Mechanical data corrections for triaxial compression testing at high pressures and high temperatures with a Paterson gas-medium mechanical testing apparatus.

Although restricted by a limited range of strain, the triaxial compression test is a mature and common technique for investigating the rheological properties of rock materials at high pressures and high temperatures, especially when establishing the constitutive equations for various flow laws. The Paterson gas-medium high-pressure and high-temperature mechanical testing apparatus (Paterson apparatus) is the best apparatus for triaxial compression testing due to its high stress resolution. However, to derive accurate mechanical information from the raw data recorded by the Paterson apparatus, some technical issues should be addressed, including the simultaneous distortion of the apparatus, the load force supported by the jacketing tube, and the change in the cross-sectional area of the specimen. In this paper, we introduce correction methods corresponding to these three technical issues for triaxial compression on a Paterson apparatus equipped with an internal load cell to significantly reduce experimental errors so that high-precision mechanical data for establishing the constitutive equations of flow laws, such as differential stress, strain, and strain rate, can be obtained. To facilitate corrections for the distortion of the apparatus and the load force supported by the jacketing tube, we determine the distortion of the Paterson apparatus as a function of axial load force by deforming tungsten steel specimens with a known Young's modulus and the high-temperature flow laws of two common jacketing materials, iron and copper, by triaxial compression experiments at confining pressures of 200-300 MPa. Previous flow laws of iron and copper established by Frost and Ashby (1982) using ambient mechanical data are carefully compared with the flow laws obtained in this study to evaluate their effectiveness for correcting jacket tube strength. Finally, the errors eliminated by each correction step are analyzed and discussed to better understand the necessity of mechanical data corrections.

Intermediate valence state in YbB4revealed by resonant x-ray emission spectroscopy.

We report the temperature dependence of the Yb valence in the geometrically frustrated compoundYbB4from 12 to 300 K using resonant x-ray emission spectroscopy at the YbLα1transition. We find that the Yb valence,v, is hybridized between thev = 2 andv = 3 valence states, increasing fromv=2.61±0.01at 12 K tov=2.67±0.01at 300 K, confirming thatYbB4is a Kondo system in the intermediate valence regime. This result indicates that the Kondo interaction inYbB4is substantial, and is likely to be the reason whyYbB4does not order magnetically at low temperature, rather than this being an effect of geometric frustration. Furthermore, the zero-point valence of the system is extracted from our data and compared with other Kondo lattice systems. The zero-point valence seems to be weakly dependent on the Kondo temperature scale, but not on the valence change temperature scaleTv.

Robust Surface States and Coherence Phenomena in Magnetically Alloyed SmB_{6}.

Samarium hexaboride is a candidate for the topological Kondo insulator state, in which Kondo coherence is predicted to give rise to an insulating gap spanned by topological surface states. Here we investigate the surface and bulk electronic properties of magnetically alloyed Sm_{1-x}M_{x}B_{6} (M=Ce, Eu), using angle-resolved photoemission spectroscopy and complementary characterization techniques. Remarkably, topologically nontrivial bulk and surface band structures are found to persist in highly modified samples with up to 30% Sm substitution and with an antiferromagnetic ground state in the case of Eu doping. The results are interpreted in terms of a hierarchy of energy scales, in which surface state emergence is linked to the formation of a direct Kondo gap, while low-temperature transport trends depend on the indirect gap.

An investigation of secondary electron emission from ZnO based nanomaterials for future applications in radiation detectors.

This paper discusses the use of nanomaterials for the improved performance of time-of-flight particle detectors based on secondary electron emission (SEE). The purpose of the research presented in this paper is to find a nanomaterial that has a higher SEE than gold. In this article, we present a measurement of the SEE properties from 1D (one-dimensional) nanostructures of ZnO and ZnO/GaN (ZnO with GaN coating) composed of a mostly regular pattern of nanotubes grown on a thin Si3N4 substrate. The study was performed with 4.77 meV/u Au beam. We observed an average increase of 2.5 in the SEE properties from the 1D ZnO nanotubes compared to gold.

