Miracle-dz/UniFAR-FTUs huggingface dataset:
HETEROGENEITY OF THE CELLULAR IMMUNE RESPONSE

Lymph node cells from guinea pigs immunized with HSA in complete Freund's adjuvant were grown in cultures containing different concentrations of specific antigen. Stimulation of thymidine incorporation was induced with progressively lower concentrations of HSA at successive intervals after sensitization. Moreover, the intensity of delayed skin reactions and the magnitude of stimulation in vitro increased over the same interval. These events are considered compatible with an evolution of the cellular immune response resulting from the selection of lymphoid cells by decreasing concentrations of antigen in vivo. Cells from animals rendered tolerant to HSA failed to respond to specific antigen in culture. As tolerance waned, stimulation was achieved at high but not low antigen concentrations. Tolerance, measured by cutaneous reactivity or by lymphocyte stimulation, was less readily induced in animals sensitized with adjuvant containing a reduced concentration of mycobacteria. Lymph nodes from these animals contained a large population of cells reactive at high antigen concentration, presumably less susceptible to the toleragenic effect of intravenous antigen. The dissociation of delayed hypersensitivity and antibody formation observed early in the immune response and upon recovery from tolerance has permitted correlation of lymphocyte stimulation with delayed hypersensitivity and cutaneous basophil hypersensitivity respectively.
Azlocillin and cefonicid penetration into bone enhanced by probenecid

Azlocillin (AZL) and cefonicid (CFD) penetration into rabbit humerus and scapula was evaluated with and without concomitantly administered probenecid. Groups of animals received either 70 mg of AZL intravenously or 20 mg of CFD intramuscularly per kg of body weight; other groups were pretreated with 40 mg of probenecid per kg before the administration of antibiotics. Peak levels of AZL in the sera of animals not receiving probenecid were 76.0 micrograms/ml at 30 min and declined to 7.7 micrograms/ml by 2.0 h. Maximum concentrations in bone were 2.7 micrograms/g in the humerus and 7.1 micrograms/g in the scapula at 1 h. Pretreatment with probenecid significantly elevated levels of AZL in both serum and bone while increasing the half-life in serum from 0.44 to 0.65 h. Maximum drug concentrations in bones of probenecid-pretreated animals were 3.9 and 11.7 micrograms/g in the humerus and scapula, respectively, with detectable levels persisting in bone for up to 4 h. The peak level of CFD alone in serum was 36.7 micrograms/ml at 30 min and declined to 0.86 micrograms/ml at 8 h. Maximum concentrations in bone were 0.66 micrograms/g in the humerus at 1 h and 1.8 micrograms/g in the scapula at 2 h. Pretreatment with probenecid significantly elevated levels of CFD in both serum and bone while increasing the half-life in serum from 1.4 to 2.94 h. Pretreatment with probenecid achieved maximum concentrations of 1.7 and 2.8 micrograms/g in the humerus and scapula, respectively. Detectable levels of CFD persisted in the humerus for up to 4 h and in the scapula for 8 h.
Fully Formatted Pdf and Full Text (html) Versions Will Be Made Available Soon. Comparing Neural Correlates of Visual Target Detection in Serial Visual Presentations Having Different Temporal Correlations

Most visual stimuli we experience on a day-today basis are continuous sequences, with spatial structure highly correlated in time. During rapid serial visual presentation (RSVP), this correlation is absent. Here we study how subjects' target detection responses, both behavioral and electrophysiological, differ between continuous serial visual sequences (CSVP), flashed serial visual presentation (FSVP) and RSVP. Behavioral results show longer reaction times for CSVP compared to the FSVP and RSVP conditions, as well as a difference in miss-rate between RSVP and the other two conditions. Using mutual information, we measure electrophysiological differences in the EEG for these three conditions. We find two peaks in the mutual information between EEG and stimulus class (target vs. distractor), with the second peak occurring 30-40ms earlier for the FSVP and RSVP conditions. In addition, we find differences in the persistence of the peak mutual information between FSVP and RSVP conditions. We further investigate these differences using a mutual information based functional connectivity analysis and find significant fronto-parietal functional coupling for RSVP and FSVP but no significant coupling for the CSVP condition. We discuss these findings within the context of attentional engagement, evidence accumulation and short-term visual memory.
A Probabilistic Rich Type Theory for Semantic Interpretation

