The rockefeller university

Taylor's power law of fluctuation scaling (TL) states that for population density, population abundance, biomass density, biomass abundance, cell mass, protein copy number, or any other nonnegative-valued random variable in which the mean and the variance are positive, variance = a(mean)(b), a > 0, or equivalently log variance = log a + b x log mean. Many empirical examples and practical applications of TL are known, but understanding of TL's origins and interpretations remains incomplete. We show here that, as time becomes large, TL arises from multiplicative population growth in which successive random factors are chosen by a Markov chain. We give exact formulas for a and b in terms of the Markov transition matrix and the values of the successive multiplicative factors. In this model, the mean and variance asymptotically increase exponentially if and only if b > 2 and asymptotically decrease exponentially if and only if b < 2. (c) 2014 Elsevier Inc. All rights reserved.

Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct (dopamine D1 receptor-expressing) and indirect (D2 receptor-expressing striatal output) pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Our results indicate that, in rats: (1) PDE10A inhibition (TP-10, 0.32-10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; (2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg). These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.

The precise mechanisms governing invasion at the leading edge of squamous cell carcinoma (SCC) and its subsequent metastasis are not fully understood. We aimed to define the cancer-related molecular changes that distinguish noninvasive tumor from invasive SCC. To this end, we combined laser capture microdissection with complementary DNA (cDNA) microarray analysis. We defined invasion-associated genes as those differentially regulated only in invasive SCC nests, but not in actinic keratosis or in situ SCC, compared with normal epidermis. There were 383 upregulated and 354 downregulated genes in the "invasion set." SCC invasion was characterized by aberrant expression of various proteolytic molecules. We noted increased expression of MMP7 and IL-24 in invasive SCC. IL-24 induced the expression of matrix metallopeptidase 7 (MMP7) in SCC cells in culture. In addition, blocking of MMP7 by a specific antibody significantly delayed the migration of SCC cells in culture. These results suggest a possible contribution of IL-24 to SCC invasion via enhancing focal expression of MMP7, although IL-24 has been suggested to have antitumor growth effects in other cancer types. Identification of regional molecular changes that regulate cancer invasion may facilitate the development of new targeted treatments for aggressive cancer.

The traditional view on visual processing emphasizes a hierarchy: local line segments are first linked into global contours, which in turn are assembled into more complex forms. Distinct from this bottom-up viewpoint, here we provide evidence for a theoretical framework whereby objects and their parts are processed almost concurrently in a bidirectional cortico-cortical loop. By simultaneous recordings from V1 and V4 in awake monkeys, we found that information about global contours in a cluttered background emerged initially in V4, started similar to 40 ms later in V1, and continued to develop in parallel in both areas. Detailed analysis of neuronal response properties implicated contour integration to emerge from both bottom-up and reentrant processes. Our results point to an incremental integration mechanism: feedforward assembling accompanied by feedback disambiguating to define and enhance the global contours and to suppress background noise. The consequence is a parallel accumulation of contour information over multiple cortical areas.

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b - dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b - migDCs). Here, we build on the observation that Langerin-CD11b - migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b - Flt3L-responsive DCs are largely CD24(+) and CX(3)CR1(low) and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b - migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8 alpha cDCs and Langerin +CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin-CD11b - dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment.

Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells. The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied. Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir C-max (13 versus 207 ng/mL) and lower systemic exposures (AUC(0t), 383 versus 1810 ngh/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 M) and 120 mg of tenofovir alafenamide (16.9 M) compared with 300 mg of tenofovir disoproxil fumarate (0.9 M). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were 0.94 log(10)copies/mL for the tenofovir disoproxil fumarate group, 1.57 log(10) copies/mL for the 40 mg of tenofovir alafenamide group and 1.71 log(10) copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were 0.36, 0.63 and 0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected. Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.

During immune responses, B lymphocytes clonally expand and undergo secondary diversification of their immunoglobulin genes in germinal centres (GCs)(1-4). High-affinity B cells are expanded through iterative interzonal cycles of division and hypermutation in the GC dark zone followed by migration to the GC light zone, where they are selected on the basis of affinity to return to the dark zone(5-10). Here we combine a transgenic strategy to measure cell division and a photoactivatable fluorescent reporter to examine whether the extent of clonal expansion and hypermutation are regulated during interzonal GC cycles. We find that both cell division and hypermutation are directly proportional to the amount of antigen captured and presented by GC B cells to follicular helper T cells in the light zone. Our data explain how GC B cells with the highest affinity for antigen are selectively expanded and diversified.

Mature oocyte cytoplasm can reprogram somatic cell nuclei to the pluripotent state through a series of sequential events including protein exchange between the donor nucleus and ooplasm, chromatin remodeling, and pluripotency gene reactivation. Maternal factors that are responsible for this reprogramming process remain largely unidentified. Here, we demonstrate that knockdown of histone variant H3.3 in mouse oocytes results in compromised reprogramming and down-regulation of key pluripotency genes; and this compromised reprogramming for developmental potentials and transcription of pluripotency genes can be rescued by injecting exogenous H3.3 mRNA, but not H3.2 mRNA, into oocytes in somatic cell nuclear transfer embryos. We show that maternal H3.3, and not H3.3 in the donor nucleus, is essential for successful reprogramming of somatic cell nucleus into the pluripotent state. Furthermore, H3.3 is involved in this reprogramming process by remodeling the donor nuclear chromatin through replacement of donor nucleus-derived H3 with de novo synthesized maternal H3.3 protein. Our study shows that H3.3 is a crucial maternal factor for oocyte reprogramming and provides a practical model to directly dissect the oocyte for its reprogramming capacity.

Type I interferons (IFNs), including various IFN-alpha isoforms and IFN-beta, are a family of homologous, multifunctional cytokines. IFNs activate different cellular responses by binding to a common receptor that consists of two subunits, IFNAR1 and IFNAR2. In addition to stimulating antiviral responses, they also inhibit cell proliferation and modulate other immune responses. We characterized various IFNs, including a mutant IFN-alpha 2 (IFN-1ant) that bound tightly to IFNAR2 but had markedly reduced binding to IFNAR1. Whereas IFN-1ant stimulated antiviral activity in a range of cell lines, it failed to elicit immuno-modulatory and antiproliferative activities. The antiviral activities of the various IFNs tested depended on a set of IFN-sensitive genes (the "robust" genes) that were controlled by canonical IFN response elements and responded at low concentrations of IFNs. Conversely, these elements were not found in the promoters of genes required for the antiproliferative responses of IFNs (the "tunable" genes). The extent of expression of tunable genes was cell type-specific and correlated with the magnitude of the antiproliferative effects of the various IFNs. Although IFN-1ant induced the expression of robust genes similarly in five different cell lines, its antiviral activity was virus-and cell type-specific. Our findings suggest that IFN-1ant may be a therapeutic candidate for the treatment of specific viral infections without inducing the immunomodulatory and antiproliferative functions of wild-type IFN.