Search

Neurons and glial cells are endowed with membranes that express a rich repertoire of ion channels, transporters, and receptors. The constant flux of ions across the neuronal and glial membranes results in voltage fluctuations that can be recorded from the extracellular matrix. The high frequency components of this voltage signal contain information about the spiking activity, reflecting the output from the neurons surrounding the recording location. The low frequency components of the signal, referred to as the local field potential (LFP), have been traditionally thought to provide information about the synaptic inputs that impinge on the large dendritic trees of various neurons. In this review, we discuss recent computational and experimental studies pointing to a critical role of several active dendritic mechanisms that can influence the genesis and the location-dependent spectro-temporal dynamics of LFPs, spanning different brain regions. We strongly emphasize the need to account for the several fast and slow dendritic events and associated active mechanisms — including gradients in their expression profiles, inter- and intra-cellular spatio-temporal interactions spanning neurons and glia, heterogeneities and degeneracy across scales, neuromodulatory influences, and activitydependent plasticity — towards gaining important insights about the origins of LFP under different behavioral states in health and disease. We provide simple but essential guidelines on how to model LFPs taking into account these dendritic mechanisms, with detailed methodology on how to account for various heterogeneities and electrophysiological properties of neurons and synapses while studying LFPs.

Introduction: GDF11 is a pleiotropic circulating blood factor and member of the transforming growth factor β (TGFβ) superfamily. In animal models of stroke, GDF11 is linked to regeneration and recovery through neovascularization, neurogenesis, and anti-inflammatory effects, among other potential mechanisms. Methods: Focal cerebral infarcts were made by permanent occlusion of the proximal right middle cerebral artery (MCA) by microbipolar coagulation, following a modification of the method of Tamura et al. rGDF11 or vehicle was delivered via multiple routes of administration to male Sprague Dawley Rats at single and multiple doses ranging from 0.1 - 4 mg/kg per dose. Dosing started ~24 hours following injury. Behavioral assessments (e.g., limb placement and body swing) were captured at days 3, 5, 7, 14, 21, and 28 post-injury. Results: Dose-dependent improvements in all behavioral assessments were seen at all animals receiving any dose level or frequency of rGDF11. Vehicle vs. rGDF11 comparisons yielded statistically significant improvements (p < 0.05) in all 3 behavioral assessments at several post-injury timepoints, including follow-up days 14 & 28. No major tolerability events were observed, and no animals were lost during the study. Histologic and serum markers indicated rGDF11’s beneficial effects on neovascularization, neurogenesis, and inflammation. Conclusions: Treatment of pMCAO rats with rGDF11 ~24hrs post-injury resulted in dose-dependent, durable improvements in motor function-focused behavioral assessments. These data support continued development of the potential clinical therapeutic application of rGDF11 in stroke and related disorders.

Delayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 silencing in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased CA1 pyramidal cell burst firing during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel activator, occluded the impairment of contextual memory upon KCC2 silencing. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that impaired rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 silencing in the adult mouse brain.

Deep Learning has revolutionized various fields, including Computer Vision, Natural Language Processing, as well as Biomedical research. Within the field of neuroscience, specifically in electrophysiological neuroimaging, researchers are starting to explore leveraging deep learning to make predictions on their data without extensive feature engineering. The availability of large-scale datasets is a crucial aspect of allowing the experimentation of Deep Learning models. We are publishing the first large-scale clinical EEG dataset that simplifies data access and management for Deep Learning. This dataset contains eyes-closed EEG data prepared from a collection of 1,574 juvenile participants from the Healthy Brain Network. We demonstrate a use case integrating this framework, and discuss why providing such neuroinformatics infrastructure to the community is critical for future scientific discoveries.

