Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: a pilot study

Background and Objective: PSEN1-H163Y carriers, at the presymptomatic stage, have reduced 18FDG-PET binding in the cerebrum of the brain (Scholl et al., Neurobiol Aging 32:1388–1399, 2011). This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes. Methods: We analyzed plasma from noncarriers (NC, n = 8) and presymptomatic PSEN1-H163Y mutation carriers (MC, n = 6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of Ab1–42/Ab1–40, using Spearman’s correlation. Altered metabolites were subjected to Ingenuity Pathway Analysis (IPA). Results: Based on principal component analysis the plasma metabolite profiles were divided into dataset A and dataset B. In dataset A, when comparing between presymptomatic MC and NC, the levels of 79 different metabolites were altered. Out of 79, only 14 were annotated metabolites. In dataset B, 37 metabolites were significantly altered between presymptomatic MC and NC and nine metabolites were annotated. In both datasets, annotated metabolites represent amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC was positively correlated, uric acid and glucose were negatively correlated with the ratio of plasma Ab1–42/Ab1–40 (P < 0.05). Interpretation: This study finds dysregulated metabolite classes, which are changed before the disease symptom onset. Also, it provides an opportunity to compare with sporadic Alzheimer’s Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer’s Disease (FAD) cohort

Is the treatment with biological or non-biological DMARDS a modifier of periodontal condition in patients with rheumatoid arthritis?

Background and objective: Experimental models suggest the use of different therapy protocols in rheumatoid arthritis (RA) as modulators on periodontal condition. This study evaluated the effects of conventional drug treatment and anti-TNF therapy in patients with RA on microbiological and periodontal condition, establishing the association of markers of periodontal infection with indexes of rheumatic activity. Materials and methods: One hundred seventy nine individuals with RA were evaluated (62 with anti-TNF-. and 115 with only DMARDs). The periodontal evaluation included plaque and gingival indexes, bleeding on probing (BOP), clinical attachment loss (CAL), pocket depth (PD) and subgingival plaque samples for microbiological analysis. Rheumatologic evaluations included a clinical examination, rheumatoid factor (RF), antibodies against cyclic-citrullinated peptides (ACPAs), and activity markers (DAS28-ERS), high sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR). Results: Anti-TNF-alpha therapy influenced periodontal microbiota with a higher frequency of T. denticola (p=0.01). Methotrexate combined with leflunomide exhibited a higher extension of CAL (p=0.005), and anti-TNF-alpha therapy with methotrexate was associated with a lower extension of CAL (p=0.05). The use of corticosteroids exerted a protective effect on the number of teeth (p=0.027). The type of DMARD affected P. gingivalis, T. forsythia and E. nodatum presence. Elevated ACPAs titers were associated with the presence of red complex periodontal pathogens (p=0.025). Bleeding on probing was associated with elevated CPR levels (p=0.05), and ESR was associated with a greater PD (p=0.044) and presence of red complex (p=0.030). Conclusion: Different pharmacological treatments for RA affect the clinical condition and subgingival microbiota

Spin-glass behavior in a three-dimensional antiferromagnet ordered phase: Magnetic structure of Co-2(OH)(PO4)

Co-2(OH)(PO4) has been prepared from hydrothermal synthesis and characterized from powder x-ray diffraction. The nuclear and magnetic structures have been determined by neutron (D2B and D1B) diffraction data. The structure consists of a three-dimensional framework in which Co(1)O-5-trigonal bipyramid dimers and Co(2)O-6-octahedra chains are simultaneously present. The EPR spectrum of Zn-2(OH)(PO4):0.1%Co at 4.2 K shows a strong anisotropy of the g factor. The values obtained for the g tensor and the hyperfine coupling constants for the octahedral symmetry were g(1)=5.890, g(2)=4.550, and g(3)=2.021 and A(1)=240x10(-4) cm(-1), A(2)=155x10(-4) cm(-1), and A(3)=85x10(-4) cm(-1). Signals corresponding to the five-coordinated Co(II) ions were also observed. Magnetization measurements show the presence of two maxima at circa 75 and 15 K, respectively. The first peak was attributed to a three-dimensional antiferromagnetic ordering and the second one reveals the existence of a spin-glass-like state. This state with a cooperative freezing was also confirmed by both ac susceptibility measurements and magnetic irreversibility observed in the zero-field-cooled-field-cooled signals. From low-temperature neutron-diffraction data, antiferromagnetic ordering is established with an ordering temperature of 71 K. The propagation vector of the magnetic structure is k=[0,0,0]. The magnetic moments at 1.7 K are ferromagnetically coupled between CoO6-octahedra chains and the Co2O10 dimers in the z direction. The values obtained for the magnetic moments are: 3.39(7)mu(B) [Co(1)] and 3.84(5)mu(B) [Co(2)]. The absence of any anomaly in both the specific heat and thermal evolution of the magnetic moments below similar to20 K confirms the blocking process of a spin glass behavior. The crystal-field splitting of the Co2+ ions causes a single ion anisotropy along the z (c-axis) direction, giving an Ising character in which the local spins from the Co(1) dimers are frozen. A magnetic frustration in the Co(1) magnetic moments is observed as due to the presence of antiferromagnetic interactions between Co(2) neighbor chains. It is to note the existence of a Co(1)-O(3)(PO3)-Co(2) superexchange angle with a value of 107degrees that involves ferromagnetic couplings between chain and dimer neighbors ferromagnetically coupled. This exchange pathway together with the anisotropy and frustration could be the responsible of the spin glass behavior observed in the three-dimensional antiferromagnetic Co-2(OH)(PO4) ordered phase.66

