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There is an interest to ensure sub-saturated water content in lines containing carbon dioxide in applications such as enhanced oil recovery and carbon sequestration, to reduce risks of hydrate blockage and corrosion. The water content of carbon dioxide at various temperatures and pressures has been measured in the past, but there is no consistent set of measurements that could be used for carbon dioxide storage and transportation design work. The solubility of water in a carbon dioxide rich gas phase at hydrate forming conditions was measured in this work. Pressures ranged from 12.06 to 29.30 bar along two isotherms, 1 °C and −7 °C, all within the gaseous carbon dioxide and hydrate stability zone. For the first time in these types of measurements, the solid phase was also characterized and confirmed to be carbon dioxide hydrate via X-ray computed tomography, simultaneous with water content measurements of the gas phase. Once carbon dioxide hydrate conversion had reached a maximum value (65% estimated by X-ray computed tomography), the equilibrium water content was measured. Prior to reaching this maximum carbon dioxide hydrate conversion, the water content in carbon dioxide was observed to decrease as liquid water converted to carbon dioxide hydrate. This slow conversion to hydrate, metastability of the hydrate phase, or unexpected phases may be responsible for the large discrepancy between prior data sets for similar carbon dioxide water content measurements.

The Compact Linear Collider (CLIC) is a mature option for the future of highenergy physics. It combines the benefits of the clean environment of $e^+e^-$colliders with operation at high centre-of-mass energies, allowing to probescales beyond the reach of the Large Hadron Collider (LHC) for many scenariosof new physics. This places the CLIC project at a privileged spot in betweenthe precision and energy frontiers, with capabilities that will significantlyextend knowledge on both fronts at the end of the LHC era. In this report wereview and revisit the potential of CLIC to search, directly and indirectly,for physics beyond the Standard Model.

The Proceedings of the 2003 SLAC Workshops on flavor physics with a highluminosity asymmetric e+e- collider. The sensitivity of flavor physics tophysics beyond the Standard Model is addressed in detail, in the context of theimprovement of experimental measurements and theoretical calculations.

We provide a mini-guide to some of the possible manifestations of weak scalesupersymmetry. For each of six scenarios we provide a brief description of thetheoretical underpinnings, the adjustable parameters, a qualitative descriptionof the associated phenomenology at future colliders, comments on how tosimulate each scenario with existing event generators.

