Directed migration by contact guidance is a poorly understood yet vital phenomenon, particularly for carcinoma cell invasion on aligned collagen fibres. We demonstrate that for single cells, aligned ...architectures providing contact guidance cues induce constrained focal adhesion maturation and associated F-actin alignment, consequently orchestrating anisotropic traction stresses that drive cell orientation and directional migration. Consistent with this understanding, relaxing spatial constraints to adhesion maturation either through reduction in substrate alignment density or reduction in adhesion size diminishes the contact guidance response. While such interactions allow single mesenchymal-like cells to spontaneously 'sense' and follow topographic alignment, intercellular interactions within epithelial clusters temper anisotropic cell-substratum forces, resulting in substantially lower directional response. Overall, these results point to the control of contact guidance by a balance of cell-substratum and cell-cell interactions, modulated by cell phenotype-specific cytoskeletal arrangements. Thus, our findings elucidate how phenotypically diverse cells perceive ECM alignment at the molecular level.
Vascular tissue exhibits marked mechanical nonlinearity when exposed to large strains. Vascular smooth muscle cells (VSMCs) are the most prevalent cell type in the artery wall, but it is unclear how ...much of the vessel nonlinearity is attributable to VSMCs. Here, we used cellular microbiaxial stretching (CμBS) to measure the large-strain mechanical properties of individual VSMCs. We find that the mechanical properties of VSMCs with native-like architectures are highly anisotropic, due to their highly aligned actomyosin cytoskeletons, and that inhibition of actomyosin contraction with rho-associated kinase inhibitor HA-1077 results in nearly isotropic material properties. We further find that when VSMCS are exposed to large strains (up to 60% stretch), the cells’ stress–strain behavior is surprisingly linear. Finally, we modified a previously published Holzapfel-Gasser-Ogden type strain energy density function to characterize individual VSMCs, to account for the observed large-deformation linearity. These data have important implications in the development of models of vascular mechanics and mechanobiology.
Wind is a great sustainable energy source for harvesting due to its abundant characteristic. Typically, large space, loud noise, and heavy equipment are essential for a general wind power plant and ...it is solely operated by big-scale wind. However, wind energy can be efficiently harvested by utilizing the triboelectric nanogenerator due to its abundance, ubiquity, and environmentally friendliness. Furthermore, a few previously reported wind-driven triboelectric nanogenerators, which have the bulk fluttering layer by wind, still show difficulty in generating electricity under the conditions of weak wind because of the static friction arisen from the inherent structure. In this case, the output performance is deteriorated as well as the generator cannot operate completely. In this work, a wind-driven triboelectric nanogenerator (wind-TENG) based on the fluttering of the PTFE strips is proposed to solve the aforementioned problems. At the minimum operating wind pressure of 0.05 MPa, this wind-driven TENG delivers the open-circuit voltage of 3.5 V, short-circuit current of 300 nA, and the associated output power density of 0.64 mW/m
at the external load resistance of 5 MΩ. Such conditions can be used to light up seven LEDs. Moreover, this wind-TENG has been utilized as a direction sensor which can sense the direction at which the wind is applied. This work thus provides the potential application of the wind-TENG as both self-driven electronics and a self-powered sensor system for detecting the direction under environmental wind.
Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) ...in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.
During preclinical evaluations of drug candidates, several physicochemical (p-chem) properties are measured and employed as metrics to estimate drug efficacy in vivo. Two such p-chem properties are ...the octanol–water partition coefficient, Log P, and distribution coefficient, Log D, which are useful in estimating the distribution of drugs within the body. Log P and Log D are traditionally measured using the shake-flask method and high-performance liquid chromatography. However, it is challenging to measure these properties for species that are very hydrophobic (or hydrophilic) owing to the very low equilibrium concentrations partitioned into octanol (or aqueous) phases. Moreover, the shake-flask method is relatively time-consuming and can require multistep dilutions as the range of analyte concentrations can differ by several orders of magnitude. Here, we circumvent these limitations by using machine learning (ML) to correlate Log P and Log D with liquid chromatography (LC) retention time (RT). Predictive models based on four ML algorithms, which used molecular descriptors and LC RTs as features, were extensively tested and compared. The inclusion of RT as an additional descriptor improves model performance (MAE = 0.366 and R 2 = 0.89), and Shapley additive explanations analysis indicates that RT has the highest impact on model accuracy.
Dengue is a major public health problem in Myanmar. The country aims to reduce morbidity by 50% and mortality by 90% by 2025 based on 2015 data. To support efforts to reach these goals it is ...important to have a detailed picture of the epidemiology of dengue, its relationship to meteorological factors and ideally to predict ahead of time numbers of cases to plan resource allocations and control efforts. Health facility-level data on numbers of dengue cases from 2012 to 2017 were obtained from the Vector Borne Disease Control Unit, Department of Public Health, Myanmar. A detailed analysis of routine dengue and dengue hemorrhagic fever (DHF) incidence was conducted to examine the spatial and temporal epidemiology. Incidence was compared to climate data over the same period. Dengue was found to be widespread across the country with an increase in spatial extent over time. The temporal pattern of dengue cases and fatalities was episodic with annual outbreaks and no clear longitudinal trend. There were 127,912 reported cases and 632 deaths from 2012 and 2017 with peaks in 2013, 2015 and 2017. The case fatality rate was around 0.5% throughout. The peak season of dengue cases was from May to August in the wet season but in 2014 peak dengue season continued until November. The strength of correlation of dengue incidence with different climate factors (total rainfall, maximum, mean and minimum temperature and absolute humidity) varied between different States and Regions. Monthly incidence was forecasted 1 month ahead using the Auto Regressive Integrated Moving Average (ARIMA) method at country and subnational levels. With further development and validation, this may be a simple way to quickly generate short-term predictions at subnational scales with sufficient certainty to use for intervention planning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Animal cells undergo a dramatic series of shape changes as they divide, which depend on re-modeling of cell-substrate adhesions. Here, we show that while focal adhesion complexes are disassembled ...during mitotic rounding, integrins remain in place. These integrin-rich contacts connect mitotic cells to the underlying substrate throughout mitosis, guide polarized cell migration following mitotic exit, and are functionally important, since adherent cells undergo division failure when removed from the substrate. Further, the ability of cells to re-spread along pre-existing adhesive contacts is essential for division in cells compromised in their ability to construct a RhoGEF-dependent (Ect2) actomyosin ring. As a result, following Ect2 depletion, cells fail to divide on small adhesive islands but successfully divide on larger patterns, as the connection between daughter cells narrows and severs as they migrate away from one another. In this way, regulated re-modeling of cell-substrate adhesions during mitotic rounding aids division in animal cells.