Silence can stem from myriad stimuli, including but not limited to quietude, speechlessness, secretiveness or repression. The oppressed and marginalised women often resort to the ‘act’ of silence to survive in a patriarchal society. Indian playwright Mahesh Dattani has raised the social problem of misogyny in several of his plays. The women in these plays are neither timid nor shy. Yet, despite being quite vocal about various aspects, they keep parts of their lives buried in deep secrecy. Their selective silence also raises pertinent questions regarding gender-based power equations. Exploring the interconnection between patriarchy and silence in Mahesh Dattani’s Where Did I Leave My Purdah? and Final Solutions, this paper attempts to analyse as to whether silence of women in these plays is a manifestation of their agency or indirect patriarchal imposition.

Polarized hyphal growth of filamentous pathogenic fungi is an essential event for host penetration and colonization. The long-range early endosomal trafficking during the hyphal growth is crucial for nutrient uptake, sensing of host-specific cues, and regulation of effector production. Bin1/Amphiphysin/Rvs167 (BAR) domain-containing proteins mediate fundamental cellular processes, including membrane remodeling and endocytosis. Here, we identified an F-BAR domain protein (ArF-BAR) in the necrotrophic fungusAscochyta rabieiand demonstrate its involvement in endosome-dependent fungal virulence on the host plant,Cicer arietinum. We show that ArF-BAR regulates endocytosis at the hyphal tip, localizes to the early endosomes, and is involved in actin dynamics. Functional studies involving gene knockout and complementation experiments reveal that ArF-BAR is essential for virulence. The loss-of-function of ArF-BAR results in delayed formation of first septa from the hyphal tip, crucial for host penetration and proliferation. ArF-BAR was induced in response to oxidative stress and infection and localized to endocytic vesicles within the fungal hyphae. We also show that ArF-BAR is able to tubulate synthetic liposomes, suggesting the functional role of F-BAR domain in membrane tubule formationin vivo. Further, our studies identified a stress-induced transcription factor, ArCRZ1 (Calcineurin-responsive zinc finger 1) as key regulator for transcriptional reprogramming of ArF-BAR. We propose a model in which ArCRZ1 functions upstream of ArF-BAR to regulate fungal pathogenesis through a mechanism that involves membrane remodeling and actin cytoskeleton regulation.Author summaryBAR-domain superfamily is known to mold amorphous lipid bilayer into defined tubular shapes and critical for endosome formation and trafficking. Although these processes are studied earlier in the context of their structural and biochemical properties, there is limited evidence on the direct role of F-BAR domain proteins in the pathophysiological development of other economically important fungi. Our study assumes functional significance for plant infection as we identified an F-BAR domain-containing protein that is regulated by a distinct transcriptional network. We characterized F-BAR in a necrotrophic fungal pathogen,Ascochyta rabieithat causes the Ascochyta blight (AB) disease in chickpea plants. Additionally, we have also identified a calcium-regulated CRZ1 transcription factor that regulates the transcription ofArF-BAR. Our study will help to understand the complex interplay underlying the endosome formation required for fungal virulence.

Muscle satellite cells (SCs) are a quiescent (non-proliferative) stem cell population in uninjured skeletal muscle. Although SCs have been investigated for nearly 60 years, the molecular drivers that transform quiescent SCs into the rapidly dividing (activated) stem/progenitor cells that mediate muscle repair after injury remain largely unknown. Here we identify a prominent FBJ osteosarcoma oncogene (Fos) mRNA and protein signature in recently activated SCs that is rapidly, heterogeneously, and transiently induced by muscle damage. We further reveal a requirement for FOS to efficiently initiate key stem cell functions, including cell cycle entry, proliferative expansion, and muscle regeneration, via induction of "pro-regenerative" target genes that stimulate cell migration, division, and differentiation. Disruption of one of these Fos/AP-1 targets, NAD(+)-consuming mono-ADP-ribosyl-transferase 1 (Art1), in SCs delays cell cycle entry and impedes progenitor cell expansion and muscle regeneration. This work uncovers an early-activated FOS/ART1/mono-ADP-ribosylation (MARylation) pathway that is essential for stem cell-regenerative responses.

A scholar of the history and memory of slavery and the slave trade, Anna Lucia Araujo has written an important book on reparations in the longue duree. Unlike most works on reparations for racial s...

