Miracle-dz/UniFAR-FTUs huggingface dataset:
Potentiation of Native and Recombinant P2X7-Mediated Calcium Signaling by Arachidonic Acid in Cultured Cortical Astrocytes and Human Embryonic Kidney 293 Cells

In the brain, arachidonic acid (AA) plays a critical role in the modulation of a broad spectrum of biological responses, including those underlying neuroinflammation. By using microfluorometry, we investigated the action of extracellular AA in the modulation of the purinoceptor P2X7-mediated elevation of [Ca2+]i in cultured neocortical type-1 astrocytes and P2X7-, P2X2-transfected human embryonic kidney (HEK) 293 cells. We report that in cultured astrocytes, AA-induced [Ca2+]i elevation is coupled to depletion of intracellular Ca2+ stores and to a sustained noncapacitative Ca2+ entry. AA also induced a robust potentiation of the astrocytic P2X7-mediated [Ca2+]i rise evoked by the selective agonist 3′-O-(4-benzoyl)benzoyl-ATP (BzATP). Pharmacological studies demonstrate that the selective P2X7 antagonists oxidized ATP and Brilliant Blue G abrogated the AA-mediated potentiation of BzATP-evoked [Ca2+]i elevation. Fluorescent dye uptake experiments showed that the AA-induced increase in [Ca2+]i was not due to a switch of the P2X7 receptor from channel to the pore mode of gating. The synergistic effect of AA and BzATP was also observed in HEK293 cells stably expressing rat and human P2X7 but not in rat P2X2. Control HEK293 cells responded to AA exposure only with a transient [Ca2+]i elevation, whereas in those expressing the P2X7 receptor, AA elicited a potentiation of the BzATP-induced [Ca2+]i rise. Together, these findings indicate that AA mediates a complex regulation of [Ca2+]i dynamics also through P2X7-mediated Ca2+ entry, suggesting that variations in AA production may be relevant to the control of both the temporal and spatial kinetics of [Ca2+]i signaling in astroglial cells.
Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

Low oxygen levels in tumors can act as a barrier to effective antitumor immunity. Mitigation of tumor hypoxia using a commonly prescribed type II diabetes drug, metformin, resulted in significant synergy with PD-1 blockade immunotherapy. Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9–16. ©2016 AACR.
Enhanced Binding of TonB to a Ligand-loaded Outer Membrane Receptor

The ferric hydroxymate uptake (FhuA) receptor from Escherichia coli facilitates transport of siderophores ferricrocin and ferrichrome and siderophore-antibiotic conjugates such as albomycin and rifamycin CGP 4832. FhuA is also the receptor for phages T5, T1, Φ80, UC-1, for colicin M and for the antimicrobial peptide microcin MccJ21. Energy for transport is provided by the cytoplasmic membrane complex TonB·ExbB·ExbD, which uses the proton motive force of the cytoplasmic membrane to transduce energy to the outer membrane. To accomplish energy transfer, TonB contacts outer membrane receptors. However, the stoichiometry of TonB· receptor complexes and their sites of interaction remain uncertain. In this study, analyses of FhuA interactions with two recombinant TonB proteins by analytical ultracentrifugation revealed that TonB forms a 2:1 complex with FhuA. The presence of the FhuA-specific ligand ferricrocin enhanced the amounts of complex but is not essential for its formation. Surface plasmon resonance experiments demonstrated that FhuA·TonB interactions are multiple and have apparent affinities in the nanomolar range. TonB also possesses two distinct binding regions: one in the C terminus of the protein, for which binding to FhuA is ferricrocin-independent, and a higher affinity region outside the C terminus, for which ferricrocin enhances interactions with FhuA. Together these experiments establish that FhuA·TonB interactions are more intricate than originally predicted, that the TonB·FhuA stoichiometry is 2:1, and that ferricrocin modulates binding of FhuA to TonB at regions outside the C-terminal domain of TonB.
Restoration Ecology: Repairing the Earth's Ecosystems in the New Millennium

