PARP-1 modulates amyloid beta peptide-induced neuronal damage.

Amyloid beta peptide (A beta) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with A beta(25-35) fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. A beta(25-35) induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following A beta(25-35) exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that A beta(25-35) induces DNA damage which in turn activates PARP-1. Challenge with A beta(25-35) is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, A beta(25-35) via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by A beta and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed

Human factors in forensic science: The cognitive mechanisms that underlie forensic feature-comparison expertise

After a decade of critique from leading scientific bodies, forensic science research is at a crossroads. Whilst emerging research has shown that some forensic feature-comparison disciplines are not foundationally valid, others are moving towards establishing reliability and validity. Forensic examiners in fingerprint, face and handwriting comparison disciplines have skills and knowledge that distinguish them from novices. Yet our understanding of the basis of this expertise is only beginning to emerge. In this paper, we review evidence on the psychological mechanisms contributing to forensic feature-comparison expertise, with a focus on one mechanism: statistical learning, or the ability to learn how often things occur in the environment. Research is beginning to emphasise the importance of statistical learning in forensic feature-comparison expertise. Ultimately, this research and broader cognitive science research has an important role to play in informing the development of training programs and selection tools for forensic feature-comparison examiners

Hereditary Deficiency of gp91(phox) Is Associated With Enhanced Arterial Dilatation Results of a Multicenter Study

Background-NADPH oxidase is believed to modulate arterial tone, but its role in humans is still unclear. The objective of this study was to evaluate whether NADPH oxidase is involved in flow-mediated arterial dilation (FMD). Methods and Results-Twenty-five patients with hereditary deficiency of gp91(phox), the catalytic core of NADPH oxidase, (X-CGD), 25 healthy subjects, and 25 obese patients matched for sex and age were recruited. FMD, platelet gp91(phox), serum levels of nitrite and nitrate as markers of nitric oxide generation, oxidized low-density lipoprotein, and urinary excretion of isoprostanes as markers of oxidative stress were determined. Platelet gp91(phox) expression was downregulated in X-CGD patients (1.0+/-0.8 mean fluorescence; P<0.001) and upregulated in obese patients (4.1+/-2.2 mean fluorescence; P=0.01) compared with healthy subjects (2.9+/-1.7 mean fluorescence). Urinary excretion of isoprostanes was reduced in X-CGD patients (41.7+/-33.3 pg/mg creatinine; P = 0.04) and increased in obese patients (154.4+/-91 pg/mg creatinine; P<0.001) compared with healthy subjects (69.5+/-52.4 pg/mg creatinine). Obese patients had higher serum oxidized low-density lipoprotein than healthy subjects (35.3+/-6.7 versus 24.8+/-9.8 U/L; P<0.001) and X-CGD patients (28.5+/-7.2 U/L; P<0.001). X-CGD patients had significantly higher FMD (14.7+/-5.9%) compared with healthy subjects (7.9+/-2.5%; P<0.001); obese patients had lower FMD (5.3+/-3.0%; P+/-0.028) compared with healthy subjects. Serum nitrite and nitrate levels were significantly higher in patients with X-CGD (36.0+/-10.8+/-mol/L; P<0.016) and lower in obese patients (9.3+/-11.0 mu mol/L; P<0.001) compared with healthy subjects (27.1+/-19.1 mu mol/L). Serum nitrite and nitrate levels significantly correlated with FMD (R-s = 0.403, P<0.001) and platelet gp91(phox) (R-s = -0.515, P<0.001). FMD inversely correlated with platelet gp91(phox) (R-s = -0.502, P<0.001) and isoprostanes (R-s = -0.513, P<0.001). Conclusion-This study provides the first evidence that, in humans, gp91(phox) is implicated in the modulation of arterial ton

Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients

Predictor variables and screening protocol for depressive and anxiety disorders in cancer outpatients

