Ferrandi Dominique Perrin Christian Rommel Rob Hooft van Huijsduijnen 《The Journal of biological chemistry》2009,284(17):11385-11395
14.
Stothard JR Sousa-Figueiredo JC Sousa-Figuereido JC Betson M Adriko M Arinaitwe M Rowell C Besiyge F Kabatereine NB 《PLoS neglected tropical diseases》2011,5(1):e938
Background
In Uganda, control of intestinal schistosomiasis with preventive chemotherapy is typically focused towards treatment of school-aged children; the needs of younger children are presently being investigated as in lakeshore communities very young children can be infected. In the context of future epidemiological monitoring, we sought to compare the detection thresholds of available diagnostic tools for Schistosoma mansoni and estimate a likely age of first infection for these children.Methods and Findings
A total of 242 infants and preschool children (134 boys and 108 girls, mean age 2.9 years, minimum 5 months and maximum 5 years) were examined from Bugoigo, a well-known disease endemic village on Lake Albert. Schistosome antigens in urine, eggs in stool and host antibodies to eggs were inspected to reveal a general prevalence of 47.5% (CI95 41.1–54.0%), as ascertained by a positive criterion from at least one diagnostic method. Although children as young as 6 months old could be found infected, the average age of infected children was between 3¼–3¾ years, when diagnostic techniques became broadly congruent.Conclusion
Whilst different assays have particular (dis)advantages, direct detection of eggs in stool was least sensitive having a temporal lag behind antigen and antibody methods. Setting precisely a general age of first infection is problematic but if present Ugandan policies continue, a large proportion of infected children could wait up to 3–4 years before receiving first medication. To better tailor treatment needs for this younger ageclass, we suggest that the circulating cathodic antigen urine dipstick method to be used as an epidemiological indicator. 相似文献15.
Belowground plant responses have received much less attention in climate change experiments than aboveground plant responses, thus hampering a holistic understanding of climate change effects on plants and ecosystems. In addition, responses of plant roots to climate change have mostly been studied in single-factor experiments. In a Danish heathland ecosystem, we investigated both individual and combined effects of elevated CO2, warming and drought on fine root length, net production and standing biomass by the use of minirhizotrons, ingrowth cores and soil coring. Warming increased the net root production from ingrowth cores, but decreased fine root number and length in minirhizotrons, whereas there were no significant main effects of drought. Across all treatments and soil depths, CO2 stimulated both the total fine root length (+44%) and the number of roots observed (+39%), with highest relative increase in root length in the deeper soil layers. Our results suggest that under future climate, plants may allocate considerable resources into roots compared to aboveground biomass. Increased carbon (C) allocation to roots may have a great impact on the overall ecosystem C balance and must be considered in modelling of future ecosystem responses to climate change. To provide models with necessary validation data, more studies are needed to investigate if higher C allocation to roots will lead to long-term C storage in more recalcitrant soil C pools or if this potential increase in soil carbon storage may be offset by increased priming activity and turnover rates for soil organic matter. 相似文献
16.
Penicillin-binding proteins (PBPs) are enzymes responsible for the polymerization of the glycan strand and the cross-linking between glycan chains as well as the target proteins for β-lactam antibiotics. Mutational alterations in PBPs can confer resistance either by reducing binding of the antibiotic to the active site or by evolving a β-lactamase activity that degrades the antibiotic. As no systematic studies have been performed to examine the potential of all PBPs present in one bacterial species to evolve increased resistance against β-lactam antibiotics, we explored the ability of fifteen different defined or putative PBPs in Salmonella enterica to acquire increased resistance against penicillin G. We could after mutagenesis and selection in presence of penicillin G isolate mutants with amino-acid substitutions in the PBPs, FtsI, DacB and DacC (corresponding to PBP3, PBP4 and PBP6) with increased resistance against β-lactam antibiotics. Our results suggest that: (i) most evolved PBPs became ‘generalists” with increased resistance against several different classes of β-lactam antibiotics, (ii) synergistic interactions between mutations conferring antibiotic resistance are common and (iii) the mechanism of resistance of these mutants could be to make the active site more accessible for water allowing hydrolysis or less binding to β-lactam antibiotics. 相似文献
17.
Shahzina Kanwal Yann Fardini Patrick Pagesy Thierry N’Tumba-Byn Cécile Pierre-Eugène Elodie Masson Cornelia Hampe Tarik Issad 《PloS one》2013,8(7)
O-GlcNAcylation (addition of N-acetyl-glucosamine on serine or threonine
residues) is a post-translational modification that regulates stability,
activity or localization of cytosolic and nuclear proteins. O-linked
N-acetylgluocosmaine transferase (OGT) uses UDP-GlcNAc, produced in the
hexosamine biosynthetic pathway to O-GlcNacylate proteins. Removal of O-GlcNAc
from proteins is catalyzed by the β-N-Acetylglucosaminidase (OGA). Recent
evidences suggest that O-GlcNAcylation may affect the growth of cancer cells.
However, the consequences of O-GlcNAcylation on anti-cancer therapy have not
been evaluated. In this work, we studied the effects of O-GlcNAcylation on
tamoxifen-induced cell death in the breast cancer-derived MCF-7 cells.
Treatments that increase O-GlcNAcylation (PUGNAc and/or glucosoamine) protected
MCF-7 cells from death induced by tamoxifen. In contrast, inhibition of OGT
expression by siRNA potentiated the effect of tamoxifen on cell death. Since the
PI-3 kinase/Akt pathway is a major regulator of cell survival, we used BRET to
evaluate the effect of PUGNAc+glucosamine on PIP3 production. We
observed that these treatments stimulated PIP3 production in MCF-7
cells. This effect was associated with an increase in Akt phosphorylation.
However, the PI-3 kinase inhibitor , which abolished the effect of
PUGNAc+glucosamine on Akt phosphorylation, did not impair the protective effects
of PUGNAc+glucosamine against tamoxifen-induced cell death. These results
suggest that the protective effects of O-GlcNAcylation are independent of the
PI-3 kinase/Akt pathway. As tamoxifen sensitivity depends on the estrogen
receptor (ERα) expression level, we evaluated the effect of PUGNAc+glucosamine
on the expression of this receptor. We observed that O-GlcNAcylation-inducing
treatment significantly reduced the expression of ERα mRNA and protein,
suggesting a potential mechanism for the decreased tamoxifen sensitivity induced
by these treatments. Therefore, our results suggest that inhibition of
O-GlcNAcylation may constitute an interesting approach to improve the
sensitivity of breast cancer to anti-estrogen therapy. LY294002相似文献
18.
The species of Adialytus Förster in Iran are taxonomically studied and new data on distribution and host associations are presented. The existence of a species complex, in the case of Adialytus ambiguus (Haliday), and the morphological variability in commonly used taxonomic characters has been discussed. In total, four valid species belonging to the genus Adialytus including Adialytus ambiguus (Haliday), Adialytus salicaphis (Fitch), Adialytus thelaxis (Starý) and Adialytus veronicaecola (Starý) have been identified and recorded from Iran. Also, we recognized two additional phenotypes: “Adialytus arvicola” (Starý) and “Adialytus cf. ambiguus” (Haliday). These phenotypes and Adialytus veronicaecola are newly recorded from Iran in association with Sipha and Aphis species, respectively. An illustrated key for identification of the species and two variable phenotypes is presented. 相似文献
19.
Kenshi Yamasaki Jun Muto Kristen R. Taylor Anna L. Cogen David Audish John Bertin Ethan P. Grant Anthony J. Coyle Amirhossein Misaghi Hal M. Hoffman Richard L. Gallo 《The Journal of biological chemistry》2009,284(19):12762-12771
Inflammation under sterile conditions is a key event in autoimmunity and
following trauma. Hyaluronan, a glycosaminoglycan released from the
extracellular matrix after injury, acts as an endogenous signal of trauma and
can trigger chemokine release in injured tissue. Here, we investigated whether
NLRP3/cryopyrin, a component of the inflammasome, participates in the
inflammatory response to injury or the cytokine response to hyaluronan. Mice
with a targeted deletion in cryopyrin showed a normal increase in Cxcl2 in
response to sterile injuries but had decreased inflammation and release of
interleukin-1β (IL-1β). Similarly, the addition of hyaluronan to
macrophages derived from cryopyrin-deficient mice increased release of Cxcl2
but did not increase IL-1β release. To define the mechanism of
hyaluronan-mediated activation of cryopyrin, elements of the hyaluronan
recognition process were studied in detail. IL-1β release was inhibited
in peritoneal macrophages derived from CD44-deficient mice, in an MH-S
macrophage cell line treated with antibodies to CD44, or by inhibitors of
lysosome function. The requirement for CD44 binding and hyaluronan
internalization could be bypassed by intracellular administration of
hyaluronan oligosaccharides (10–18-mer) in lipopolysaccharide-primed
macrophages. Therefore, the action of CD44 and subsequent hyaluronan
catabolism trigger the intracellular cryopyrin → IL-1β pathway.