[Finite element analysis of evaluating the change of the hip joint biomechanics following femoral neck shortening after cannulated screw fixation for osteoporotic femoral neck fracture].

Objective: To evaluate the stress status of femoral head and neck, screws and acetabulum caused by femoral neck shortening after internal fixation of femoral neck fracture with finite element method, and to analyze the stress of proximal femoral neck and acetabulum from the mechanical point of view. Methods: CT scan data of hip of a healthy adult female were collected. Three-dimensional reconstruction MICs and related module function simulation was used to establish the postoperative shortening model of femoral neck fracture with Pauwells angle>50°, which was treated with cannulated screws. The models were divided into four groups: normal femoral neck without shortening, shortening for 2.5 mm, shortening for 7.5 mm and shortening for 12.5 mm. The finite element analysis software MSC. Nastran2012 was used to do the mechanical analysis. The acetabulum surface, femoral head surface, proximal femur and the maximum stress, stress nephogram and other relevant data were collected. Results: The maximum tensile stress and the maximum stress at the fracture site of the femoral neck increased gradually with the increasing of shortening of femoral neck, however, the maximum compressive stress under the femoral neck and the medial cortex decreased gradually; the maximum stress on the surface of the femoral head was 14.9, 15.0, 16.3 and 16.3 MPa, respectively; the maximum stress on the surface of the acetabulum was 10.1, 10.1 and 10.5,11.7 MPa, respectively. Conclusion: The mechanical environment of the hip joint changes with femoral neck shortening. With the increasing of femoral neck shortening, the peak stress of the acetabulum increases continuously. When the femoral neck is shortened seriously, the load distribution is uneven and the complex mobility of hip joint is decreased. In addition, the change of shortening might play a role in the necrosis of femoral head.

Quadrupolar ordering and exotic magnetocaloric effect in RB4 (R = Dy, Ho).

The interplay of charge, spin, orbital and lattice degrees of freedom has recently received great interest due to its potential to improve the magnetocaloric effect (MCE) for the purpose of magnetic cooling applications. Here, a new mechanism for a large entropy change with low magnetic fields in rare-earth tetraborides, especially for Ho1-xDyxB4 (x = 0.0, 0.5, and 1.0), is proposed. For x = 0.0, 0.5, and 1.0, the maximum entropy changes of the giant inverse MCE are found to be 22.7 J/kgK, 19.6 J/kgK, and 19.0 J/kgK with critical fields of 25 kOe, 40 kOe, and 50 kOe, respectively. For all compounds, systematic study on how the entropy changes as a function of the field and temperature is performed to investigate their correlation with consecutive double transitions, i.e., the magnetic dipolar order at T = TN and the quadrupolar order at T = TQ (TQ < TN). Based on Landau theory, it is found that this behaviour is attributed to the strong coupling between magnetic dipoles and quadrupoles in the presence of strong spin-orbit coupling and geometric frustration. Our work offers new insights into both academic and industrial interests in the discovery of giant MCE with various applications for magnetic cooling systems.

Identification of transfusion-transmitted hepatitis A through postdonation information in Korea: results of an HAV lookback (2007-2012).

BACKGROUND AND OBJECTIVES: Despite safety measures to minimize the risk of transfusion-transmitted infections, a residual risk remains. To trace and review some such cases, we ask donors to notify the blood centre if they are diagnosed with an infection after they donate blood. MATERIALS AND METHODS: We analysed all data on postdonation cases of hepatitis A reported between 2007 and 2012. Archived specimens from these donors were tested for hepatitis A virus (HAV) using anti-HAV IgM/IgG and HAV-PCR as markers. If any of the test results were positive, we reviewed the medical records of the recipients and, if necessary, tested them for hepatitis A. RESULTS: Fifteen blood donors notified the blood centres of having been diagnosed with hepatitis A after donation. All archived samples except for one were HAV-PCR-positive and anti-HAV IgM/IgG-negative. Of the donated components, four RBCs and 14 FFPs had not been transfused to patients and were recalled. Among 26 recipients of the implicated components, fourteen were still alive when they were notified. Two patients showed clinical symptoms of hepatitis A and had positive results with anti-HAV IgM. CONCLUSION: Transfusion-transmitted hepatitis A is rare but exists. To reduce the risk, donors should be told to notify the blood centre if they are diagnosed with blood-borne diseases after they donate blood. Physicians should consider the possibility of transfusion-transmitted hepatitis A if a transfused patient has hepatitis A but no history of travel or route of faecal-oral infection.

