The rockefeller university

Biomarkers are important in stress biology in relation to assessing individual and population health. They facilitate tapping meaningfully into the complex, non-linear interactions that affect the brain and multiple systems of the body and promote adaptation or, when dysregulated, they can accelerate disease processes. This has demanded a multifactorial approach to the choice of biomarkers. This is necessary in order to adequately describe and predict how an individual embedded in a particular social and physical environment, and with a unique genotype and set of lifetime experiences, will fare in terms of health and disease risk, as well as how that individual will respond to an intervention. Yet, at the same time, single biomarkers can have a predictive or diagnostic value when combined with carefully designed longitudinal assessment of behavior and disease related to stress. Moreover, the methods of brain imaging, themselves the reflection of the complexity of brain functional architecture, have provided new ways of diagnosing, and possibly differentiating, subtypes of depressive illness and anxiety disorders that are precipitated or exacerbated by stress. Furthermore, postmortem assessment of brain biomarkers provides important clues about individual vulnerability for suicide related to depression and this may lead to predictive biomarkers to better treat individuals with suicidal depression. Once biomarkers are available, approaches to prevention and treatment should take advantage of the emerging evidence that activating brain plasticity together with targeted behavioral interventions is a promising strategy. (C) 2015 Elsevier Inc. All rights reserved.

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

The production of Z bosons is studied in the dimuon and dielectron decay channels in PbPb and pp collisions at root s(NN) = 2.76TeV, using data collected by the CMS experiment at the LHC. The PbPb data sample corresponds to an integrated luminosity of about 166 mu b(-1), while the pp data sample collected in 2013 at the same nucleon-nucleon centre-of-mass energy has an integrated luminosity of 5.4 pb(-1). The Z boson yield is measured as a function of rapidity, transverse momentum, and collision centrality. The ratio of PbPb to pp yields, scaled by the number of inelastic nucleon-nucleon collisions, is found to be 1.06 +/- 0.05 (stat) +/- 0.08 (syst) in the dimuon channel and 1.02 +/- 0.08 (stat) +/- 0.15 (syst) in the dielectron channel, for centrality-integrated Z boson production. This binary collision scaling is seen to hold in the entire kinematic region studied, as expected for a colourless probe that is unaffected by the hot and dense QCD medium produced in heavy ion collisions.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN- immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

Primordial germ cells (PGCs) are the earliest population of germ cells established during embryonic development and constitute the beginning of the totipotent state. A recent study provides a new protocol for the efficient generation of PGC-like cells from human embryonic stem cells, providing an in vitro platform to study human PGC differentiation and specification.

Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency of innate immunity. This is the case of a previous healthy toddler and his sibling, who both died of fulminant sepsis due to Pseudomonas aeruginosa. Subsequent genetic analysis demonstrated IRAK-4 deficiency with compound heterozygous splice mutations. Fulminant fatal P. aeruginosa sepsis may be the first manifestation of IRAK-4 deficiency.

In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34(+) hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues.

Electronics companies throughout Asia recognize the benefits of Green Supply Chain Management (GSCM) for gaining competitive advantage. A large majority of electronics companies in Taiwan have recently adopted the Electronic Industry Citizenship Coalition (EICC) Code of Conduct for defining and managing their social and environmental responsibilities throughout their supply chains. We surveyed 106 Tier 1 suppliers to the Taiwanese computer industry to determine their environmental performance using the EICC Code of Conduct (EICC Code) and performed Analysis of Variance (ANOVA) on the 63/106 questionnaire responses collected. We test the results to determine whether differences in product type, geographic area, and supplier size correlate with different levels of environmental performance. To our knowledge, this is the first study to analyze questionnaire data on supplier adoption to optimize the implementation of GSCM. The results suggest that characteristic classification of suppliers could be employed to enhance the efficiency of GSCM.

The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 mu g/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment. IMPORTANCE Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.