A series of experiments were conducted on Phormia regina , a forensically important blow fly species, that met the requirements needed to create statistically valid development models. Experiments were conducted over 11 temperatures (7.5 to 32.5 °C, at 2.5 °C intervals) with a 16:8 L:D cycle. Experimental units contained 20 eggs, 10 g of beef liver, and 2.5 cm of sand. Each life stage (egg to adult) had five sampling times. Each sampling time was replicated four times for a total of 20 measurements per life stage. For each sampling time, the cups were pulled from the chambers, and the stage of each maggot was documented morphologically through posterior spiracular slits and cephalopharyngeal development. Data were normally distributed with the later larval (L3m) and pupation stages having the most variation within and transitioning between stages, particularly between 12.5 °C and 20.0 °C. The biological minimum was between 10.0 °C and 12.5 °C, with little egg development and no egg emergence at 7.5 °C and no maturation past L1 at 10.0 °C. Phormia regina did not display increased mortality associated with the upper temperature of 32.5 °C. The development data generated illustrate the advantages of large data sets in modeling blow fly development and the need for curvilinear models in describing development at environmental temperatures near the biological minima and maxima.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with a poorly understood etiology. An accurate diagnosis of idiopathic PD remains challenging as misdiagnosis is common in routine clinical practice. Moreover, current therapeutics focus on symptomatic management rather than curing or slowing down disease progression. Therefore, identification of potential PD biomarkers and providing a better understanding of the underlying disease pathophysiology are urgent. Herein, hydrophilic interaction liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-TOF MS) based metabolomics approaches were used to profile the serum metabolome of 50 patients with different stages of idiopathic PD (early, mid and advanced) and 45 age-matched controls. Levels of 57 metabolites including cysteine-S-sulfate and N-acetyl tryptophan were significantly higher in patients with PD compared to controls, with lower amounts of additional 51 metabolites including vanillic acid, and N-acetylaspartic acid. Xanthines, including caffeine and its downstream metabolites, were lowered in patients with PD relative to controls indicating a potential role caffeine and its metabolites against neuronal damage. Seven metabolites, namely cysteine-S-sulfate, 1-methylxanthine, vanillic acid, N-acetylaspartic acid, 3-N-acetyl tryptophan, 5-methoxytryptophol, and 13-HODE yielded a ROC curve with a high classification accuracy (AUC 0.977). Comparison between different PD stages showed that cysteine-S-sulfate levels were significantly increasing with the advancement of PD stages while LPI 20:4 was significantly decreasing with disease progression. Our findings provide new biomarker candidates to assist in the diagnosis of PD and monitor its progression. Unusual metabolites like cysteine-S-sulfate might point to therapeutic targets that could enhance the development of novel PD treatments, such as NMDA antagonists., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Parkinson's disease (PD) is a highly prevalent neurodegenerative movement disorder with an unclear etiology and a lack of definite diagnostic tests and effective treatments. About 95% of PD cases are idiopathic, in which none of the well-known genes underlying familial parkinsonism are mutated. We used untargeted liquid chromatography-mass spectrometry (LC-MS/MS) to profile the serum lipidome of 50 patients with different stages of idiopathic PD (early, mid, or advanced) and 45 age-matched controls. When comparing the PD patients to the control subjects, 169 lipids were significantly altered in both a univariate analysis and a multivariate partial least-squares discriminant analysis (PLS-DA). Compared to the controls, the patients with PD had higher levels of unsaturated triacylglycerides (e.g., TG O-56:9 and TG 52:3), saturated lysophosphatidylcholines (LPC 17:0, 16:0, and 15:0), and hydroxyeicosatetraenoic acid (12-HETE), while lower levels of phosphatidylserines (e.g., PS 40:4 and PS 16:0_22:4), sphingomyelins (SM 42:1), and ceramides (e.g., Cer 40:0 and 42:0) were found between the PD patients and the controls. A panel of 10 significantly altered lipids (PS 40:0, Cer 40:0, Cer 42:0, LPC 17:0, LPC 15:0, PC 37:7, PE O-40:8, PC O-42:4, FA 23:0, and SM 42:1) resulted in a strong receiver operating characteristic curve with an AUC = 0.974. This panel may, therefore, be useful for diagnosing PD. In addition, lipid panels may prove useful for distinguishing among the progression stages of PD. Using one-way ANOVA, 155 lipid species were significantly altered among the PD stages. Parkinson's disease progressed from the early to advanced stages with decreasing levels of PC 31:1, PC 38:4, and LPE 22:5. Conversely, LPC-O 20:0, PC O-42:3, FA 19:0, and FA 22:2 showed an increase in their levels with disease progression. Overall, this study shows an intriguing number of robust changes in specific serum lipids that may become useful for diagnosing PD and its progression, once panels have been validated in larger clinical trials and prospective studies.

Emerging technologies like enhanced oil recovery and carbon sequestration rely on carbon dioxide water content data to ensure that pipelines remain sub-saturated to avoid corrosion and hydrate flow assurance issues. To improve throughput and confidence in the hydrate phase equilibria data to avoid pipeline blockages, further research into the carbon dioxide water content must be conducted. However, the liquid carbon dioxide regime is experimentally difficult to study and the available data disagree between studies. This work aims to provide the critical and accurate data for liquid carbon dioxide for a high pressure range (13.8 to 103.4 bar) and temperature range (20 and -30 °C) utilizing a small volume microfluidic reactor (<20 microliter) coupled with Raman spectroscopy, which can reveal any phase metastability in the system. The small volume of the microfluidic system (<20 microliter) allowed experiments to be run in a few hours, compared to a whole week for prior larger scale measurements. The carbon dioxide water content results from this work agree well with both model predictions and available literature data in the gas region; however, once carbon dioxide was converted to liquid, the data showed a weak function of pressure, similar to model predictions and some previous data sets. The discrepancies between literature data are attributed to metastable phases present in the equilibrium cells, as the data is usually taken in the carbon dioxide near critical region, close to carbon dioxide's dew point, and near the hydrate phase transition. For these reasons, it is important to observe and qualify all phases in the cell, as was done in this novel study with in situ Raman spectroscopy coupled to Midstream on a chip, to ensure accurate water content of the carbon dioxide fluid phase is being measured.

Purpose: Higher levels of estrogen in obese patients may lead to incomplete inhibition by aromatase inhibitors (AIs). The aim of this study was to determine the impact of body mass index (BMI) on efficacy of AIs in patients with metastatic hormone receptor (HR)-positive breast cancer (BC)., Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001 and 2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause., Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. Of the 219 patients, 56% (123) had a low BMI (defined as < 27 kg/m 2 ) and 44% (96) had a high BMI (≥ 27 kg/m 2 ). The median PFS was 21.9 months (95% CI 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI 14.3 to 27.5) in the high BMI group (p = 0.73)., Conclusion: While BMI influences efficacy of AIs in the adjuvant setting, our results suggest that in the metastatic setting, BMI may not impact the efficacy of AIs. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The carrion insect species that most quickly deposit offspring on a corpse are, when available, likely to yield a more useful estimate of postmortem interval (PMI) compared to later arrivals. This is in part because the age of the oldest larva will be as close as possible to the PMI when doing a development analysis, and because the preappearance interval (PAI), the time the corpse was exposed before insect colonization, corresponds to the narrowest window of time since death for an insect-free corpse when doing a succession analysis. Given replicated training data a prediction of exposure time for a corpse can be in the form of a confidence set, and the maximum value of that set for an insect-free corpse is a probabilistic version of PAI. To discover the insect species likely to be useful in the early postmortem period in the United Arab Emirates we exposed 216 rat carcasses outdoors at two sites in Dubai over three-day periods during winter. Rats were sampled twice each day without replacement and kept in the lab to allow carrion insects to complete development to the adult stage. The fly species produced in this way were Sarcophaga dux, S. ruficornis, Wohlfahrtia nuba, W. indigens (Sarcophagidae), Chrysomya albiceps (Calliphoridae), and Musca domestica (Muscidae). To the best of our knowledge this is the first record of W. indigens larvae feeding on carrion. While adult C. albiceps and M. domestica were abundant on the carcasses, C. albiceps colonized too slowly to be useful for this type of succession analysis within this time frame, and M. domestica emerged from a single rat. The Sarcophagidae were rapid colonizers, and under these conditions the probability is>90% that a carcass would remain free of S. dux larvae not more than 57 h and free of W. nuba larvae for not more than 51 h., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Various emerging carbon capture technologies depend on being able to reliably and consistently grow carbon dioxide hydrate, particularly in packed media. However, there are limited kinetic data for carbon dioxide hydrates at this length scale. In this work, carbon dioxide hydrate propagation rates and conversion were evaluated in a high pressure silicon microfluidic device. The carbon dioxide phase boundary was first measured in the microfluidic device, which showed little deviation from bulk predictions. Additionally, measuring the phase boundary takes on the order of hours compared to weeks or longer for larger scale experimental setups. Next, propagation rates of carbon dioxide hydrate were measured in the channels at low subcoolings (<2 K from phase boundary) and moderate pressures (200-500 psi). Growth was dominated by mass transfer limitations until a critical pressure was reached, and reaction kinetics limited growth upon further increases in pressure. Additionally, hydrate conversion was estimated from Raman spectroscopy in the microfluidics channels. A maximum value of 47% conversion was reached within 1 h of a constant flow experiment, nearly 4% of the time required for similar results in a large scale system. The rapid reaction times and high throughput allowed by high pressure microfluidics provide a new way for carbon dioxide gas hydrate to be characterized.

Motivation: Despite increasing understanding of the molecular characteristics of cancer, chemotherapy success rates remain low for many cancer types. Studies have attempted to identify patient and tumor characteristics that predict sensitivity or resistance to different types of conventional chemotherapies, yet a concise model that predicts chemosensitivity based on gene expression profiles across cancer types remains to be formulated. We attempted to generate pan-cancer models predictive of chemosensitivity and chemoresistance. Such models may increase the likelihood of identifying the type of chemotherapy most likely to be effective for a given patient based on the overall gene expression of their tumor., Results: Gene expression and drug sensitivity data from solid tumor cell lines were used to build predictive models for 11 individual chemotherapy drugs. Models were validated using datasets from solid tumors from patients. For all drug models, accuracy ranged from 0.81 to 0.93 when applied to all relevant cancer types in the testing dataset. When considering how well the models predicted chemosensitivity or chemoresistance within individual cancer types in the testing dataset, accuracy was as high as 0.98. Cell line-derived pan-cancer models were able to statistically significantly predict sensitivity in human tumors in some instances; for example, a pan-cancer model predicting sensitivity in patients with bladder cancer treated with cisplatin was able to significantly segregate sensitive and resistant patients based on recurrence-free survival times ( P  = .048) and in patients with pancreatic cancer treated with gemcitabine ( P  = .038). These models can predict chemosensitivity and chemoresistance across cancer types with clinically useful levels of accuracy., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Purpose: Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a "liquid biopsy" for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations., Methods: Blood and biopsies of 1-3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA., Results: Sequencing of plasma DNA identified 27.94 ± 11.81% (mean ± SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem., Conclusions: The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling., Trial Registration: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).

