Signal transducer and activator of transcription 3 (Stat3) is known to induce cell proliferation and inflammation by regulating gene transcription. Recent studies showed that Stat3 modulates nociceptive transmission by reducing spinal astrocyte proliferation. However, it is unclear whether Stat3 also contributes to the modulation of nociceptive transmission by regulating inflammatory response in spinal astrocytes. This study aimed at investigating the role of Stat3 on neuroinflammation during development of pain in rats after intrathecal injection of lipopolysaccharide (LPS).
Stat3 specific siRNA oligo and synthetic selective inhibitor (Stattic) were applied to block the activity of Stat3 in primary astrocytes or rat spinal cord, respectively. LPS was used to induce the expression of proinflammatory genes in all studies. Immunofluorescence staining of cells and slices of spinal cord was performed to monitor Stat3 activation. The impact of Stat3 inhibition on proinflammatory genes expression was determined by cytokine antibody array, enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mechanical allodynia, as determined by the threshold pressure that could induce hind paw withdrawal after application of standardized von Frey filaments, was used to detect the effects of Stat3 inhibition after pain development with intrathecal LPS injection.
Intrathecal injection of LPS activated Stat3 in reactive spinal astrocytes. Blockade of Stat3 activity attenuated mechanical allodynia significantly and was correlated with a lower number of reactive astrocytes in the spinal dorsal horn. In vitro study demonstrated that Stat3 modulated inflammatory response in primary astrocytes by transcriptional regulation of chemokine expression including Cx3cl1, Cxcl5, Cxcl10 and Ccl20. Similarly, inhibition of Stat3 reversed the expression of these chemokines in the spinal dorsal horn.
Stat3 acted as a transcriptional regulator of reactive astrocytes by modulating chemokine expression. Stat3 regulated inflammatory response in astrocytes and contributed to pain modulation. Blockade of Stat3 represents a new target for pain control.
The drawbacks of estrogen restrict the clinical use of hormone replacement therapy, and it would be most helpful to explore new estrogenic substances that could prevent bone loss and be free from any adverse effects. We synthesized a new compound named bone-seeking estrogen (SE2) by combining 17β-estradiol (E2) with iminodiacetic acid through the Mannich reaction. E2 and SE2 were labeled with isotope 3H, and the tissue distribution tests of E2-3H and SE2-3H were analyzed by the radioactivity. The specific nuclear binding of E2 and SE2 in osteoblasts was measured. SE2 exhibited significantly greater affinity for bone but lower affinity for ovary and uterus than did E2, and SE2 maintained a high affinity for the estrogen receptor alpha similar to that of E2. SE2 administration did not induce uterine hypertrophy. Body weight increase was significantly suppressed by treatment with E2 but not by SE2 after ovariectomy (OVX). SE2 decreased bone turnover as E2 after OVX detected by serum biochemical markers. Bone histology and micro-CT analysis revealed that SE2 administration, similar to E2, could improve bone mass and trabecular architecture after OVX. Biomechanical analyses showed that SE2 treatment effectively increased mechanical properties after OVX. The results suggested that SE2 was effective in preventing OVX-induced bone loss and exhibited few side effects on body weight and uterine hypertrophy, which was beneficial in reducing the adverse effects caused by E2. SE2 may be a better choice than E2 for the prevention of postmenopausal osteoporosis.
Bone-seeking estrogen; Estrogen; Postmenopausal osteoporosis; Side effects; Trabecular architecture
FRAT1 positively regulates the Wnt/β-catenin signaling pathway by inhibiting GSK-3-mediated phosphorylation of β-catenin. It was originally characterized as a protein frequently rearranged in advanced T cell lymphoma, but has recently also been identified as a proto-oncogene involved in tumorigenesis. Our previous studies showed that FRAT1 was dramatically overexpressed in gliomas and its expression level was significantly increased along with clinicopathological grades.
In the current study, we used RT-PCR and Western blotting to assess the mRNA and protein levels of FRAT1 in three glioma cell lines. In addition, to evaluate its functional role in gliomas, we examined the effects of FRAT1 knockdown on proliferation, migration and invasion in vitro and tumor growth in vivo using glioblastoma U251 cells and RNAi.
