Falling between the "War of Movement" in 1914 and the major
attrition battles of 1916, 1915 was a critical year in the First
World War. As France failed in ever-larger offensives to break
through the ...German trenches, Britain shifted its strategy from
defence of empire to total commitment to the continental war. In
the second of three planned volumes, Roy Prete analyzes the
political and military policies and strategies of Britain and
France and their joint command relationship on the Western Front in
1915. The opposing strategies of the two governments proved to be
the main determinant in the sometimes ragged relations between the
French commander-in-chief, Joseph Joffre, and his British
counterpart, Sir John French, as they sought to drive the German
army out of France and to aid their hard-pressed Russian ally. With
an impressive marshalling of evidence, Strategy and
Command demonstrates that the increased British commitment to
the continental war, manifested in sending Kitchener's New Armies
to France in 1915, was largely due to the disastrous situation of
the Russian army on the Eastern Front and the perceived weakness of
the French government. Based on extensive research in French and
British political and military archives, this new in-depth study of
Anglo-French military relations on the Western Front in 1915 fills
a major gap in the unfolding drama of the First World War.
Dopamine and Addiction Wise, Roy A; Robble, Mykel A
Annual review of psychology,
01/2020, Letnik:
71, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Addiction is commonly identified with habitual nonmedical self-administration of drugs. It is usually defined by characteristics of intoxication or by characteristics of withdrawal symptoms. Such ...addictions can also be defined in terms of the brain mechanisms they activate; most addictive drugs cause elevations in extracellular levels of the neurotransmitter dopamine. Animals unable to synthesize or use dopamine lack the conditioned reflexes discussed by Pavlov or the appetitive behavior discussed by Craig; they have only unconditioned consummatory reflexes. Burst discharges (phasic firing) of dopamine-containing neurons are necessary to establish long-term memories associating predictive stimuli with rewards and punishers. Independent discharges of dopamine neurons (tonic or pacemaker firing) determine the motivation to respond to such cues. As a result of habitual intake of addictive drugs, dopamine receptors expressed in the brain are decreased, thereby reducing interest in activities not already stamped in by habitual rewards.
T cells are critical for protective immune responses to pathogens and tumors. The T-cell receptor (TCR)–CD3 complex is composed of a diverse αβ TCR heterodimer noncovalently associated with the ...invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates recognition of antigenic peptides bound to MHC molecules (pMHC), whereas the CD3 molecules transduce activation signals to the T cell. Whereas much is known about downstream T-cell signaling pathways, the mechanism whereby TCR engagement by pMHC is first communicated to the CD3 signaling apparatus, a process termed early T-cell activation, remains largely a mystery. In this review, we examine the molecular basis for TCR activation in light of the recently determined cryoEM structure of a complete TCR–CD3 complex. This structure provides an unprecedented opportunity to assess various signaling models that have been proposed for the TCR. We review evidence from single-molecule and structural studies for force-induced conformational changes in the TCR–CD3 complex, for dynamically-driven TCR allostery, and for pMHC-induced structural changes in the transmembrane and cytoplasmic regions of CD3 subunits. We identify major knowledge gaps that must be filled in order to arrive at a comprehensive model of TCR activation that explains, at the molecular level, how pMHC-specific information is transmitted across the T-cell membrane to initiate intracellular signaling. An in-depth understanding of this process will accelerate the rational design of immunotherapeutic agents targeting the TCR–CD3 complex.
Excitatory afferents to the nucleus accumbens (NAc) are thought to facilitate reward seeking by encoding reward-associated cues. Selective activation of different glutamatergic inputs to the NAc can ...produce divergent physiological and behavioral responses, but mechanistic explanations for these pathway-specific effects are lacking. Here, we compared the innervation patterns and synaptic properties of ventral hippocampus, basolateral amygdala, and prefrontal cortex input to the NAc. Ventral hippocampal input was found to be uniquely localized to the medial NAc shell, where it was predominant and selectively potentiated after cocaine exposure. In vivo, bidirectional optogenetic manipulations of this pathway attenuated and enhanced cocaine-induced locomotion. Challenging the idea that any of these inputs encode motivationally neutral information, activation of each discrete pathway reinforced instrumental behaviors. Finally, direct optical activation of medium spiny neurons proved to be capable of supporting self-stimulation, demonstrating that behavioral reinforcement is an explicit consequence of strong excitatory drive to the NAc.
► Hippocampal input is predominant in the medial NAc shell and potentiated by cocaine ► Activity in hippocampal axons in the NAc drives cocaine-induced locomotion ► Irrespective of the pathway, mice work for photostimulation of glutamate axons in NAc ► Mice work to obtain direct optogenetic stimulation of NAc shell neurons
Britt et al. characterize hippocampal, amygdala, and prefrontal cortex input to the nucleus accumbens. Hippocampal input is shown to be predominant in the medial accumbens shell, yet photostimulation of axons from each pathway is sufficient to reinforce instrumental behaviors.
Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy ...in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.
To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset.
Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined.
Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay.
Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.
These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.
Strategy and command Prete, Roy A
Strategy and command,
c2009, 20090601, 2014, 2009, 2009-06-01
eBook
In the first of three projected volumes, Prete crafts a behind-the-scenes look at Anglo-French command relations during World War I, from the start of the conflict until 1915, when trench warfare ...drastically altered the situation. Drawing on extensive archival research, Prete argues that the British government's primary interest lay in the defence of the empire; the small expeditionary force sent to France was progressively enlarged because the French, especially Commander-in-Chief Joseph Joffre, dragged their British ally into a progressively greater involvement. Several crises in Anglo-French command relations derived from these competing strategic objectives. New information gleaned from French public and private archives - including private diaries - enlarge our understanding of key players in the allied relationship.
Abstract Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic ...methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3′-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.
Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are among the most complex known enzymes from secondary metabolism and are responsible for the biosynthesis of highly diverse ...bioactive polyketides. However, most of these metabolites remain uncharacterized, since trans-AT PKSs frequently occur in poorly studied microbes and feature a remarkable array of non-canonical biosynthetic components with poorly understood functions. As a consequence, genome-guided natural product identification has been challenging. To enable de novo structural predictions for trans-AT PKS-derived polyketides, we developed the trans-AT PKS polyketide predictor (TransATor). TransATor is a versatile bio- and chemoinformatics web application that suggests informative chemical structures for even highly aberrant trans-AT PKS biosynthetic gene clusters, thus permitting hypothesis-based, targeted biotechnological discovery and biosynthetic studies. We demonstrate the applicative scope in several examples, including the characterization of new variants of bioactive natural products as well as structurally new polyketides from unusual bacterial sources.
A phase-field model for the phase transition between austenite and martensite and twinning between two martensitic variants is presented from our previous theory 1 with the main focus on the ...influence of interfacial stress that is consistent with the sharp interface limit. Each variant-variant transformation can be represented by only one order parameter. Thus, it allows us to get the analytical solution of interface energy and width. Coupled phase-field and elasticity equations are solved for cubic-to-tetragonal phase transformation in NiAl shape memory alloy. The effects of interfacial stress are studied for martensite-martensite interfaces in detail, which was absent in 1. Additionally, stress and temperature-induced growth of the martensitic phase inside austenite and twining are simulated. Some of the nontrivial experimentally observed microstructures reproduced in the simulations 1 are analyzed in detail. It includes tip splitting and bending, and twins crossing. This theory can be extended for electric, reconstructive, and magnetic phase transformations.
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