Markov Chain Monte–Carlo (MCMC) is an increasingly popular method for obtaining information about distributions, especially for estimating posterior distributions in Bayesian inference. This article ...provides a very basic introduction to MCMC sampling. It describes what MCMC is, and what it can be used for, with simple illustrative examples. Highlighted are some of the benefits and limitations of MCMC sampling, as well as different approaches to circumventing the limitations most likely to trouble cognitive scientists.
There is growing interest in diffusion models to represent the cognitive and neural processes of speeded decision making. Sequential-sampling models like the diffusion model have a long history in ...psychology. They view decision making as a process of noisy accumulation of evidence from a stimulus. The standard model assumes that evidence accumulates at a constant rate during the second or two it takes to make a decision. This process can be linked to the behaviors of populations of neurons and to theories of optimality. Diffusion models have been used successfully in a range of cognitive tasks and as psychometric tools in clinical research to examine individual differences. In this review, we relate the models to both earlier and more recent research in psychology.
We propose a linear ballistic accumulator (LBA) model of decision making and reaction time. The LBA is simpler than other models of choice response time, with independent accumulators that race ...towards a common response threshold. Activity in the accumulators increases in a linear and deterministic manner. The simplicity of the model allows complete analytic solutions for choices between any number of alternatives. These solutions (and freely-available computer code) make the model easy to apply to both binary and multiple choice situations. Using data from five previously published experiments, we demonstrate that the LBA model successfully accommodates empirical phenomena from binary and multiple choice tasks that have proven difficult for other theoretical accounts. Our results are encouraging in a field beset by the tradeoff between complexity and completeness.
The European Union's position on “one China” has stood since the establishment of diplomatic relations with the People's Republic of China (PRC) in 1975. As a union of distinct member states, the ...nature of the European Union's (EU) foreign policymaking complicates efforts to maintain coherent common positions. Its effective “one China policy” (and those of its member states) is no exception. In recent years, the edges of the bloc's long-standing policy have started to fray as the EU–PRC relationship has become more fraught and many member states have sought to deepen their effective, if “unofficial,” engagement with Taiwan. I explore these changes to the EU's effective “one China policy” by employing a subsystems framework, starting from the position that the EU has foreign policies (rather than a singular policy) created through three subsystems. Through the Normative Power Europe lens, I explore the extent to which the actors pulling at these “threads” at the edges of the EU's policy are motivated by normative concerns. I argue that the “fraying” of the EU's “one China policy” is not the result of a conscious decision by the EU as a collective normative actor but stems from shifting preferences within the national and supranational subsystems.
Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, ...neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this ...process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins. Rather, BOK is controlled at the level of protein stability by components of the endoplasmic reticulum (ER)-associated degradation pathway. BOK is ubiquitylated by the AMFR/gp78 E3 ubiquitin ligase complex and targeted for proteasomal degradation in a VCP/p97-dependent manner, which allows survival of the cell. When proteasome function, VCP, or gp78 activity is compromised, BOK is stabilized to induce MOMP and apoptosis independently of other BCL-2 proteins.
Display omitted
•BOK induces mitochondrial apoptosis in the absence of BAX and BAK•The proapoptotic activity of BOK is independent of other BCL-2 family proteins•BOK activity is regulated via endoplasmic-reticulum-associated degradation (ERAD)•ERAD components AMFR/gp78 and VCP/p97 and the proteasome carry out BOK degradation
The BCL-2 family member BOK offers a path to mitochondrial outer membrane permeabilization and apoptosis that can be executed in the absence of BAX and BAK and that is controlled at the level of protein stability by ER-associated degradation.
