Due to the high content of binder and low water to cement ratio, ultra-high performance concrete (UHPC), exhibits higher levels of autogenous shrinkage compared to ordinary concrete. This shrinkage ...has been shown to lead to a reduction in strength over time as a result of the formation of thermal and shrinkage cracks. Aiming to mitigate the negative impacts associated with shrinkage, the efficacy of three different techniques to reduce the impact of shrinkage are investigated, namely: reducing the binder content; incorporating high levels of shrinkage reducing admixture; and using crushed ice to partially replace mixing water. The effects of these techniques are experimentally investigated and the underlying mechanisms of the actions are characterized. It is found that autogenous shrinkage predominates the overall shrinkage of UHPC and that the three techniques can effectively reduce shrinkage without significantly compromising its mechanical strength. The results also suggest, that from the perspective of reducing shrinkage: the optimal binder-to-sand ratio is in the range of 1–1.1; the optimal dosage rate of shrinkage reducing admixture is 1%; and replacing of mixing water by crushed ice up to 50% by weight has also induced a significant reduction in shrinkage.
Brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures, with in general a poor clinical outcome due to high recurrence. ...One of the underlying causes for this somber prognostic is the presence of brain tumor initiating cells (BTIC) endowed with self-renewal potential, multi-lineage differentiation and resistance to treatment. One promising therapeutic avenue for brain tumors is targeting BTIC self-renewal potential and forcing their differentiation. A compelling candidate is one-carbon metabolism shown to play a key role in maintaining stem cell self-renewal in several lineages. Here, we focus on dihydrofolate reductase (DHFR), a key enzyme in one-carbon metabolism, and demonstrate this enzyme's overexpression in several human brain tumors and its expression in human BTIC. We show that DHFR inhibition, either by Methotrexate (MTX) or EphB activation with synthetic ligands, reduces the tumorigenic potential of 4 human BTIC lines, by reducing their self-renewal capacities both in vitro and in a cerebral organoid glioma (GLICO) model. Our data indicate that driving BTIC differentiation by inhibiting DHFR may provide a new therapeutic approach to treating highly refractory aggressive tumors.
•Description of DHFR expression and Eph:Ephrin signalling in human brain tumor samples.•Eph activation reduces DHFR expression and activity in BTIC.•Eph activation counteracts the increased DHFR protein level following MTX treatment.•Inhibition of DHFR activity impinges on BTIC self-renewal in vitro.•Inhibition of DHFR activity limits the expansion of BTIC grafted in human cerebral organoids.
In this work, we used quantum chemical methods and chemical kinetic models to answer the question of whether or not formaldehyde (CH
O) and ammonia (NH
) can be produced from gas phase hydration of ...methylenimine (CH
NH). The potential energy surfaces (PESs) of CH
NH + H
O → CH
O + NH
and CH
NH + 2H
O → CH
O + NH
+ H
O reactions were computed using CCSD(T)/6-311++G(3d,3pd)//M06-2X/6-311++G(3d,3pd) level. The temperature-and pressure-dependent rate constants were calculated using variational transition state theory (VTST), microcanonical variational transition state theory Formula: see text and Rice-Ramsperger-Kassel-Marcus/master equation (RRKM/ME) simulations. The PES along the reaction path forming a weakly bound complex (CH
NH⋯H
O) was located using VTST and Formula: see textVTST, however, the PES along the tight transition state was characterized by VTST with small curvature tunneling (SCT) approach. The results show that the formation of CH
NH + H
O → CH
NH⋯H
O is pressure -and temperature-dependent. The calculated atmospheric lifetimes of CH
NH⋯H
O (~ 8 min) are too short to undergo secondary bimolecular reactions with other atmospheric species. Our results suggest that the formation of CH
O and NH
likely to occur in the combustion of biomass burning but the rate of formation CH
O and NH
is predicted to be negligible under atmospheric conditions. When a second water molecule is added to the reaction, the results suggest that the rates of formation of CH
O and NH
remain negligible.