Diabetes Is an Independent Risk Factor for Severe Nocturnal Hypoxemia in Obese Patients. A Case-Control Study

Type 2 diabetes mellitus (T2DM) and obesity have become two of the main threats to public health in the Western world. In addition, obesity is the most important determinant of the sleep apnea-hypopnea syndrome (SAHS), a condition that adversely affects glucose metabolism. However, it is unknown whether patients with diabetes have more severe SAHS than non-diabetic subjects. The aim of this cross-sectional case-control study was to evaluate whether obese patients with T2DM are more prone to severe SAHS than obese non-diabetic subjects.Thirty obese T2DM and 60 non-diabetic women closely matched by age, body mass index, waist circumference, and smoking status were recruited from the outpatient Obesity Unit of a university hospital. The exclusion criteria included chronic respiratory disease, smoking habit, neuromuscular and cerebrovascular disease, alcohol abuse, use of sedatives, and pregnancy. Examinations included a non-attended respiratory polygraphy, pulmonary function testing, and an awake arterial gasometry. Oxygen saturation measures included the percentage of time spent at saturations below 90% (CT90). A high prevalence of SAHS was found in both groups (T2DM:80%, nondiabetic:78.3%). No differences in the number of sleep apnea-hypopnea events between diabetic and non-diabetic patients were observed. However, in diabetic patients, a significantly increase in the CT90 was detected (20.2+/-30.2% vs. 6.8+/-13,5%; p = 0.027). In addition, residual volume (RV) was significantly higher in T2DM (percentage of predicted: 79.7+/-18.1 vs. 100.1+/-22.8; p<0.001). Multiple linear regression analyses showed that T2DM but not RV was independently associated with CT90.T2DM adversely affects breathing during sleep, becoming an independent risk factor for severe nocturnal hypoxemia in obese patients. Given that SAHS is a risk factor of cardiovascular disease, the screening for SAHS in T2DM patients seems mandatory

Influence of antenatal physical exercise on haemodynamics in pregnant women: a flexible randomisation approach

Background: Normal pregnancy is associated with marked changes in haemodynamic function, however theinfluence and potential benefits of antenatal physical exercise at different stages of pregnancy and postpartumremain unclear. The aim of this study was therefore to characterise the influence of regular physical exercise onhaemodynamic variables at different stages of pregnancy and also in the postpartum period.Methods: Fifty healthy pregnant women were recruited and randomly assigned (2 × 2 × 2 design) to a land orwater-based exercise group or a control group. Exercising groups attended weekly classes from the 20th week ofpregnancy onwards. Haemodynamic assessments (heart rate, cardiac output, stroke volume, total peripheralresistance, systolic and diastolic blood pressure and end diastolic index) were performed using the Task Forcehaemodynamic monitor at 12–16, 26–28, 34–36 and 12 weeks following birth, during a protocol including posturalmanoeurvres (supine and standing) and light exercise.Results: In response to an acute bout of exercise in the postpartum period, stroke volume and end diastolic indexwere greater in the exercise group than the non-exercising control group (p = 0.041 and p = 0.028 respectively).Total peripheral resistance and diastolic blood pressure were also lower (p = 0.015 and p = 0.007, respectively) in theexercise group. Diastolic blood pressure was lower in the exercise group during the second trimester (p = 0.030).Conclusions: Antenatal exercise does not appear to substantially alter maternal physiology with advancinggestation, speculating that the already vast changes in maternal physiology mask the influences of antenatalexercise, however it does appear to result in an improvement in a woman’s haemodynamic function (enhancedventricular ejection performance and reduced blood pressure) following the end of pregnancy

Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

<p>Abstract</p> <p>Background</p> <p>The JAK2^V617Fmutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1.</p> <p>Methods</p> <p>Pharmacological inhibition of JAK2/STAT5 signaling in JAK2^V617Fmutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins.</p> <p>Results</p> <p>Treatment of JAK2^V617Fmutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2^V617Fmutant cell viability and sensitized the cells to JAK2 inhibition.</p> <p>Conclusions</p> <p>We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2^V617Fcell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic myeloproliferative neoplasms.</p

Efficient Identification of Critical Residues Based Only on Protein Structure by Network Analysis

Despite the increasing number of published protein structures, and the fact that each protein's function relies on its three-dimensional structure, there is limited access to automatic programs used for the identification of critical residues from the protein structure, compared with those based on protein sequence. Here we present a new algorithm based on network analysis applied exclusively on protein structures to identify critical residues. Our results show that this method identifies critical residues for protein function with high reliability and improves automatic sequence-based approaches and previous network-based approaches. The reliability of the method depends on the conformational diversity screened for the protein of interest. We have designed a web site to give access to this software at http://bis.ifc.unam.mx/jamming/. In summary, a new method is presented that relates critical residues for protein function with the most traversed residues in networks derived from protein structures. A unique feature of the method is the inclusion of the conformational diversity of proteins in the prediction, thus reproducing a basic feature of the structure/function relationship of proteins

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let