Purpose: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies., Experimental Design: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER + breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy., Results: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival., Conclusions: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER + breast cancer., (©2020 American Association for Cancer Research.)

Purpose: We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis., Experimental Design: Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro . The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi., Results: Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro , and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA., Conclusions: Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage., (©2019 American Association for Cancer Research.)

Background: Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse events, warranting the identification of a biomarker of chemosensitivity., Objective: Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes., Methods: We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer., Results: Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response., Conclusions: Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes., Competing Interests: The authors have declared that no competing interests exist.

Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)-positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β-estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient-derived xenografts, C7-2-HI and C4-HI murine mammary adenocarcinomas, and long-term estrogen-deprived MCF-7 cells. As another means to reactivate ER, the anti-estrogen fulvestrant was withdrawn from fulvestrant-resistant MCF-7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β-estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β-estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long-term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β-estradiol treatment and anti-estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β-estradiol treatment should be considered as a therapeutic option for anti-estrogen-resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Future neutron-antineutron (n-n[over ¯]) oscillation experiments, such as at the European Spallation Source and the Deep Underground Neutrino Experiment, aim to find first evidence of baryon number violation. We investigate implications of an improved n-n[over ¯] oscillation search for baryogenesis via interactions of n-n[over ¯] mediators, parametrized by an effective field theory (EFT). We find that even in a minimal EFT setup there is overlap between the parameter space probed by n-n[over ¯] oscillation and the region that can realize the observed baryon asymmetry of the Universe. The mass scales of exotic new particles are in the tera-electron-volt-peta-electron-volt regime, inaccessible at the LHC or its envisioned upgrades. Given the innumerable high energy theories that can match, or resemble, the minimal EFT that we discuss, future n-n[over ¯] oscillation experiments could probe many viable theories of baryogenesis beyond the reach of other experiments.

Background: Pulmonary contusion (PC) is a common injury that often results in priming for exaggerated inflammatory responses to a second hit. Previous studies used a mouse model of pulmonary contusion and showed an early and sustained reduction of SIRT1 protein and activity in the lung and bronchoalveolar lavage (BAL) cells of injured mice. Sustained decrease in SIRT1 was associated with a primed phenotype in injured mice challenged with an inflammatory stimulus. This study tests the hypothesis that pulmonary contusion induces oxidant production that modifies and decreases SIRT1 and primes the lung for the second-hit response., Methods: A mouse model of pulmonary contusion was used to investigate injury-induced oxidant changes in SIRT1. Second-hit responses were evaluated by infection (Streptococcus pneumoniae) and inflammatory challenge using bacterial lipopolysaccharide. BAL, lung tissue, and blood were collected and used to evaluate inflammatory responses and SIRT1 levels, oxidant modification, and activity. Levels of NO in the BAL from mice and patients with PC were also assessed., Results: We found that oxidants produced as a result of pulmonary contusion resulted in modification of SIRT1. S-Nitrosylation was observed and correlated with increased inducible nitric oxide synthase expression after injury. Anti-oxidant treatment of injured mice preserved SIRT1 activity, decreased second hit responses and improved lung function. Elevated NO levels in the BAL of PC patients was associated with acute respiratory distress syndrome or diagnosis of pneumonia., Conclusions: We conclude that oxidative stress in the lung after injury induces redox modification of SIRT1 and contributes to priming of the lung for a second-hit response. Antioxidant treatment suggests that SIRT1 activity after injury may be beneficial in suppressing second-hit responses.

HER2 ( ERBB2 ) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR -mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2 -amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2 , termed miR-4728 , that targets the mRNA of the Estrogen Receptor α ( ESR1 ). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA , mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR -mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes., Competing Interests: Conflict of interest statement: J.D.L. and A.J.S. are employees and shareholders of AbbVie Inc., (Copyright © 2018 the Author(s). Published by PNAS.)

Common DNA-based species determination methods fail to distinguish some blow flies in the forensically and medically important genus Lucilia Robineau-Desvoidy. This is a practical problem, and it has also been interpreted as casting doubt on the validity of some morphologically defined species. An example is Lucilia illustris and L. caesar , which co-occur in Europe whilst only L. illustris has been collected in North America. Reports that these species shared both mitochondrial and nuclear gene sequences, along with claims that diagnostic morphological characters are difficult to interpret, were used to question their separate species status. We report here that amplified fragment length polymorphism profiles strongly support the validity of both species based on both assignment and phylogenetic analysis, and that traditional identification criteria based on male and female genital morphology are more reliable than has been claimed.

Neurofibromatosis type 1 is a disease caused by mutation of neurofibromin 1 ( NF1 ), loss of which results in hyperactive Ras signaling and a concomitant increase in cell proliferation and survival. Patients with neurofibromatosis type 1 frequently develop tumors such as plexiform neurofibromas and malignant peripheral nerve sheath tumors. Mutation of NF1 or loss of the NF1 protein is also observed in glioblastoma, lung adenocarcinoma, and ovarian cancer among other sporadic cancers. A therapy that selectively targets NF1 deficient tumors would substantially advance our ability to treat these malignancies. To address the need for these therapeutics, we developed and conducted a synthetic lethality screen to discover molecules that target yeast lacking the homolog of NF1 , IRA2 . One of the lead candidates that was observed to be synthetic lethal with ira2Δ yeast is Y100. Here, we describe the mechanisms by which Y100 targets ira2Δ yeast and NF1-deficient tumor cells. Y100 treatment disrupted proteostasis, metabolic homeostasis, and induced the formation of mitochondrial superoxide in NF1-deficient cancer cells. Previous studies also indicate that NF1/Ras-dysregulated tumors may be sensitive to modulators of oxidative and ER stress. We hypothesize that the use of Y100 and molecules with related mechanisms of action represent a feasible therapeutic strategy for targeting NF1 deficient cells., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

Being able to efficiently differentiate between male and female individuals in the immature forms of insects allows for investigations into sexually dimorphic patterns of growth rates and gene expression. For species lacking sex-specific morphological characteristics during these periods, alternative methods must be devised. Commonly, isolation of sex determination genes reveals sex-specific band patterns and allows for markers that can be used in insect control. For blow flies, a family that includes flies of medical and forensic importance, sex has previously been identified in some members using the male-specific exon in the transformer gene. This gene is relatively conserved between members of the genera Cochliomyia and Lucilia (Diptera: Calliphoridae), and we isolated a portion of this gene in an additional forensically and medically important blow fly genus using the widespread Chrysomya megacephala (F.). We found a relatively high level of conservation between exons 1 and 2 of transformer and were able to amplify a region containing the male-specific exon in C. megacephala. A sex-specific molecular diagnostic test based on the presence of sexually dimorphic PCR product bands showed the expected genotype for adults and intrapuparial period specimens of known sex. The same result could be obtained from single third-instar larval specimens, opening up the possibility to not only determine if development rates are sex dependent, but also to investigate the development of sexually dimorphic traits of interest in C. megacephala., (© The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The Compact Linear Collider (CLIC) is an option for a future [Formula: see text] collider operating at centre-of-mass energies up to [Formula: see text], providing sensitivity to a wide range of new physics phenomena and precision physics measurements at the energy frontier. This paper is the first comprehensive presentation of the Higgs physics reach of CLIC operating at three energy stages: [Formula: see text], 1.4 and [Formula: see text]. The initial stage of operation allows the study of Higgs boson production in Higgsstrahlung ([Formula: see text]) and [Formula: see text]-fusion ([Formula: see text]), resulting in precise measurements of the production cross sections, the Higgs total decay width [Formula: see text], and model-independent determinations of the Higgs couplings. Operation at [Formula: see text] provides high-statistics samples of Higgs bosons produced through [Formula: see text]-fusion, enabling tight constraints on the Higgs boson couplings. Studies of the rarer processes [Formula: see text] and [Formula: see text] allow measurements of the top Yukawa coupling and the Higgs boson self-coupling. This paper presents detailed studies of the precision achievable with Higgs measurements at CLIC and describes the interpretation of these measurements in a global fit.

