![PubReading [338] - A Systems Biology Approach to Investigate Kinase Signal Transduction Networks That Are Involved in Triple Negative Breast Cancer Resistance to Cisplatin - N. Mukherjee, A. Eustace et al.](https://is1-ssl.mzstatic.com/image/thumb/Podcasts122/v4/7c/f8/ab/7cf8ab48-19d8-bd52-8841-ab48d666a60e/mza_17472500819476796018.jpg/250x250bb.jpg)
Afleveringen
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A workshop held last June by the National Institutes of Health (NIH) Directorâs Office, Nature Publishing Group, and Science focused on the role that journals play in supporting scientific research that is reproducible, robust, and transparent. The âPrinciples and Guidelines for Reporting Preclinical Researchâ that emerged from the workshop have since been endorsed by nearly 80 societies, journals, and associations.VOL.290,NO.50,pp.29692â29694 - 2015
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The gender imbalance in science, technology, engineering, and math (STEM) fields has remained constant for decades and increases the farther up the STEM career pipeline one looks. Why does the underrepresentation of women endure? This study investigated the role of parenthood as a mechanism of gender-differentiated attrition from STEM employment. Using a nationally representative 8-year longitudinal sample of US STEM professionals, we examined the career trajectories of new parents after the birth or adoption of their first child. We found substantial attrition of new mothers: 43% of women leave full-time STEM employment after their first child. New mothers are more likely than new fathers to leave STEM, to switch to part-time work, and to exit the labor force. These gender differences hold irrespective of variation by discipline, race, and other demographic factors. However, parenthood is not just a âmotherâs problemâ; 23% of new fathers also leave STEM after their first child. Suggesting the difficulty of combining STEM work with caregiving responsibilities generally, new parents are more likely to leave full-time STEM jobs than otherwise similar childless peers and even new parents who remain employed full time are more likely than their childless peers to exit STEM for work elsewhere. These results have implications for policymakers and STEM workforce scholars; whereas parenthood is an important mechanism of womenâs attrition, both women and men leave at surprisingly high rates after having children. Given that most people become parents during their working lives, STEM fields must do more to retain professionals with children.doi/10.1073/pnas.1810862116 - 2019
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Carbon nanomaterials (CNMs) are an incredibly versatile class of materials that can be used as scaffolds to construct anticancer nanocarrier systems. The ease of chemical functionalisation, biocompatibility, and intrinsic therapeutic capabilities of many of these nanoparticles can be leveraged to design effective anticancer systems. This article is the first comprehensive review of CNM-based nanocarrier systems that incorporate approved chemotherapy drugs, and many different types of CNMs and chemotherapy agents are discussed. Almost 200 examples of these nanocarrier systems have been analysed and compiled into a database. The entries are organised by anticancer drug type, and the composition, drug loading/release metrics, and experimental results from these systems have been compiled. Our analysis reveals graphene, and particularly graphene oxide (GO), as the most frequently employed CNM, with carbon nanotubes and carbon dots following in popularity. Moreover, the database encompasses various chemotherapeutic agents, with antimicrotubule agents being the most common payload due to their compatibility with CNM surfaces. The benefits of the identified systems are discussed, and the factors affecting their efficacy are detailed.doi.org/10.3390/pharmaceutics15051545 - 2023
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Human tissues are invaluable resources for pharmaceutical research. They provide information about disease pathophysiology - and equally importantly, healthy function; confirmation (or refutation) of potential drug targets; validation (or otherwise) of other models employed; and functional models for assessing drugsâ effects, whether beneficial or undesirable, in the most appropriate environment that can be replicated outside the human body. While human tissues have long been prized by pathologists in furthering our under- standing of disease processes, there is a growing appreciation of their value at the late pre-clinical stage of drug discovery. Human tissuesâ potential to contribute to earlier phases of the process, before significant resources have been expended, is also now gaining recognition. Mounting concern over high rates of clinical stage drug failures mandates exploration of avenues for improving efficiency. Human tissue-based assays could play a key role in improving the translation process, as well as in moving towards stratified or personalised medicines. This editorial highlights some of the potential benefits of introducing human biosamples at each stage of the research process as a drug moves from concept to clinic. Some of the challenges with respect to obtaining tissues, minimising variability and gaining acceptance are also discussed.https://doi.org/10.1517/17460441.2012.689282 - 2012
