In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway.

BACKGROUND: Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. METHODS: Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student's t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey's correction for multiple pairwise comparisons. RESULTS: CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the α and γ subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. CONCLUSIONS: Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB

Genetic architecture of reciprocal social behavior in toddlers: Implications for heterogeneity in the early origins of autism spectrum disorder

Impairment in reciprocal social behavior (RSB), an essential component of early social competence, clinically defines autism spectrum disorder (ASD). However, the behavioral and genetic architecture of RSB in toddlerhood, when ASD first emerges, has not been fully characterized. We analyzed data from a quantitative video-referenced rating of RSB (vrRSB) in two toddler samples: a community-based volunteer research registry (n = 1,563) and an ethnically diverse, longitudinal twin sample ascertained from two state birth registries (n = 714). Variation in RSB was continuously distributed, temporally stable, significantly associated with ASD risk at age 18 months, and only modestly explained by sociodemographic and medical factors (r2 = 9.4%). Five latent RSB factors were identified and corresponded to aspects of social communication or restricted repetitive behaviors, the two core ASD symptom domains. Quantitative genetic analyses indicated substantial heritability for all factors at age 24 months (h2 ≥ .61). Genetic influences strongly overlapped across all factors, with a social motivation factor showing evidence of newly-emerging genetic influences between the ages of 18 and 24 months. RSB constitutes a heritable, trait-like competency whose factorial and genetic structure is generalized across diverse populations, demonstrating its role as an early, enduring dimension of inherited variation in human social behavior. Substantially overlapping RSB domains, measurable when core ASD features arise and consolidate, may serve as markers of specific pathways to autism and anchors to inform determinants of autism\u27s heterogeneity

Loss of Biological Diversity: A Global Crisis Requiring International Solutions: A Report to the National Science Board

Executive Summary Biological diversity refers to the variety and variability among living organisms and the ecological complexes in which they occur. Diversity can be defined as the number of different items and their relative frequency. For biological diversity, these items are organized at many levels, ranging from complete ecosystems to the chemical structures that are the molecular basis of heredity. Thus, the term encompasses different ecosystems, species, genes, and their relative abundance (OTA, 1987). There is an ongoing, unprecedented loss of the variety as well as absolute numbers of organisms-from the smallest microorganism to the largest and most spectacular of mammals. Loss of tropical moist forests, which contain over half the total species of organisms, has been well documented by scientists and is now widely reported in the media. Many other ecosystems are also threatened; as human populations and their support systems expand, natural ecosystems at all latitudes are altered or converted. At its meeting on October 15, 1987, the National Science Board concluded that the world\u27s decreasing biological diversity is a critical scientific issue requiring immediate attention. The National Science Board\u27s Committee on International Science was asked to study the scientific and international aspects of the decline of biological diversity and to recommend a course of action. This report describes what the National Science Foundation (NSF) can do to influence the U.S. science and education base, articulates where international scientific cooperation is needed, and suggests roles for other agencies and organizations (both national and international) which have scientific, educational, and management responsibilities. The current disappearance of biota has several causes: the destruction or degradation of entire ecosystems; the accelerating loss of individual species from communities or ecosystems as a result of human disturb;mce; and the loss of genetically distinct parts of populations due to human-induced selective pressures. Although not all parts of the planet are equally affected, the problem is global, and human activities are the primary cause. The loss of biological diversity is important because human existence depends on the biological resources of 1 the earth. Human prosperity is based very largely on the ability to utilize biological diversity: to take advantage of the properties of plants, animals, fungi, and microorganisms for food, clothing, medicine, and shelter. Scientific knowledge about the earth\u27s biological diversity has huge gaps. This lack of information hampers society\u27s ability either to estimate the magnitude of the problem or to prevent further losses. It is impossible to identify all the biological resources at risk, since there is no complete inventory of all the life forms on earth. Approximately 1.4 million species have been given scientific names, but estimates of actual numbers range from 5 million to 80 million species. Although knowledge of some taxa is extensive, the vast majority of groups are largely unknown. The current wave of extinction is destroying both known biotic resources and those still undiscovered. As is proving to be the case with most environmental problems, neither the loss of biological diversity nor its solution is the exclusive province of any one nation. International cooperation is necessary to develop both scientific knowledge and successful mitigation and management strategies. The root causes of the problem include sociological and economic processes which operate on an global scale; a thorough understanding will require investigation and elucidation of both biological and non-biological components. There are several reasons for increasing National Science Foundation (NSF) involvement in biodiversity studies: the economic and social importance of biodiversity (and the risk of opportunity lost due to accelerating extinction); the contributions such leadership can make toward to conservation of biological diversity; the important role of such studies in the international growth of science, especially in tropical countries; the potential impact of such studies on the future course of biology as a whole; and enhancing public awareness of the issues. NSF should assume a scientific leadership position with respect to agencies in the U.S. and throughout the world. By insisting on the central importance of biodiversity, the NSF could encourage collaborative support for the actions recommended below. 1. The Committee believes that the role of the NSF is clear-NSF should, as a matter of National Science Board Policy, provide leadership to undertake the inventory of the world\u27s biodiversity. 2. The scientific basis for conservation biology, restoration ecology, and environmental management must be strengthened. 3. Educational and public awareness programs related to biodiversity need increased support. 4. The economic and social aspects of the biodiversity crisis need additional study. 5. Enhance support for developing country scientists and institutions for biodiversity research and conservation