The election of the first African-American president prompted something of a renaissance for films about slavery and race as audiences became more receptive to this new history. During Obama’s presidency, films including Lincoln, Django Unchained, 12 Years a Slave, The Birth of a Nation, and 13th were released. These movies have helped popularize a more holistic history of slavery and its legacy, and in doing so have broadened the space in public discourse to consider the role of racism in the United States today.

In 1865, William Lloyd Garrison wondered whether he had become a Lincoln emancipationist or Abraham Lincoln had become a Garrisonian abolitionist. This article traces the evolution of Lincoln’s views on slavery and race, from free soil to abolition and from colonization to black citizenship. It argues that at the end of his life, Lincoln inhabited abolitionist ground when he called for limited black suffrage and came to accept the idea of blacks as citizens of the American Republic.

Attrition rates are typically higher in English-medium university programs in the Arab Gulf States than in programs offered in Arabic. This paper reports on the results of a study of academic engagement at a private regional university in the Sultanate of Oman. The longitudinal study sought to identify causes of attrition, including push factors such as financial difficulties, pull factors such as marriage or employment and fallout factors such as disillusionment and lack of academic progress. The study used a 45-item Arabic-language five-point Likert scale response key questionnaire featuring 15 dimensions of beliefs about university education with students and semi-structured interviews with a subset of students who dropped out. The first round of data collection in academic year 2013–2014 included 48 participants in the questionnaire stage, while the second round in academic year 2014–2015 included a subset of 18 questionnaire participants in addition to 18 semi-structured interviews with participants from the first stage who had dropped out. Results suggest a number of pull factors such as employment and family proximity, as well as fallout factors such as disillusionment with teaching and learning culture, were major contributors to dropout rates.

A twelve-year-old African-American female presented with two week history of progressively worsening headache and fatigue, and vision difficulties for the past week. The physical examination was normal. The neurological evaluation was normal, except for cranial nerves (CN) testing, which showed bilateral restriction of adduction (CN III) and up gaze (CN IV) motions, vertical nystagmus, and left side facial paresis of central origin (CN VII). The bilateral exotropia and ophthalmoplegia are characteristics of WEBINO (Wall-Eyed Bilateral Intranuclear Ophthalmoplegia) syndrome, associated to a brain stem structural lesion. The following causes were evaluated and ruled out: tumor, infection, ischemic stroke, non-infectious inflammation. Pediatric Acquired Demyelinating Syndromes were then considered. Neuromyelitis Optica was ruled out in the absence of neuritis and normal spinal cord MRI. The differential diagnosis between Clinically Isolated Syndrome and Acute Demyelinating Encephalomyelitis, causing an isolated brain stem syndrome, is discussed.

This book on the politics of slavery in the early American republic ought to surpass and replace previous works on this subject. Broadly synthetic and, at the same time, well researched and well wr...

The admission by the International Monetary Fund (IMF) that it did not accurately estimate the damage that austerity will do to the Greek economy is yet another failure of the world body. It has admitted making similar mistakes in the past in handling economic crises in Mexico, Russia and Argentina. What was the exact nature of the Greek financial crisis? And how did the IMF handle this crisis? What were the Fund’s follies in its handling of the Greek crisis? Is there a pattern in the follies of the Fund in handling economic crises? If yes, then what does it tell us about the IMF and its governance of the world economy? This article seeks to answer these questions in the wake of long-pending reforms of the Fund’s governing structure and voting rights. Obviously, there is a need for more than just ‘fine-tuning’ of the Fund’s lending policies. Reforms such as expansion of the governing committee and increasing the quota share of developing countries are crucial for ‘re-imagining’ a stronger and more effective IMF that is more in tune with the changing global order of the twenty-first century. This article will take stock of the IMF quota and governance reforms initiated by the Fund in 2010 and review some other reform proposals that reflect the significant shifts in global economic power in the twenty-first century.