Follicular helper T (Tfh) cells are crucial for germinal center (GC) formation and humoral adaptive immunity. Mechanisms underlying Tfh cell differentiation in peripheral and mucosal lymphoid organs ...are incompletely understood. We report here that mTOR kinase complexes 1 and 2 (mTORC1 and mTORC2) are essential for Tfh cell differentiation and GC reaction under steady state and after antigen immunization and viral infection. Loss of mTORC1 and mTORC2 in T cells exerted distinct effects on Tfh cell signature gene expression, whereas increased mTOR activity promoted Tfh responses. Deficiency of mTORC2 impaired CD4+ T cell accumulation and immunoglobulin A production and aberrantly induced the transcription factor Foxo1. Mechanistically, the costimulatory molecule ICOS activated mTORC1 and mTORC2 to drive glycolysis and lipogenesis, and glucose transporter 1-mediated glucose metabolism promoted Tfh cell responses. Altogether, mTOR acts as a central node in Tfh cells by linking immune signals to anabolic metabolism and transcriptional activity.
Display omitted
•Raptor or Rictor deletion impairs GC and Tfh responses and IgA production•mTORC2 but not mTORC1 signals via Foxo1 inhibition to drive Tfh cell differentiation•mTORC1 and mTORC2 promote foreign antigen and LCMV-induced GC and Tfh responses•mTOR links ICOS and Glut1 to anabolic metabolism for Tfh cell differentiation
Follicular helper T (Tfh) cells are essential for efficient humoral immune responses. Zeng et al. identify mTOR signaling and glucose metabolism as critical regulators of Tfh cell differentiation in response to foreign antigen challenge and at steady state in Peyer’s patches.
Homology search and DNA strand-exchange reactions are central to homologous recombination in meiosis. During meiosis, these processes are regulated such that the probability of choosing a homolog ...chromatid as recombination partner is enhanced relative to that of choosing a sister chromatid. This regulatory process occurs as homologous chromosomes pair in preparation for assembly of the synaptonemal complex. Two strand-exchange proteins, Rad51 and Dmc1, cooperate in regulated homology search and strand exchange in most organisms. Here, we summarize studies on the properties of these two proteins and their accessory factors. In addition, we review current models for the assembly of meiotic strand-exchange complexes and the possible mechanisms through which the interhomolog bias of recombination partner choice is achieved.
Context effects occur when a choice between 2 options is altered by adding a 3rd alternative. Three major context effects-similarity, compromise, and attraction-have wide-ranging implications across ...applied and theoretical domains, and have driven the development of new dynamic models of multiattribute and multialternative choice. We propose the multiattribute linear ballistic accumulator (MLBA), a new dynamic model that provides a quantitative account of all 3 context effects. Our account applies not only to traditional paradigms involving choices among hedonic stimuli, but also to recent demonstrations of context effects with nonhedonic stimuli. Because of its computational tractability, the MLBA model is more easily applied than previous dynamic models. We show that the model also accounts for a range of other phenomena in multiattribute, multialternative choice, including time pressure effects, and that it makes a new prediction about the relationship between deliberation time and the magnitude of the similarity effect, which we confirm experimentally.
In the current study we investigated the effects of resisted sprint training on sprinting performance and underlying mechanical parameters (force-velocity-power profile) based on two different ...training protocols: (i) loads that represented maximum power output (Lopt) and a 50% decrease in maximum unresisted sprinting velocity and (ii) lighter loads that represented a 10% decrease in maximum unresisted sprinting velocity, as drawn from previous research (L10).
Soccer n = 15 male and rugby n = 21; 9 male and 12 female club-level athletes were individually assessed for horizontal force-velocity and load-velocity profiles using a battery of resisted sprints, sled or robotic resistance respectively. Athletes then performed a 12-session resisted (10 × 20-m; and pre- post-profiling) sprint training intervention following the L10 or Lopt protocol.
Both L10 and Lopt training protocols had minor effects on sprinting performance (average of -1.4 to -2.3% split-times respectively), and provided trivial, small and unclear changes in mechanical sprinting parameters. Unexpectedly, Lopt impacted velocity dominant variables to a greater degree than L10 (trivial benefit in maximum velocity; small increase in slope of the force-velocity relationship), while L10 improved force and power dominant metrics (trivial benefit in maximal power; small benefit in maximal effectiveness of ground force orientation).
Both resisted-sprint training protocols were likely to improve performance after a short training intervention in already sprint trained athletes. However, widely varied individualised results indicated that adaptations may be dependent on pre-training force-velocity characteristics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
