Acoustic Correlates of Information Structure.

This paper reports three studies aimed at addressing three questions about the acoustic correlates of information structure in English: (1) do speakers mark information structure prosodically, and, to the extent they do; (2) what are the acoustic features associated with different aspects of information structure; and (3) how well can listeners retrieve this information from the signal? The information structure of subject-verb-object sentences was manipulated via the questions preceding those sentences: elements in the target sentences were either focused (i.e., the answer to a wh-question) or given (i.e., mentioned in prior discourse); furthermore, focused elements had either an implicit or an explicit contrast set in the discourse; finally, either only the object was focused (narrow object focus) or the entire event was focused (wide focus). The results across all three experiments demonstrated that people reliably mark (1) focus location (subject, verb, or object) using greater intensity, longer duration, and higher mean and maximum F0, and (2) focus breadth, such that narrow object focus is marked with greater intensity, longer duration, and higher mean and maximum F0 on the object than wide focus. Furthermore, when participants are made aware of prosodic ambiguity present across different information structures, they reliably mark focus type, so that contrastively focused elements are produced with greater intensity, longer duration, and lower mean and maximum F0 than noncontrastively focused elements. In addition to having important theoretical consequences for accounts of semantics and prosody, these experiments demonstrate that linear residualisation successfully removes individual differences in people's productions thereby revealing cross-speaker generalisations. Furthermore, discriminant modelling allows us to objectively determine the acoustic features that underlie meaning differences

Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine Production

BACKGROUND: The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents.METHODOLOGY/PRINCIPAL FINDINGS: We find that combining ?CTLA-4 and ?4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-? production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with ?4-1BB alone.CONCLUSIONS/SIGNIFICANCE: This study shows that combining T-cell co-inhibitory blockade with ?CTLA-4 and active co-stimulation with ?4-1BB promotes rejection of B16 melanoma in the context of a suitable vaccine. In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma

Vitalism in contemporary chiropractic: a help or a hinderance?

Background: Chiropractic emerged in 1895 and was promoted as a viable health care substitute in direct competition with the medical profession. This was an era when there was a belief that one cause and one cure for all disease would be discovered. The chiropractic version was a theory that most diseases were caused by subluxated (slightly displaced) vertebrae interfering with “nerve vibrations” (a supernatural, vital force) and could be cured by adjusting (repositioning) vertebrae, thereby removing the interference with the body’s inherent capacity to heal. DD Palmer, the originator of chiropractic, established chiropractic based on vitalistic principles. Anecdotally, the authors have observed that many chiropractors who overtly claim to be “vitalists” cannot define the term. Therefore, we sought the origins of vitalism and to examine its effects on chiropractic today. Discussion: Vitalism arose out of human curiosity around the biggest questions: Where do we come from? What is life? For some, life was derived from an unknown and unknowable vital force. For others, a vital force was a placeholder, a piece of knowledge not yet grasped but attainable. Developments in science have demonstrated there is no longer a need to invoke vitalistic entities as either explanations or hypotheses for biological phenomena. Nevertheless, vitalism remains within chiropractic. In this examination of vitalism within chiropractic we explore the history of vitalism, vitalism within chiropractic and whether a vitalistic ideology is compatible with the legal and ethical requirements for registered health care professionals such as chiropractors. Conclusion: Vitalism has had many meanings throughout the centuries of recorded history. Though only vaguely defined by chiropractors, vitalism, as a representation of supernatural force and therefore an untestable hypothesis, sits at the heart of the divisions within chiropractic and acts as an impediment to chiropractic legitimacy, cultural authority and integration into mainstream health care

Postmodern Literary Labyrinths: Spaces of Horror Reimagined

Cox examines horror in Angela Carter’s The Passion of New Eve (1977) and Mark Z. Danielewski’s House of Leaves (2000) as the confrontation with labyrinthine architecture that represents bodily and psychological reflections of self as monstrous, disorientating, and feminine. The reimagined space (re)absorbs and so threatens the protagonists with existential nothingness. Drawing on the abject body, there is an inevitable confrontation with an active maternal origin. Horror is elicited, not by the expected confrontation with the monster, but by encounter with the anthropomorphic labyrinth’s ability to entrap, nullify, and transform. Surprisingly, the experience of these labyrinths, as a reimagined space of horror, typically results in positive transformation. The labyrinth is both the locus of horror and a means to understand and move on from trauma

The use of tandem mass spectrometry as a problem‐solving tool in the industrial environment

This paper deals with a number of the benefits associated with a variety of tandem mass spectrometer geometries and the way in which these configurations have been applied to the solution of real problems. It discusses the use made of a variety of tandem mass spectrometry approaches to the study of analytical problems of industrial relevance. ICIs utilization of tandem mass spectrometry has grown substantially from an initial involvement in the early 1980s to a point where a number of instruments have been installed and used predominantly for trace analysis, structural studies and in the characterization of complex mixtures. We have selected a small number of examples of the use of the various tandem mass spectrometry approaches emphasizing the unique features of the technique.</p