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This paper examines the freezing and thawing resistance of high early-strength concrete (HESC) developed for rapid repair of pavements and bridge decks. The cement types chosen for this study included ASTM Type III, ASTM Type V, and Calcium Sulfoaluminate (CSA). A cement content of 386 kg/m3 was maintained for all studied concretes. Specimens were tested after 24 hours and 28 days of curing in order to evaluate compressive and flexural strengths. In addition, the opening time was determined based on the required time to achieve the minimum compressive strength of 20.7 MPa. The freezing and thawing (F–T) resistance of the test samples were evaluated in accordance with the F–T duration of 96 hours per cycle for a total of 25 cycles. Test results revealed that at the opening time and after 24 hours curing, CSA cement concrete displayed the highest compressive and flexural strengths, but lowest resistance to freezing and thawing with de-icing salt. The 28-day cured Type V cement concrete produced the highest strength and de-icing salt resistance, while CSA cement concrete produced the contrary.

The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 μM) at −70 mV with an lC50 against steady-state responses of 182.1 ± 12.1 μM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties. [ABSTRACT FROM AUTHOR]

This study examines the suitability of ASTM Type V cement concrete for rapid repair applications. To this end, experimental results on transport and durability properties of high early-strength concretes using ASTM Type V cement were compared with those of a more traditional cement used for rapid repair, i.e. Type III cement. A cement content of 445 kg/m3 (750 lb/yd3) was maintained for all studied concretes. The experimental program included compressive strength, absorption, rapid chloride migration, corrosion resistance, and mass loss due to freezing and thawing regimes. The results of this study revealed that use of Type III and V cements were both effective for concrete rapid repair applications. The opening time to reach the minimum compressive strength of 21 MPa (3000 psi) was found dissimilar. Type III cement concrete showed better strength properties at early ages due to its high fineness. However, as curing age was extended to 24 hours and 28 days, Type V cement concrete produced higher strength results. Moreover, Type III cement concretes failed to display better performance in transport properties, corrosion, and frost resistance when compared to that of the studied Type V cement concretes.

This paper examines the abrasion resistance of high early-strength concrete developed for rapid repair of highways and bridge decks. The cement types chosen for this study included ASTM Type III, ASTM Type V, and Calcium Sulfoaluminate (CSA) cements. A cement content of 386 kg/m3 (650 lb/yd3) was maintained for all studied concretes. Test samples were tested after 24 hours and 28 days of curing in order to evaluate compressive strength and depth of wear. Test results revealed that the opening time to attain minimum required compressive strength for CSA cement concrete was one hour, whereas the values for Type V and Type III cement concretes were 8.5 and 6 hours, respectively. After 24 hours curing, CSA cement concrete displayed the highest strength, but lowest resistance to wear. The 28-day cured CSA cement concrete produced the highest strength and resistance to abrasion, while Type III cement concrete showed a similar strength, but lower resistance to wear, when compared to those of the Type V cement concrete.

This study presents two experiments that explored consolidation of implicit sequence learning based on two dependent variables-reaction time (RT) and correct anticipations to clarify the role of sleep, and whether the manual component is necessary for consolidation processes. Experiment 1 (n = 37) explored the performance of adults using an ocular variant of the serial reaction time task (O-SRT) with manual activation (MA), and Experiment 2 (n = 37) used the ocular activation (OA) version of the task. Each experiment consisted of a Day and a Night group that performed two sessions of the O-SRT with an intervening 12-h offline period (morning/evening in Day group, evening/following morning in Night group). Night offline had an advantage only when manual response was required and when correct anticipations (i.e., accuracy) but not RT (i.e., speed) were measured. We associated this finding with the dual-learning processes required in the MA O-SRT that led to increased sequence specific learning overnight. When using the OA O-SRT, both groups demonstrated similar rates after offline in RT and correct anticipations. We interpreted this finding to reflect stabilization, which confirmed our hypothesis. As expected, all the groups demonstrated reduced performance when another sequence was introduced, thus reflecting sequence-specific learning. This study used a powerful procedure that allows measurement of implicit sequence learning in several ways: by evaluating two different measures (RT, correct anticipations) and by isolating different aspects of the task (i.e., with/without the manual learning component, more/less general skill learning), which are known to affect learning and consolidation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored., Methods: In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3)., Findings: We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments., Interpretation: We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact., Funding: See the Acknowledgements section., Competing Interests: Declaration of interests B. Plosnita is employed by TissueGnostics GmbH, Vienna. Dr Baur considers to submit a patent. Dr. Eberhardt and Prof. Vera-Gonzalez reports grants from German Ministry of Education and Research (BMBF), during the conduct of the study. The other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility-driven multi-organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro-inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang-(1-7)-an anti-inflammatory heptapeptide of the renin-angiotensin system, which reduced the fibrosis-evoking aptitude of RDEB cells. In vivo, systemic administration of Ang-(1-7) efficiently attenuated progression of multi-organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down-modulation of pro-inflammatory immunity may mitigate injury-induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as an irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear. Using human monocytes, primary human keratinocytes, and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β. IL-1β release required priming by phorbol-ester or toll-like receptor stimulation and was prevented by inhibition of K + efflux, NLRP3 depletion or caspase-1 inhibition, identifying chromium (VI) as a hapten activator of the NLRP3 inflammasome. Inflammasome activation was initiated by mitochondrial reactive oxygen species production triggered by chromium (VI), as indicated by sensitivity to treatment with the ROS scavenger N-acetyl cysteine and a coinciding failure of K + efflux, caspase-1, or NLRP3 inhibition to prevent mitochondrial reactive oxygen species accumulation. IL-1β release further correlated with cytotoxicity that was secondary to reactive oxygen species, K + efflux, and NLRP3 activation. Trivalent chromium was unable to induce mitochondrial reactive oxygen species production, inflammasome activation, and cytotoxicity, suggesting that oxidation state-specific differences in mitochondrial reactivity may determine inflammasome activation and allergic/irritant capacity of different chromium compounds., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Current medication procedures for Alzheimer's dementia (AD) such as inhibitors of acetyl cholinesterase or Memantine and future therapeutic approaches demand improved early diagnostics. However, the differentiation between early cognitive impairments due to primary progressive demential conditions and cognitive deficits in geriatric or depressive people is a great clinical challenge. The detection of biochemical markers such as beta-amyloid peptide and tau proteins in the cerebrospinal fluid can lead to improved diagnostics of the early stages and premonitory symptoms of AD. As a result, future preventive drug treatment strategies can be employed early and selectively.

