Explore the vast range of titles available.

\"Since 2008 the financial sector has been the subject of extensive criticism. Much of this criticism has focussed on the morality the actors involved in the crisis and its extended aftermath. This book analyses the key moral and political philosophical issues of the crisis and relates them to the political economy of finance. It also examines to what extent the financial sector can or should be reformed.This book is unified by the view that the financial sector had been a self-serving and self-regulating elite consumed by greed, speculation and even lawlessness with little sense of responsibility to the wider society or common good. In light of critical analysis by authors from a variety of backgrounds and persuasions, suggestions for reform and improvement are proposed, in some cases radical reform. By placing the world of finance under a microscope this book analyses the assumptions that have led from hubris to disgrace as it provides suggestions for an improved society.Rooted in philosophical reflection this book invites a critical reassessment of finance and its societal role in the 21st century. This book will be of interest to academics, politicians, central bankers and financial regulators who wish to improve the morality of finance. \"-- Provided by publisher.

Most brain activity occurs in an ongoing manner not directly locked to external events or stimuli. Regional ongoing activity fluctuates in unison with some brain regions but not others, and the degree of long-range coupling is called functional connectivity, often measured with correlation. Strength and spatial distributions of functional connectivity dynamically change in an ongoing manner over seconds to minutes, even when the external environment is held constant. Direct evidence for any behavioral relevance of these continuous large-scale dynamics has been limited. Here, we investigated whether ongoing changes in baseline functional connectivity correlate with perception. In a continuous auditory detection task, participants perceived the target sound in roughly one-half of the trials. Very long (22–40 s) interstimulus intervals permitted investigation of baseline connectivity unaffected by preceding evoked responses. Using multivariate classification, we observed that functional connectivity before the target predicted whether it was heard or missed. Using graph theoretical measures, we characterized the difference in functional connectivity between states that lead to hits vs. misses. Before misses compared with hits and task-free rest, connectivity showed reduced modularity, a measure of integrity of modular network structure. This effect was strongest in the default mode and visual networks and caused by both reduced within-network connectivity and enhanced across-network connections before misses. The relation of behavior to prestimulus connectivity was dissociable from that of prestimulus activity amplitudes. In conclusion, moment to moment dynamic changes in baseline functional connectivity may shape subsequent behavioral performance. A highly modular network structure seems beneficial to perceptual efficiency.

\"A thousand years from now, Vance Astro, Yondu, Martinex and Charlie-27 will rise to free the enslaved planet Earth -- as the Guardians of the Galaxy! Soon, Captain America, Doctor Strange, the Thing, the Hulk and more join the time-spanning heroes in the war to reclaim the future! Threats arise from other worlds -- as well as new allies Nikki and the uncanny Starhawk! But when Guardians and Avengers join forces in the present day, will even the combined might of two millennia be enough to stop the deranged demigod Michael Korvac? Plus: the Silver Surfer, Ms. Marvel, Spider-Man and Adam Warlock!\"-- Amazon.com description.

Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic animals is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of β-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against β-cell dysfunction in diabetes. β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.

Systems neuroscience approaches with a focus on large-scale brain organization and network analysis are advancing foundational knowledge of how cognitive control processes are implemented in the brain. Over the past decade, technological and computational innovations in the study of brain connectivity have led to advances in our understanding of how brain networks function, inspiring new conceptualizations of the role of prefrontal cortex (PFC) networks in the coordination of cognitive control. In this review, we describe six key PFC networks involved in cognitive control and elucidate key principles relevant for understanding how these networks implement cognitive control. Implementation of cognitive control in a constantly changing environment depends on the dynamic and flexible organization of PFC networks. In this context, we describe major empirical and theoretical models that have emerged in recent years and describe how their functional architecture and dynamic organization supports flexible cognitive control. We take an overarching view of advances made in the past few decades and consider fundamental issues regarding PFC network function, global brain dynamics, and cognition that still need to be resolved. We conclude by clarifying important future directions for research on cognitive control and their implications for advancing our understanding of PFC networks in brain disorders.

Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be stored for longer periods of time through active maintenance or rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behaviour. Empirical studies of working memory using neuroscientific techniques, such as neuronal recordings in monkeys or functional neuroimaging in humans, have advanced our knowledge of the underlying neural mechanisms of working memory. This rich dataset can be reconciled with behavioural findings derived from investigating the cognitive mechanisms underlying working memory. In this paper, I review the progress that has been made towards this effort by illustrating how investigations of the neural mechanisms underlying working memory can be influenced by cognitive models and, in turn, how cognitive models can be shaped and modified by neuroscientific data. One conclusion that arises from this research is that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the prefrontal cortex (PFC), is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.

Bisphosphoglycerate mutase (BPGM) drives phosphoglycerate mutase 1 (PGAM1) phosphorylation, which is required for glycolytic flux. Loss of BPGM is partially compensated by 1,3-BPG directly phosphorylating PGAM1, sustaining glycolytic flux but diverting metabolites for serine synthesis. Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active. We show that the primary PGAM1 histidine phosphate donor is 2,3-bisphosphoglycerate (2,3-BPG), which is made from the glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) by bisphosphoglycerate mutase (BPGM). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1. In this case, PGAM1 phosphorylation and activity are decreased, but nevertheless sufficient to maintain normal glycolytic flux and cellular growth rate. 3-PG, however, accumulates, leading to increased serine synthesis. Thus, one biological function of BPGM is controlling glycolytic intermediate levels and thereby serine biosynthetic flux.