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•Cells re-model adhesions as they round up upon entry into mitosis•These cell-substrate adhesions are essential for division in non-transformed cells•Adhesions can guide migration to divide cells with a compromised actomyosin ring
Dix et al. show that the integrin-positive adhesive contacts that remain following mitotic rounding are essential for division in non-transformed adherent cells in culture. Further, these adhesion sites guide polarized daughter cell migration—a process that is sufficient to drive abscission in the absence of a visible contractile actomyosin ring.
To divide in a tissue, both normal and cancer cells become spherical and mechanically stiffen as they enter mitosis. We investigated the effect of oncogene activation on this process in normal ...epithelial cells. We found that short-term induction of oncogenic RasV12 activates downstream mitogen-activated protein kinase (MEK-ERK) signaling to alter cell mechanics and enhance mitotic rounding, so that RasV12-expressing cells are softer in interphase but stiffen more upon entry into mitosis. These RasV12-dependent changes allow cells to round up and divide faithfully when confined underneath a stiff hydrogel, conditions in which normal cells and cells with reduced levels of Ras-ERK signaling suffer multiple spindle assembly and chromosome segregation errors. Thus, by promoting cell rounding and stiffening in mitosis, oncogenic RasV12 enables cells to proliferate under conditions of mechanical confinement like those experienced by cells in crowded tumors.
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•Ras-ERK signaling controls cell shape in mitosis•Activation of Ras alters cell mechanics to enhance mitotic stiffening•Cells expressing Ras are better able to round up to divide under stiff gels•Ras limits DNA segregation errors normally observed in confined cell division
Matthews et al. show that activation of the oncogenic Ras-ERK signaling pathway changes the shape and mechanical properties of normal epithelial cells in mitosis. This enables Ras-activated cells to round up and accurately segregate chromosomes when dividing in conditions of mechanical confinement.
The Burma Terrane (Myanmar) played an important role in the India‐Asia collision and moved over 2,000 km northward on the Indian Plate during the Cenozoic, before colliding with the Asian margin. ...However, the timing of this collision and its correlation to regional uplift phases, sedimentary provenance, and basin development remain poorly constrained. We report sedimentological, paleomagnetic, and geochronological data from the late Eocene to early Miocene strata of the Chindwin Basin in the Burmese forearc, constraining the paleogeographic evolution of the Burma Terrane and the Eastern Himalayan orogen. Our results highlight two unconformities of late Eocene‐middle Oligocene and latest Oligocene‐early Miocene age, revealing a two‐stage interaction of the Burma Terrane with the Asian margin during its northward translation. The first unconformity follows rapid ~0.6 m/ky subsidence in the Burmese forearc, as shown by magnetostratigraphy. The transition to a fluvial depositional environment and the occurrence of reworked sediments at this first unconformity likely records the commencing collision of India and the northern extent of the Burma Terrane with the Asian margin. The second unconformity shows drastic changes in magnetic properties, mineralogy, and provenance, with high‐grade metamorphic grains and early Miocene apatite U‐Pb and fission‐track ages indicating that it is coeval to a major deformation phase in Myanmar and the Eastern Himalayan orogen. It likely records the indentation of the Burma Terrane into the Eastern Himalayan collision zone, forming the modern Eastern Himalayan Syntaxis.
Plain Language Summary
The evolution of the India‐Asia collision and the resulting formation of the dramatic Himalayan mountain chain are highly debated among geologists. One of the reasons is that the easternmost extent of this mountain range is understudied compared to its central part. In Myanmar, at the eastern end of the Himalayas, this is partly caused by political and scientific isolation over the past 70 years, limited road access, and jungle covering much of the exposure. This study helps to constrain the paleogeographic evolution of the Burma Terrane, the microplate including most of Myanmar. To this end, we used a variety of methods including describing sedimentary deposits of the Burma Terrane, dating these deposits and determining their corresponding source regions. With this new information, we were able to determine that the deposition of these sediments occurred from ~40 to 23 million years ago but was discontinuous with two large hiatuses of millions of years long. Our results show that these two hiatuses are a consequence of a two‐stage process during the large northward motion of the Burma Terrane involving (1) the first collision of India and the northern Burma Terrane with Asia and (2) the indentation of Burma into the Himalayan collision zone.
Key Points
The Eocene to Lower Miocene sedimentary infill of the Chindwin forearc basin of the Burma Terrane is punctuated by two major unconformities
The first late Eocene‐middle Oligocene unconformity records the initial collision of India and the northern Burma Terrane with Asia
The second late Oligocene‐early Miocene unconformity marks major deformation in the Eastern Himalayas due to Burma Terrane northward motion
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