This article surveys the work done by the Committee on Trade and Environment (CTE) in the World Trade Organization (WTO) and evaluates its success in fulfilling its mandate. It looks at the genesis of the CTE so as to comprehend the specific factors that led to its establishment, in the light of which its work is surveyed in detail. The article concludes that the CTE has been instrumental in identifying and understanding the relationship between trade and environment. By providing the WTO Members with a forum for debate and discussion the CTE has become fertile ground for the germination of new proposals, some of which have been incorporated into the Doha negotiating agenda, thereby making a positive contribution towards smoothening the fault lines between trade and environment.

The sesquicentennial of the Emancipation Proclamation, issued in the midst of the Civil War in 1863, has proven to be a veritable boon to emancipation studies. Several recently published books, including those considered in this essay, have added depth and dimension to the story of the coming of emancipation. The question remains whether they add anything to the history that has now become familiar to scholars of the period. The broad outlines of a new and dynamic understanding of emancipation were first sketched by historians involved in the Freedmen’s and Southern Society project, the collation and publication of documents from the National Archives in a multivolume set nearly a quarter of a century ago and still ongoing. They first delineated emancipation as a process that involved many historical actors. Often caricatured as positing a “self-emancipation” thesis, the Freedom series carefully illustrated the unfolding of emancipation at various levels, the movement of slaves toward the Union Army, the actions of soldiers and generals in the field, congressional acts and resolutions, decisions made by the Lincoln administration, black military service, and the attempt of former slaves to define their own freedom. This pioneering work underlies all three books. James Oakes’ Freedom National builds on that project and even adopts the subtitle of the first volume, The Destruction of Slavery. But Oakes adds to that story considerably and shifts the focus from the slaves themselves to Republi

Smart Meter is an advance meter which measures electricity, gas & water consumption and gives more detailed information than a traditional meter. Implementation of AMI software into these meters will give variety of controls, facilities and features. In this work, customer service benefits such as managing demand response, flexible billing cycle, pricing structure, distributed network management, AMI standards, cost estimate and communication infrastructure of AMI with respect to Indian protocols are discussed regarding electricity measurement only.

Homeostatic and regenerative replacement of skeletal muscle fibers requires the activity of a dedicated pool of myogenic stem cells, called satellite cells, that are activated by muscle injury and act as a renewable source of muscle-forming cells throughout adult life. Satellite cell function is controlled by both intrinsic and extrinsic regulatory cues, whose integration determines the success of muscle regenerative responses. Pathological deregulation of satellite cell function through perturbation of these signaling pathways appears to play an important role in age-dependent deterioration of muscle function and in muscle dystrophic disease. The regenerative activity of skeletal muscle also appears to be tightly linked to metabolism, and alterations in metabolic state can directly influence the activity of these tissue-specific stem cells. Here, we review recent and emerging insights into the molecular and biochemical signals that control satellite cell function and discuss these in the context of muscle degenerative diseases such as dystrophy and sarcopenia. Novel discoveries from this ongoing work bring new opportunities to enhance or restore muscle repair and are likely to facilitate satellite cell transplantation in clinical applications.

Social policy impact is partly determined by how policy is articulated and advocated, including which values are highlighted and how. In this paper, we examine the influence of policy framing and reframing on outcomes, with particular reference to the policies of the Delhi state government in India that target the practices of female feticide, infanticide and neglect that underlie the ‘daughter deficit’. Using Snow and Benford's categories for understanding reframing processes, the paper outlines and applies a ‘model’ of reframing disputed issues derived from looking at two famous campaigns – Gandhi's 1930 Salt March in the struggle for Indian freedom from British rule and the African-American civil rights struggle of the 1950s and 1960s. It argues that ‘carrot and stick’ policy measures, such as financial incentives and legal prohibitions, to counteract the ‘daughter deficit’ must be complemented by well crafted discursive interventions.

