Miracle-dz/UniFAR-FTUs huggingface dataset:
Antibodies against Alpha-Synuclein Reduce Oligomerization in Living Cells

Recent research implicates soluble aggregated forms of α-synuclein as neurotoxic species with a central role in the pathogenesis of Parkinson's disease and related disorders. The pathway by which α-synuclein aggregates is believed to follow a step-wise pattern, in which dimers and smaller oligomers are initially formed. Here, we used H4 neuroglioma cells expressing α-synuclein fused to hemi:GFP constructs to study the effects of α-synuclein monoclonal antibodies on the early stages of aggregation, as quantified by Bimolecular Fluorescence Complementation assay. Widefield and confocal microscopy revealed that cells treated for 48 h with monoclonal antibodies internalized antibodies to various degrees. C-terminal and oligomer-selective α-synuclein antibodies reduced the extent of α-synuclein dimerization/oligomerization, as indicated by decreased GFP fluorescence signal. Furthermore, ELISA measurements on lysates and conditioned media from antibody treated cells displayed lower α-synuclein levels compared to untreated cells, suggesting increased protein turnover. Taken together, our results propose that extracellular administration of monoclonal antibodies can modify or inhibit early steps in the aggregation process of α-synuclein, thus providing further support for passive immunization against diseases with α-synuclein pathology.
IsoStack - Highly Efficient Network Processing on Dedicated Cores

Sharing data between the processors becomes increasingly expensive as the number of cores in a system grows. In particular, the network processing overhead on larger systems can reach tens of thousands of CPU cycles per TCP packet, for just hundreds of "useful" instructions. Most of these cycles are spent waiting - when the CPU is stalled while accessing "bouncing" cache lines of network control data shared by all processors in the system - and synchronizing access to this shared state. In many cases, the resulting excessive CPU utilization limits the overall system performance. We describe an IsoStack architecture which eliminates the unnecessary sharing of network control state at all stack layers, from the low-level device access, through the transport protocol, to the socket interface layer. The IsoStack "offloads" network stack processing to a dedicated processor core; multiple applications running on the rest of the cores invoke the IsoStack services in parallel, using a thin access layer that emulates the standard sockets API, without introducing new dependencies between the processors. We present a prototype implementation of this architecture, and provide detailed performance analysis. We demonstrate the ability to scale up the number of application threads and scale down the size of messages. In particular, we show an order of magnitude performance improvement for short messages, reaching the 10Gb/s line speed at 40% CPU utilization even for 64 byte messages, while the unmodified system is choked when driving 11 times less throughput.
Adolescents' help-seeking behaviour: the difference between self- and other-referral.

This study examines the difference between adolescents' willingness to seek help for themselves and their willingness to refer others for help. Participants were 512 Israeli adolescents (219 males, 293 females) in grade 10. Adolescents' willingness to seek help from five sources was evaluated with respect to themselves and others, for both severe and minor problems. Adolescents were more willing to refer another person than themselves to most of the sources of support. Differences were more pronounced for severe problems and referrals to psychologists, school counsellors and teachers. Girls were more willing than boys to seek help from their parents and friends. Actual help-seeking behaviour was positively related to willingness to seek help from various sources of support. The results are discussed with reference to the threat to self mechanism and other costs.
BK Virus-Hemorrhagic Cystitis Following Allogeneic Stem Cell Transplantation: Clinical Characteristics and Utility of Leflunomide Treatment

Objective: BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC. Materials and Methods: From January 2005 to June 2014, among the 69 patients that underwent Allo-SCT in our institution, the patients who experienced BKV-HC were investigated retrospectively. Results: HC was observed in 30 patients (43.5%), and among them, 18 of the cases (26.1%) were identified as BKV-HC. The median age of the patients (12 males and 6 females) was 45 years (minimum-maximum: 13-63). Patients received Allo-SCT for acute myeloid leukemia (n=11), aplastic anemia (n=4), myelodysplastic syndrome (n=2), and non-Hodgkin lymphoma (n=1). The donor types were human leukocyte antigen (HLA)-matched sibling donor for six patients, HLA-matched unrelated donor for nine, and haploidentical familial donor for two. The median onset and duration of BKV-HC was on day 21 after transplantation (minimum-maximum: 7-97) and 22 days (minimum-maximum: 6-107). Eleven patients (62.1%) had grade I-II HC and seven patients (38.9%) had grade III-IV (high-grade) HC. Among the seven patients who had high-grade HC, one had complete response, one had partial response, and five had no response. Among the five nonresponders, one died of BKV-HC associated complications. The remaining four patients were treated with leflunomide, achieving complete response (n=2) and partial response (n=2). The median duration from the start of leflunomide therapy to response was 13 days (minimum-maximum: 8-17 days). All patients tolerated the leflunomide treatment well, with three patients having mild gastrointestinal symptoms, including anorexia and abdominal bloating. Conclusion: BKV-HC was commonly observed in patients with HC following Allo-SCT. In high-grade BKV-HC patients who do not respond to supportive care, leflunomide may be a feasible option without significant toxicity.
Direct observation of actin filament severing by gelsolin and binding by gCap39 and CapZ