We propose a probabilistic type theory in which a situations is judged to be of a typeT with probabilityp. In addition to basic and functional types it includes, inter alia, record types and a notion of typing based on them. The type system is intensional in that types of situations are not reduced to sets of situations. We specify the fragment of a compositional semantics in which truth conditions are replaced by probability conditions. The type system is the interface between classifying situations in perception and computing the semantic interpretations of phrases in natural language.
Palliative care provision for people with intellectual disabilities: a questionnaire survey of specialist palliative care professionals

There is a growing interest in the palliative care needs of people with intellectual disabilities (ID). There are indications that palliative care staff face particular problems providing care to this group, but empirical data about the extent of the problem are lacking. This study aims to gain insight into the current use of palliative care services by people with ID in London, to identify the prevalence and severity of problems faced by palliative care professionals and to identify strategies that will facilitate an improvement in access and delivery of palliative care services to people with ID. A postal questionnaire was developed for this study and returned by 543 professionals working in 53 specialist palliative care services in London (57% response rate). Sixty-seven percent of respondents had supported a patient with ID at some point in their palliative care career. Problems arising from the patient’s difficulty in understanding the illness and treatment were reported as the most pertinent. Other prevalent problems included difficulty around communication, assessment and patient fear. Respondents emphasised the need for collaboration with carers and other services. Link worker schemes, training and access to background information were seen as most helpful. The authors conclude that palliative care services appear to be under-used by people with ID. There is a distinct set of problems related to the provision of palliative care for people with ID. Palliative care services should assess the nature and level of their service provision for people with ID. Future research should include epidemiological studies to assess need and include people with ID as informants to evaluate the effectiveness of palliative care provision.
A Design Science Approach To Gamify Education: From Games To Platforms

Recent research shows that gamification is a valuable tool to improve students’ learning effectiveness. However, its application continues to be limited. Educators remain reluctant to use games due to factors like limited resources, game complexity, inadaptability to various learning-outcomes, weak student involvement, and difficulty to integrate in course structures. In this article we argue that, when purposefully designed, educational games can address those factors that hinder adoption. Accordingly, we identified seven design principles that, if satisfied, are expected to yield educational games that are useful to both educators and students. The principles accentuate the importance of designing educational platforms over which games can be created and played. Game platforms must (1) adapt to various educational purposes, (2) enable educators control over student engagement (switching on/off game features like rewards, personifications, etc.), (3) scale up/down to achieve the desired level of complexity, and (4) maintain student arousal by dynamically balancing the challenge level with skill level. To evaluate the design principles, we intend to design a business game platform with educators that reflect the seven proposed principles and evaluate it in class settings. If fruitful, this research will advance extant knowledge on learning strategies and specifically the design of educational games.
The Tissue Plasminogen Activator (Tpa/Plasmin) Extracellular Proteolytic System Regulates Seizure-Induced Hippocampal Mossy Fiber Outgrowth through a Proteoglycan Substrate

Short seizure episodes are associated with remodeling of neuronal connections. One region where such reorganization occurs is the hippocampus, and in particular, the mossy fiber pathway. Using genetic and pharmacological approaches, we show here a critical role in vivo for tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen to plasmin, to induce mossy fiber sprouting. We identify DSD-1-PG/phosphacan, an extracellular matrix component associated with neurite reorganization, as a physiological target of plasmin. Mice lacking tPA displayed decreased mossy fiber outgrowth and an aberrant band at the border of the supragranular region of the dentate gyrus that coincides with the deposition of unprocessed DSD-1-PG/phosphacan and excessive Timm-positive, mossy fiber termini. Plasminogen-deficient mice also exhibit the laminar band and DSD- 1-PG/phosphacan deposition, but mossy fiber outgrowth through the supragranular region is normal. These results demonstrate that tPA functions acutely, both through and independently of plasmin, to mediate mossy fiber reorganization.
Inhibition of cathepsin B activity reduces apoptosis by preventing cytochrome c release from mitochondria in porcine parthenotes