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Albert Einstein once eloquently stated âWe still do not know one thousandth of one percent of what nature has revealed to us.â Mother Nature has proven time and again to be the best engineer, architect, scientist, and doctor. This fact has not been lost on mankind, and since time immemorial, we have looked to nature for answers to human conditions and diseases. Indeed, our first evidence dates back to preliterary history as long as 50,000 years ago, in archaeological discoveries from a Middle Eastern grave site at Shanidar, Iraq, of a Neanderthal man which contained plant specimens, of which are still used in local traditional medicine. Since then, the use and application of herbal medicine has been recorded in every society from Traditional Chinese, Ayurvedic, Yunani, and other cultures in the developing world.DOI: 10.1097/FJC.0000000000001278 - 2022
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Triple negative breast cancer (TNBC) remains a therapeutic challenge due to the lack of targetable genetic alterations and the frequent development of resistance to the standard cisplatin-based chemotherapies. Here, we have taken a systems biology approach to investigate kinase signal transduction networks that are involved in TNBC resistance to cisplatin. Treating a panel of cisplatin- sensitive and cisplatin-resistant TNBC cell lines with a panel of kinase inhibitors allowed us to reconstruct two kinase signalling networks that characterise sensitive and resistant cells. The analysis of these networks suggested that the activation of the PI3K/AKT signalling pathway is critical for cisplatin resistance. Experimental validation of the computational model predictions confirmed that TNBC cell lines with activated PI3K/AKT signalling are sensitive to combinations of cisplatin and PI3K/AKT pathway inhibitors. Thus, our results reveal a new therapeutic approach that is based on identifying targeted therapies that synergise with conventional chemotherapies.doi.org/10.3390/jpm12081277 - 2022
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Meta-research, or the science of science, is a powerful technique that scientists can use to improve science, however most scientists are unaware that meta-research exists and courses are rare. This initiative demonstrates the feasibility of a participant-guided âlearn by doingâ approach, in which a multidisciplinary, global team of early career researchers learned meta-research skills by working together to design, conduct and publish a meta-research study.https://doi.org/10.1371/journal.pbio.3001073 - 2021
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Mechanically interlocked molecules such as rotaxanes and catenanes contain free-moving components that cannot dissociate and have enabled the investigation and control of various translational and rotational molecular motions. The architecture of pseudo-rotaxanes and of some kinetically labile rotaxanes is comparable to that of rotaxanes but their components are reversibly associated and not irreversibly interlocked. In other words, pseudo-rotaxanes may fall apart. This Account focuses on a peculiar family of rotaxane-like architectures termed foldaxanes. Foldaxanes consist of a helically folded oligomer wound around a rod-like dumbbell-shaped guest. Winding of the helix around the rod thus entails an unwindingârewinding process that creates a kinetic barrier. It follows that foldaxanes, albeit reversibly assembled, have significant lifetimes and may not fall apart while defined molecular motions are triggered. Foldaxanes based on helically folded aromatic oligoamide hosts and oligo(alkyl carbamate) guests can be designed rationally through the inclusion of complementary binding motifs on the rod and at the inner rim of the helix so that helix length and rod length match. Single helical foldaxanes (bimolecular species) and double helical foldaxanes (trimolecular species) have thus been produced as well as poly[n]foldaxanes, in which several helices bind to long rods with multiple binding stations. When the binding stations differ and are organized in a certain sequence, a complementary sequence of different stacked helices, each matching with their binding station, can be assembled, thus reproducing in an artificial system a sort of translation process.https://doi.org/10.1021/acs.accounts.2c00050 - 2022