FRAT1 was highly expressed in all three glioma cell lines. RNAi-mediated down-regulation of endogenous FRAT1 in human glioblastoma U251 cells resulted in suppression of cell proliferation, arrest of cell cycle, inhibition of cell migration and invasion in vitro. Moreover, FRAT1 depletion significantly impaired tumor xenograft growth in nude mice.
Our results highlight the potential role of FRAT1 in tumorigenesis and progression of glioblastoma. These findings provide a biological basis for FRAT1 as a potential molecular marker for improved pathological grading and as a novel candidate therapeutic target for glioblastoma management.
The risk of large, devastating tsunamis in the South China Sea and its surrounding coastal region is commonly underestimated or unrecognized due to the difficulty of differentiating tsunami from storm deposits. As a consequence, few convincing records have documented tsunami deposits in this region. Here we report preliminary evidence from Xisha Islands in the South China Sea for a large tsunami around AD 1024. Sand layers in lake sediment cores and their geochemical characteristics indicate a sudden deposition event around AD 1024, temporally consistent with a written record of a disastrous event characterized by high waves in AD 1076. Heavy coral and shell fossils, which are older than AD 1024, deposited more than 200 meters into the island, further support the occurrence of a high-energy event such as a tsunami or an unusually large storm. Our results underscore the importance of acknowledging and understanding the tsunami hazard in this area.
Advanced glycation end products (AGEs), formed from proteins and peptides by nonenzymatic glycoxidation after contact with aldose sugars, have been implicated in the pathogenesis of age-related cardiac and vascular dysfunction. Our previous study demonstrated significantly elevated levels of AGE and the receptor for AGE (RAGE) in human abdominal aortic aneurysm (AAA) tissues. Inhibition of AGE signaling by targeted gene deletion of RAGE markedly reduced the development of aneurysm in a mouse model of AAA. We also showed that AGE may stimulate aneurysm formation by promoting metalloproteinase (MMP)-9 expression. In this study, we investigated the molecular mechanism underlying this novel function of AGE.
The murine macrophage cell line RAW 264.7 was pretreated with AGE, TGF-β, and MAPK inhibitors. The protein was collected for Western blot analysis. Culture supernatants were collected to determine MMP-9 activity by gelatin zymography.
We found that AGE induced the production of MMP-9 in macrophages in a dose-dependent manner. This induction of MMP-9 was markedly diminished by pretreatment with TGF-β. To delineate the underlying molecular mechanism, we showed that AGE increased phosphorylation of p44/42 ERK, p38, JNK, and PI3K in macrophages. Moreover, AGE induced active p65 subunit of NF-κB. Inhibition of ERK (UO126) or p38 (SB203580), but not PI3K (LY294002 or wortmannin), blocked AGE-induced MMP-9 expression. In contrast, inhibition of JNK (SP-600125) significantly enhanced the stimulatory effect of AGE on MMP-9. Furthermore, TGF-β suppressed AGE-induced expression of the active p65 subunit of NF-κB.
Our data indicate that AGE induces MMP-9 through activation of ERK, p38 mitogen-activated protein and NF-κB, a pathway that is antagonized by TGF-β. This finding in conjunction with previously reported AGE functions in inflammation suggests that anti-AGE therapies could be effective in the prevention of human AAA development and progression.
MAP kinases; abdominal aortic aneurysm; signaling; TGF-beta
The clinical occurrence of non-intervention-related vascular spasm following coronary stenting is rare. In the present study, 2 cases are reported. One patient developed continuous spasms in the proximal segment of the left anterior descending (LAD) and left circumflex (LCX) arteries following LAD artery stenting. The second patient developed an intense spasm in the right coronary artery (RCA) following LAD artery stenting. Clinical course and prognosis are dangerous. The main treatment for this condition is a combination of repeated injections of nitroglycerin into the coronary artery and the administration of calcium antagonists. In the clinic, intervention-related vascular spasms are common in percutaneous coronary intervention (PCI) due to the mechanical stimulation caused by balloon dilatation or stent expansion. Injections of a vasodilator into the coronary artery are able to mitigate the spasms and the consequent prognosis is good.