Decreased levels of beta-amyloid peptide 1-42 (Abeta1-42) in cerebrospinal fluid (CSF) are a characteristic feature of Alzheimer's disease (AD) but recently were also observed in Creutzfeldt-Jakob disease (CJD). We analyzed the CSF of patients with CJD, and AD and nondemented controls using a quantitative urea-based Abeta sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot. Like in AD and nondemented controls, we found a highly conserved pattern of carboxyterminally truncated Abeta1-37/38/39 in addition to Abeta1-40/42 also in CJD patients. By the introduction of the ratio Abeta1-39 to Abeta1-42, CJD and AD can effectively be differentiated. We conclude that the immunoblot shows disease-specific CSF Abeta peptide patterns in CJD and AD and suppose that measurement of the Abeta peptide pattern seems to be a promising diagnostic tool in the differential diagnosis of dementias.

The spectrum of action of flupirtine includes analgesic, muscle-relaxant and neuroprotective properties. The substance's mechanism of action has yet to be fully explained. Over the past few years, however, evidence has accumulated that flupirtine interacts with the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor. Although it was not possible to demonstrate a direct effect on the NMDA receptor, all of the findings pointed to an indirect influence on the NMDA receptor in the sense of a functional NMDA antagonism. It was thus postulated that a site of action "up- or downstream" of the NMDA receptor is influenced. Such a site of action proved to be the G-protein-activated inwardly rectifying K+ channels (GIRK), the opening of which leads to a stabilization of the resting membrane potential of neuronal cells and thus causes an indirect inhibition of the NMDA receptor. At therapeutically relevant concentrations, flupirtine is a neuronal potassium channel opener. This mechanism may explain the spectrum of action of flupirtine. Selective neuronal potassium channel opening (SNEPCO) thus proves to be a new principle of action, making flupirtine the prototype of a new substance class with analgesic, muscle-relaxant and neuroprotective properties. The experimental basis for this working hypothesis and the resulting model concepts are presented from the perspective of a four-stage approach.

The continuation of the primary and secondary antibody response to human serum albumin (HSA), induced in vivo, was followed in explanted chicken spleen fragments. The effect of actinomycin D (AMD) on the in vitro response was studied in spleens from chickens injected with various doses of HSA and removed at differing intervals after injection. The antibody response of "early spleen" cultures was AMD-sensitive, while cultures of spleens removed later were AMD-resistant. It was suggested that this shift represented the development of cells with in vivo preformed RNA involved in specific immunoglobulin synthesis. With increasing doses of HSA, the AMD-sensitive phase was prolonged, suggesting the delay of mRNA formation or some other AMD-inhibitable process in vivo. With large doses of HSA, the immune response in vitro was decreased, starting after a 1-2 day delay and not occurring in the presence of AMD. Massive doses of HSA completely inhibited the continuation of the response in vitro by spleen fragments removed between the 2nd and 5th day after injection. The results point to the controlling role of antigen dose in determining the onset of macromolecular synthesis during immunocyte maturation.