Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but ...can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.
Abstract Objectives To explore the association between electronic media exposure (television viewing time, personal computer/video game use, total screen time), and waist circumference and body mass ...index, and study whether this association is independent of cardiorespiratory fitness, in a representative sample of adolescents from Montería, Colombia. Design Cross-sectional study analyzing data from 546 students aged 11–18 years, from fourteen randomly selected schools. Z -scores for WC and BMI were calculated. Methods The physical activity module of the Global School Health Survey 2007 was used to determine EME, and the shuttle run test was used to assess CRF. Linear regression models adjusted by age, school location, physical activity level, type of institution (public or private), consumption of sweetened beverages, fast food, and fried food were used. Results Among boys, independently of cardiorespiratory fitness, high television viewing time (≥2 h/day) ( β = +0.22; p < 0.02), was positively associated with waist circumference. High total screen time (>3 h/day) was positively associated with waist circumference ( β = +0.34; p < 0.01), and body mass index ( β = +0.39; p < 0.01). Among girls, sedentary behavior was not associated with adiposity, but cardiorespiratory fitness ( β = −0.04; p < 0.02) was negatively associated with body mass index. Conclusions These findings support the evidence on the negative impact of excessive electronic media exposure and low cardiorespiratory fitness, and highlight the need for interventions and prevention strategies.
We analyzed the incidence, clinicopathological features, risk factors and prognosis of patients with EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) in 288 adults undergoing ...umbilical cord blood transplantation (UCBT) at a single institution. Twelve patients developed proven EBV-PTLD at a median time of 73 days (range, 36-812). Three-year cumulative incidence (CI) of EBV-PTLD was 4.3% (95% CI: 1.9-6.7). All patients presented with extranodal involvement. Most frequently affected sites were the liver, spleen, central nervous system (CNS), Waldeyer's ring and BM in 7, 6, 4, 3 and 3 patients, respectively. One patient had polymorphic and 11 had monomorphic EBV-PTLD (7 diffuse large B-cell lymphomas not otherwise specified, 4 plasmablastic lymphomas). We confirmed donor origin and EBV infection in all histological samples. EBV-PTLD was the cause of death in 11 patients at a median time of 23 days (range, 1-84). The 3-year CI of EBV-PTLD was 12.9% (95% CI: 3.2-22.5) and 2.6% (95% CI: 0.5-4.7) for patients receiving reduced-intensity conditioning (RIC) and myeloablative conditioning, respectively (P<0.0001). In conclusion, adults with EBV-PTLD after UCBT showed frequent visceral and CNS involvement. The prognosis was poor despite routine viral monitoring and early intervention. An increased risk of EBV-PTLD was noted among recipients of RIC regimens.
Animal models are a key element in disease research and treatment. In the field of neuropsychiatric lupus research, inbred, transgenic and disease-induced mice provide an opportunity to study the ...pathogenic routes of this multifactorial illness. In addition to achieving a better understanding of the immune mechanisms underlying the disease onset, supplementary metabolic and endocrine influences have been discovered and investigated. The ever-expanding knowledge about the pathologic events that occur at disease inception enables us to explore new drugs and therapeutic approaches further and to test them using the same animal models. Discovery of the molecular targets that constitute the pathogenic basis of the disease along with scientific advancements allow us to target these molecules with monoclonal antibodies and other specific approaches directly. This novel therapy, termed “targeted biological medication” is a promising endeavor towards producing drugs that are more effective and less toxic. Further work to discover additional molecular targets in lupus’ pathogenic mechanism and to produce drugs that neutralize their activity is needed to provide patients with safe and efficient methods of controlling and treating the disease.