vascular intense spasm; stent implantation; coronary artery
Traditional Chinese medicine (TCM) has been demonstrated to have potent cytotoxic activity against certain malignant tumors. Ionizing radiation (IR) is one of the most effective methods used in the clinical treatment of cancer. The drawback of a single formula is that it limits the treatment efficacy for cancer, while comprehensive strategies require additional theoretical support. However, a combination of different antitumor treatment modalities is advantageous in restricting the non-specific toxicity often observed with an extremely high dose of a single regimen. The induction of apoptotic cell death is a significant process in tumor cells following radiotherapy or chemotherapy, and resistance to these treatments has been linked to a low propensity for apoptosis. Autophagy is a response of cancer cells to IR or chemotherapy, and involves the prominent formation of autophagic vacuoles in the cytoplasm. In this review, the synergistic effects of TCM and radiotherapy are summarized and the underlying mechanisms are illustrated, providing new therapeutic strategies for cancer.
traditional Chinese medicine; apoptosis; autophagy; radiosensitization; cancer treatment
The purpose of this 42-day study was to investigate the effects of methionine (Met) deficiency on immune function by determining the relative weight, morphological and ultrastructural changes of bursae of Fabricius, cell cycle, and apoptosis of bursa cells. One hundred and twenty one-day-old avian broilers were randomly divided into two groups and fed on a control diet (starter diet, Met 0.50%; grower diet, Met 0.40%) and Met-deficient diet (starter diet, Met 0.26%; grower diet, Met 0.28%) for six weeks. The relative weight of bursae was decreased with Met deficiency when compared to that of the control group. Lesions were also observed in the Met-deficient group. Histopathologically, the numbers of lymphocytes in the follicles were decreased. Ultrastructurally, the mitochondria of lymphocytes were swollen in the Met-deficient group. As measured by flow cytometry, bursal cells in the G0G1 phase were significantly higher (P < 0.01), and bursal cells in the S, G2M phases and proliferating index were obviously lower (P < 0.01) with Met deficiency than in the control group. Moreover, the percentage of apoptotic cells in the bursae were significantly increased in Met-deficient birds (P < 0.01). It was concluded that Met deficiency restrained the development of the bursae of Fabricius and affected the humoral immunity of the chickens.
broilers; bursa of Fabricius; flow cytometry (FCM); methionine deficiency; pathology
To determine risk for avian influenza virus infection, we conducted serologic surveillance for H5 and H9 subtypes among poultry workers in Beijing, China, 2009–2010, and assessed workers’ understanding of avian influenza. We found that poultry workers had considerable risk for infection with H9 subtypes. Increasing their knowledge could prevent future infections.
Avian influenza; influenza; viruses; poultry workers; serologic survey; knowledge; attitudes; practices
Ca2+ channels and calmodulin are two prominent signaling hubs1 that synergistically impact functions as diverse as cardiac excitability2, synaptic plasticity3, and gene transcription4. It is thereby fitting that these hubs are in some sense coordinated, as the opening of CaV1-2 Ca2+ channels are regulated by a single calmodulin (CaM) constitutively complexed with channels5. The Ca2+-free form of CaM (apoCaM) is already preassociated with the IQ domain on the channel carboxy terminus, and subsequent Ca2+ binding to this ‘resident’ CaM drives conformational changes that then trigger regulation of channel opening6. Another potential avenue for channel-CaM coordination could arise from the absence of Ca2+ regulation in channels lacking a preassociated CaM6,7. Natural fluctuations in CaM levels might then influence the fraction of regulatable channels, and thereby the overall strength of Ca2+ feedback. However, the prevailing view has been that the ultra-strong affinity of channels for apoCaM ensures their saturation with CaM8, yielding a significant form of concentration independence between Ca2+ channels and CaM. Here, we reveal significant exceptions to this autonomy, by combining electrophysiology to characterize channel regulation, with optical FRET sensor determination of free apoCaM concentration in live cells9. This approach translates quantitative CaM biochemistry from the traditional test-tube context, into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of CaV1.3 and CaV1.4 channels include a distal carboxy tail10-12 that resembles an enzyme competitive inhibitor, which retunes channel affinity for apoCaM so that natural CaM variations affect the strength of Ca2+ feedback modulation. Given the ubiquity of these channels13,14, the connection between ambient CaM levels and Ca2+ entry via channels is broadly significant for Ca2+ homeostasis. Strategies like ours promise key advances for the in situ analysis of signaling molecules resistant to in vitro reconstitution, such as Ca2+ channels.
