This review summarizes the recent advances in utilizing halogen bond-driven cocrystal formation as a design element in the creation of optical or photoresponsive materials, notably cocrystals and ...liquid crystals. The extensive work over a relatively short time has demonstrated halogen bonding as a versatile supramolecular interaction capable of creating libraries of fluorescent, phosphorescent, dichroic, photoswitchable, as well as photomechanical crystals and liquid crystals. Such rapid development, and the diversity of materials properties that have been designed or fine-tuned with success, signal the emergence of halogen-bonded cocrystallization as an exciting new playground for crystal engineers, chemists, and physicists to develop next-generation optical materials.
Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative ...colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.
Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association ...studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. Availability: http://www.broad.mit.edu/mpg/haploview/ Contact: jcbarret@broad.mit.edu
The Arctic‐wide melt season has lengthened at a rate of 5 days decade−1 from 1979 to 2013, dominated by later autumn freezeup within the Kara, Laptev, East Siberian, Chukchi, and Beaufort seas ...between 6 and 11 days decade−1. While melt onset trends are generally smaller, the timing of melt onset has a large influence on the total amount of solar energy absorbed during summer. The additional heat stored in the upper ocean of approximately 752 MJ m−2 during the last decade increases sea surface temperatures by 0.5 to 1.5 °C and largely explains the observed delays in autumn freezeup within the Arctic Ocean's adjacent seas. Cumulative anomalies in total absorbed solar radiation from May through September for the most recent pentad locally exceed 300–400 MJ m−2 in the Beaufort, Chukchi, and East Siberian seas. This extra solar energy is equivalent to melting 0.97 to 1.3 m of ice during the summer.
Key Points
Melt season has lengthenedIncreased sea surface temperatures led to a delay in autumn freezeupIncreased solar absorption melts an extra 1 m of ice
How extinct, non-avian theropod dinosaurs moved is a subject of considerable interest and controversy. A better understanding of non-avian theropod locomotion can be achieved by better understanding ...terrestrial locomotor biomechanics in their modern descendants, birds. Despite much research on the subject, avian terrestrial locomotion remains little explored in regards to how kinematic and kinetic factors vary together with speed and body size. Here, terrestrial locomotion was investigated in twelve species of ground-dwelling bird, spanning a 1,780-fold range in body mass, across almost their entire speed range. Particular attention was devoted to the ground reaction force (GRF), the force that the feet exert upon the ground. Comparable data for the only other extant obligate, striding biped, humans, were also collected and studied. In birds, all kinematic and kinetic parameters examined changed continuously with increasing speed, while in humans all but one of those same parameters changed abruptly at the walk-run transition. This result supports previous studies that show birds to have a highly continuous locomotor repertoire compared to humans, where discrete 'walking' and 'running' gaits are not easily distinguished based on kinematic patterns alone. The influences of speed and body size on kinematic and kinetic factors in birds are developed into a set of predictive relationships that may be applied to extinct, non-avian theropods. The resulting predictive model is able to explain 79-93% of the observed variation in kinematics and 69-83% of the observed variation in GRFs, and also performs well in extrapolation tests. However, this study also found that the location of the whole-body centre of mass may exert an important influence on the nature of the GRF, and hence some caution is warranted, in lieu of further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The formation of co-crystals by the assembly of molecules with complementary molecular recognition functionalities is a popular strategy to design or improve a range of solid-state properties, ...including those relevant for pharmaceuticals, photo- or thermoresponsive materials and organic electronics. Here, we report halogen-bonded co-crystals of a fluorinated azobenzene derivative with a volatile component-either dioxane or pyrazine-that can be cut, carved or engraved with low-power visible light. This cold photo-carving process is enabled by the co-crystallization of a light-absorbing azo dye with a volatile component, which gives rise to materials that can be selectively disassembled with micrometre precision using low-power, non-burning laser irradiation or a commercial confocal microscope. The ability to shape co-crystals in three dimensions using laser powers of 0.5-20 mW-substantially lower than those used for metals, ceramics or polymers-is rationalized by photo-carving that targets the disruption of weak supramolecular interactions, rather than the covalent bonds or ionic structures targeted by conventional laser beam or focused ion beam machining processes.
BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors ...(PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.
We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.
RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor.
Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.
We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute ...lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules-but not their wild-type counterparts-rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.
Genome-wide association studies (GWASs) have revolutionized human disease genetics by discovering tens of thousands of associations between common variants and complex diseases. In parallel, huge ...technological advances in DNA sequencing have made it possible to measure and analyze rare variation in populations. This review considers these two stories and how they have come together. We first review the history of GWASs and sequencing. We then consider how to understand the biological mechanisms that drive signals of strong association in the absence of rare-variant studies. We describe how rare-variant studies complement these approaches and highlight both data generation and statistical challenges in their interpretation. Finally, we consider how certain special study designs, such as those for families and isolated populations, fit in this paradigm.
We present a statistically complete sample of very X-ray luminous galaxy clusters detected in the MAssive Cluster Survey (MACS). This second MACS release comprises all 34 MACS clusters with nominal ...X-ray fluxes in excess of 2 × 10−12 erg s−1 cm−2 (0.1–2.4 keV) in the ROSAT Bright Source Catalogue; two-thirds of them are new discoveries. Extending over the redshift range from 0.3 to 0.5, this subset complements the complete sample of the 12 most distant MACS clusters (z > 0.5) published in 2007 and further exemplifies the efficacy of X-ray selection for the compilation of samples of intrinsically massive galaxy clusters. Extensive follow-up observations with Chandra/ACIS led to three additional MACS cluster candidates being eliminated as (predominantly) X-ray point sources. For another four clusters – which, however, remain in our sample of 34 – the point-source contamination was found to be about 50 per cent. The median X-ray luminosity of 1.3 × 1045 erg s−1 (0.1–2.4 keV, Chandra, within r500) of the clusters in this subsample demonstrates the power of the MACS strategy to find the most extreme and rarest clusters out to significant redshift. A comparison of the optical and X-ray data for all clusters in this release finds a wide range of morphologies with no obvious bias in favour of either relaxed or merging systems.
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