Summary Heterochromatin plays a key role in protection of chromosome integrity by suppressing homologous recombination. In Saccharomyces cerevisiae , Sir2p, Sir3p, and Sir4p are structural components of heterochromatin found at telomeres and the silent mating-type loci. Here we have investigated whether incorporation of Sir proteins into minichromosomes regulates early steps of recombinational repair in vitro. We find that addition of Sir3p to a nucleosomal substrate is sufficient to eliminate yRad51p-catalyzed formation of joints, and that this repression is enhanced by Sir2p/Sir4p. Importantly, Sir-mediated repression requires histone residues that are critical for silencing in vivo. Moreover, we demonstrate that the SWI/SNF chromatin-remodeling enzyme facilitates joint formation by evicting Sir3p, thereby promoting subsequent Rad54p-dependent formation of a strand invasion product. These results suggest that recombinational repair in the context of heterochromatin presents additional constraints that can be overcome by ATP-dependent chromatin-remodeling enzymes.

Repair of chromosomal DNA double-strand breaks by homologous recombination is essential for cell survival and genome stability. Within eukaryotic cells, this repair pathway requires a search for a homologous donor sequence and a subsequent strand invasion event on chromatin fibers. We employ a biotin-streptavidin minichromosome capture assay to show that yRad51 or hRad51 presynaptic filaments are sufficient to locate a homologous sequence and form initial joints, even on the surface of a nucleosome. Furthermore, we present evidence that the Rad54 chromatin-remodeling enzyme functions to convert these initial metastable products of the homology search to a stable joint molecule that is competent for subsequent steps of the repair process. Thus, contrary to popular belief, nucleosomes do not pose a potent barrier for successful recognition and capture of homology by an invading presynaptic filament.

What are the implications for the existence of subthreshold ion channels, their localization profiles, and plasticity on local field potentials (LFPs)? Here, we assessed the role of hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in altering hippocampal theta-frequency LFPs and the associated spike phase. We presented spatiotemporally randomized, balanced theta-modulated excitatory and inhibitory inputs to somatically aligned, morphologically realistic pyramidal neuron models spread across a cylindrical neuropil. We computed LFPs from seven electrode sites and found that the insertion of an experimentally constrained HCN-conductance gradient into these neurons introduced a location-dependent lead in the LFP phase without significantly altering its amplitude. Further, neurons fired action potentials at a specific theta phase of the LFP, and the insertion of HCN channels introduced large lags in this spike phase and a striking enhancement in neuronal spike-phase coherence. Importantly, graded changes in either HCN conductance or its half-maximal activation voltage resulted in graded changes in LFP and spike phases. Our conclusions on the impact of HCN channels on LFPs and spike phase were invariant to changes in neuropil size, to morphological heterogeneity, to excitatory or inhibitory synaptic scaling, and to shifts in the onset phase of inhibitory inputs. Finally, we selectively abolished the inductive lead in the impedance phase introduced by HCN channels without altering neuronal excitability and found that this inductive phase lead contributed significantly to changes in LFP and spike phase. Our results uncover specific roles for HCN channels and their plasticity in phase-coding schemas and in the formation and dynamic reconfiguration of neuronal cell assemblies.

Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-alpha) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF-alpha and signature mutations in pancreatic tumor genesis and progression, TGFalpha transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGFalpha animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16(Ink4a) by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16(Ink4a). All tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16(Ink4a) and p19(Arf)-p53 in the development of SCA in mice, demonstrating that p16(Ink4a) is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.

The development of functional genomic resources is essential to understand and utilize information generated from genome sequencing projects. Central to the development of this technology is the creation of high-quality cDNA resources and improved technologies for analyzing coding and noncoding mRNA sequences. The isolation and mapping of cDNAs is an entrée to characterizing the information that is of significant biological relevance in the genome of an organism. However, a bottleneck is often encountered when attempting to bring to full-length (or at least full-coding) a number of incomplete cDNAs in parallel, since this involves the nonsystematic, time consuming, and labor-intensive iterative screening of a number of cDNA libraries of variable quality and/or directed strategies to process individual clones (e.g., 5′ rapid amplification of cDNA ends). Here, we review the current state of the art in cDNA library generation, as well as present an analysis of the different steps involved in cDNA library generation.