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Despite the recent approval of new agents for metastatic melanoma, its treatment remains challenging. Moreover, few available immunotherapies induce a strong cellular immune response, and selection of the correct immunoadjuvant is crucial for overcoming this obstacle. Here, we studied the immunomodulatory properties of arazyme, a bacterial metalloprotease, which was previously shown to control metastasis in a murine melanoma B16F10-Nex2 model. The antitumor activity of arazyme was independent of its proteolytic activity, since heat-inactivated protease showed comparable properties to the active enzyme; however, the effect was dependent on an intact immune system, as antitumor properties were lost in immunodeficient mice. The protective response was IFN gamma-dependent, and CD8(+) T lymphocytes were the main effector antitumor population, although B and CD4(+) T lymphocytes were also induced. Macrophages and dendritic cells were involved in the induction of the antitumor response, as arazyme activation of these cells increased both the expression of surface activation markers and proinflammatory cytokine secretion through TLR4-MyD88-TRIF-dependent, but also MAPK-dependent pathways. Arazyme was also effective in the murine breast adenocarcinoma 4T1 model, reducing primary and metastatic tumor development, and prolonging survival. To our knowledge, this is the first report of a bacterial metalloprotease interaction with TLR4 and subsequent receptor activation that promotes a proinflammatory and tumor protective response. Our results show that arazyme has immunomodulatory properties, and could be a promising novel alternative for metastatic melanoma treatment.

Primate face processing depends on a distributed network of interlinked face-selective areas composed of face-selective neurons. In both humans and macaques, the network is divided into a ventral stream and a dorsal stream, and the functional similarities of the areas in humans and macaques indicate they are homologous. Neural correlates for face detection, holistic processing, face space, and other key properties of human face processing have been identified at the single neuron level, and studies providing causal evidence have established firmly that face-selective brain areas are central to face processing. These mechanisms give rise to our highly accurate familiar face recognition but also to our error-prone performance with unfamiliar faces. This limitation of the face system has important implications for consequential situations such as eyewitness identification and policing.

This paper describes the algorithms used by the CMS experiment to reconstruct and identify tau -> hadrons + nu(tau) decays during Run 1 of the LHC. The performance of the algorithms is studied in proton-proton collisions recorded at a centre-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The algorithms achieve an identification efficiency of 50-60%, with misidentification rates for quark and gluon jets, electrons, and muons between per mille and per cent levels.

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change containing variation acquired from archaic hominins or adaptive variants in specific populations improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.

A search is presented for a singly produced excited bottom quark (b*) decaying to a top quark and a W boson in the all-hadronic, lepton+jets, and dilepton final states in proton-proton collisions at root s = 8 TeV recorded by the CMS experiment at the CERN LHC. Data corresponding to an integrated luminosity of 19.7 fb(-1) are used. No significant excess of events is observed with respect to standard model expectations. We set limits at 95% confidence on the product of the b* quark production cross section and its branching fraction to tW. The cross section limits are interpreted for scenarios including left-handed, right-handed, and vector-like couplings of the b* quark and are presented in the two-dimensional coupling plane based on the production and decay coupling constants. The masses of the left-handed, right-handed, and vector-like b* quark states are excluded at 95% confidence below 1390, 1430, and 1530 GeV, respectively, for benchmark couplings. This analysis gives the most stringent limits on the mass of the b* quark to date.

The history of experimental approaches to the nervous system forms the backdrop for new opportunities of using stem cell technologies in neuroendocrine systems. The emphasis of this chapter is on attempts at therapeutic maneuvers.

Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop. IMPORTANCE The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.

A search is performed for the production of heavy resonances decaying into top-antitop quark pairs in proton-proton collisions at root s = 8 TeV. Data used for the analyses were collected with the CMS detector and correspond to an integrated luminosity of 19.7 fb(-1). The search is performed using events with three different final states, defined by the number of leptons (electrons and muons) from the t (t) over bar. WbWb decay. The analyses are optimized for reconstruction of top quarks with high Lorentz boosts, where jet substructure techniques are used to enhance the sensitivity. Results are presented for all channels and a combination is performed. No significant excess of events relative to the expected yield from standard model processes is observed. Upper limits on the production cross section of heavy resonances decaying to t (t) over bar are calculated. A narrow leptophobic topcolor Z' resonance with a mass below 2.4 TeV is excluded at 95% confidence level. Limits are also derived for a broad Z' resonance with a 10% width relative to the resonance mass, and a Kaluza-Klein excitation of the gluon in the Randall-Sundrum model. These are the most stringent limits to date on heavy resonances decaying into top-antitop quark pairs.

MicroRNAs play diverse roles in both normal and malignant stem cells. Focusing on miRs and/or miR*s abundant in squamous cell carcinoma (SCC) stem cells, we engineer an efficient, strand-specific expression library, and apply functional genomics screening in mice to identify which of 169 cancer-associated miRs are key drivers in malignant progression. Not previously linked functionally to cancer, miR-21* was the second top hit, surfacing in >12% of tumours. miR-21* also correlates with poor prognosis in human SCCs and enhances tumour progression in xenografts. On deleting the miR-21 gene and rescuing each strand separately, we document the dual, but independent, oncogenicity of miR-21 and miR-21*. A cohort of predicted miR-21* targets inversely correlate with miR-21* in SCCs. Of particular interest is Phactr4, which we show is a miR-21* target in SCCs, acting through the Rb/E2F cell cycle axis. Through in vivo physiological miR screens, our findings add an interesting twist to an increasingly important oncomiR locus.

The brain is the central organ for adaptation to experiences, including stressors, which are capable of changing brain architecture as well as altering systemic function through neuroendocrine, autonomic, immune, and metabolic systems. Because the brain is the master regulator of these systems, as well as of behavior, alterations in brain function by chronic stress can have direct and indirect effects on cumulative allostatic overload, which refers to the cost of adaptation. There is much new knowledge on the neural control of systemic physiology and the feedback actions of physiologic mediators on brain regions regulating higher cognitive function, emotional regulation, and self-regulation. The healthy brain has a considerable capacity for resilience, based upon its ability to respond to interventions designed to open "windows of plasticity" and redirect its function toward better health. As a result, plasticity-facilitating treatments should be given within the framework of a positive behavioral intervention; negative experiences during this window may even make matters worse. Indeed, there are no magic bullets and drugs cannot substitute for targeted interventions that help an individual become resilient, of which mindfulness-based stress reduction and meditation are emerging as useful tools.