Sediment Cores from White Pond, South Carolina, contain a Platinum Anomaly, Pyrogenic Carbon Peak, and Coprophilous Spore Decline at 12.8 ka

A widespread platinum (Pt) anomaly was recently documented in Greenland ice and 11 North American sedimentary sequences at the onset of the Younger Dryas (YD) event (~12,800 cal yr BP), consistent with the YD Impact Hypothesis. We report high-resolution analyses of a 1-meter section of a lake core from White Pond, South Carolina, USA. After developing a Bayesian age-depth model that brackets the late Pleistocene through early Holocene, we analyzed and quantified the following: (1) Pt and palladium (Pd) abundance, (2) geochemistry of 58 elements, (3) coprophilous spores, (4) sedimentary organic matter (OC and sedaDNA), (5) stable isotopes of C (δ13C) and N (δ15N), (6) soot, (7) aciniform carbon, (8) cryptotephra, (9) mercury (Hg), and (10) magnetic susceptibility. We identified large Pt and Pt/Pd anomalies within a 2-cm section dated to the YD onset (12,785 ± 58 cal yr BP). These anomalies precede a decline in coprophilous spores and correlate with an abrupt peak in soot and C/OC ratios, indicative of large-scale regional biomass burning. We also observed a relatively large excursion in δ15N values, indicating rapid climatic and environmental/hydrological changes at the YD onset. Our results are consistent with the YD Impact Hypothesis and impact-related environmental and ecological changes

NOD2 Mutations and Anti-Saccharomyces cerevisiae Antibodies Are Risk Factors for Crohn's Disease in African Americans

NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with Crohn’s disease (CD), ileal involvement and complicated disease behavior in whites. ASCA and the three common NOD2 mutations have not been assessed in African American (AA) adults with CD

Functional imaging of cognition in an old-old population: A case for portable functional near-infrared spectroscopy

In this study, functional near-infrared spectroscopy (fNIRS) was used to record brain activa- tion during cognitive testing in older individuals (88±6yo; N = 19) living in residential care communities. This population, which is often associated with loss of personal independence due to physical or cognitive decline associated with aging, is also often under-represented in neuroscience research because of a limited means to participate in studies which often take place in large urban or university centers. In this study, we demonstrate the feasibility and initial results using a portable 8-source by 4-detector fNIRS system to measure brain activity from participants within residential care community centers. Using fNIRS, brain sig- nals were recorded during a series of computerized cognitive tests, including a Symbol Digit Coding test (SDC), Stroop Test (ST), and Shifting Attention Test (SAT). The SDC and SAT elicited greater activity in the left middle frontal region of interest. Three components of the ST produced increases in the right middle frontal and superior frontal, and left superior frontal regions. An association between advanced age and increased activation in the right middle frontal region was observed during the incongruent ST. Although none of the partici- pants had clinical dementia based on the short portable mental status questionnaire, the group performance was slightly below age-normed values on these cognitive tests. These results demonstrate the capability for obtaining functional neuroimaging measures in resi- dential settings, which ultimately may aid in prognosis and care related to dementia in older adults

AKT1 polymorphisms are associated with risk for metabolic syndrome

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations

Photovoltaic restoration of sight with high visual acuity

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration