Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and ...folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
Metabolic rate determines the physiological and life-history performances of ectotherms. Thus, the extent to which such rates are sensitive and plastic to environmental perturbation is central to an ...organism's ability to function in a changing environment. Little is known of long-term metabolic plasticity and potential for metabolic adaptation in marine ectotherms exposed to elevated pCO2. Consequently, we carried out a series of in situ transplant experiments using a number of tolerant and sensitive polychaete species living around a natural CO2 vent system. Here, we show that a marine metazoan (i.e. Platynereis dumerilii) was able to adapt to chronic and elevated levels of pCO2. The vent population of P. dumerilii was physiologically and genetically different from nearby populations that experience low pCO2, as well as smaller in body size. By contrast, different populations of Amphiglena mediterranea showed marked physiological plasticity indicating that adaptation or acclimatization are both viable strategies for the successful colonization of elevated pCO2 environments. In addition, sensitive species showed either a reduced or increased metabolism when exposed acutely to elevated pCO2. Our findings may help explain, from a metabolic perspective, the occurrence of past mass extinction, as well as shed light on alternative pathways of resilience in species facing ongoing ocean acidification.
In direct-drive inertial confinement fusion, the laser bandwidth reduces the laser imprinting seed of hydrodynamic instabilities. The impact of varying bandwidth on the performance of direct-drive ...DT-layered implosions was studied in targets with different hydrodynamic stability properties. The stability was controlled by changing the shell adiabat from (αF ≃ 5) (more stable) to (αF ≃ 3.5) (less stable). Herein these experiments show that the performance of lower adiabat implosions improves considerably as the bandwidth is raised indicating that further bandwidth increases, beyond the current capabilities of OMEGA, would be greatly beneficial. These results suggest that the future generation of ultra-broadband lasers could enable achieving high convergence and possibly high gains in direct drive ICF.
Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity ...properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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•Pathologic protein networks and their engagement in clinic are monitored by imaging•Real-time tumor pharmacometric data are obtained at the level of individual tumors•Theranostic and clinical assay combined provide quantitative tumor measurements•The platform provides dose and schedule information for epichaperome targeting
Pillarsetty et al. demonstrate the ability to visualize the epichaperome, a pathologic protein-protein interaction network, and to measure inhibitor engagement from mice and patients at single-tumor resolution in real time, which facilitates the optimization of dose and schedule selection.
We present Searches After Gravitational-waves Using ARizona Observatories (SAGUARO), a comprehensive effort dedicated to the discovery and characterization of optical counterparts to ...gravitational-wave (GW) events. SAGUARO utilizes ground-based facilities ranging from 1.5 to 10 m in diameter, located primarily in the Northern Hemisphere. We provide an overview of SAGUARO's telescopic resources, its pipeline for transient detection, and its database for candidate visualization. We describe SAGUARO's discovery component, which utilizes the 5 deg2 field of view optical imager on the Mt. Lemmon 1.5 m telescope, reaching limits of 21.3 AB mag while rapidly tiling large areas. We also describe the follow-up component of SAGUARO, used for rapid vetting and monitoring of optical candidates. With the onset of Advanced LIGO/Virgo's third observing run, we present results from the first three SAGUARO searches following the GW events S190408an, S190425z and S190426c, which serve as a valuable proof-of-concept of SAGUARO. We triggered and searched 15, 60, and 60 deg2 respectively, 17.6, 1.4, and 41.8 hr after the initial GW alerts. We covered 7.8%, 3.0%, and 5.1% of the total probability within the GW event localizations, reaching 3 limits of 19.8, 21.3, and 20.8 AB mag, respectively. Although no viable counterparts associated with these events were found, we recovered six known transients and ruled out five potential candidates. We also present Large Binocular Telescope spectroscopy of PS19eq/SN2019ebq, a promising kilonova candidate that was later determined to be a supernova. With the ability to tile large areas and conduct detailed follow-up, SAGUARO represents a significant addition to GW counterpart searches.
Bovine leukaemia virus (BLV) is the causative agent of enzootic bovine leucosis, which has been reported worldwide. BLV has been found recently in human tissue and it could have a significant impact ...on human health. A possible hypothesis regarding viral entry to humans is through the consumption of infected foodstuffs. This study was aimed at detecting the presence of BLV DNA in raw beef and fresh milk for human consumption. Nested PCR directed at the BLV gag gene (272 bp) was used as a diagnostic test. PCR products were confirmed by Sanger sequencing. Forty-nine per cent of the samples proved positive for the presence of proviral DNA. This is the first study highlighting the presence of the BLV gag gene in meat products for human consumption and confirms the presence of the viral DNA in raw milk, as in previous reports. The presence of viral DNA in food products could suggest that viral particles may also be found. Further studies are needed to confirm the presence of infected viral particles, even though the present findings could represent a first approach to BLV transmission to humans through foodstuff consumption.
Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and ...psychological impact of CES by conducting a survey study of English‐speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.
The aMICRA score was used to assess impact, including distress, uncertainty and positivity (reversed scored) of the genetic test results on the parents. On average, the aMICRA was 12 points higher (more negative impact) in parents who interpreted the results as positive and 7 points higher for those who interpreted the results as uncertain compared to those who interpreted the results as negative (P < .0001, P = .02). Overall, the majority of parents correctly interpreted their child's exome sequencing results. Parental misinterpretation occurred most frequently when the clinician interpreted the results as uncertain.
Soybean Glycine max (L.) Merrill plant introductions (PIs) are potential sources of useful genes for breeding. We mapped quantitative trait loci (QTL) for yield and other agronomic traits, and ...determined QTL x environment (QTL x E) and epistatic interactions for yield in three backcross (BC) populations. The populations were developed using PIs as donor parents and 'Beeson 80', 'Kenwood', and 'Lawrence' as recurrent parents (RP). Sixty-eight BC2F5-derived lines in the Beeson 80 population, 74 BC1F5-derived lines in the Kenwood population, and 94 BC3F2-derived lines in the Lawrence population were tested along with the RP and checks in 2003 and 2004. Nineteen QTL for three other agronomic traits were identified, as well as 13 yield QTL. The yield-increasing allele was from the PI parent for eight yield QTL. Yield-increasing alleles were associated with delayed maturity for three yield QTL, and one allele was associated with increased lodging and plant height. All yield QTL mapped to regions where yield QTL have been reported previously. The significant QTL x E interaction was due to undetectable or weak QTL effects in some environments. Nine digenic interactions for yield were detected in the Kenwood population, and were mostly between loci exhibiting epistatic effects only. Our results support previous findings that the current elite North American soybean gene pool is more diverse than would have been predicted by the number of contributing ancestors.
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