Background Cancer patients are at increased risk of persistent depressive and anxiety symptoms and disorders compared to the general population. However, these issues are not always identified, which may worsen the prognosis and increase morbidity and mortality. Therefore, the objectives of this study are to identify predictor variables (demographic and clinical) for the development of mood and anxiety disorders in cancer outpatients and to propose a probabilistic screening protocol considering these variables and certain standardized screening instruments. Methods A total of 1,385 adults, of both genders, receiving outpatient cancer care were evaluated using a questionnaire and screening instruments. Thereafter, 400 of these subjects responded to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID-IV) by telephone to confirm or rule out the presence of a Current Major Depressive Episode (CMDE) or Anxiety Disorder (AD). Results Of the patients surveyed, 64% met the criteria for CMDE and 41% for AD. Female gender was found to be a risk factor for both disorders, and the presence of previous psychiatric history and marital status (divorced and widowed) were risk factors for anxiety disorders. When scoring above the recommended cutoff score, the screening instruments also indicated a risk of the studied disorders. Based on these findings, a screening protocol and nomograms were created for the quantification, combination and probabilistic estimate of risk, with accuracy indicators >0.68. Conclusion The prevalence rates for the disorders under study are extremely high in cancer patients. The use of the proposed protocol and nomogram can facilitate rapid and wide screening, thus refining triage and supporting the establishment of criteria for referral to mental health professionals, so that patients can be properly diagnosed and treated.info:eu-repo/semantics/publishedVersio

Mapping Kinetic Energy Hotspots in the Persian Gulf and Oman Sea Using Surface Current Derived by Geodetic Observations and Data Assimilation

Harnessing ocean kinetic energy has emerged as a promising renewable energy solution in recent years. However, identifying optimal locations for extracting this energy remains a significant challenge. This study presents a novel scheme to estimate the total surface current (TSC) as permanent surface current by integrating geodetic data and in-situ measurements. The TSC is typically a combination of the geostrophic current, derived from dynamic topography, and the Ekman current. We utilize NOAA’s Ekman current data to complement the geostrophic current and obtain the TSC. To further enhance the accuracy of the TSC estimates, we employ a 3DVAR data assimilation method, incorporating local current meter observations. The results are verified against two control current meter stations. The data-assimilation process resulted in an improvement of 4 to 15 cm/s in the precision of calculated TSC. Using the assimilated TSC data, we then assess the kinetic energy potential and identify six regions with the most significant promise for marine kinetic energy extraction. This innovative approach can assist researchers and policymakers in targeting the most suitable locations for harnessing renewable ocean energy

Morphological Analysis of the Polarized Synchrotron Emission with WMAP and Planck

The bright polarized synchrotron emission, away from the Galactic plane, originates mostly from filamentary structures. We implement a filament finder algorithm which allows the detection of bright elongated structures in polarized intensity maps. We analyse the sky at 23 and 30 GHz as observed respectively by WMAP and Planck. We identify 19 filaments, 13 of which have been previously observed. For each filament, we study the polarization fraction, finding values typically larger than for the areas outside the filaments, excluding the Galactic plane, and a fraction of about 30% is reached in two filaments. We study the polarization spectral indices of the filaments, and find a spectral index consistent with the values found in previous analysis (about -3.1) for more diffuse regions. Decomposing the polarization signals into the $E$ and $B$ families, we find that most of the filaments are detected in $P_E$, but not in $P_B$. We then focus on understanding the statistical properties of the diffuse regions of the synchrotron emission at 23 GHz. Using Minkowski functionals and tensors, we analyse the non-Gaussianity and statistical isotropy of the polarized intensity maps. For a sky coverage corresponding to 80% of the fainter emission, and on scales smaller than 6 degrees ($\ell > 30$), the deviations from Gaussianity and isotropy are significantly higher than 3$\sigma$. The level of deviation decreases for smaller scales, however, it remains significantly high for the lowest analised scale ($\sim 1.5^\circ$). When 60% sky coverage is analysed, we find that the deviations never exceed 3$\sigma$. Finally, we present a simple data-driven model to generate non-Gaussian and anisotropic simulations of the synchrotron polarized emission. The simulations are fitted in order to match the spectral and statistical properties of the faintest 80% sky coverage of the data maps.Comment: 35 pages, 17 figure

Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis