The rockefeller university

BACKGROUND AND OBJECTIVE Taylor's law (TL) typically describes a linear relationship between the logarithm of the variance and the logarithm of the mean of population densities. It has been verified for many non-human species in ecology, and recently, for Norway's human population. In this article, we test TL for human mortality. METHOD We use death counts and exposures by single age (0 to 100) and calendar year (1960 to 2009) for countries of the Human Mortality Database to compute death rates as well as their rates of change in time. For both mortality measures, we test temporal forms of TL: In cross-age-scenarios, we analyze temporal variance to mean relationships at different ages in a certain country, and in cross-country-scenarios, we analyze temporal variance to mean relationships in different countries at a certain age. RESULTS The results reveal almost log-linear variance to mean relationships in both scenarios; exceptions are the cross-country-scenarios for the death rates, which appear to be clustered together, due to similar mortality levels among the countries. CONCLUSIONS TL appears to describe a regular pattern in human mortality. We suggest that it might be used (1) in mortality forecasting (to evaluate the quality of forecasts and to justify linear mortality assumptions) and (2) to reveal minimum mortality at some ages.

Immune checkpoint blockade of the programmed cell death protein 1 (PD-1) pathway by monoclonal antibodies (Abs) has shown promising clinical benefit in the treatment of multiple cancer types. We elucidated the contribution of the fragment crystallizable (Fc) domains of anti-PD-1 and anti-PD-ligand 1 (L1) Abs for their optimal anti-tumor activity. We revealed that distinct Fey receptor (Fc gamma Rs) dependency and mechanisms account for the in vivo activity of anti-PD-1 versus anti-PD-L1 Abs. Anti-PD-1 Abs were found to be Fc gamma R independent in vivo; the presence of Fc gamma R-binding capacity compromises their anti-tumor activity. In contrast, the anti-PD-L1 Abs show augmented anti-tumor activity when activating Fc gamma R binding is introduced into the molecules, altering myeloid subsets within the tumor microenvironment.

Background: Institutional review boards (IRBs) distinguish health care quality improvement (QI) and health care quality improvement research (QIR) based primarily on the rigor of the methods used and the purported generalizability of the knowledge gained. Neither of these criteria holds up upon scrutiny. Rather, this apparently false dichotomy may foster under-protection of participants in QI projects and over-protection of participants within QIR. Discussion: Minimal risk projects should entail minimal oversight including waivers for informed consent for both QI and QIR projects. Minimizing the burdens of conducting QIR, while ensuring minimal safeguards for QI projects, is needed to restore this imbalance in oversight. Potentially, such ethical oversight could be provided by the integration of Institutional Review Boards and Clinical Ethical Committees, using a more integrated and streamlined approach such as a two-step process involving a screening review, followed by a review by committee trained in QIR. Standards for such ethical review and training in these standards, coupled with rapid review cycles, could facilitate an appropriate level of oversight within the context of creating and sustaining learning health care systems. Summary: We argue that QI and QIR are not reliably distinguishable. We advocate for approaches that improve protections for QI participants while minimizing over-protection for participants in QIR through reasonable ethical oversight that aligns risk to participants in both QI and QIR with the needs of a learning health care system.

Filamentous fungi are the predominant source of lignocellulolytic enzymes used in industry for the transformation of plant biomass into high-value molecules and biofuels. The rapidity with which new fungal genomic and post-genomic data are being produced is vastly outpacing functional studies. This underscores the critical need for developing platforms dedicated to the recombinant expression of enzymes lacking confident functional annotation, a prerequisite to their functional and structural study. In the last decade, the yeast Pichia pastoris has become increasingly popular as a host for the production of fungal biomass-degrading enzymes, and particularly carbohydrate-active enzymes (CAZymes). This study aimed at setting-up a platform to easily and quickly screen the extracellular expression of biomass-degrading enzymes in P. pastoris. We first used three fungal glycoside hydrolases (GHs) that we previously expressed using the protocol devised by Invitrogen to try different modifications of the original protocol. Considering the gain in time and convenience provided by the new protocol, we used it as basis to set-up the facility and produce a suite of fungal CAZymes (GHs, carbohydrate esterases and auxiliary activity enzyme families) out of which more than 70% were successfully expressed. The platform tasks range from gene cloning to automated protein purifications and activity tests, and is open to the CAZyme users' community.

The Bose-Einstein condensation of bound pairs made of oppositely charged fermions in a magnetic field is investigated. We find that the condensation temperature shows the magnetic catalysis effect in weak coupling and the inverse magnetic catalysis effect in strong coupling. The different responses to the magnetic field can be attributed to the competition between the dimensional reduction by Landau orbitals in pairing dynamics and the anisotropy of the kinetic spectrum of fluctuations (bound pairs in the normal phase).

The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-kappa B, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein-coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wildtype (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.

Nuclear pore complexes (NPCs) form a selective filter that allows the rapid passage of transport factors (TFs) and their cargoes across the nuclear envelope, while blocking the passage of other macromolecules. Intrinsically disordered proteins (IDPs) containing phenylalanyl-glycyl (FG)-rich repeats line the pore and interact with TFs. However, the reason that transport can be both fast and specific remains undetermined, through lack of atomic-scale information on the behavior of FGs and their interaction with TFs. We used nuclear magnetic resonance spectroscopy to address these issues. We show that FG repeats are highly dynamic IDPs, stabilized by the cellular environment. Fast transport of TFs is supported because the rapid motion of FG motifs allows them to exchange on and off TFs extremely quickly through transient interactions. Because TFs uniquely carry multiple pockets for FG repeats, only they can form the many frequent interactions needed for specific passage between FG repeats to cross the NPC.

H1 and ZEUS have published single-differential cross sections for inclusive D*(+/-)-meson production in deep-inelastic ep scattering at HERA from their respective final data sets. These cross sections are combined in the common visible phase-space region of photon virtuality Q(2) > 5 GeV2, electron inelasticity 0.02 < y < 0.7 and the D*(+/-) meson's transverse momentum p(T)(D*) > 1.5 GeV and pseudorapidity vertical bar eta(D*)vertical bar < 1.5. The combination procedure takes into account all correlations, yielding significantly reduced experimental uncertainties. Double-differential cross sections d(2)sigma/dQ(2)dy are combined with earlier D*(+/-) data, extending the kinematic range down to Q(2) > 1.5 GeV2. Perturbative next-to-leading-order QCD predictions are compared to the results.