Key Points Recent studies have reported rostro-caudal distinctions in frontal cortex activity based on the level of abstractness of action representations. Moreover, some have proposed that these differences reflect a hierarchical organization, whereby anterior frontal regions influence processing by posterior frontal regions during the realization of abstract action goals as motor acts. However, if such a processing hierarchy indeed exists, systematic rostro-caudal patterns should be evident in the anatomy and function of the frontal cortex. Evidence from single-unit recording and lesion studies of behavioural rule learning, conditional action selection and response sequencing in non-human primates suggest that prefrontal cortex neurons code for more abstract rules and categories of responses than do premotor neurons, which are located in the more-caudal frontal cortex. Studies using functional MRI of humans have consistently shown systematic within-subject differences in activation from premotor cortex (caudal) to the frontal pole (rostral) based on the degree of abstraction entailed by an action selection problem. Data from effective connectivity analysis of functional MRI data in humans suggests a rostral-to-caudal flow of influence, which is indirectly consistent with a rostro-caudal hierarchy of processing. Recent, preliminary evidence from lesion studies provides the first direct support for such a hierarchy by showing deficits in more-abstract action selection after caudal frontal lesions but no deficits in more-concrete action selection after rostral frontal lesions. There is a gradient of laminar organization within the frontal cortex from the most anterior (least differentiated) to posterior portions. In this scheme, less differentiated areas, such as those in rostral prefrontal cortex (PFC; areas 10, 9 and 46), have more diffuse projections and are thus well situated to be at the top of a hierarchy. In contrast, more differentiated areas, such as those in caudal PFC (areas 9/46 and 8), have more intrinsic connections and are well situated to be lower in a hierarchy. Afferent and efferent projections within the frontal cortex follow a principle of contiguity along the rostro-caudal dimension, such that each region projects to immediately adjacent regions that are rostral and caudal to it. Thus, area 9/46d projects to area 10 and area 6. However, the frontal cortex is not fully connected. For example, no direct connections are found between 9/46d and 9/46v, even though they are adjacent to one another. Non-adjacent regions follow an asymmetry principle from rostral to caudal within the frontal cortex. Thus, area 10 projects to area 6 but there are no projections from area 6 to area 10. The most rostrally localized area 10 does not project directly to parietal, temporal and occipital areas, but more-caudal frontal regions (areas 9/46 and 6) do have massive bidirectional connections with these areas. During development, separate regions along the rostro-caudal axis of the frontal cortex mature at different rates. Although the premotor cortex matures the earliest, development does not progress uniformly back to front. Rather, the most caudal and rostral portions of the frontal cortex mature first, followed by the interposed lateral frontal regions. Studies into the role of different frontal cortex areas in cognitive control have suggested that there is a rostral-to-caudal processing gradient. Drawing on anatomical and functional data from humans and monkeys, Badre and D'Esposito discuss whether this gradient might reflect a hierarchical organization. The frontal lobes in the brain are a component of the cerebral system that supports goal-directed behaviour. However, their functional organization remains controversial. Recent studies have reported rostro-caudal distinctions in frontal cortex activity based on the abstractness of action representations. In addition, some have proposed that these differences reflect a hierarchical organization, whereby anterior frontal regions influence processing by posterior frontal regions during the realization of abstract action goals as motor acts. However, few have considered whether the anatomy and physiology of the frontal lobes support such a scheme. To address this gap, this Review surveys anatomical, neuroimaging, electrophysiological and developmental findings, and considers the question: could the organization of the frontal cortex be hierarchical?

Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their activation. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and act directly on host cells to cause cytotoxicity. Surface-induced AQ cytotoxicity is independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. We further show that packaging of AQs in outer-membrane vesicles (OMVs) increases their cytotoxicity to host cells but not their ability to stimulate downstream quorum sensing pathways in bacteria. OMVs lacking AQs are significantly less cytotoxic, suggesting these molecules play a role in OMV cytotoxicity, in addition to their previously characterized role in OMV biogenesis. AQ reporters also enabled us to dissect the signal transduction pathways downstream of the two known regulators of surface-dependent virulence, the quorum sensing receptor, LasR, and the putative mechanosensor, PilY1. Specifically, we show that PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AlgR then induces RhlR, which can induce the AQ biosynthesis operon under specific conditions. These findings collectively suggest that the induction of AQs upon surface association is both necessary and sufficient to explain surface-induced P. aeruginosa virulence.

Working memory is characterized by neural activity that persists during the retention interval of delay tasks. Despite the ubiquity of this delay activity across tasks, species and experimental techniques, our understanding of this phenomenon remains incomplete. Although initially there was a narrow focus on sustained activation in a small number of brain regions, methodological and analytical advances have allowed researchers to uncover previously unobserved forms of delay activity various parts of the brain. In light of these new findings, this Review reconsiders what delay activity is, where in the brain it is found, what roles it serves and how it may be generated.The short-term retention of working memory is accompanied by neural delay activity. Sreenivasan and D’Esposito describe how delay activity can be assessed, discuss where in the brain it occurs and why, and examine the possible mechanisms that underlie it.