The extent of human‐induced change and damage to Earth's ecosystems renders ecosystem repair an essential part of our future survival strategy, and this demands that restoration ecology provide effective conceptual and practical tools for this task. We argue that restoration ecology has to be an integral component of land management in today's world, and to be broadly applicable, has to have a clearly articulated conceptual basis. This needs to recognize that most ecosystems are dynamic and hence restoration goals cannot be based on static attributes. Setting clear and achievable goals is essential, and these should focus on the desired characteristics for the system in the future, rather than in relation to what these were in the past. Goal setting requires that there is a clear understanding of the restoration options available (and the relative costs of different options). The concept of restoration thresholds suggests that options are determined by the current state of the system in relation to biotic and abiotic thresholds. A further important task is the development of effective and easily measured success criteria. Many parameters could be considered for inclusion in restoration success criteria, but these are often ambiguous or hard to measure. Success criteria need to relate clearly back to specific restoration goals. If restoration ecology is to be successfully practiced as part of humanity's response to continued ecosystem change and degradation, restoration ecologists need to rise to the challenges of meshing science, practice and policy. Restoration ecology is likely to be one of the most important fields of the coming century.
Generation of a Single Chain Antibody Variable Fragment (scFv) to Sense Selectively RhoB Activation

Determining the cellular level of activated form of RhoGTPases is of key importance to understand their regulatory functions in cell physiopathology. We previously reported scFvC1, that selectively bind to the GTP-bound form of RhoA, RhoB and RhoC. In this present study we generate, by molecular evolution, a new phage library to isolate scFvs displaying high affinity and selectivity to RhoA and RhoB. Using phage display affinity maturation against the GTP-locked mutant RhoAL63, we isolated scFvs against RhoA active conformation that display Kd values at the nanomolar range, which corresponded to an increase of affinity of three orders of magnitude compared to scFvC1. Although a majority of these evolved scFvs remained selective towards the active conformation of RhoA, RhoB and RhoC, we identified some scFvs that bind to RhoA and RhoC but not to RhoB activated form. Alternatively, we performed a substractive panning towards RhoB, and isolated the scFvE3 exhibiting a 10 times higher affinity for RhoB than RhoA activated forms. We showed the peculiar ability of scFvE3 to detect RhoB but not RhoA GTP-bound form in cell extracts overexpressing Guanine nucleotide Exchange Factor XPLN as well as in EGF stimulated HeLa cells. Our results demonstrated the ability of scFvs to distinguish RhoB from RhoA GTP-bound form and provide new selective tools to analyze the cell biology of RhoB GTPase regulation.
Efficient algorithms for function approximation with piecewise linear sigmoidal networks

This paper presents a computationally efficient algorithm for function approximation with piecewise linear sigmoidal nodes. A one hidden layer network is constructed one node at a time using the well-known method of fitting the residual. The task of fitting an individual node is accomplished using a new algorithm that searches for the best fit by solving a sequence of quadratic programming problems. This approach offers significant advantages over derivative-based search algorithms (e.g., backpropagation and its extensions). Unique characteristics of this algorithm include: finite step convergence, a simple stopping criterion, solutions that are independent of initial conditions, good scaling properties and a robust numerical implementation. Empirical results are included to illustrate these characteristics.
Seasonal distribution of phytoplankton community in a subtropical estuary of the south-eastern coast of Bangladesh

AbstractPhytoplankton are the basic component of the aquatic food chain. To date phytoplankton communities from the coastal waters of Bangladesh have received only little scientific attention. Consequently, the abundance and community composition of phytoplankton and their relationship with some abiotic factors were studied during December 2014 to August 2015 in the Reju Khal estuary of the south-eastern coast of Bangladesh. Marked seasonal differences were observed for all of the measured abiotic factors. The density of the phytoplankton cells ranged between 9408 and 21,964 cells L−1 and had significant differences among seasons. Over all seasonal samples, 27 genera were identified of which Biddulphia was found to be the most contributory one (13.6%) followed by Coscino discus (7.9%) and Nostoc (7.8%). Marked seasonal differences in the community structure of phytoplankton were confirmed by the multivariate analyses. Further, phytoplankton populations had strong positive correlations with pH, salinity, t.
Optimal Joint Target Detection and Parameter Estimation by MIMO Radar

We consider multiple-input multiple-output (MIMO) radar systems with widely spaced antennas. Such antenna configuration facilitates capturing the inherent diversity gain due to independent signal dispersion by the target scatterers. We consider a new MIMO radar framework for detecting a target that lies in an unknown location. This is in contrast with conventional MIMO radars which break the space into small cells and aim at detecting the presence of a target in a specified cell. We treat this problem through offering a novel composite hypothesis testing framework for target detection when 1) one or more parameters of the target are unknown and we are interested in estimating them, and 2) only a finite number of observations are available. The test offered optimizes a metric which accounts for both detection and estimation accuracies. In this paper, as the parameter of interest we focus on the vector of time-delays that the waveforms undergo from being emitted by the transmit antennas until being observed by the receive antennas. The analytical and empirical results establish that for the proposed joint target detection and time-delay estimation framework, MIMO radars exhibit significant gains over phased-array radars for extended targets which consist of multiple independent scatterers. For point targets modeled as single scatterers, however, the detection/estimation accuracies of MIMO and phased-array radars for this specific setup (joint target detection and time-delay estimation) are comparable.
A Tandem Cycling Program: Feasibility and Physical Performance Outcomes in People With Parkinson Disease

Background and Purpose: Individuals with Parkinson disease (PD) have motor and nonmotor impairments that interfere with exercise participation. The purpose of this study was to examine the feasibility and physical performance outcomes of a community-based indoor tandem cycling program that was designed to facilitate a higher cadence, consistency, and intensity of training. Methods: Forty-one participants with mild to moderate PD were enrolled. A high-cadence cycling protocol using mechanically augmented (or forced) exercise on a tandem bicycle was adapted for our program. Participants cycled 3 times per week for 10 weeks. Feasibility measures included program retention, attendance, and adverse events, as well as the ability to reach training goals for heart rate (HR) and cadence. Physical performance outcomes included the Berg Balance Scale (BBS), Short Physical Performance Battery (SPPB), Five-Times-Sit-to-Stand (FTSTS) Test, Timed Up and Go (TUG), and gait parameters during usual and fast-paced walking. Results: Program feasibility was demonstrated with a high attendance rate (96%) and retention rate (100%). There were no adverse events. The majority of participants reached their exercise training goals for target HR (87%) and cadence (95%). Statistically significant physical performance improvement (P < 0.05) was observed across domains of gait, balance, and mobility, suggesting a slowing or reversal of functional decline as a result of this cycling program. Discussion and Conclusion: Program feasibility and improved physical performance outcomes were demonstrated in individuals with mild to moderate PD participating in a community-based indoor tandem cycling program. Video Abstract available for more insights from the authors (see supplemental digital content 1, http://links.lww.com/JNPT/A146).
Recent Sea Ice Decline Did Not Significantly Increase the Total Liquid Freshwater Content of the Arctic Ocean

The freshwater stored in the Arctic Ocean is an important component of the global climate system. Currently the Arctic liquid freshwater content (FWC) has reached a record high since the beginning of the last century. In this study we use numerical simulations to investigate the impact of sea ice decline on the Arctic liquid FWC and its spatial distribution. The global unstructured-mesh ocean general circulation model Finite Element Sea Ice–Ocean Model (FESOM) with 4.5-km horizontal resolution in the Arctic region is applied. The simulations show that sea ice decline increases the FWC by freshening the ocean through sea ice meltwater and modifies upper ocean circulation at the same time. The two effects together significantly increase the freshwater stored in the Amerasian basin and reduce its amount in the Eurasian basin. The salinification of the upper Eurasian basin is mainly caused by the reduction in the proportion of Pacific Water and the increase in that of Atlantic Water (AW). Consequently, the sea ice decline did not significantly contribute to the observed rapid increase in the Arctic total liquid FWC. However, the changes in the Arctic freshwater spatial distribution indicate that the influence of sea ice decline on the ocean environment is remarkable. Sea ice decline increases the amount of Barents Sea branch AW in the upper Arctic Ocean, thus reducing its supply to the deeper Arctic layers. This study suggests that all the dynamical processes sensitive to sea ice decline should be taken into account when understanding and predicting Arctic changes.
Retention and the career motives of IT professionals

Motivated by organizational concerns related to the recruitment and retention of IT professionals, the objective of this paper is to develop and investigate an explanatory model of IT professionals' joining and staying/leaving behaviors. The underlying conceptual base for the model draws upon recent work on psychological contracts. A key dimension in this work is the preferred duration of the employment relationship. We elaborate the theory of psychological contracts with additional constructs representing an IT professional's career motives. In particular, our version of the theory suggests that, in addition to preferred length of the employment relationship, important individual factors that help form the psychological contract are the career stage of an individual and the individual's personal career anchor or orientation. Specific hypotheses related to the effects of these variables on staying/leaving behavior are presented. Empirical data gathered from a field study of 130 IT professionals were used to test the research hypotheses. Results indicate that the hypothesized variables exhibit significant effects on IT professionals' intentions to stay with their current employer. In addition, results point to directions where fruitful future research is warranted.
Real-time sociometrics from audio-visual features for two-person dialogs