Cathepsin B, a lysosomal cysteine protease of the papain family, has recently been implicated in the quality and developmental competence of bovine preimplantation embryos. In this study, to determine whether inhibition of cathepsin B activity can improve porcine oocyte maturation and early embryo developmental competence, we supplemented in vitro maturation or embryo culture media with E-64, a cathepsin B inhibitor. Cathepsin B activity was high in poor quality germinal vesicle stage oocytes, but no differences in mRNA expression or protein localization were observed between good and poor quality oocytes, which were categorized based on morphology. Following treatment with 1 μM E-64, cathepsin B activity sharply decreased in 4-cell and blastocyst stage embryos. E-64 had no effect on cell number but significantly (P < 0.05) increased blastocyst formation and decreased the number of apoptotic cells in blastocysts. It also significantly (P < 0.05) enhanced mitochondrial membrane potential in blastocysts, reducing the release of cytochrome c and resulting in decreased expression of Caspase-3 and Caspase-9. In conclusion, inhibition of cathepsin B activity in porcine parthenotes using 1 μM E-64 resulted in attenuation of apoptosis via a reduction in the release of cytochrome c from mitochondria.
Effects of the 2003 European heatwave on the Central Mediterranean Sea surface layer: a numerical simulation

The effects of anomalous weather conditions on the sea surface layer over the Central Mediterranean were studied with an eddy resolving regional ocean model by performing a 5-year long simulation from 2000 to 2004. The focus was on surface heat fluxes, temperature and dynamics. The analysis of the time series of the selected variables permitted us to identify and quantify the anomalies of the analysed parameters. In order to separate the part of variability not related to the annual cycle and to locate the anomalies in the time-frequency domain, we performed a wavelet analysis of anomalies time series. We found the strongest anomalous event was the overheating affecting the sea surface in the summer of 2003. This anomaly was strictly related to a strong increase of air temperature, a decrease of both wind stress and upward heat fluxes in all their components. The simulated monthly averages of the sea surface temperature were in a good agreement with the remotely-sensed data, although the ocean regional model tended to underestimate the extreme events. We also found, on the basis of the long-wave period of the observed anomaly, this event was not limited to the few summer months, but it was probably part of a longer signal, which also includes negative perturbations of the involved variables. The atmospheric parameters responsible for the overheating of the sea surface also influenced the regional surface and sub-surface dynamics, especially in the Atlantic Ionian Stream and the African Modified Atlantic Water current, in which flows seem to be deeply modified in that period.
Be Selfish and Avoid Dilemmas: Fork After Withholding (FAW) Attacks on Bitcoin

In the Bitcoin system, participants are rewarded for solving cryptographic puzzles. In order to receive more consistent rewards over time, some participants organize mining pools and split the rewards from the pool in proportion to each participant's contribution. However, several attacks threaten the ability to participate in pools. The block withholding (BWH) attack makes the pool reward system unfair by letting malicious participants receive unearned wages while only pretending to contribute work. When two pools launch BWH attacks against each other, they encounter the miner's dilemma: in a Nash equilibrium, the revenue of both pools is diminished. In another attack called selfish mining, an attacker can unfairly earn extra rewards by deliberately generating forks. In this paper, we propose a novel attack called a fork after withholding (FAW) attack. FAW is not just another attack. The reward for an FAW attacker is always equal to or greater than that for a BWH attacker, and it is usable up to four times more often per pool than in BWH attack. When considering multiple pools --- the current state of the Bitcoin network -- the extra reward for an FAW attack is about 56% more than that for a BWH attack. Furthermore, when two pools execute FAW attacks on each other, the miner's dilemma may not hold: under certain circumstances, the larger pool can consistently win. More importantly, an FAW attack, while using intentional forks, does not suffer from practicality issues, unlike selfish mining. We also discuss partial countermeasures against the FAW attack, but finding a cheap and efficient countermeasure remains an open problem. As a result, we expect to see FAW attacks among mining pools.
Leukotriene B4 Release and Polymorphonuclear Cell Infiltration in Spinal Cord Injury