Kemampuan kelas VI SDN Munungkerep 2 dalam matapelajaran Matematika tentang Bilangan Bulat sangat rendah. Walaupun Guru telah menggunakan media pembelajaran, namun hanya beberapa peserta didik saja ...yang terlibat langung untuk memperagakannya. Penelitian Tindakan Kelas (PTK) merupakan salah satu cara untuk meningkatkan kemampuan seluruh peserta didik dalam memahami operasi hitung bilangan bulat agar memenuhi KKM. Tujuan penelitian ini untuk meningkatkan kemampuan peserta didik dalam memahami operasi hitung bilangan bulat secara aktif terlibat seluruh peserta didik. Subyek penelitian peserta didik kelas VI SDN Munungkerep 2 yang berjumlah 28 orang. Sumber data penelitian melalui observasi, dokumentasi, tes dan catatan lapangan. Penelitian ini dilaksanakan dua siklus, dan setiap siklus dua pertemuan. Sebelum PTK, hanya 38% peserta didik yang memenuhi KKM. Setelah siklus pertama, didapat peningkatan 57% peserta didik yang memenuhi KKM dan pada siklus kedua meningkat menjadi 93%. Ada seorang peserta didik yang tidak memenuhi KKM akan diadakan perlakuan khusus. Hasil penelitian dapat disimpulkan bahwa penggunaan media Permainan Panbilbul pada materi operasi bilangan bulat dapat meningkatkan sehingga peserta didik dapat memenuhi harapan yang ingin dicapai peneliti.
In today's technology, a sheer number of Internet of Things applications use hardware security modules for secure communications. The widely used algorithms in security modules, for example, digital ...signatures and key agreement, are based upon elliptic curve cryptography (ECC). A core operation used in ECC is the point multiplication, which is computationally expensive for many Internet of things applications. In many IoT applications, such as intelligent transportation systems and distributed control systems, thousands of safety messages need to be signed and verified within a very short time-frame. Considerable research has been conducted in the design of a fast elliptic curve arithmetic on finite fields using residue number systems (RNS). In this article, we propose an RNS-based ECC core hardware for the two families of elliptic curves that are short Weierstraß and twisted Edwards curves. Specifically, we present RNS implementations for SECP256K1 and ED25519 standard curves. We propose an RNS hardware architecture supporting fast elliptic curve point-addition (ECPA), point-doubling (ECPD), and point-tripling (ECPT). We implemented different ECC point multiplication algorithms on the Xilinx FPGA platform. The test results confirm that the performance of our fully RNS ECC point multiplication is better than the fastest ECC point multiplication cores in the literature.
One of the central regulators of cell growth, proliferation, and metabolism is the mammalian target of rapamycin, mTOR, which exists in two structurally and functionally different complexes: mTORC1 ...and mTORC2; unlike m TORC2, mTORC1 is activated in response to the sufficiency of nutrients and is inhibited by rapamycin. mTOR complexes have critical roles not only in protein synthesis, gene transcription regulation, proliferation, tumor metabolism, but also in the regulation of the programmed cell death mechanisms such as autophagy and apoptosis. Autophagy is a conserved catabolic mechanism in which damaged molecules are recycled in response to nutrient starvation. Emerging evidence indicates that the mTOR signaling pathway is frequently activated in tumors. In addition, dysregulation of autophagy was associated with the development of a variety of human diseases, such as cancer and aging. Since mTOR can inhibit the induction of the autophagic process from the early stages of autophagosome formation to the late stage of lysosome degradation, the use of mTOR inhibitors to regulate autophagy could be considered a potential therapeutic option. The present review sheds light on the mTOR and autophagy signaling pathways and the mechanisms of regulation of mTOR-autophagy.
To analyze the trends in biologics use at a specialized center over a period of 20 years.
We performed a retrospective analysis of 571 patients diagnosed with psoriatic arthritis enrolled in the ...Toronto cohort who initiated biologic therapy between January 1, 2000, and July 7, 2020. The probability of drug persistence over time was estimated nonparametrically. The time to discontinuation of first and second treatment was analyzed using Cox regression models, whereas a semiparametric failure time model with a gamma frailty was used to analyze the discontinuation of treatment over successive administrations of biologic therapy.