Additive printing techniques are regarded as revolutionary and versatile methods of advanced device manufacturing, stemming from the possibility to pattern materials on a custom-based approach and ...the potential to create novel microstructures and achieve new functionalities. Despite these advantages, the inherent anisotropy of the printing process is a source of property gradients within the printed materials, often associated with variable and/or poor performance. Up to date, the evolutionary pathways associated with printing have largely remained unaddressed, mainly owing to the difficulty to study the transformations induced in the material during processing. Time-resolved coherent X-ray scattering techniques, such as X-ray photon correlation spectroscopy, enable the in situ study of transient nanoscale and mesoscale states in a large variety of materials, including amorphous ones, by directly accessing the most relevant timescales and length scales of their nanoscale and mesoscale dynamics, self-assembly, and mesostructure evolution. We conduct inoperando studies of continuous-flow direct writing with colloidal inks, focusing on how the ink formulation and ink-substrate interactions affect the processes that determine the macroscopic properties of the printed materials. We find fundamental differences in the ink structural relaxations emerging from the primary colloid properties (monodisperse versus aggregated colloids) and the substrates surface energy and mechanical properties. Our work helps to reveal and quantify the basic science governing the evolution of 3D-printed materials during processing, ultimately improving engineering criteria for the design of printable materials.
Ink relaxation dynamics, mesostructure evolution, and ink-substrate interactions in continuous-flow direct ink writing are explored by X-ray photon correlation spectroscopy. Display omitted
•Coherent X-rays reveal structural and dynamic evolution in 3D printed inks.•Ink-substrate interactions affect the mesoscale evolution during printing process.•Temporal heterogeneities are associated with the formation of structural defects.
Antiphospholipid syndrome (APS) affects coagulation and the brain by autoimmune mechanisms. The major antigen in APS is beta-2-glycoprotein I (β2-GPI) is known to complex with annexin A2 (ANXA2), and ...antibodies to ANXA2 have been described in APS. We measured these antibodies in mice with experimental APS (eAPS) induced by immunization with β2-GPI. Sera of these mice reacted significantly with recombinant ANXA2 by enzyme-linked immunosorbent assay (ELISA) and the eAPS mice had significantly high levels of immunoglobulin G (IgG) in the brain by immunoblot assays compared to adjuvant immunized controls. Immunoprecipitation performed by mixing eAPS brain tissue with protein-G beads resulted in identification of two autoantigens unique to the eAPS group, one of which was ANXA2. In order to study more directly and methodically the specific role of anti-ANXA2 antibodies in APS, we immunized mice with β2-GPI which contained no ANXA2 or with ANXA2 and measured antibodies to these proteins. Levels of antibodies to ANXA2 measured by ELISA were 0.72 ± 0.007 arbitrary units (a.u), 0.24 ± 0.03 and 0.02 ± 0.01 a.u for sera from ANXA2, β2-GPI and control mice, respectively (
p
< 0.0001 and
p
= 0.037 for the comparison of the ANXA2 and β2-GPI groups to the controls). Purified IgG from β2-GPI sera did not show cross-binding with ANXA2. Antibodies to β2-GPI and phospholipids were found in the β2-GPI immunized group only. The present study suggests an immune response to the β2-GPI–ANXA2 complex in eAPS and provides a novel ANXA2 immunization model which will serve to study the role of ANXA2 antibodies in of APS.
We describe incidence, clinical features, serological data, response to therapy and outcome of autoimmune cytopenias (ACs), including autoimmune hemolytic anemia (AIHA) and autoimmune ...thrombocytopenia (AIT) in a series of 281 consecutive adults with hematological malignancies that received single-unit umbilical cord blood transplantation (UCBT) at a single institution. AIHA was diagnosed in 15 patients at a median time of 181 days (range, 25-543), 12 of them had cold antibodies (IgM). The 3-year cumulative incidence (CI) of AIHA was 5.4% (CI 95% 2.7-8.1). Concomitant infections at the time of AIHA were present in 10 patients. Five out of nine patients that received corticosteroids achieved either a PR or a CR, whereas six out of eight patients that received rituximab responded. Four patients developed AIT giving a 3-year CI of 1.4% (CI 95% 0-2.8), concomitant infections were present in three of them. Multivariable analysis showed that development of chronic GVHD (relative risk (RR) 4; 95% CI 1.1-13.7; P=0.03) and diagnosis of CML (RR 4.3; 95% CI 1.5-12.7; P=0.008) were associated with an increased risk of AC. In conclusion, AIHA and AIT are relevant and clinically significant complications in UCBT recipients, especially among those that develop chronic GVHD. Response to therapy is sub-optimal, and rituximab should be considered as a therapeutic option, in this setting were most patients had cold AIHA and a serological profile similar to that seen in cold agglutinin disease.