The association between subclass-specific IgG Fc N-glycosylation profiles and hypertension in the Uygur, Kazak, Kirgiz, and Tajik populations.

Hypertension results from the interaction of genetic and acquired factors. IgG occurs in the form of different subclasses, of which the effector functions show significant variation. The detailed differences between the glycosylation profiles of the individual IgG subclasses may be lost in a profiling method for total IgG N-glycosylation. In this study, subclass-specific IgG Fc glycosylation profile was investigated in the four northwestern Chinese minority populations, namely, Uygur (UIG), Kazak (KZK), Kirgiz (KGZ), and Tajik (TJK), composed of 274 hypertensive patients and 356 healthy controls. The results showed that ten directly measured IgG N-glycan traits (i.e., IgG1G0F, IgG2G0F, IgG2G1FN, IgG2G1FS, IgG2G2S, IgG4G0F, IgG4G1FS, IgG4G1S, IgG4G2FS, and IgG4G2N) representing galactosylation and sialylation are significantly associated with hypertension, with IgG4 consistently showing weaker associations of its sialylation, across the four ethnic groups. We observed a modest improvement on the AUC of ROC curve when the IgG Fc N-glycan traits are added into the glycan-based model (difference between AUCs, 0.044, 95% CI: 0.016-0.072, P = 0.002). The AUC of the diagnostic model indicated that the subclass-specific IgG Fc N-glycan profiles provide more information reinforcing current models utilizing age, gender, BMI, and ethnicity, and demonstrate the potential of subclass-specific IgG Fc N-glycosylation profiles to serve as a biomarker for hypertension. Further research is however required to determine the additive value of subclass-specific IgG Fc N-glycosylation on top of biomarkers, which are currently used.

Application of emitter-sample hybrid terahertz time-domain spectroscopy to investigate temperature-dependent optical constants of doped InAs.

We investigate temperature-dependent carrier dynamics of InAs crystal by using reflection-type terahertz time-domain spectroscopy, particularly with a recently developed emitter-sample hybrid structure. We successfully obtain the optical conductivity in a terahertz frequency of bulk InAs whose dc conductivity is in the range of 100-150 Ω-1 cm-1. We find that both real and imaginary parts of the optical conductivity can be fit well with the simple Drude model, and the free-carrier density and the scattering rate obtained from the fit are in good agreement with corresponding values obtained by using other techniques, such as the Hall measurement and the dc-resistivity measurement. These results clearly demonstrate that the proposed technique of adopting the emitter-sample hybrid structure can be exploited to determine temperature-dependent optical constants in a reflection geometry and hence to investigate electrodynamics of bulk metallic systems.

[A comparative study on characterizations of genetic recombination hotspots in PPARG gene between Kirgiz and Uyghur ethnic groups in Xinjiang].