The highest 3-year persistence probability was observed with certolizumab when used as first biologic treatment, while interleukin-17 inhibitors had the lowest probability. However, when used as second medication, certolizumab had the lowest drug survival even when accounting for selection bias. Depression and/or anxiety were associated with a higher rate of drug discontinuation due to all causes (relative risk RR 1.68, P = 0.01), while having higher education was associated with lower rates (RR 0.65, P = 0.03). In the analysis accommodating multiple courses of biologics, a higher tender joint count was associated with a higher rate of discontinuation due to all causes (RR 1.02, P = 0.01). Older age at the start of first treatment was associated with a higher rate of discontinuation due to side effects (RR 1.03, P = 0.01), while obesity had a protective role (RR 0.56, P = 0.05).
Persistence in taking biologics depends on whether the biologic was used as first or second treatment. Depression and anxiety, higher tender joint count, and older age lead to drug discontinuation.
Breast Cancer is a serious threat and one of the largest causes of death of women throughout the world. The identification of cancer largely depends on digital biomedical photography analysis such as ...histopathological images by doctors and physicians. Analyzing histopathological images is a nontrivial task, and decisions from investigation of these kinds of images always require specialised knowledge. However, Computer Aided Diagnosis (CAD) techniques can help the doctor make more reliable decisions. The state-of-the-art Deep Neural Network (DNN) has been recently introduced for biomedical image analysis. Normally each image contains structural and statistical information. This paper classifies a set of biomedical breast cancer images (BreakHis dataset) using novel DNN techniques guided by structural and statistical information derived from the images. Specifically a Convolutional Neural Network (CNN), a Long-Short-Term-Memory (LSTM), and a combination of CNN and LSTM are proposed for breast cancer image classification. Softmax and Support Vector Machine (SVM) layers have been used for the decision-making stage after extracting features utilising the proposed novel DNN models. In this experiment the best Accuracy value of 91.00% is achieved on the 200x dataset, the best Precision value 96.00% is achieved on the 40x dataset, and the best F-Measure value is achieved on both the 40x and 100x datasets.
Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit ...the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.
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•MCRS1 interacts with Rheb and activates mTORC1•MCRS1 is essential for mTORC1 activity and its associated cellular functions•MCRS1 maintains Rheb at lysosomes in active GTP-bound form to activate mTORC1•Absence of amino acids and MCRS1 delocalizes lysosomal Rheb but not lysosomal TSC2
Frequently misregulated in cancers, mTOR signaling can be stimulated by amino acids through Rheb. Fawal et al. identify MCRS1 as the link between Rheb and mTORC1 activation at the lysosome. MCRS1 maintains active Rheb at the lysosome and prevents its interaction with inhibitor TSC2 and localization to recycling endocytic vesicles.
A series of 18 iridium complexes (Ir) have been prepared and studied. Their abilities to initiate both a ring‐opening cationic polymerization (CP) using an Ir/iodonium salt couple and a free radical ...polymerization (FRP) in the presence of an Ir/amine/alkyl halide system under very soft irradiation (i.e., halogen lamp) or upon exposure to laser diodes @457 nm and @532 nm are investigated. Interestingly, these photoinitiating systems operate through an oxidative or a reductive photoredox catalytic cycle, respectively. Excellent polymerization profiles are obtained (reactive function conversions >70% for the CP of an epoxide and >60% for the FRP of low viscosity triacrylate). The photochemical mechanisms are studied by fluorescence, steady state photolysis, cyclic voltammetry, and electron spin resonance spin trapping experiments.
A series of iridium complexes are prepared and studied. These photoinitiating systems operate through an oxidative or a reductive photoredox catalytic cycle, respectively. Excellent polymerization profiles are obtained. The photochemical mechanisms are studied by fluorescence, steady state photolysis, cyclic voltammetry, and electron spin resonance spin trapping experiments.
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