One factor that influences estimates of time since death using entomological evidence is whether or not blow flies nocturnally oviposit. Field studies focusing on egg laying have found it occurs on an inconsistent basis. A key but poorly understood factor in nocturnal oviposition is a blow fly's ability to locate carrion under low light levels. It has been speculated that blow flies are more likely to walk than fly to carrion during the night, but this has not been empirically tested. We directly compared guided walking versus flying using infrared sensors under low light levels in laboratory conditions for Chrysomya megacephala (F.) (Diptera: Calliphoridae), a blow fly previously described to be nocturnal. We found C. megacephala is more likely to walk than fly toward carrion under low light levels (p=0.016). We did not, however, find differences between males and females for walking (p=0.48) or flying (p=0.42) despite male C. megacephala possessing eyes better suited for increased light capture. These results demonstrate the need to better understand where blow flies go at night, as bodies found within a fly's walking distance are more likely to be colonized., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Male Chrysomya megacephala (F.) blow fly compound eyes contain an unusual area of enlarged dorsal facets believed to allow for increased light capture. This region is absent in females and has been hypothesized to aid in mate tracking in low light conditions or at greater distances. Many traits used in the attraction and capture of mates are allometric, growing at different rates relative to body size. Previous reports concerning C. megacephala eye properties did not include measurements of body size, making the relationship between the specialized eye region and body size unclear. We examined different morphological features of the eye among individuals of varying sizes. We found total eye size scaled proportionately to body size, but the number of enlarged dorsal facets increased as body size increased. This demonstrated that larger males have an eye that is morphologically different than smaller males. On the basis of external morphology, we hypothesized that since larger males have larger and a greater number of dorsally enlarged facets, and these facets are believed to allow for increased light capture, larger males would be active in lower light levels than smaller males and females of equal size. In a laboratory setting, larger males were observed to become active earlier in the morning than smaller males, although they did not remain active later in the evening. However, females followed the same pattern at similar light levels suggesting that overall body size rather than specialized male eye morphology is responsible for increased activity under low light conditions., (© The Author 2015. Published by Oxford University Press on behalf of the Entomological Society of America.)

Background: Pulmonary contusion (PC) is a common, potentially lethal injury that results in priming for exaggerated inflammatory responses to subsequent immune challenge like infection (second hit). The molecular mechanism of priming and the second hit phenomenon after PC remain obscure. With the use of a mouse model of PC, this study explores the role of sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, in priming for a second hit after injury., Methods: With the use of a mouse model of PC, injury-primed second-hit host responses were tested at 24 hours after PC by (1) in vivo infectious challenge of injured mice or (2) ex vivo inflammatory challenge of isolated immune cells from injured mice. SIRT activators or repressors were used to test for SIRT1 participation in these second-hit responses., Results: PC-injured mice given an in vivo infectious challenge by cecal ligation and puncture (CLP) had significantly increased mortality compared with injury or infectious challenge alone. Isolated bronchoalveolar lavage (BAL) cells from injured mice given an ex vivo inflammatory challenge with bacterial lipopolysaccharide (LPS) had increased levels of tumor necrosis factor α messenger RNA compared with uninjured mice. We found that PC reduced SIRT1 protein, messenger RNA, and SIRT1 enzymatic activity in injured lung tissue. We also found decreased SIRT1 protein levels in BAL cells from injured mice. We further found that injured mice treated with a SIRT1 activator, resveratrol, showed significantly decreased polymorphonuclear leukocytes (PMN) in the BAL in response to intratracheal LPS and increased survival from CLP., Conclusion: These results showed that PC decreased SIRT1 levels in the lung correlated with enhanced responses to infectious or inflammatory stimuli in injured mice. Treatment of injured mice with a SIRT1 activator, resveratrol, decreased LPS inflammatory response and increased survival after CLP. Our results suggest that SIRT1 participates in the second-hit response after injury.

Many authors produced carrion insect development data for predicting the age of an insect from a corpse. Under some circumstances, this age value is a minimum postmortem interval. There are no standard protocols for such experiments, and the literature includes a variety of sampling methods. To our knowledge, there has been no investigation of how the choice of sampling method can be expected to influence the performance of the resulting predictive model. We calculated 95 % inverse prediction confidence limits for growth curves of the forensically important carrion flies Chrysomya megacephala and Sarconesia chlorogaster (Calliphoridae) at a constant temperature. Confidence limits constructed on data for entire age cohorts were considered to be the most realistic and were used to judge the effect of various subsampling schemes from the literature. Random subsamples yielded predictive models very similar to those of the complete data. Because taking genuinely random subsamples would require a great deal of effort, we imagine that it would be worthwhile only if the larval measurement technique were especially slow and/or expensive. However, although some authors claimed to use random samples, their published methods suggest otherwise. Subsampling the largest larvae produced a predictive model that performed poorly, with confidence intervals about an estimate of age being unjustifiably narrow and unlikely to contain the true age. We believe these results indicate that most forensic insect development studies should involve the measurement of entire age cohorts rather than subsamples of one or more cohorts.