OBJECTIVE: To investigate the characterizations of genetic recombination hotspots and linkage disequilibrium (LD) patterns in peroxisome proliferative activated receptor gamma (PPARG) gene in Kirgiz and Uyghur ethnic groups. METHODS: Blood samples were collected from 100 Kirgiz (50 healthy controls and 50 patients with type 2 diabetes mellitus) residents in Halajun County, Artux City, Kizilsu Kirgiz Autonomous Prefecture, Xinjiang in August 2013, and 50 healthy Uyghur residents in Hotan Prefecture of Xinjiang Uygur Autonomous Region in May 2012.Thirty-one tagSNPs in PPARG gene were genotyped using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) method.The recombination hotspots and LD patterns within the PPARG gene were estimated by analyzing the SNP genotying data using the Hotspot Fisher program and Haploview software, respectively. RESULTS: Eighteen tagSNPs (rs1151999, rs1175540, rs1875796, rs1899951, rs2292101, rs2921190, rs2938397, rs2959272, rs2959273, rs2972162, rs3856806, rs4135247, rs4135275, rs709151, rs4135354, rs6805419, rs17036700 and rs4135304) were same with relatively higher recombination rates between the patients with type 2 diabetes mellitus (T2DM) and healthy controls of Kirgiz ethnic group, and healthy controls of Uyghur ethnic group.Five haplotype blocks with LD coefficient D' value of 1, indicating no genetic recombination occurred within the region, were observed in the healthy controls of Kirgiz ethnic groups, whereas five haplotype blocks with LD coefficient D' value less than 1 were observed in the Kirgiz patients with T2DM, indicating historical recombination events occurred within the region.Four haplotype blocks with LD coefficient D' value of 1 were observed in the Uyghur healthy controls, indicating no genetic recombination occurred within the region.There were significantly different recombination hotspot profiles between the Kirgiz, Uyghur, Utah residents with Northern and Western European ancestry (CEU), Yoruban in Ibadan, Nigeria (YRI) and Han Chinese in Beijing (CHB) and Japanese in Tokyo (JPT) samples.There are six recombination hotspots in the HapMap profile of genetic recombination.The last 5 SNPs within the PPARG gene were shown with lower recombination rates in the Kirgiz, whereas no recombination hotspot was found in the Uyghur. CONCLUSIONS: Variable recombination rates may be present in certain chromosome region between patients and healthy controls within the same or between the different ethnic groups.There may be presence of recombination hotspots of ethnic specificity and with variable recombination rates.

In vitro validation of effects of BDNF-expressing mesenchymal stem cells on neurodegeneration in primary cultured neurons of APP/PS1 mice.

Alzheimer's disease (AD), the most common type of dementia, is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal loss in defined regions of the brain including the hippocampus and cortex. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) offers a safe and potentially effective tool for treating neurodegenerative disorders. However, the therapeutic effects of BM-MSCs on AD pathology remain unclear and their mechanisms at cellular and molecular levels still need to be addressed. In this study, we developed a unique neuronal culture made from 5xFAD mouse, an APP/PS1 transgenic mouse model (FAD neurons) to investigate progressive neurodegeneration associated with AD pathology and efficacy of brain-derived neurotrophic factor expressing-MSCs (BDNF-MSCs). Analyses of the expression of brain-derived neurotrophic factor (BDNF), synaptic markers and survival/apoptotic signals indicate that pathological features of cultured neurons made from these mice accurately mimic AD pathology, suggesting that our protocol provided a valid in vitro model of AD. We also demonstrated amelioration of AD pathology by MSCs in vitro when these FAD neurons were co-cultured with MSCs, a paradigm that mimics the in vivo environment of post-transplantation of MSCs into damaged regions of brains. To overcome failed delivery of BDNF to the brain and to enhance MSCs releasing BDNF effect, we created BDNF-MSCs and found that MSCs protection was enhanced by BDNF-MSCs. This protection was abolished by BDNF-blocking peptides, suggesting that BDNF supply from BDNF-MSCs was enough to prevent AD pathology.

Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia.

PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a bona fide dual lipid and protein phosphatase with cytoplasmic (Cy) and nuclear localization. PTEN nuclear exclusion has been associated with tumorigenesis. Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia (AML) and displays Cy localization in mutated nucleophosmin (NPMc+) AML. Here we show that NPM1 directly interacts with herpes virus-associated ubiquitin specific protease (HAUSP), which is known as a PTEN deubiquitinating enzyme. Strikingly, PTEN is aberrantly localized in AML carrying NPMc+. Mechanistically, NPM1 in the nucleus opposes HAUSP-mediated deubiquitination and this promotes the shuttle of PTEN to the cytoplasm. In the cytoplasm, NPMc+ prevents HAUSP from deubiquitinating PTEN, causing the latter to stay in the cytoplasm where it is polyubiquitinated and degraded. Our findings delineate a new NPM1-HAUSP molecular interaction controlling PTEN deubiquitination and trafficking.

Inhibition of ß-amyloid1-42 internalization attenuates neuronal death by stabilizing the endosomal-lysosomal system in rat cortical cultured neurons.

A number of recent studies have indicated that accumulation of ß amyloid (Aß) peptides within neurons is an early event which may trigger degeneration of neurons and subsequent development of Alzheimer's disease (AD) pathology. However, very little is known about the internalization and/or subcellular sites involved in trafficking of Aß peptides into the neurons that are vulnerable in AD pathology. To address this issue we evaluated internalization of fluoroscein conjugated Aß1-42 (FAß1-42) and subsequent alteration of endosomal-lysosomal (EL) markers such as cathepsin D, Rab5 and Rab7 in rat cortical cultured neurons. It is evident from our results that internalization of FAß1-42, which occurred in a dose- and time-dependent manner, triggered degeneration of neurons along with increased levels and/or altered distribution of cathepsin D, Rab5 and Rab7. Our results further revealed that FAß1-42 internalization was attenuated by phenylarsine oxide (a general inhibitor of endocytosis) and sucrose (an inhibitor of clathrin-mediated endocytosis) but not by antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors. Additionally, inhibition of FAß1-42 endocytosis not only protected neurons against toxicity but also reversed the altered levels/distributions of EL markers. These results, taken together, suggest that internalization of exogenous Aß1-42, which is partly mediated via a clathrin-dependent process, can lead to degeneration of neurons, possibly by activating the EL system. Inhibition of FAß endocytosis attenuated toxicity, thus suggesting a potential strategy for preventing loss of neurons in AD pathology.

The effects of cognitive training on community-dwelling elderly Koreans.

The objective of this study was to apply and test the effects of cognitive training on community-dwelling, elderly Koreans. The cognitive training was applied for 24 weeks to 129 elderly participants. The participants were divided into two groups to receive either cognitive training followed by observational period, or observational period followed by cognitive training. The primary outcome measures were the geriatric depression scale (Geriatric Depression Scale Short Form-Korean, GDS-SF-K) and mini-mental status examination (Mini-Mental State Examination in the Korean version, MMSE-KC) scores. There were no differences between the average GDS-SF-K and MMSE-KC scores of the two groups. However, the participants with cognitive dysfunction (defined as baseline MMSE below the 16th percentile according to age, sex and educational level) who received cognitive training initially had significantly improved MMSE-KC score on weeks 8 and 16, compared with the participants with cognitive dysfunction who were observed first. However, the participants who received cognitive training later did in fact catch up with the other group in terms of MMSE-KC score. Cognitive training by visiting nursing services was more effective in the elderly with cognitive dysfunction.

Extracardiac lesions and chromosomal abnormalities associated with major fetal heart defects: comparison of intrauterine, postnatal and postmortem diagnoses.

OBJECTIVES: The clinical outcome of prenatally diagnosed congenital heart defects (CHD) continues to be affected significantly by associated extracardiac and chromosomal abnormalities. We sought to: determine the frequency and type of major extracardiac abnormalities (with impact on quality of life) and chromosomal abnormalities associated with fetal CHD; and compare the extracardiac abnormalities detected prenatally to the postnatal and autopsy findings in affected fetuses, to find the incidence of extracardiac abnormalities missed on prenatal ultrasound. METHODS: We reviewed the computerized database of the Division of Cardiology of the Hospital for Sick Children in Toronto to identify all cases of major CHD detected prenatally from 1990 to 2002. Medical records, fetal echocardiograms and ultrasound, cytogenetic and autopsy reports were reviewed. The types of CHD detected were grouped into categories and the frequencies of major extracardiac and chromosomal abnormalities in these categories were noted. Prenatal ultrasound findings were compared with those at autopsy or postnatal examination. RESULTS: Of 491 fetuses with major structural CHD, complete data were obtained for 382. Of these, there were 141 (36.9%) with major extracardiac abnormalities at autopsy or postnatal exam, of which 46 had chromosomal abnormalities and 95 did not. In the absence of chromosomal abnormalities, the organ systems most affected were urogenital (12.2%) and gastrointestinal (11.6%). CHDs with the highest incidence of extracardiac abnormalities (>25%) included: heterotaxy, single left ventricle and tricuspid atresia, hypoplastic left heart syndrome and tetralogy of Fallot. Ninety-four of 334 (28.1%) fetuses tested had chromosomal abnormalities. The most common chromosomal abnormalities were trisomies 21 (43.6%), 18 (19.1%) and 13 (9.6%), monosomy X (7.4%) and 22q11.2 deletion (7.4%). Of 289 extracardiac abnormalities from the complete series, 134 (46.4%) were not identified prenatally. Of the missed extracardiac abnormalities, 65 were considered not detectable at prenatal ultrasound, so 23.9% (69/289) of detectable extracardiac abnormalities were missed prenatally. CONCLUSIONS: Major extracardiac and chromosomal abnormalities are common in fetuses with major fetal CHD. Many important associated extracardiac abnormalities may be missed prenatally, which should be taken into consideration in the prenatal counseling for fetal CHD.