Autophagy has attracted attentions as a novel mechanism for tumor development. In this study Human ovarian carcinoma cell line SKOV3 and multidrug-resistant phenotype SKVCR cells were used and the roles of autophagy in radiation-induced cell death were analyzed.
Methods and materials
Cell viability was examined by colony formation and cell counting kit-8 (CCK-8) assay, 3MA and ZVAD were used to block autophagy and apoptosis, respectively. Quantitative real-time PCR was used to detect mRNA level and Western blot was used to detect protein expression, monodansylcadaverine (MDC) staining and flow cytometery were used for autophagy, apoptosis and cell cycle dynamics, respectively.
(1) The radiosensitivity exhibited differently in SKOV3 and SKVCR cells (SKOV3: D0=3.37, SKVCR: D0= 4.18); compared with SKOV3 the constitutive expression of MAPLC3 in SKVCR was higher, but no change of Caspase-3 and cleaved Caspase-3. (2) The ionizing radiation (IR)- induced apoptosis and autophagy were significant in both cells (P<0.05); inhibition of apoptosis with ZVAD showed no impact on survival of SKOV3 and SKVCR cells after radiation, while inhibition of autophagy significantly decreased viability in SKVCR cells, for SKVO3 cells only low level of radiation (2 Gy and 4 Gy) could decrease the viability(P<0.05). (3) ZVAD inhibited apoptosis and autophagy in both cells, 3MA inhibit apoptosis in SKOV3, and promote apoptosis in SKVCR, together with inhibition of autophagy. (4) G2/M arrest was induced by radiation in both cells; the accumulation of G2/M was more significant in SKOV3, 3MA attenuated the radiation-induced S phase delay in SKVCR.
IR-induced autophagy provides a self-protective mechanism against radiotherapy in SKVCR cells, the use of autophagy inhibitor, 3MA, increases the killing effects of radiation by inhibiting autophagy and radiation- induced S phase delay, also by the increase of apoptosis, which suggests a better therapeutic strategy in drug- resistant SKVCR ovarian cancer cells.
Autophagy; Radiosensitivity; Multidrug resistance; Ovarian cancer; Apoptosis
YN strain shows severe pathogenicity in chickens.
A virulent avian infectious bronchitis virus (IBV) was isolated from 30-day-old broiler chickens that exhibited respiratory symptoms, nephropathologic lesions, and a high proportion of deaths in the People’s Republic of China during 2005. The strain, designated YN, was genetically and pathologically characterized. Phylogenetic analysis showed that YN and most of the previously characterized IBV isolates found in China were phylogenetically classified into 2 main genetic clusters. The YN isolate caused severe lesions and resulted in deaths of 65% in experimental infections of 30-day-old specific-pathogen–free chickens. Tracheal and severe kidney lesions developed in all infected birds, confirming the ability of YN strain to induce both respiratory and renal disease. IBV antigens were detected by immunohistochemical analysis in the trachea, lung, kidney, and bursa, consistent with histopathologic observations, virus isolation, and reverse transcription PCR detection. We showed that YN IBV exhibits severe pathogenicity in chickens, and that similar viruses are prevalent in China.
Avian infectious bronchitis virus; virulence; pathogenicity; tissue tropism; phylogenetic analysis; viruses; People’s Republic of China; chickens
Ni2O3- γ-Fe2O3 composite nanoparticles coated with a layer of 2FeCl3·5H2O can be prepared by co-precipitation and processing in FeCl2 solution. Using vibrating sample magnetometer (VSM), X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) diffraction techniques, the dependence of the preparation on the concentration of the FeCl2 treatment solution is revealed.
