Many biomolecular motors catalyze the hydrolysis of chemical fuels, such as adenosine triphosphate, and use the energy released to direct motion through information ratchet mechanisms. Here we ...describe chemically-driven artificial rotary and linear molecular motors that operate through a fundamentally different type of mechanism. The directional rotation of 2- and 3catenane rotary molecular motors and the transport of substrates away from equilibrium by a linear molecular pump are induced by acid-base oscillations. The changes simultaneously switch the binding site affinities and the labilities of barriers on the track, creating an energy ratchet. The linear and rotary molecular motors are driven by aliquots of a chemical fuel, trichloroacetic acid. A single fuel pulse generates 360° unidirectional rotation of up to 87% of crown ethers in a 2catenane rotary motor.
Molecular machines are among the most complex of all functional molecules and lie at the heart of nearly every biological process. A number of synthetic small-molecule machines have been developed, ...including molecular muscles, synthesizers, pumps, walkers, transporters and light-driven and electrically driven rotary motors. However, although biological molecular motors are powered by chemical gradients or the hydrolysis of adenosine triphosphate (ATP), so far there are no synthetic small-molecule motors that can operate autonomously using chemical energy (that is, the components move with net directionality as long as a chemical fuel is present). Here we describe a system in which a small molecular ring (macrocycle) is continuously transported directionally around a cyclic molecular track when powered by irreversible reactions of a chemical fuel, 9-fluorenylmethoxycarbonyl chloride. Key to the design is that the rate of reaction of this fuel with reactive sites on the cyclic track is faster when the macrocycle is far from the reactive site than when it is near to it. We find that a bulky pyridine-based catalyst promotes carbonate-forming reactions that ratchet the displacement of the macrocycle away from the reactive sites on the track. Under reaction conditions where both attachment and cleavage of the 9-fluorenylmethoxycarbonyl groups occur through different processes, and the cleavage reaction occurs at a rate independent of macrocycle location, net directional rotation of the molecular motor continues for as long as unreacted fuel remains. We anticipate that autonomous chemically fuelled molecular motors will find application as engines in molecular nanotechnology.
Carbohydrate receptors with a chiral framework have been generated by combining a tetra-aminopyrene and a
-symmetrical triamine
isophthalamide spacers bearing water-solubilising groups. These ..."synthetic lectins" are the first to show enantiodiscrimination in aqueous solution, binding
-acetylglucosamine (GlcNAc) with 16 : 1 enantioselectivity. They also show exceptional affinities. GlcNAc is bound with
up to 1280 M
, more than twice that measured for previous synthetic lectins, and three times the value for wheat germ agglutinin, the lectin traditionally employed to bind GlcNAc in glycobiological research. Glucose is bound with
= 250 M
, again higher than previous synthetic lectins. The results suggest that chirality can improve complementarity to carbohydrate substrates and may thus be advantageous in synthetic lectin design.
IntroductionRecently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants ...with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC).Methods/designThis study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1–3 and one meal/day in months 4–6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1–2 pounds per week.Ethics and disseminationThe National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563).Trial registration number NCT04780477.
Oncogenesis in PLAG1‐rearranged tumors often results from PLAG1 transcription factor overexpression driven by promoter‐swapping between constitutively expressed fusion partners. PLAG1‐rearranged ...tumors demonstrate diverse morphologies. This study adds to this morphologic heterogeneity by introducing two tumors with PLAG1 rearrangements that display distinct histologic features. The first arose in the inguinal region of a 3‐year‐old, appeared well‐circumscribed with a multinodular pattern, and harbored two fusions: ZFHX4‐PLAG1 and CHCHD7‐PLAG1. The second arose in the pelvic cavity of a 15‐year‐old girl, was extensively infiltrative and vascularized with an adipocytic component, and demonstrated a COL3A1‐PLAG1 fusion. Both showed low‐grade cytomorphology, scarce mitoses, no necrosis, and expression of CD34 and desmin. The ZFHX4‐/CHCHD7‐PLAG1‐rearranged tumor showed no evidence of recurrence after 5 months. By contrast, the COL3A1‐PLAG1‐rearranged tumor quickly recurred following primary excision with positive margins; subsequent re‐excision with adjuvant chemotherapy resulted in no evidence of recurrence after 2 years. While both tumors show overlap with benign and malignant fibroblastic and fibrovascular neoplasms, they also display divergent features. These cases highlight the importance of appropriate characterization in soft tissue tumors with unusual clinical and histologic characteristics.
Synthetic molecular walkers Leigh, David A; Lewandowska, Urszula; Lewandowski, Bartosz ...
Topics in current chemistry,
01/2014, Letnik:
354
Journal Article
Recenzirano
In biological systems, molecular motors have been developed to harness Brownian motion and perform specific tasks. Among the cytoskeletal motor proteins, kinesins ensure directional transport of ...cargoes to the periphery of the cell by taking discrete steps along microtubular tracks. In the past decade there has been an increasing interest in the development of molecules that mimic aspects of the dynamics of biological systems and can became a starting point for the creation of artificial transport systems.To date, both DNA-based and small-molecule walkers have been developed, each taking advantage of the different chemistries available to them. DNA strollers exploit orthogonal base pairing and utilize strand-displacement reactions to control the relative association of the component parts. Small-molecule walkers take advantage of the reversibility of weak noncovalent interactions as well as the robustness of dynamic covalent bonds in order to transport molecular fragments along surfaces and molecular tracks using both diffusional processes and ratchet mechanisms. Here we review both types of synthetic systems, including their designs, dynamics, and how they are being used to perform functions by controlled mechanical motion at the molecular level.
Pan-cancer analysis of whole genomes Campbell, Peter J; Getz, Gad; Korbel, Jan O ...
Nature (London),
02/2020, Letnik:
578, Številka:
7793
Journal Article
Recenzirano
Odprti dostop
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale
. Here we report the integrative ...analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter
; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation
; analyses timings and patterns of tumour evolution
; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity
; and evaluates a range of more-specialized features of cancer genomes
.
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature
. Here, as part of the Pan-Cancer Analysis of Whole ...Genomes (PCAWG) Consortium
of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses
, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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