This paper proposes a real time sociometric system to analyze social behavior from audio-visual recordings of two-person face-to-face conversations in English. The novelty of the proposed system lies in this automatic inference of ten social indicators in real time. The system comprises of a Microsoft kinect device that captures RGB and depth data to compute visual cues and microphones to capture speech cues from an on-going conversation. With these non-verbal cues as features, machine learning algorithms are implemented in the system to extract multiple indicators of social behavior including empathy, confusion and politeness. The system is trained and tested on two carefully annotated corpora that consist of two person dialogs. Based on leave-one-out cross-validation test, the accuracy range of developed algorithms to infer social behaviors is 50% - 86% for audio corpus, and 62% - 92% for audio-visual corpus.
Changes in Primate Social Behavior After Treatment with Alpha‐Methyl‐Para‐Tyrosine

&NA; The catecholamine hypothesis of the affective disorders relates the depressive syndromes in man to a deficiency of dopamine and norepinephrine. Two subjects within a social group of nonhuman primates were treated with alpha‐methyl‐paratyrosine, an inhibitor of the synthesis of these catecholamines. Quantifiable social interactions and appearance changed with drug treatment. Both treated animals initiated fewer total social interactions, including grooming, threats and attacks. Total social responses and social‐sexual presentations remained stable. The animals showed retarded motor activity and assumed withdrawn postures, huddled with arms crossed and heads hung low. Their social‐affective responses and facial expressions suggested a lack of concern with the environment. These behaviors, similar in some ways to the depressive state as seen in man, were reversible, and were accompanied by a decreased excretion of two metabolites of norepinephrine. An attempt to reverse the syndrome in 1 animal using L‐DOPA was unsuccessful. This model may provide some insight into the neurochemical mechanisms of the human depressive syndromes. Further efforts to reverse the syndrome may have therapeutic relevance as well.
A matter of life and death: controversy at the interface between clinical and legal decision-making in prolonged disorders of consciousness

Best interests decision-making and end-of-life care for patients in permanent vegetative or minimally conscious states (VS/MCS) is a complex area of clinical and legal practice, which is poorly understood by most clinicians, lawyers and members of the public. In recent weeks, the Oxford Shrieval lecture by Mr Justice Baker (‘A Matter of Life and Death’, 11 October 2016) and its subsequent reporting in the public press has sparked debate on the respective roles of clinicians, the Court of Protection and the Mental Capacity Act 2005 in decisions to withhold or withdraw life-sustaining treatments from patients with disorders of consciousness. The debate became polarised and confused by misquotation and inaccurate terminology, and highlighted a lack of knowledge about how patients in VS/MCS die in the absence of court approval. This article sets out the background and discussion and attempts to give a more accurate representation of the facts. In the spirit of transparency, I present a mortality review of all the patients in VS/MCS who have died under the care of my own unit in the last decade—with or without referral to the court, but always in accordance with the law. These data demonstrate that clinicians regularly undertake best interests decision-making in conjunction with families that may include life and death decisions (sometimes even the withdrawal or withholding of clinically assisted nutrition and hydration); and that these can be made within the current legal framework without necessarily involving the court in all cases. This is the first published case series of its kind.
Developmental regulation of myosin gene expression in mouse cardiac muscle

Expression of the two isoforms of cardiac myosin heavy chain (MHC), MHC alpha and MHC beta, in mammals is regulated postnatally by a variety of stimuli, including serum hormone levels. Less is known about the factors that regulate myosin gene expression in rapidly growing cardiac muscle in embryos. Using isoform-specific 35S-labeled cRNA probes corresponding to the two MHC genes and the two myosin alkali light chain (MLC) genes expressed in cardiac muscle, we have investigated the temporal and spatial pattern of expression of these different genes in the developing mouse heart by in situ hybridization. Between 7.5 and 8 d post coitum (p.c.), the newly formed cardiac tube begins to express MHC alpha, MHC beta, MLC1 atrial (MLC1A), and MLC1 ventricular (MLC1V) gene transcripts at high levels throughout the myocardium. As a distinct ventricular chamber forms between 8 and 9 d p.c. , MHC beta mRNAs begin to be restricted to ventricular myocytes. This process is complete by 10.5 d p.c. During this time, MHC alpha mRNA levels decrease in ventricular muscle cells but continue to be expressed at high levels in atrial muscle cells. MHC alpha transcripts continue to decrease in ventricular myocytes until 16 d p.c. , when they are detectable at low levels, but then increase, and finally replace MHC beta mRNAs in ventricular muscle by 7 d after birth. Like MHC beta, MLC1V transcripts become restricted to ventricular myocytes, but at a slower rate. MLC1V mRNAs continue to be detected at low levels in atrial cells until 15.5 d p.c. MLC1A mRNA levels gradually decrease but are still detectable in ventricular cells until a few days after birth. This dynamic pattern of changes in the myosin phenotype in the prenatal mouse heart suggests that there are different regulatory mechanisms for cell-specific expression of myosin isoforms during cardiac development.