RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of ...diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered "undruggable" genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic ...targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.
Genetic programming method for modelling of maximum height of deep drawn high strength sheet materials is proposed in this paper. Genetic programming (GP) is an evolutionary computation approach ...which uses the principles of Darwin's natural selection to develop effective solutions for different problems. The aim of the research was the modelling of cylindrical cup height in deep drawing process and analysis of the impact of process parameters on material formability. High strength steel sheet materials (DP1180HD and DP780) were formed by deep drawing using different punch speeds and blank holder forces. The heights of specimens before cracks occur were measured. Therefore, four input parameters (yield stress, tensile strength, blank holder force, punch speed) and one output parameter (cup height) were used in the research. The experimental data were the basis for obtaining various accurate prediction models for the cup heights by the genetic programming method. Results showed that proposed genetic modelling method can successfully predict fracture problems in a process of deep drawing.
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IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT BACKGROUND: High-energy Lisfranc injuries are relatively uncommon but can lead to severe disability and morbidity. Primary fusion is a treatment option that can improve outcomes and reduce ...the reoperation rate. The aim of this study was to evaluate our series of primary fusions for high-energy Lisfranc injuries, looking specifically at type of fusion, time to union, non-union rates, reoperation rates and quality of reduction METHODS: Patients who underwent surgery for Lisfranc injuries were identified from the REDCap surgical database and then retrieved from records. Only cases of primary fusion in adults were included. We excluded low-energy sprains and athletic injuries, ipsilateral lower limb injuries and cases where reduction and fixation were done. Radiographs were analysed from the iSite Enterprise PACS system (Philips® RESULTS: Between 2013 and 2018, 12 cases of high-energy Lisfranc injuries were identified where primary fusion was done. Seven patients (58%) underwent fusion of the first, second and third tarsometatarsal (TMT) joints. The first and second TMT joints were fused in only one case (8%), and the second and third TMT joints were fused in four cases (33%). Only one patient (8%) had removal of implants. Compression plating was the technique of choice used for fusion. There was l0o% union rate and average time to union was 84 days. Acceptable reduction was observed in nine cases (75%). Three cases (25%) of malreduction were found, among which one patient had pre-existing hallux valgus CONCLUSION: The majority of patients who underwent primary fusion of at least one TMT joint had good radiological outcome. Further studies with better clinical follow-up are needed Level of evidence: Level 4 Keywords: Lisfranc, tarsometatarsal, outcome, fusion
A significant amount of red mud generated as a by-product of the Bayer
process in the aluminum industry may cause environmental problems if
appropriate treatment is not carried out. The presented ...research dealt with
the possibility of application of red mud as a pigment or as raw material
for use in the construction material industry. In relation to the aim of
this work, the physicochemical characterization was performed and the
natural radioactivity of red mud as an industrial waste and a geopolymer
sample based on it was determined. The presented research is a
contribution to the potential solution for environmental protection through
the synthesis of possible construction material based on red mud.
The radiological hazard orginating from 226Ra, 232Th, and 40K in the
samples was assesed throught the absorbed dose rate and the annual effective
dose rate, calculated in accordance with the UNSCEAR 2010 report.
Physicochemical characterization of all samples was conducted using X-ray
diffraction and diffuse reflectance infrared Fourier transform spectroscopy.
The first study on a general technology for arriving at valued nonracemic allylic alcohols using asymmetric ligand-accelerated catalysis by copper hydride is described.
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IJS, KILJ, NUK, PNG, UL, UM
Humidity sensing is important to a variety of technologies and industries, ranging from environmental and industrial monitoring to medical applications. Although humidity sensors abound, few ...available solutions are thin, transparent, compatible with large-area sensor production and flexible, and almost none are fast enough to perform human respiration monitoring through breath detection or real-time finger proximity monitoring via skin humidity sensing. This work describes chemiresistive graphene-based humidity sensors produced in few steps with facile liquid phase exfoliation followed by Langmuir-Blodgett assembly that enables active areas of practically any size. The graphene sensors provide a unique mix of performance parameters, exhibiting resistance changes up to 10% with varying humidity, linear performance over relative humidity (RH) levels between 8% and 95%, weak response to other constituents of air, flexibility, transparency of nearly 80%, and response times of 30 ms. The fast response to humidity is shown to be useful for respiration monitoring and real-time finger proximity detection, with potential applications in flexible touchless interactive panels.
Organic chemists are able to synthesize molecules in greater number and chemical complexity than ever before. Yet, a majority of these compounds go untested in biological systems, and those that do ...are often tested long after the chemist can incorporate the results into synthetic planning. We propose the use of high-dimensional “multiplex” assays, which are capable of measuring thousands of cellular features in one experiment, to annotate rapidly and inexpensively the biological activities of newly synthesized compounds. This readily accessible and inexpensive “real-time” profiling method can be used in a prospective manner to facilitate, for example, the efficient construction of performance-diverse small-molecule libraries that are enriched in bioactives. Here, we demonstrate this concept by synthesizing ten triads of constitutionally isomeric compounds via complexity-generating photochemical and thermal rearrangements and measuring compound-induced changes in cellular morphology via an imaging-based “cell painting” assay. Our results indicate that real-time biological annotation can inform optimization efforts and library syntheses by illuminating trends relating to biological activity that would be difficult to predict if only chemical structure were considered. We anticipate that probe and drug discovery will benefit from the use of optimization efforts and libraries that implement this approach.
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IJS, KILJ, NUK, PNG, UL, UM
Piperlongumine (PL) is a naturally occurring small molecule previously shown to induce cell death preferentially in cancer cells relative to non-cancer cells. An initial effort to synthesize analogs ...highlighted the reactivities of both of piperlongumine's α,β-unsaturated imide functionalities as key features determining PL's cellular effects. In this study, a second-generation of analogs was synthesized and evaluated in cells to gain further insight into how the reactivity, number, and orientation of PL's reactive olefins contribute to its ability to alter the physiology of cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Stuck on an sp2 carbon: A new route to geometrically defined α‐alkoxycarbonyl‐substituted vinylboronates consists of the chemo‐ and stereoselective 1,2‐addition of copper hydride to acetylenic esters ...followed by stereoretentive transmetalation with pinacolborane. This strategy is applied to the generation of an aryl acrylate intermediate in the synthesis of the antiinflammatory drug naproxen (see scheme).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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