Dynamic behavior of actin filaments in cells is the basis of many different cellular activities. Remodeling of the actin filament network involves polymerization and depolymerization of the filaments. Proteins that regulate these behaviors include proteins that sever and/or cap actin filaments. This report presents direct observation of severing of fluorescently-labeled actin filaments. Coverslips coated with gelsolin, a multi-domain, calcium-dependent capping and severing protein, bound rhodamine-phalloidin-saturated filaments along their length in the presence of EGTA. Upon addition of calcium, attached filaments bent as they broke. Actophorin, a low molecular weight, monomer sequestering, calcium-independent severing protein did not sever phalloidin-saturated filaments. Both gCap 39, a gelsolin-like, calcium-dependent capping protein that does not sever filaments, and CapZ, a heterodimeric, non- calcium-dependent capping protein, bound the filaments by one end to the coverslip. Visualization of individual filaments also revealed severing activity present in mixtures of actin-binding proteins isolated by filamentous actin affinity chromatography from early Drosophila embryos. This activity was different from either gelsolin or actophorin because it was not inhibited by phalloidin, but was calcium independent. The results of these studies provide new information about the molecular mechanisms of severing and capping by well-characterized proteins as well as definition of a novel type of severing activity.
Asynchronous Implementation of Distributed Coordination Algorithms: Conditions Using Partially Scrambling and Essentially Cyclic Matrices

Given a distributed coordination algorithm (DCA) for agents coupled by a network, which can be characterized by a stochastic matrix, we say that the DCA can be asynchronously implemented if the consensus property is preserved when the agents are activated to update their states according to their own clocks. This paper focuses on two central problems in asynchronous implementation of DCA: which class of DCA can be asynchronously implemented, and which other cannot. We identify two types of stochastic matrices, called partially scrambling and essentially cyclic matrices, for which we prove that DCA associated with a partially scrambling matrix can be asynchronously implemented, and there exists at least one asynchronous implementation sequence, which fails to realize consensus for DCA associated with an essentially cyclic matrix.
The Explanation of Crime: Context, Mechanisms, and Development

Introduction: Toward a unified approach to crime and its explanation Per-Olof H. Wikstrom and Robert J. Sampson 1. A systematic perspective on crime Mario Bunge 2. How does community context matter? Social mechanisms and the explanation of crime rates Robert J. Sampson 3. Individuals, settings and acts of crime: situational mechanisms and the explanation of crime Per-Olof H. Wikstrom 4. Evidence from behavioral genetics for environmental contributions to antisocial conduct Terrie Moffitt and Avshalom Caspi 5. A three-dimensional, cumulative developmental model of serious delinquency Rolf Loeber, N. Wim Slot and Magda Stouthamer-Loeber 6. Self-control and social control of deviant behavior in context: development and interactions along the life course Marc LeBlanc 7. Desistance, social bonds and human agency: a theoretical explanation Anthony Bottoms Index.
Evaluation of protein adsorption and preferred binding regions in multimodal chromatography using NMR

NMR titration experiments with labeled human ubiquitin were employed in concert with chromatographic data obtained with a library of ubiquitin mutants to study the nature of protein adsorption in multimodal (MM) chromatography. The elution order of the mutants on the MM resin was significantly different from that obtained by ion-exchange chromatography. Further, the chromatographic results with the protein library indicated that mutations in a defined region induced greater changes in protein affinity to the solid support. Chemical shift mapping and determination of dissociation constants from NMR titration experiments with the MM ligand and isotopically enriched ubiquitin were used to determine and rank the relative binding affinities of interaction sites on the protein surface. The results with NMR confirmed that the protein possessed a distinct preferred binding region for the MM ligand in agreement with the chromatographic results. Finally, coarse-grained ligand docking simulations were employed to study the modes of interaction between the MM ligand and ubiquitin. The use of NMR titration experiments in concert with chromatographic data obtained with protein libraries represents a previously undescribed approach for elucidating the structural basis of protein binding affinity in MM chromatographic systems.
Review of "Liberalizing Vocational Study: Democratic Approaches to Career Education"