The magnetization of the as-prepared products varied non-monotonically as the FeCl2 concentration increased from 0.020 M to 1.000 M. The Experimental results show that for the composite nanoparticles, the size of the γ-Fe2O3 phase is constant at about 8 nm, the Ni2O3 phase decreased and the 2FeCl3·5H2O phase increased with increasing concentration of FeCl2 solution. The magnetization of the as-prepared products mainly results from the γ-Fe2O3 core, and the competition between the reduction of the Ni2O3 phase with the increase of the 2FeCl3·5H2O phase resulted in the apparent magnetization varying non-monotonically.
When the concentration of FeCl2 treatment solution did not exceed 0.100 M, the products are spherical nanoparticles of size about 11 nm; their magnetization increased monotonically with increasing the concentration of FeCl2 solution due to the decreasing proportion of Ni2O3 phase.
Composite; Nanoparticles; FeCl2 solution; Concentration
Epitope-based vaccination might play an important role in the protective immunity against Japanese encephalitis virus (JEV) infection. The purpose of the study is to evaluate the immune characteristics of recombinant MVA carrying multi-epitope gene of JEV (rMVA-mep). The synthetic gene containing critical epitopes (B-cell, CTL and Th) of JEV was cloned into the eukaryotic expression vector pGEM-K1L, and the rMVA-mep was prepared. BALB/c mice were immunized with different dosages of purified rMVA-mep and the immune responses were determined in the form of protective response against JEV, antibodies titers (IgG1 and IgG2a), spleen cell lymphocyte proliferation, and the levels of interferon-γ and interleukin-4 cytokines. The results showed that live rMVA-mep elicited strongly immune responses in dose-dependent manner, and the highest level of immune responses was observed from the groups immunized with 107 TCID50 rMVA-mep among the experimental three concentrations. There were almost no difference of cytokines and neutralizing antibody titers among 107 TCID50 rMVA-mep, recombinant ED3 and inactivated JEV vaccine. It was noteworthy that rMVA-mep vaccination potentiates the Th1 and Th2-type immune responses in dose-dependent manner, and was sufficient to protect the mice survival against lethal JEV challenge. These findings demonstrated that rMVA-mep can produce adequate humoral and cellular immune responses, and protection in mice, which suggested that rMVA-mep might be an attractive candidate vaccine for preventing JEV infection.
Japanese encephalitis virus; rMVA-mep; Immune response; Protection response
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
Although previous research has shown that positive affect (PA) and negative affect (NA) modulate attentional functioning in distinct ways, few studies have considered whether the links between affect and attentional functioning may vary as a function of age. Using the Attention Network Test (Fan et al., 2002), we tested whether participants’ current state of PA and NA influenced distinct attentional functions (i.e., alerting, orienting, and executive attention) and how the relationships between affective states and attentional functioning differ in younger (18–25 years) and older (60–85 years) age groups. While there were age differences in alerting efficiency, these age differences were mediated by PA, indicating that the higher state PA found in older adults may contribute to age differences in alerting. Furthermore, age group moderated the relationship between PA and orienting as well as NA and orienting. That is, higher levels of PA and lower levels of NA were associated with enhanced orienting efficiency in older adults. Neither PA nor NA had any influence on executive attention. The current results suggest that PA and NA may influence attentional functioning in distinct ways, but that these patterns may depend on age groups.
affect; age differences; attentional networks; individual differences; attention
Deoxycytidine kinase (dCK) is a rate limiting enzyme critical for phosphorylation of endogenous deoxynucleosides for DNA synthesis and exogenous nucleoside analogues for anticancer and antiviral drug actions. dCK is activated in response to DNA damage; however, how it functions in the DNA damage response is largely unknown. Here, we report that dCK is required for the G2/M checkpoint in response to DNA damage induced by ionizing radiation (IR). We demonstrate that the ataxia–telangiectasia-mutated (ATM) kinase phosphorylates dCK on Serine 74 to activate it in response to DNA damage. We further demonstrate that Serine 74 phosphorylation is required for initiation of the G2/M checkpoint. Using mass spectrometry, we identified a protein complex associated with dCK in response to DNA damage. We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. Together, our results highlight the novel function of dCK and provide molecular insights into the G2/M checkpoint regulation in response to DNA damage.
