Cross-linked networks feature exceptional chemical and mechanical resilience but consequently lack recyclability. Vitrimers have emerged as a class of materials that feature the robustness of ...thermosets and the recyclability of thermoplastics without compromising network integrity. Most examples of vitrimers have involved new polymers with exchangeable bonds within their backbones. In pursuit of a more universal, commercially viable route, we propose a method utilizing commercially available and inexpensive reagents to prepare vitrimers from vinyl monomer-derived prepolymers that contain cross-linkable β-ketoester functional groups. Controlled radical copolymerization of methyl methracrylate and (2-acetoacetoxy)ethyl methacrylate afforded linear prepolymers that were converted into vitrimers in a single step by treatment with a trifunctional amine. These materials displayed the characteristic features and reprocessability of vitrimers over as many as six (re)processing cycles. Critically, the networks prepared through this process largely retain the chemical and thermal properties of their linear counterparts, suggesting this method holds significant utility as a user-friendly and commercially relevant approach to the rational design of vitrimers with diverse properties.
Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular ...cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, which are a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. We illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.
Matrix metalloproteinases (MMPs) participate from the initial phases of cancer onset to the settlement of a metastatic niche in a second organ. Their role in cancer progression is related to their ...involvement in the extracellular matrix (ECM) degradation and in the regulation and processing of adhesion and cytoskeletal proteins, growth factors, chemokines and cytokines. MMPs participation in cancer progression makes them an attractive target for cancer therapy. MMPs have also been used for theranostic purposes in the detection of primary tumor and metastatic tissue in which a particular MMP is overexpressed, to follow up on therapy responses, and in the activation of cancer cytotoxic pro-drugs as part of nano-delivery-systems that increase drug concentration in a specific tumor target.
Herein, we review MMPs molecular characteristics, their synthesis regulation and enzymatic activity, their participation in the metastatic process, and how their functions have been used to improve cancer treatment.
Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is ...difficult. Here, we report an optically-clear prkdc−/−, il2rga−/− zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.
Display omitted
•prkdc−/−, il2rga−/− zebrafish reared at 37°C engraft a wide array of human cancers•Growth and therapy responses can be dynamically visualized at single-cell resolution•Combination olaparib and temozolomide kill xenografted human rhabdomyosarcoma•Engrafting patient-derived cancers opens new avenues for personalized therapy
Robust engraftment of human cancers into optically-clear, immune-deficient zebrafish at physiological temperatures enables dynamic visualization of cell biological phenotypes and therapy responses in single cancer cells over time.
Mosquitoes that carry Wolbachia endosymbionts may help control the spread of arboviral diseases, such as dengue, Zika and chikungunya. Wolbachia frequencies systematically increase only when the ...frequency-dependent advantage due to cytoplasmic incompatibility exceeds frequency-independent costs, which may be intrinsic to the Wolbachia and/or can be associated with the genetic background into which Wolbachia are introduced. Costs depend on field conditions such as the environmental pesticide load. Introduced mosquitoes need adequate protection against insecticides to ensure survival after release. We model how insecticide resistance of transinfected mosquitoes determines the success of local Wolbachia introductions and link our theoretical results to field data. Two Ae. aegypti laboratory strains carrying Wolbachia were released in an isolated district of Rio de Janeiro, Brazil: wMelBr (susceptible to pyrethroids) and wMelRio (resistant to pyrethroids). Our models elucidate why releases of the susceptible strain failed to result in Wolbachia establishment, while releases of the resistant strain led to Wolbachia transforming the native Ae. aegypti population. The results highlight the importance of matching insecticide resistance levels in release stocks to those in the target natural populations during Wolbachia deployment.
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate and invertebrate nervous system. GABAA receptors are activated by GABA and their agonists, and modulated by a ...wide variety of recognized drugs, including barbiturates, anesthetics, and benzodiazepines. The phenols propofol, thymol, chlorothymol, carvacrol and eugenol act as positive allosteric modulators on GABAA-R receptor. These GABAergic phenols interact with the lipid membrane, therefore, their anesthetic activity could be the combined result of their specific activity (with receptor proteins) as well as nonspecific interactions (with surrounding lipid molecules) modulating the supramolecular organization of the receptor environment. Therefore, we aimed to contribute to a description of the molecular events that occur at the membrane level as part of the mechanism of general anesthesia, using a molecular dynamic simulation approach. Equilibrium molecular dynamics simulations indicate that the presence of GABAergic phenols in a DPPC bilayer orders lipid acyl chains for carbons near the interface and their effect is not significant at the bilayer center. Phenols interacts with the polar interface of phospholipid bilayer, particularly forming hydrogen bonds with the glycerol and phosphate group. Also, potential of mean force calculations using umbrella sampling show that propofol partition is mainly enthalpic driven at the polar region and entropic driven at the hydrocarbon chains. Finally, potential of mean force indicates that propofol partition into a gel DPPC phase is not favorable. Our in silico results were positively contrasted with previous experimental data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Temperature as a modulator of sexual selection García‐Roa, Roberto; Garcia‐Gonzalez, Francisco; Noble, Daniel W.A. ...