In his text, Liberalizing Vocational Study: Democratic Approaches to Career Education, Emery J. HyslopMargison attempts to break down the binary opposition between liberal education and vocational studies; this dichotomy has remained pervasive in that it has defined the Western educational context for the last twenty-five hundred years. Using a philosophical backdrop, Hyslop-Margison takes this historical clash and thrusts it into a contemporary context, providing substantial evidence to support that this division is not only constructed but that it provides ideological grounds for the systematic devaluing of educational democratic ideals, specifically in the realm of career education. Hyslop-Margison’s text sets up the dominant, polarizing, perspectives on the roles and values of education. However, the text is not limited by this superficial tension. A surface articulation of this dichotomy would be to position opposing arguments one against the other, explaining their philosophical basis, while demonstrating a preference of one over the other. However, HyslopMargison’s argument does not simply present both sides of the spectrum; it marginalizes the spectrum itself by providing alternative arguments that cannot be maintained by the limited confines of a singledimensional and linear structure. An example of this is his telling of historical debates within vocational education which depict three major positions: social inclusion, social efficiency and radical perspectives. The social inclusion and social efficiency perspectives of vocational education are examples of the fundamental philosophical debate that has occurred and remains visible in a contemporary context. Social inclusion theory argues that vocational education is a means of integrating otherwise disadvantaged populations into the workforce, in an attempt to even out the social economic playing field. The third option proposed is the radical perspective. Adherents to this perspective propose that humans are legitimately ends-in-themselves and are not completely vulnerable to dominant power structures. Lying well within the tradition of critical theory, this perspective takes human agency and personal empowerment to be necessary and legitimate concerns in the field of vocational training. If we considered the social inclusion and social efficiency perspectives to be on opposite sides of a spectrum, the radical perspective would wind around this spectrum; the radical perspective takes the spectrum into consideration only in that it acts as a response to it, but refuses to be limited by it. Problematizing the dichotomy offers new perspectives on debates that have been occurring for centuries. “As Aristotle realized more than twenty-five hundred years ago, and I have attempted to confirm, the inescapable connection between the productive, practical and theoretical dimensions of human experience are ignored at our individual and collective peril” (p.98). The concluding remarks of Hyslop-Margison’s text demonstrate a heightened sensitivity to the weaknesses in both liberal and
Minimization of Expected Cycle Time in Manufacturing Cells with Uncontrollable Behavior

Finding optimal working sequences for flexible manufacturing systems (FMS) is a challenging task, especially if uncontrollable events, such as machine breakdowns, can occur in these systems. In this paper, we continue our previous work within the area of FMS scheduling by extending our methods to uncontrollable systems. For this sake, the ideas of probabilistic finite automata are combined with the modeling formalism of extended finite automata. Next, an A*-based scheduling algorithm, minimizing the expectation value of the FMS cycle time is designed.
Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum

Brain cells expend large amounts of energy sequestering calcium (Ca2+), while loss of Ca2+ compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P), a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum (ER) to sequester Ca2+. This led to the hypothesis that G6P regulates Ca2+ accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA). Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio-isotopic assays, 45Ca2+ accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi) coupled with Ca2+ accumulation was quantified. Addition of G6P significantly and decreased Ca2+ accumulation in a dose-dependent fashion (1–10 mM). The reduction in Ca2+ accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca2+ accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca2+ uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca2+ dystasis caused by altered G6P regulation of SERCA activity.
Planning, anticipatory systems, and kinds of actors

Anticipation and planning have much in common. Anticipation means being ahead of things. Planning means not only anticipating on things to come, but also trying to determine a course of action to reach a goal. Planning is investigated in many domains, for example, in economy, biology, and in the cognitive sciences. Each of these domains uses its own research methodologies, languages, ontologies, and models. Although there are many differences between the various approaches and models, there must of course also be similarities, since they all deal with establishing a future course of actions to reach a goal. We will compare several planning approaches on a number of aspects, e.g., the kind of entity that makes the plan (natural or artificial), whether the plan is executed by the planner or by another entity, representational issues, and the domain that the plan is executed in. Our article focuses on analytical dimensions in the extended field of planning. We do not discuss empirical results.
Functional role of NMDA receptor subunit composition in metaplasticity

