AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy ...homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.
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•MAGE-A3/6 are normally testis restricted and aberrantly expressed in many cancers•MAGE-A3/6 are driver oncogenes competent to transform cells•MAGE-A3/6-TRIM28 ubiquitinates and degrades the AMPK tumor suppressor•MAGE-A3/6-TRIM28 suppresses autophagy and potentiates mTOR signaling
A cancer-specific E3 ubiquitin ligase ubiquitinates and degrades AMPK, resulting in downregulation of autophagy and increased mTOR signaling. This regulatory axis demonstrates how altered cellular metabolism can act as an oncogenic driver in cancer.
Pauli channels are fundamental in the context of quantum computing as they model the simplest kind of noise in quantum devices. We propose a quantum algorithm for simulating Pauli channels and extend ...it to encompass Pauli dynamical maps (parametrized Pauli channels). A parametrized quantum circuit is employed to accommodate for dynamical maps. We also establish the mathematical conditions for an N-qubit transformation to be achievable using a parametrized circuit where only one single-qubit operation depends on the parameter. The implementation of the proposed circuit is demonstrated using IBM's quantum computers for the case of one qubit, and the fidelity of this implementation is reported.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autophagy is commonly altered in cancer and has a complicated, but important role in regulation of tumor growth. Autophagy is often tumor suppressive in the early stages of cancer development, but ...contributes to the late stages of tumor growth. Because of this, putative oncogenes that modulate autophagy signaling are especially interesting. Here we discuss our recent work detailing the function of the MAGEA-TRIM28 ubiquitin ligase as an oncogene product that targets PRKAA1/AMPKα1 for ubiquitination and proteasome-mediated degradation. Degradation of AMPK, a master cellular energy sensor and regulator, by MAGEA-TRIM28 results in significantly reduced autophagy and changes in cellular metabolism, including upregulation of MTOR signaling. Overall, expression of MAGEA3 (or MAGEA6) and degradation of AMPK is sufficient to induce transformation of normal cells and promote multiple hallmarks of cancer.
Bolted joints are fundamental to numerous structural components in engineering practice. Nevertheless, their failure or even their loosening can lead to insufficient performance and reduced ...structural safety. This study presents a theoretical development and experimental investigation into nonlinear guided-wave mixing for integrity monitoring of bolted joints in plates. Combinational harmonics generated due to nonlinear Lamb wave mixing and contact acoustic nonlinearity at the bolted joints were used to evaluate the applied torque level in the joint. The area of the power spectral density in the region of the sum combinational harmonic bandwidth is found to be highly correlated to the applied torque level at the joint. Moreover, the effect of the number of cycles and thus the time duration of the excitation is investigated. The results show that the combinational harmonics remain robust for different numbers of cycles in detecting bolt loosening. The findings presented in this study also provide physical insight into the phenomena of nonlinear Lamb wave mixing for evaluating applied torque in bolted joints, and the results help further advance the use of nonlinear guided waves for damage detection.
Guided waves have been extensively studied in the past few years, and more recently nonlinear guided waves have attracted significant research interest for their potential for early damage detection ...and material state characterization. Combined harmonic generation due to wave mixing can offer some advantages over second harmonic generation. However, studies focused on Lamb wave mixing are still very limited, and have mainly focused on collinear wave mixing and used plane wave assumption. In this paper, numerical simulations and experiments are conducted to understand the interaction of mixing non-collinear Lamb wave pulses with non-planar wavefronts. The results demonstrate that the generated secondary wave is cumulative under internal resonance conditions and the sum-frequency component of the combined harmonics is useful for characterizing material nonlinearities.
Dynamics of ranking Iñiguez, Gerardo; Pineda, Carlos; Gershenson, Carlos ...
Nature communications,
03/2022, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Virtually anything can be and is ranked; people, institutions, countries, words, genes. Rankings reduce complex systems to ordered lists, reflecting the ability of their elements to perform relevant ...functions, and are being used from socioeconomic policy to knowledge extraction. A century of research has found regularities when temporal rank data is aggregated. Far less is known, however, about how rankings change in time. Here we explore the dynamics of 30 rankings in natural, social, economic, and infrastructural systems, comprising millions of elements and timescales from minutes to centuries. We find that the flux of new elements determines the stability of a ranking: for high flux only the top of the list is stable, otherwise top and bottom are equally stable. We show that two basic mechanisms - displacement and replacement of elements - capture empirical ranking dynamics. The model uncovers two regimes of behavior; fast and large rank changes, or slow diffusion. Our results indicate that the balance between robustness and adaptability in ranked systems might be governed by simple random processes irrespective of system details.