Hemorrhagic fever with renal syndrome (HFRS) is an important infectious disease caused by different species of hantaviruses. As a rodent-borne disease with a seasonal distribution, external environmental factors including climate factors may play a significant role in its transmission. The city of Shenyang is one of the most seriously endemic areas for HFRS. Here, we characterized the dynamic temporal trend of HFRS, and identified climate-related risk factors and their roles in HFRS transmission in Shenyang, China.
The annual and monthly cumulative numbers of HFRS cases from 2004 to 2009 were calculated and plotted to show the annual and seasonal fluctuation in Shenyang. Cross-correlation and autocorrelation analyses were performed to detect the lagged effect of climate factors on HFRS transmission and the autocorrelation of monthly HFRS cases. Principal component analysis was constructed by using climate data from 2004 to 2009 to extract principal components of climate factors to reduce co-linearity. The extracted principal components and autocorrelation terms of monthly HFRS cases were added into a multiple regression model called principal components regression model (PCR) to quantify the relationship between climate factors, autocorrelation terms and transmission of HFRS. The PCR model was compared to a general multiple regression model conducted only with climate factors as independent variables.
A distinctly declining temporal trend of annual HFRS incidence was identified. HFRS cases were reported every month, and the two peak periods occurred in spring (March to May) and winter (November to January), during which, nearly 75% of the HFRS cases were reported. Three principal components were extracted with a cumulative contribution rate of 86.06%. Component 1 represented MinRH0, MT1, RH1, and MWV1; component 2 represented RH2, MaxT3, and MAP3; and component 3 represented MaxT2, MAP2, and MWV2. The PCR model was composed of three principal components and two autocorrelation terms. The association between HFRS epidemics and climate factors was better explained in the PCR model (F = 446.452, P < 0.001, adjusted R2 = 0.75) than in the general multiple regression model (F = 223.670, P < 0.000, adjusted R2 = 0.51).
The temporal distribution of HFRS in Shenyang varied in different years with a distinctly declining trend. The monthly trends of HFRS were significantly associated with local temperature, relative humidity, precipitation, air pressure, and wind velocity of the different previous months. The model conducted in this study will make HFRS surveillance simpler and the control of HFRS more targeted in Shenyang.
The pyrolytic kinetics of Phragmites australis was investigated using thermogravimetric analysis (TGA) method with linear temperature programming process under an inert atmosphere. Kinetic expressions for the degradation rate in devolatilization and combustion steps have been obtained for P. australis with Dollimore method. The values of apparent activation energy, the most probable mechanism functions, and the corresponding preexponential factor were determined. The results show that the model agrees well with the experimental data and provide useful information for the design of pyrolytic processing system using P. australis as feedstock to produce biofuel.
China is a country that is most seriously affected by hemorrhagic fever with renal syndrome (HFRS) with 90% of HFRS cases reported globally. At present, HFRS is getting worse with increasing cases and natural foci in China. Therefore, there is an urgent need for monitoring and predicting HFRS incidence to make the control of HFRS more effective. In this study, we applied a stochastic autoregressive integrated moving average (ARIMA) model with the objective of monitoring and short-term forecasting HFRS incidence in China.
Chinese HFRS data from 1975 to 2008 were used to fit ARIMA model. Akaike Information Criterion (AIC) and Ljung-Box test were used to evaluate the constructed models. Subsequently, the fitted ARIMA model was applied to obtain the fitted HFRS incidence from 1978 to 2008 and contrast with corresponding observed values. To assess the validity of the proposed model, the mean absolute percentage error (MAPE) between the observed and fitted HFRS incidence (1978-2008) was calculated. Finally, the fitted ARIMA model was used to forecast the incidence of HFRS of the years 2009 to 2011. All analyses were performed using SAS9.1 with a significant level of p < 0.05.
The goodness-of-fit test of the optimum ARIMA (0,3,1) model showed non-significant autocorrelations in the residuals of the model (Ljung-Box Q statistic = 5.95,P = 0.3113). The fitted values made by ARIMA (0,3,1) model for years 1978-2008 closely followed the observed values for the same years, with a mean absolute percentage error (MAPE) of 12.20%. The forecast values from 2009 to 2011 were 0.69, 0.86, and 1.21per 100,000 population, respectively.