With new opportunities and challenges from additive manufacturing (AM), novel characterization approaches are needed to realize reliable and industry-transferrable material systems and processes. The ...Complex Scattering Program at the National Synchrotron Light Source II (NSLS-II), a Department of Energy (DOE) Office of Science User Research Facility located at Brookhaven National Laboratory, has capabilities on three beamlines to support in situ and operando soft material additive manufacturing measurements. These beamlines include: the Coherent Hard X-ray (CHX) beamline specializing in X-ray Photon Correlation Spectroscopy (XPCS), the Soft Matter Interfaces (SMI) and Complex Materials Scattering (CMS) beamlines specializing in time-resolved Small-Angle X-ray Scattering (SAXS) and Wide-Angle X-ray Scattering (WAXS) techniques. All three beamlines work in both transmission and grazing incidence geometries. Technical specifications for the beamlines are summarized in Table 1 with further details at https://www.bnl.gov/ps/beamlines/. In this article, we describe some of the additive manufacturing capabilities that have been implemented on these beamlines, including in-line 3D printers for Continuous-flow Direct Writing (CDW), Fused Filament Fabrication (FFF) printing, and an instrument for Electrospray Deposition (ESD). We also describe a development program in autonomous experimentation that will be critical for addressing the complexity involved in optimizing additive manufacturing processes and materials. These capabilities and approaches have been co-developed in partnership with Brookhaven’s Center for Functional Materials (CFN) as well as collaborative users from universities (Stony Brook and Yale University), government labs (Air Force Research Laboratory, National Institute of Standards and Technology, Lawrence Berkeley National Laboratory), and industry (Henkel Inc.).
To study the factors associated with an adverse pregnancy outcome in women with systemic lupus erythematosus (SLE).
SLE women from LUMINA of Hispanic, African American and Caucasian ethnicity were ...studied. Adverse pregnancy outcome was a miscarriage or abortion (<20 weeks), a stillbirth (> or = 20) and/or a moderate to severe preterm-baby (<34 weeks); good outcome was either a mild preterm-baby (> or = 34 weeks) or a full-term baby C-section or vaginal delivery (38-42 weeks). Pregnancies occurring after SLE diagnosis (TD) were included; pregnancy outcome was the unit of analyses. The relationship between selected variables and pregnancy outcomes was examined by univariable and multivariable analyses.
Adverse outcomes occurred in 63.7% of 102 pregnancies. In the univariable analyses, Texan Hispanic and African American ethnicities, fewer years of education, higher number of ACR criteria, renal involvement, glucocorticoid exposure and the maximum dose of glucocorticoids used prior to the pregnancy outcome were associated with an adverse pregnancy outcome. Renal involvement was independently associated with an adverse pregnancy outcome Odds ratio (OR)=5.219 (95% Confidence Interval (CI) 1.416-19.239, p=0.0131 as were the maximum dose of glucocorticoids used prior to the pregnancy outcome (OR=1.028; CI:1.002-1.054; p=0.0315) and fewer years of education (OR=1.204; CI:1.006-1.472; p=0.0437). Ethnicity was not retained in the multivariable model.
Renal involvement, the maximum dose of glucocorticoids used prior to pregnancy and fewer years of education were associated with adverse pregnancy outcomes. These data have implications for the management of women with lupus planning to become pregnant.
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