Abstract: Activation of arachidonic acid occurs after spinal cord injury. Leukotriene B4 is a lipoxygenase metabolite of arachidonic acid. In a rat model of experimental spinal cord injury, we found that the leukotriene B4 content was less than the sensitivity of our assay (8 pg/mg of protein) in non‐traumatized spinal cord. Leukotriene B4 was detectable in raumatized cord (mean ± SE, 25 ± 5 pg/mg of protein; n = 3). Release of leukotriene B4 from spinal cord slices into the incubation medium was also noted after trauma (9 ± 1 pg/mg of protein; n = 12) and was enhanced by exposure of traumatized spinal cord slices to the calcium ionophore A23187 (375 ± 43 pg/mg of protein; n = 12). The amount of leukotriene B4 released corresponded to the extent of post‐traumatic polymorphonuclear cell infiltration determined by a myeloperoxidase assay. Results from this study suggest that the source of leukotriene B4 in spinal cord injury is infiltrating polymorphonuclear cells.
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain‐to‐bone signaling pathway

Regulation of bone development, growth, and remodeling traditionally has been thought to depend on endocrine and autocrine/paracrine modulators. Recently, however, brain‐derived signals have emerged as key regulators of bone metabolism, although their mechanisms of action have been poorly understood. We reveal the existence of an ancient parathyroid hormone (Pth)4 in zebrafish that was secondarily lost in the eutherian mammals' lineage, including humans, and that is specifically expressed in neurons of the hypothalamus and appears to be a central neural regulator of bone development and mineral homeostasis. Transgenic fish lines enabled mapping of axonal projections leading from the hypothalamus to the brainstem and spinal cord. Targeted laser ablation demonstrated an essential role for of pth4‐expressing neurons in larval bone mineralization. Moreover, we show that Runx2 is a direct regulator of pth4 expression and that Pth4 can activate cAMP signaling mediated by Pth receptors. Finally, gain‐of‐function experiments show that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Based on our discovery and characterization of Pth4, we propose a model for evolution of bone homeostasis in the context of the vertebrate transition from an aquatic to a terrestrial lifestyle. —Suarez‐Bregua, P., Torres‐Nuñez, E. , Saxena, A. , Guerreiro, P., Braasch, I. , Prober, D.A. , Moran, P., Cerda‐Reverter, J. M. , Du, S. J., Adrio, F. , Power, D. M. , Canario, A. V. M. , Postlethwait, J. H. , Bronner, M E. , Cañestro, C. , Rotllant, J. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain‐to‐bone signaling pathway. FASEB J. 31, 569–583 (2017). http://www.fasebj. org
Natural Transformation in Mesophilic and Thermophilic Bacteria: Identification and Characterization of Novel, Closely Related Competence Genes in Acinetobacter sp. Strain BD413 andThermus thermophilus HB27