These findings support the hypothesis that hyaluronan works through IL-1β
and the cryopyrin system to signal sterile inflammation.Inflammation, as defined by changes in vascular permeability and leukocyte
recruitment, is an essential step for the control of microbial invasion.
Specific microbial products trigger this process through a diverse array of
innate immune pattern recognition receptors. However, an inflammatory response
independent of infection is also an important process for maintenance of
biological homeostasis. For example, normal wound healing requires a
controlled inflammatory response to enable the recruitment of monocytes and
the release of growth factors required for repair. This response can occur in
the absence of microbial stimuli. Furthermore, inflammation and the release of
proinflammatory mediators is also associated with many diseases such as
rheumatoid arthritis and Crohn disease
(1). These diseases are not
well understood in terms of their triggers but rather are described by the
subsequent release of proinflammatory mediators. Identification of the
triggers of sterile inflammation represents an important goal with immediate
diagnostic and therapeutic significance.Recent work has begun to elucidate pathways of inflammation that occur in
the absence of microbial stimuli. Stress signals such as heat-shock proteins,
intracellular components of necrotic cells not normally seen by immune cells,
and components of the extracellular matrix have all been implicated as
endogenous triggers of injury
(2–4).
Among this group is the glycosaminoglycan hyaluronan
(HA),6 an important
structural component of the extracellular matrix that is also a common
component of bacterial surfaces. HA is synthesized at the cell surface and
typically exists as a high molecular mass polymer greater than 106
Da and composed of repeating disaccharide units of
N-acetylglucosamine and glucuronic acid
(5,
6). Unlike other
glycosaminoglycans such as heparan sulfate or chondroitin sulfates that encode
specific activity by use of a diverse disaccharide sequence, HA is not
sulfated or epimerized, and only changes in HA size, concentration, and
location affect function.We have previously developed murine models of sterile injury to identify
the innate elements that recognize and mediate sterile inflammation
(7). Our results demonstrated
that (a) the initiation of a sterile intrinsic inflammatory process
is dependent on TLR4 activation, (b) sterile injury induces HA
accumulation at the injured site, and (c) sterile intrinsic
inflammation resembles signaling events that are activated by HA. Furthermore,
we have defined a novel alternative recognition complex for HA that involves
TLR4, MD-2, and CD44 (7). Taken
together with other work associating HA and innate pattern recognition
(4,
8–10),
these observations have provided new insight into mechanisms responsible for
sterile inflammation.Recently, the NLR (nucleotide-binding domain and leucine rich
repeat-containing) family has been extensively analyzed as a group of
intracellular pattern recognition receptors
(11). NLRs have a leucine-rich
repeat that recognizes pathogen-associated molecular patterns including
bacterial cell wall components and viral nucleic acids. NOD2 and NLR family,
pyrin containing 3 (NLRP3)/cryopyrin are two of the best
characterized NLRs. NOD2 recognizes the bacterial peptidoglycan-derived
molecule muramyl dipeptide and activates the NF-κB pathway to induce
inflammatory responses (12).
Mutations of the NOD2 gene were identified in individuals with
chronic inflammatory disorders such as Crohn disease
(13,
14) and Blau syndrome
(15). Mouse knockin mutants of
NOD2, which have the same mutation in NOD2 as human patients
with Crohn disease, showed elevated proinflammatory cytokines following
muramyl dipeptide challenge or dextran sodium sulfate-induced bowel
inflammation (16).
NLRP3, also known as cyropyrin, CIAS1, NALP3, PYPAF1, forms
an “inflammasome” with ASC (apoptosis-associated speck-like
protein containing a CARD) and caspase-1 to convert pro-IL-1β to active
IL-1β (17). Mutations in
NLRP3 were identified in individuals with familial cold
autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal onset
multisystem inflammatory disease
(18–20).
These individuals have recurrent or chronic inflammatory symptoms, including
fever, arthritis, and a urticaria-like eruption characterized by neutrophilic
infiltration. In FCAS, symptoms can be elicited by cold provocation by a
mechanism that appears to be mediated through the skin
(15,
21).Because disorders associated with mutations in NLRP3 are examples
of inflammation under sterile conditions and HA has been shown to be a trigger
of sterile inflammation, we sought to further understand the mechanism of the
response to HA by examining the role of cryopyrin during injury and after
exposure to HA. Our results show that cryopyrin and IL-1β are integral to
sterile inflammation and the response to HA. These observations provide new
insight into the function of HA as a “danger signal” of
injury. 相似文献