Modification of synapses by neural activity has been proposed to be the substrate for experiencedependent brain development, learning, and recovery of function after brain damage. In the visual cortex, the trength of cortical synapses can be bidiredionally modified, where in response to a critical level of postsynaptic activation, synapses are strengthened (long-term potentiation; LTP) and below this level, synapses are weakened (long-term depression; LTD). Previous work in visual cortex has suggested that the threshold for synaptic modifications is dependent on the recent history of visual experience, a phenomenon called metaplaticity. Recent mechanistic studies have shown that experience-dependent adjutments of the modification threshold correlate with changes in the subunit composition and function of NMDA-type glutamate receptors (NMDARs). However, causality has not been conclusively eltablished. Here we examined the mechanistic basis of metaplaticity, and Pecifically how this process is mediated by a switch in NMDAR subunit composition by focusing on the NR2A subunit of the NMDA receptor in visual cortex. We provide evidence for the fundional significance of the NR2A subunit in metaplastic changes both in synaptic platicity elicited in vitro and in naturallyoccurring platicity in vivo. We also performed a comparison of in vitro methods of inducing plasticity and those which subserve in vivo experience-dependent changes in synaptic strength. These findings represent an important step forward in understanding how plasticity thresholds are regulated in the brain. Thesis Supervisor: Mark F. Bear, Ph.D Title: Picower Professor of Neuroscience Thesis Committee: / , Martha Contantine-Paton, Ph.D Professor of Neuroscience, Carlos Lois, M.D, Ph.D Assistant Professor of Neuroscience, Alfredo Kirkwood, Ph.D Associate Professor of Neuroscience. KATHLEEN K.A. CHO kcho@mit.edu
Scalable hosting of web applications

Modern Web sites have evolved from simple monolithic systems to complex multitiered systems. In contrast to traditional Web sites, these sites do not simply deliver pre-written content but dynamically generate content using (one or more) multi-tiered Web applications. In this thesis, we addressed the question: How to host multi-tiered Web applications in a scalable manner? Scaling up a Web application requires scaling its individual tiers. To this end, various research works have proposed techniques that employ replication or caching solutions at different tiers. However, most of these techniques aim to optimize the performance of individual tiers and not the entire application. A key observation made in our research is that there exists no elixir technique that performs the best for allWeb applications. Effective hosting of a Web application requires careful selection and deployment of several techniques at different tiers. To this end, we present several caching and replication strategies, such as GlobeCBC, GlobeDB and GlobeTP, to improve the scalability of different tiers of a Web application. While these techniques and systems improve the performance of the individual tiers (and eventually the application), an application's administrator is not only interested in the performance of its individual tiers but also in its endto- end performance. To this end, we propose a resource provisioning approach that allows us to choose the best resource configuration for hosting a Web application such that its end-to-end response time can be optimized with minimum usage of resources. The proposed approach is based on an analytical model for multi-tier systems, which allows us to derive expressions for estimating the mean end-to-end response time and its variance.
Depolarization‐stimulated catecholamine biosynthesis: involvement of protein kinases and tyrosine hydroxylase phosphorylation sites in situ

Depolarizing stimuli increase catecholamine (CA) biosynthesis, tyrosine hydroxylase (TH) activity, and TH phosphorylation at Ser19, Ser31, and Ser40 in a Ca2+‐dependent manner. However, the identities of the protein kinases that phosphorylate TH under depolarizing conditions are not known. Furthermore, although increases in Ser31 or Ser40 phosphorylation increase TH activity in vitro, the relative influence of phosphorylation at these sites on CA biosynthesis under depolarizing conditions is not known. We investigated the participation of extracellular signal‐regulated protein kinase (ERK) and cAMP‐dependent protein kinase (PKA) in elevated K+‐stimulated TH phosphorylation in PC12 cells using an ERK pathway inhibitor, PD98059, and PKA‐deficient PC12 cells (A126‐B1). In the same paradigm, we measured CA biosynthesis. TH phosphorylation stoichiometry (PS) was determined by quantitative blot‐immunolabeling using site‐ and phosphorylation state‐specific antibodies. Treatment with elevated K+ (+ 58 mm) for 5 min increased TH PS at each site in a Ca2+‐dependent manner. Pretreatment with PD98059 prevented elevated K+‐stimulated increases in ERK phosphorylation and Ser31 PS. In A126‐B1 cells, Ser40 PS was not significantly increased by forskolin, and elevated K+‐stimulated Ser40 PS was three‐ to five‐fold less than that in PC12 cells. In both cell lines, CA biosynthesis was increased 1.5‐fold after treatment with elevated K+ and was prevented by pretreatment with PD98059. These results suggest that ERK phosphorylates TH at Ser31 and that PKA phosphorylates TH at Ser40 under depolarizing conditions. They also suggest that the increases in CA biosynthesis under depolarizing conditions are associated with the ERK‐mediated increases in Ser31 PS.