Biological reviews of the Cambridge Philosophical Society,
December 2020, Letnik:
95, Številka:
6
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
A central question in ecology and evolution is to understand why sexual selection varies so much in strength across taxa; it has long been known that ecological factors are crucial to this. ...Temperature is a particularly salient abiotic ecological factor that modulates a wide range of physiological, morphological and behavioural traits, impacting individuals and populations at a global taxonomic scale. Furthermore, temperature exhibits substantial temporal variation (e.g. daily, seasonally and inter‐seasonally), and hence for most species in the wild sexual selection will regularly unfold in a dynamic thermal environment. Unfortunately, studies have so far almost completely neglected the role of temperature as a modulator of sexual selection. Here, we outline the main pathways through which temperature can affect the intensity and form (i.e. mechanisms) of sexual selection, via: (i) direct effects on secondary sexual traits and preferences (i.e. trait variance, opportunity for selection and trait–fitness covariance), and (ii) indirect effects on key mating parameters, sex‐specific reproductive costs/benefits, trade‐offs, demography and correlated abiotic factors. Building upon this framework, we show that, by focusing exclusively on the first‐order effects that environmental temperature has on traits linked with individual fitness and population viability, current global warming studies may be ignoring eco‐evolutionary feedbacks mediated by sexual selection. Finally, we tested the general prediction that temperature modulates sexual selection by conducting a meta‐analysis of available studies experimentally manipulating temperature and reporting effects on the variance of male/female reproductive success and/or traits under sexual selection. Our results show a clear association between temperature and sexual selection measures in both sexes. In short, we suggest that studying the feedback between temperature and sexual selection processes may be vital to developing a better understanding of variation in the strength of sexual selection in nature, and its consequences for population viability in response to environmental change (e.g. global warming).
The constant growth of pathologies affecting human mobility has led to developing of different assistive devices to provide physical and cognitive assistance. Smart walkers are a particular type of ...these devices since they integrate navigation systems, path-following algorithms, and user interaction modules to ensure natural and intuitive interaction. Although these functionalities are often implemented in rehabilitation scenarios, there is a need to actively involve the healthcare professionals in the interaction loop while guaranteeing safety for them and patients. This work presents the validation of two visual feedback strategies for the teleoperation of a simulated robotic walker during an assisted navigation task. For this purpose, a group of 14 clinicians from the rehabilitation area formed the validation group. A simple path-following task was proposed, and the feedback strategies were assessed through the kinematic estimation error (KTE) and a usability survey. A KTE of 0.28 m was obtained for the feedback strategy on the joystick. Additionally, significant differences were found through a Mann–Whitney–Wilcoxon test for the perception of behavior and confidence towards the joystick according to the modes of interaction (p-values of 0.04 and 0.01, respectively). The use of visual feedback with this tool contributes to research areas such as remote management of therapies and monitoring rehabilitation of people’s mobility.
How to control single-molecule rotation Simpson, Grant J; García-López, Víctor; Daniel Boese, A ...
Nature communications,
10/2019, Letnik:
10, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The orientation of molecules is crucial in many chemical processes. Here, we report how single dipolar molecules can be oriented with maximum precision using the electric field of a scanning ...tunneling microscope. Rotation is found to occur around a fixed pivot point that is caused by the specific interaction of an oxygen atom in the molecule with the Ag(111) surface. Both directions of rotation are realized at will with 100% directionality. Consequently, the internal dipole moment of an individual molecule can be spatially mapped via its behavior in an applied electric field. The importance of the oxygen-surface interaction is demonstrated by the addition of a silver atom between a single molecule and the surface and the consequent loss of the pivot point.
Traditional vector control approaches such as source reduction and insecticide spraying have limited effect on reducing Aedes aegypti population. The endosymbiont Wolbachia is pointed as a promising ...tool to mitigate arbovirus transmission and has been deployed worldwide. Models predict a rapid increase on the frequency of Wolbachia-positive Ae. aegypti mosquitoes in local settings, supported by cytoplasmic incompatibility (CI) and high maternal transmission rate associated with the wMelBr strain.
Wolbachia wMelBr strain was released for 20 consecutive weeks after receiving >87% approval of householders of the isolated community of Tubiacanga, Rio de Janeiro. wMelBr frequency plateued~40% during weeks 7-19, peaked 65% but dropped as releases stopped. A high (97.56%) maternal transmission was observed. Doubling releases and deploying mosquitoes with large wing length and low laboratory mortality produced no detectable effects on invasion trend. By investigating the lab colony maintenance procedures backwardly, pyrethroid resistant genotypes in wMelBr decreased from 68% to 3.5% after 17 generations. Therefore, we initially released susceptible mosquitoes in a local population highly resistant to pyrethroids which, associated with the over use of insecticides by householders, ended jeopardizing Wolbachia invasion. A new strain (wMelRio) was produced after backcrossing wMelBr females with males from field to introduce mostly pyrethroid resistance alleles. The new strain increased mosquito survival but produced relevant negative effects on Ae. aegypti fecundity traits, reducing egg clutche size and egg hatch. Despite the cost on fitness, wMelRio successful established where wMelBr failed, revealing that matching the local population genetics, especially insecticide resistance background, is critical to achieve invasion.
Local householders support was constantly high, reaching 90% backing on the second release (wMelRio strain). Notwithstanding the drought summer, the harsh temperature recorded (daily average above 30°C) did not seem to affect the expression of maternal transmission of wMel on a Brazilian background. Wolbachia deployment should match the insecticide resistance profile of the wild population to achieve invasion. Considering pyrethroid-resistance is a widely distributed phenotype in natural Ae. aegypti populations, future Wolbachia deployments must pay special attention in maintaining insecticide resistance in lab colonies for releases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