Epithelial-mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial ...phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.
Cancer is a public health problem worldwide, and one of the crucial steps within tumor progression is the invasion and metastasis of cancer cells, which are directly related to cancer‐associated ...deaths in patients. Recognizing the molecular markers involved in invasion and metastasis is essential to find targeted therapies in cancer. Interestingly, about 50% of the discovered drugs used in chemotherapy have been obtained from natural sources such as plants, including isoflavonoids. Until now, most drugs are used in chemotherapy targeting proliferation and apoptosis‐related molecules. Here, we review recent studies about the effect of isoflavonoids on molecular targets and signaling pathways related to invasion and metastasis in cancer cell cultures, in vivo assays, and clinical trials. This review also reports that glycitein, daidzein, and genistein are the isoflavonoids most studied in preclinical and clinical trials and displayed the most anticancer activity targeting invasion‐related proteins such as MMP‐2 and MMP‐9 and also EMT‐associated proteins. Therefore, the diversity of isoflavonoids is promising molecules to be used as chemotherapeutic in invasive cancer. In the future, more clinical trials are needed to validate the effectiveness of the various natural isoflavonoids in the treatment of invasive cancer.
Bats have evolved behavioral specializations that are unique among mammals, including self-propelled flight and echolocation. However, areas of motor cortex that are critical in the generation and ...fine control of these unique behaviors have never been fully characterized in any bat species, despite the fact that bats compose ∼25% of extant mammalian species. Using intracortical microstimulation, we examined the organization of motor cortex in Egyptian fruit bats (Rousettus aegyptiacus), a species that has evolved a novel form of tongue-based echolocation.1,2 We found that movement representations include an enlarged tongue region containing discrete subregions devoted to generating distinct tongue movement types, consistent with their behavioral specialization generating active sonar using tongue clicks. This magnification of the tongue in motor cortex is comparable to the enlargement of somatosensory representations in species with sensory specializations.3–5 We also found a novel degree of coactivation between the forelimbs and hindlimbs, both of which are involved in altering the shape and tension of wing membranes during flight. Together, these findings suggest that the organization of motor cortex has coevolved with peripheral morphology in bats to support the unique motor demands of flight and echolocation.
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•The first motor map of any bat species using intracortical microstimulation•Rousettus, a lingual echolocating bat, has an enlarged tongue motor representation•Forelimb movements are usually coupled with hindlimb movements•Motor organization is consistent with adaptations for flight and echolocation
Using ICMS, Halley et al. describe the first motor map in any species of bat. In a species that uses its tongue to echolocate, they find an exceptionally large representation of the tongue. Forelimb movements are most often coupled with hindlimb movements. Together, this suggests that motor cortex in bats is adapted for echolocation and flight.
Abstract
Objective
The aim of this exercise from the OMERACT Ultrasound subgroup on Sjögren’s syndrome was to develop and assess the reliability of a consensus-based semiquantitative colour Doppler ...US scoring system for pathologic salivary gland vascularization in patients with primary Sjögren's syndrome (pSS).
Methods
Using the Delphi method, a colour Doppler semiquantitative scoring system for vascularization of bilateral parotid and submandibular glands was developed and tested in static images and on patients (9 pSS patients and 9 sonographers). Intra-reader and inter-reader reliability of grading the salivary glands were computed by weighted Cohen and Light’s kappa analysis, respectively.
Results
The consensus-based semiquantitative score was: grade 0, no visible vascular signals; grade 1, focal, dispersed vascular signals; grade 2, diffuse vascular signals detected in <50% of the gland; grade 3, diffuse vascular signals in >50% of the gland. In static images, the intra- and inter-reader reliability showed excellent kappa values (95% CI) of 0.90 (0.87, 0.93) and 0.80 (0.74, 0.84), respectively, for all four salivary glands together. In patients, the intra- and inter-reader reliability for all four salivary glands together was kappa = 0.84 (0.73, 0.92) and 0.70 (0.64, 0.76), respectively.
Conclusion
The consensus-based colour Doppler US scoring for the evaluation of salivary gland vascularization in pSS showed a good inter-reader reliability and excellent intra-reader reliability in static images and in patients. The clinical application of the developed scoring system should be tested in clinical settings.
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