Validation of tissue-specific promoter-driven tumor-targeting trans-splicing ribozyme system as a multifunctional cancer gene therapy device in vivo.

A trans-splicing ribozyme that can specifically reprogram human telomerase reverse transcriptase (hTERT) RNA was previously suggested as a useful tool for tumor-targeted gene therapy. In this study, we applied transcriptional targeting with the RNA replacement approach to target liver cancer cells by combining a liver-selective promoter with an hTERT-mediated cancer-specific ribozyme. To validate effects of this system in vivo, we constructed an adenovirus encoding for the hTERT-targeting trans-splicing ribozyme under the control of a liver-selective phosphoenolpyruvate carboxykinase promoter. We observed that intratumoral injection of this virus produced selective and efficient regression of tumors that had been subcutaneously inoculated with hTERT-positive liver cancer cells in mice. Importantly, the trans-splicing reaction worked equally well in a nude mouse model of hepatocarcinoma-derived peritoneal carcinomatosis, inducing the highly specific expression of a transgene, and moreover, the efficient regression of the hTERT-positive liver tumors with minimal liver toxicity when systemically delivered with the adenovirus. In addition to the observed hTERT-dependent therapeutic gene induction, significant reductions in the levels of hTERT RNA (approximately 75%) were also observed. In conclusion, this study demonstrates that a cancer-specific RNA replacement approach using trans-splicing ribozyme with a tissue-selective promoter represents a promising strategy for cancer treatment.

Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation.

It has been suggested that accumulation of beta-amyloid (Abeta) peptide triggers neurodegeneration, at least in part, via glutamate-mediated excitotoxicity in Alzheimer's disease (AD) brain. This is supported by observations that toxicity induced by Abeta peptide in cultured neurons and in adult rat brain is known to be mediated by activation of glutamatergic N-methyl-d-aspartate (NMDA) receptors. Additionally, recent clinical studies have shown that memantine, a noncompetitive NMDA receptor antagonist, can significantly improve cognitive functions in some AD patients. However, very little is currently known about the potential role of memantine against Abeta-induced toxicity. In the present study, we have shown that Abeta(1-42)-induced toxicity in rat primary cortical cultured neurons is accompanied by increased extracellular and decreased intracellular glutamate levels. We subsequently demonstrated that Abeta toxicity is induced by increased phosphorylation of tau protein and activation of tau kinases, i.e. glycogen synthase kinase-3beta and extracellular signal-related kinase 1/2. Additionally, Abeta treatment induced cleavage of caspase-3 and decreased phosphorylation of cyclic AMP response element binding protein, which are critical in determining survival of neurons. Memantine treatment significantly protected cultured neurons against Abeta-induced toxicity by attenuating tau-phosphorylation and its associated signaling mechanisms. However, this drug did not alter either conformation or internalization of Abeta(1-42) and it was unable to attenuate Abeta-induced potentiation of extracellular glutamate levels. These results, taken together, provide new insights into the possible neuroprotective action of memantine in AD pathology.

Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: a cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China.

Severe acute respiratory syndrome (SARS), caused by infection with a novel coronavirus (SARS-CoV), was the first major novel infectious disease at the beginning of the 21st century, with China especially affected. SARS was characterized by high infectivity, morbidity and mortality, and the confined pattern of the disease spreading among the countries of South-East and East Asia suggested the existence of susceptible factor(s) in these populations. Studies in the populations of Hong Kong and Taiwan showed an association of human leucocyte antigen (HLA) polymorphisms with the development and/or severity of SARS, respectively. The aim of the present study was to define the genotypic patterns of HLA-A, -B and -DRB1 loci in SARS patients and a co-resident population of Guangdong province, southern China, where the first SARS case was reported. The samples comprised 95 cases of recovered SARS patients and 403 unrelated healthy controls. HLA -A, -B and -DRB1 alleles were genotyped using polymerase chain reaction with sequence-specific primers. The severity of the disease was assessed according to the history of lung infiltration, usage of assisted ventilation and occurrence of lymphocytopenia. Although the allelic frequencies of A23, A34, B60, DRB1*12 in the SARS group were slightly higher, and A33, -B58 and -B61 were lower than in the controls, no statistical significance was found when the Pc value was considered. Similarly, no association of HLA alleles with the severity of the disease was detected. Thus, variations in the major histocompatibility complex are unlikely to have contributed significantly to either the susceptibility or the severity of SARS in the population of Guangdong.

Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons.

The invariant characteristic features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid beta (Abeta) peptide, intracellular neurofibrillary tangles containing hyper-phosphorylated tau protein and the loss of basal forebrain cholinergic neurons. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that in vivo accumulation of Abeta(1-42) may initiate the process of neurodegeneration observed in AD brains. However, the cause of degeneration of the basal forebrain cholinergic neurons and their association to Abeta peptides or phosphorylated tau protein have not been clearly established. In the present study, using rat primary septal cultures, we have shown that Abeta(1-42), in a time (1-48 h) and concentration (0.01-20 microM)-dependent manner, induce toxicity in cultured neurons. Subsequently, we have demonstrated that Abeta toxicity is mediated via activation of cysteine proteases, i.e., calpain and caspase, and proteolytic breakdown of their downstream substrates tau, microtubule-associated protein-2 and alpha II-spectrin. Additionally, Abeta-treatment was found to induce phosphorylation of tau protein along with decreased levels of phospho-Akt and phospho-Ser(9)glycogen synthase kinase-3beta. Exposure to specific inhibitors of caspase or calpain can partially protect cultured neurons against Abeta-induced toxicity but their effects are not found to be additive. These results, taken together, suggest that Abeta peptide can induce toxicity in rat septal cultured neurons by activating multiple intracellular signaling molecules. Additionally, evidence that inhibitors of caspase and calpains can partially protect the cultured basal forebrain neurons raised the possibility that their inhibitors could be of therapeutic relevance in the treatment of AD pathology.

Skp2 regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1-S transition.

The tumor suppressor RASSF1A is inactivated in many human cancers and is implicated in regulation of microtubule stability, cell cycle progression and apoptosis. However, the precise mechanisms of RASSF1A action and their regulation remain unclear. Here we show that Skp2, an oncogenic subunit of the Skp1-Cul1-F-box ubiquitin ligase complex, interacts with, ubiquitinates, and promotes the degradation of RASSF1A at the G1-S transition of the cell cycle. This Skp2-dependent destruction of RASSF1A requires phosphorylation of the latter on serine-203 by cyclin D-cyclin-dependent kinase 4. Interestingly, mutation of RASSF1A-phosphorylation site Ser(203) to alanine results in a delay in cell cycle progression from G1 to S phase. Moreover, enforced expression of Skp2 abolishes the inhibitory effect of RASSF1A on cell proliferation. Finally, the delay in G1-S progression after Skp2 removal is normalized by depletion of RASSF1A. These findings suggest that the Skp2-mediated degradation of RASSF1A plays an important role in cell proliferation and survival.