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[Ru(phen)2 (dppz)]2+ has been studied since the 1990s due to its âlight-switchâ properties. It can be used as a luminescent DNA probe, with emission switched on through DNA binding. The luminescence observed is dependent on the solvent accessibility of the pyrazine nitrogen atoms, and therefore is sensitive to changes in both binding site of the cation and chromophore orientation. The compound is also chiral, and there are distinct differences between the enantiomers in terms of the emission behaviour when bound to a variety of DNA sequences. Whilst a number of binary DNA-complex X-ray crystal structures are available, most include the lambda enantiomer and there is very little structural information about binding of the delta enantiomer. Here, we present the first X-ray crystal structure of a delta enantiomer bound to well-matched DNA, in the absence of the other, lamda enantiomer. We show how the binding site observed here can be related to a more general pattern of motifs in the crystallographic literature and propose that the delta enantiomer can bind with five different binding modes, offering a new hypothesis for the interpretation of solution data.doi: 10.1093/nar/gkw753 - 2016
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The movement towards open science is a consequence of seemingly pervasive failures to replicate previous research. This transition comes with great benefits but also significant challenges that are likely to affect those who carry out the research, usually early career researchers (ECRs). Here, we describe key benefits, including reputational gains, increased chances of publication, and a broader increase in the reliability of research. The increased chances of publication are supported by exploratory analyses indicating null findings are substantially more likely to be published via open registered reports in comparison to more conventional methods. These benefits are balanced by challenges that we have encountered and that involve increased costs in terms of flexibility, time, and issues with the current incentive structure, all of which seem to affect ECRs acutely. Although there are major obstacles to the early adoption of open science, overall open science practices should benefit both the ECR and improve the quality of research. We review 3 benefits and 3 challenges and provide suggestions from the perspective of ECRs for moving towards open science practices, which we believe scientists and institutions at all levels would do well to consider.https:// doi.org/10.1371/journal.pbio.3000246 - 2019
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We describe an isothermal, single-reaction method for assembling multiple overlapping DNA molecules by the concerted action of a 5' exonuclease, a DNA polymerase and a DNA ligase. First we recessed DNA fragments, yielding single-stranded DNA overhangs that specifically annealed, and then covalently joined them. This assembly method can be used to seamlessly construct synthetic and natural genes, genetic pathways and entire genomes, and could be a useful molecular engineering tool.DOI:10.1038/NMETH.1318 - 2009
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Formation of natural intramolecular triple-helical structures of DNA is still an intriguing research topic in view of the possible involvement of these structures in biological processes. The biochemical and biophysical properties of DNA triplex structures have been extensively studied, and experimental data show that H-DNA is likely to form in vivo and may regulate the expression of various genes. However, direct and unambiguous evidence of the possible biological roles of these structures is yet elusive. This review focuses on the basic facts that are in favor of, or against, the hypothesis of the presence and function of natural DNA triple-helical structures in vivo, and outlines the different methods and probes that have been used to support these facts.DOI 10.1007/s00018-003-3046-3 - 2003
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In STEM, and particularly in science, many early career researchers find themselves isolated and lacking guidance. There is an enormous need to connect early career scientists with experienced professionals outside their immediate work environment. A new initiative aims to create a supportive community to foster communication between scientists through all stages of their career.https://doi.org/10.1016/j.molmed.2019.08.007 - 2019
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Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocys- tis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology.https://doi.org/10 .1128/mBio.02878-19 - 2020
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Myeloid derived suppressors cells (MDSC) play major roles in regulating immune homeostasis and immune responses in many conditions, including cancer. MDSC interact with cancer cells within the tumor microenvironment (TME) with direct and indirect mechanisms: production of soluble factors and cytokines, expression of surface inhibitory molecules, metabolic rewiring and exosome release. The two-way relationship between MDSC and tumor cells results in immune evasion and cancer outgrowth. In multiple myeloma (MM), MDSC play a major role in creating protumoral TME conditions. In this minireview, we will discuss the interplay between MDSC and MM TME and the possible strategies to target MDSC.doi: 10.3389/fimmu.2022.1102471 - 2023