ARIMA models applied to historical HFRS incidence data are an important tool for HFRS surveillance in China. This study shows that accurate forecasting of the HFRS incidence is possible using an ARIMA model. If predicted values from this study are accurate, China can expect a rise in HFRS incidence.
This review serial outlines practical and scientifically-based approaches to conducting contemporary drug metabolism studies considered good practice for drug development and regulatory filing. The present part addresses analytical methods used in the drug metabolism studies and evaluates advantages and disadvantages of these methods as well as the related sample preparations. The methods described here cover from conventional radioactive labeling of drugs, which includes selection of a proper radioisotope, its labeling position, and modern radio-pharmacokinetics employed in microdosing by using a radionuclide to visualize drug distribution in vivo, to currently widely-used liquid chromatography (LC) in conjunction with mass spectrometry (MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) for quantitative detection of metabolites and characterization of their structures. Although the analytical tools have progressed sufficiently to allow determination of metabolites, proper in vitro models and in vivo studies have to be carefully designed in order to understand drug metabolism. Points for consideration when conducting in vivo drug metabolism studies include interspecies differences in systemic exposure and metabolism pathways, identification of the major metabolites and unique human metabolites that become the regulatory focus, local metabolism in addition to liver metabolism, time points for sampling, and synthesis of the authentic metabolites to confirm their formation. The next part of this serial article will focus on in vitro drug metabolism studies.
Analytical techniques; drug regulations; in vivo drug metabolism; interspecies differences; major drug metabolites; metabolite identification; radiolabeled drug; pharmacokinetics
In vitro drug metabolism studies, which are inexpensive and readily carried out, serve as an adequate screening mechanism to characterize drug metabolites, elucidate their pathways, and make suggestions for further in vivo testing. This publication is a sequel to part I in a series and aims at providing a general framework to guide designs and protocols of the in vitro drug metabolism studies considered good practice in an efficient manner such that it would help researchers avoid common pitfalls and misleading results. The in vitro models include hepatic and non-hepatic microsomes, cDNA-expressed recombinant human CYPs expressed in insect cells or human B lymphoblastoid, chemical P450 inhibitors, S9 fraction, hepatocytes and liver slices. Important conditions for conducting the in vitro drug metabolism studies using these models are stated, including relevant concentrations of enzymes, co-factors, inhibitors and test drugs; time of incubation and sampling in order to establish kinetics of reactions; appropriate control settings, buffer selection and method validation. Separate in vitro data should be logically integrated to explain results from animal and human studies and to provide insights into the nature and consequences of in vivo drug metabolism. This article offers technical information and data and addresses scientific rationales and practical skills related to in vitro evaluation of drug metabolism to meet regulatory requirements for drug development.
Cytochrome P450 enzymes; drug regulations; hepatocytes; in vitro drug metabolism; microsomes
The relative importance of north–south migrations of the intertropical convergence zone (ITCZ) versus El Niño-Southern Oscillation and its associated Pacific Walker Circulation (PWC) variability for past hydrological change in the western tropical Pacific is unclear. Here we show that north–south ITCZ migration was not the only mechanism of tropical Pacific hydrologic variability during the last millennium, and that PWC variability profoundly influenced tropical Pacific hydrology. We present hydrological reconstructions from Cattle Pond, Dongdao Island of the South China Sea, where multi-decadal rainfall and downcore grain size variations are correlated to the Southern Oscillation Index during the instrumental era. Our downcore grain size reconstructions indicate that this site received less precipitation during relatively warm periods, AD 1000–1400 and AD 1850–2000, compared with the cool period (AD 1400–1850). Including our new reconstructions in a synthesis of tropical Pacific records results in a spatial pattern of hydrologic variability that implicates the PWC.
Tropical Pacific hydrology affects the global climate through the strength of the Pacific Walker Circulation. Yan et al. reconstruct variations in the Pacific Walker Circulation in the South China Sea over the last millennium and find that less precipitation fell during warmer and more rainfall during cool periods.