ABSTRACT The mesophile Acinetobacter sp. strain BD413 and the extreme thermophile Thermus thermophilus HB27 display high frequencies of natural transformation. In this study we identified and characterized a novel competence gene in Acinetobacter sp. strain BD413, comA, whose product displays significant similarities to the competence proteins ComA and ComEC inNeisseria and Bacillus species. Transcription of comA correlated with growth phase-dependent transcriptional regulation of the recently identified pilin-like factors of the transformation machinery. This finding strongly suggests that comA is part of a competence regulon. Examination of the genome sequence of T. thermophilus HB27 led to detection of a comA/comEC-like open reading frame (ORF) which is flanked by an ORF whose product shows significant similarities to the Bacillus subtilis competence protein ComEA. To examine whether these two ORFs, designated comEC andcomEA, are implicated in natural transformation of T. thermophilus HB27, both were disrupted by using a thermostable kanamycin resistance marker. Natural transformation in comEC mutants was reduced 1,000-fold, whereas in comEA mutants the natural transformation phenotype was completely eliminated. These results strongly suggest that both genes, comEC and comEA, are required for natural transformation in T. thermophilus HB27. Several transmembrane α-helices are predicted based on the amino acid sequences of ComA in Acinetobacter sp. strain BD413 and ComEC in T. thermophilus HB27, which suggests that ComA and ComEC are located in the inner membrane and function in DNA transport through the cytoplasmic membrane.
Acute Bacterial Osteoarticular Infections: Eight-Year Analysis of C-Reactive Protein for Oral Step-Down Therapy

BACKGROUND: One of the most important decisions in the treatment of osteoarticular infections is the time at which parenteral therapy can be changed to oral therapy. C-reactive protein (CRP) is an acute inflammatory indicator with a half-life of 19 hours and thus can be helpful in assessing the adequacy of therapy for bacterial infections. At our institution, a combination of CRP and clinical findings is used to determine the transition to oral therapy. METHODS: A search of 8 years of electronic records identified children with osteoarticular infections. Only children with culture-positive acute bacterial arthritis (ABA) or acute bacterial osteomyelitis (ABO) were studied further. A primary chart review of demographic and clinical data was conducted, and a secondary chart review of complicated outcomes was performed. RESULTS: Of 194 total patients, complicated outcomes occurred in 40, of which 35 were prolonged therapy. Only 1 microbiologic failure occurred, presumably due to a retained intra-articular fragment of infected bone. CRP was highest initially among patients with simultaneous ABO + ABA and among those with complicated outcomes, and was lower at the transition to oral therapy in the complicated outcome group (1.5 vs 2.1 mg/dL; P = .012). CONCLUSIONS: The combination of clinical findings and CRP is a useful tool to transition children with osteoarticular infections to oral therapy. Complicated outcomes were associated with higher early CRP at diagnosis and lower CRP at the end of parenteral therapy, suggesting that clinicians were more conservative with prolonged initial parenteral therapy in this group.
The Src Family Kinases Hck and Fgr Are Dispensable for Inside-Out, Chemoattractant-Induced Signaling Regulating β2 Integrin Affinity and Valency in Neutrophils, but Are Required for β2 Integrin-Mediated Outside-In Signaling Involved in Sustained Adhesion1

Neutrophil β2 integrins are activated by inside-out signaling regulating integrin affinity and valency; following ligand binding, β2 integrins trigger outside-in signals regulating cell functions. Addressing inside-out and outside-in signaling in hck−/−fgr−/− neutrophils, we found that Hck and Fgr do not regulate chemoattractant-induced activation of β2 integrin affinity. In fact, β2 integrin-mediated rapid adhesion, in static condition assays, and neutrophil adhesion to glass capillary tubes cocoated with ICAM-1, P-selectin, and a chemoattractant, under flow, were unaffected in hck−/−fgr−/− neutrophils. Additionally, examination of integrin affinity by soluble ICAM-1 binding assays and of β2 integrin clustering on the cell surface, showed that integrin activation did not require Hck and Fgr expression. However, after binding, hck−/−fgr−/− neutrophil spreading over β2 integrin ligands was reduced and they rapidly detached from the adhesive surface. Whether alterations in outside-in signaling affect sustained adhesion to the vascular endothelium in vivo was addressed by examining neutrophil adhesiveness to inflamed muscle venules. Intravital microscopy analysis allowed us to conclude that Hck and Fgr regulate neither the number of rolling cells nor rolling velocity in neutrophils. However, arrest of hck−/−fgr−/− neutrophils to >60 μm in diameter venules was reduced. Thus, Hck and Fgr play no role in chemoattractant-induced inside-out β2 integrin activation but regulate outside-in signaling-dependent sustained adhesion.