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Early career researchers face uncertainties with respect to their job prospects due to dwindling job markets, decreased availability of funding and undefined career paths. As basic researchers and clinicians tend to have different approaches to scientific problems, there are many advantages from successful collaborations between them. Here, we discuss how collaborations between basic and clinical scientists should be promoted early in their careers. To achieve this, researchers, both basic and clinical, must be proactive during their training and early stages of their careers. Mentors can further augment collaborative links in many ways. We suggest that universities and institutions might reassess their involvement in promoting collaborations between basic and clinical researchers. We hope that this paper will serve as a reminder of the importance of such collaborations, and provide the opportunity for all members of the scientific community to reflect on and ame- liorate their own contributions.DOI: 10.1111/jth.13447 - 2016
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DNA has emerged as an attractive medium for archival data storage due to its durability and high information density. Scalable parallel random access to information is a desirable property of any storage system. For DNA-based storage systems, however, this still needs to be robustly established. Here we report on a thermoconfined polymerase chain reaction, which enables multiplexed, repeated random access to compartmentalized DNA files. The strategy is based on localizing biotin-functionalized oligonucleotides inside thermoresponsive, semipermeable microcapsules. At low temperatures, microcapsules are permeable to enzymes, primers and amplified products, whereas at high temperatures, membrane collapse prevents molecular crosstalk during amplification. Our data show that the platform outperforms non-compartmentalized DNA storage compared with repeated random access and reduces amplification bias tenfold during multiplex polymerase chain reaction. Using fluorescent sorting, we also demonstrate sample pooling and data retrieval by microcapsule barcoding. Therefore, the thermoresponsive microcapsule technology offers a scalable, sequence-agnostic approach for repeated random access to archival DNA files.https://doi.org/10.1038/s41565-023-01377-4 - 2023
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Induced pluripotent stem cells (iPSCs) enable the generation of previously unattainable, scalable quantities of disease- relevant tissues from patients suffering from essentially any genetic disorder. This cellular material has proven instrumental for drug screening efforts on these disorders, and has facilitated the identification of novel therapeutics for patients. Here we will review the foundational technologies that have enabled iPSCs, the power and limitations of iPSC-based compound screens along with screening guidelines, and recent examples of screening efforts. Additionally we will provide a brief commentary on the future scientific roadmap using pluripotent- and 3D organoid-based, combinatorial approaches.doi: 10.1093/hmg/ddy186 - 2018
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Improving the reproducibility of neuroscience research is of great concern, especially to early-career researchers (ECRs). Here I outline the potential costs for ECRs in adopting practices to improve reproducibility. I highlight the ways in which ECRs can achieve their career goals while doing better science and the need for established researchers to support them in these efforts.https://doi.org/10.1016/j.neuron.2018.11.030 - 2019
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Precipitation of DNA is performed frequently in molecular biology laboratories for the purpose of purification and concentration of samples and also for transfer of DNA into cells. Metal ions are used to facilitate these processes, though their precise functions are not well characterized. In the current study we have investigated the precipitation of double-stranded DNA by group 1 and group 2 metal ions. Double-stranded DNAs were not sedimented efficiently by metals alone, even at high concentrations. Increasing the pH to 11 or higher caused strong DNA precipitation in the presence of the divalent group 2 metals magnesium, calcium, strontium and barium, but not group 1 metals. Group 2 sedimentation profiles were distinctly different from that of the transition metal zinc, which caused precipitation at pH 8. Analysis of DNAs recovered from precipitates formed with calcium revealed that structural integrity was retained and that sedimentation efficiency was largely size-independent above 400 bp. Several tests supported a model whereby single-stranded DNA regions formed by denaturation at high pH became bound by the divalent metal cations. Neutralization of negative surface charges reduced the repulsive forces between molecules, leading to formation of insoluble aggregates that could be further stabilized by cation bridging (ionic crosslinking).doi:10.1016/j.ab.2020.114099 - 2021
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