The rockefeller university

Theories like predictive coding propose that lower-order brain areas compare their inputs to predictions derived from higher-order representations and signal their deviation as a prediction error. Here, we investigate whether the macaque face-processing system, a three-level hierarchy in the ventral stream, employs such a coding strategy. We show that after statistical learning of specific face sequences, the lower-level face area ML computes the deviation of actual from predicted stimuli. But these signals do not reflect the tuning characteristic of ML. Rather, they exhibit identity specificity and view invariance, the tuning properties of higher-level face areas AL and AM. Thus, learning appears to endow lower-level areas with the capability to test predictions at a higher level of abstraction than what is afforded by the feedforward sweep. These results provide evidence for computational architectures like predictive coding and suggest a new quality of functional organization of information-processing hierarchies beyond pure feedforward schemes.

The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The impact of age, race/ethnicity, healthcare insurance, and selected clinical variables on statin-preventable ASCVD were quantified in adults aged 21 to 79years from National Health and Nutrition Examination Surveys 2007-2012 using the 2013 American College of Cardiology/American Heart Association guideline on the treatment of cholesterol. Among approximate to 42.4 million statin-eligible, untreated adults, 52.6% were hypertensive and 71% were younger than 65years. Of approximate to 232000 statin-preventable ASCVD events annually, most occur in individuals younger than 65years, with higher proportions in blacks and Hispanics than whites (73.0% and 69.2% vs 56.9%, respectively; P<.01). Among adults younger than 65years, the ratio of statin-eligible but untreated to statin-treated adults was higher in blacks and Hispanics than whites (3.0 and 2.9 vs 1.3, respectively; P<.01), and blacks, men, hypertensives, and cigarette smokers were more likely to be statin eligible than their statin-ineligible counterparts by multivariable logistic regression. Two thirds of untreated statin-eligible adults had two or more healthcare visits per year. Identifying and treating more statin-eligible adults in the healthcare system could improve cardiovascular health equity.

STUDY QUESTION: Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems? SUMMARY ANSWER: A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders. WHAT IS KNOWN ALREADY: In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues. STUDY DESIGN, SIZE, DURATION: Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations. MAIN RESULTS AND THE ROLE OF CHANCE: A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion. LIMITATIONS, REASONS FOR CAUTION: All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary. WIDER IMPLICATIONS OF THE FINDINGS: Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A

Germinal centers (GCs) are micro-domains where B cells mature to develop high affinity antibodies. Inside a GC, B cells compete for antigen and T cell help, and the successful ones continue to evolve. New experimental results suggest that, under identical conditions, a wide spectrum of clonal diversity is observed in different GCs, and high affinity B cells are not always the ones selected. We use a birth, death and mutation model to study clonal competition in a GC over time. We find that, like all evolutionary processes, diversity loss is inherently stochastic. We study two selection mechanisms, birth-limited and death limited selection. While death limited selection maintains diversity and allows for slow clonal homogenization as affinity increases, birth limited selection results in more rapid takeover of successful clones. Finally, we qualitatively compare our model to experimental observations of clonal selection in mice.

The mammalian circadian clock is built on a feedback loop in which PER and CRY proteins repress their own transcription. We found that in mouse liver nuclei all three PERs, both CRYs, and Casein Kinase-1 delta (CK1 delta) are present together in an similar to 1.9-MDa repressor assembly that quantitatively incorporates its CLOCK-BMAL1 transcription factor target. Prior to incorporation, CLOCK-BMAL1 exists in an similar to 750-kDa complex. Single-particle electron microscopy (EM) revealed nuclear PER complexes purified from mouse liver to be quasi-spherical similar to 40-nm structures. In the cytoplasm, PERs, CRYs, and CK1 delta were distributed into several complexes of similar to 0.9-1.1 MDa that appear to constitute an assembly pathway regulated by GAPVD1, a cytoplasmic trafficking factor. Single-particle EM of two purified cytoplasmic PER complexes revealed similar to 20-nmand similar to 25-nm structures, respectively, characterized by flexibly tethered globular domains. Our results define the macromolecular assemblies comprising the circadian feedback loop and provide an initial structural view of endogenous eukaryotic clock machinery.

Army ants are top arthropod predators in tropical forests around the world. The colonies of many army ant species undergo stereotypical behavioral and reproductive cycles, alternating between brood care and reproductive phases. In the brood care phase, colonies contain a cohort of larvae that are synchronized in their development and have to be fed. In the reproductive phase larvae are absent and oviposition takes place. Despite these colony cycles being a striking feature of army ant biology, their adaptive significance is unclear. Here we use a modeling approach to show that cyclic reproduction is favored under conditions where per capita foraging costs decrease with the number of larvae in a colony ("High Cost of Entry" scenario), while continuous reproduction is favored under conditions where per capita foraging costs increase with the number of larvae ("Resource Exhaustion" scenario). We argue that the former scenario specifically applies to army ants, because large raiding parties are required to overpower prey colonies. However, once raiding is successful it provides abundant food for a large cohort of larvae. The latter scenario, on the other hand, will apply to non-army ants, because in those species local resource depletion will force workers to forage over larger distances to feed large larval cohorts. Our model provides a quantitative framework for understanding the adaptive value of phasic colony cycles in ants. (C) 2017 Elsevier Ltd. All rights reserved.

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-g and TNF-a upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.

We here report for the first time the synergistic implementation of structured illumination microscopy (SIM) and multifocus microscopy (MFM). This imaging modality is designed to alleviate the problem of insufficient volumetric acquisition speed in superresolution biological imaging. SIM is a wide-field super-resolution technique that allows imaging with visible light beyond the classical diffraction limit. Employing multifocus diffractive optics we obtain simultaneous wide-field 3D imaging capability in the SIM acquisition sequence, improving volumetric acquisition speed by an order of magnitude. Imaging performance is demonstrated on biological specimens. (C) 2017 Optical Society of America

In the past decade, NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented. The major inflammatory conditions were suppurative pleuropneumonia and bronchopneumonia with abscess formation, from which Pasteurella pneumotropica was commonly isolated, followed by otitis media. Both inflammatory and degenerative lesions of the genital tract were identified, along with neoplasms such as endometrial yolk sac carcinomas and granulosa cell tumors. Novel conditions identified included renal tubular degeneration and necrosis associated with 2 concurrent types of intranuclear inclusions, focal or multifocal hyperostosis of the skull, and neuroendocrine tumors of the mesometrium. The majority of degenerative lesions that affected the genital tract, endocrine, and skeletal systems did not represent the actual underlying cause of death but rather were considered incidental findings. This study indicates that both inflammatory and neoplastic conditions contribute to morbidity and mortality in experimentally manipulated aged female NSG mice.