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Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.

The next generation of water Cherenkov neutrino telescopes in the Mediterranean Sea are under construction offshore France (KM3NeT/ORCA) and Sicily (KM3NeT/ARCA). The KM3NeT/ORCA detector features an energy detection threshold which allows to collect atmospheric neutrinos to study flavour oscillation. This paper reports the KM3NeT/ORCA sensitivity to this phenomenon. The event reconstruction, selection and classification are described. The sensitivity to determine the neutrino mass ordering was evaluated and found to be 4.4σ if the true ordering is normal and 2.3σ if inverted, after 3 years of data taking. The precision to measure Δm322 and θ23 were also estimated and found to be 85.10-6eV2 and (-3.1+1.9)∘ for normal neutrino mass ordering and, 75.10-6eV2 and (-7.0+2.0)∘ for inverted ordering. Finally, a unitarity test of the leptonic mixing matrix by measuring the rate of tau neutrinos is described. Three years of data taking were found to be sufficient to exclude event rate variations larger than 20% at 3σ level.

The detection of cosmic neutrinos with energies above a teraelectronvolt (TeV) offers a unique exploration into astrophysical phenomena 1 , 2 – 3 . Electrically neutral and interacting only by means of the weak interaction, neutrinos are not deflected by magnetic fields and are rarely absorbed by interstellar matter: their direction indicates that their cosmic origin might be from the farthest reaches of the Universe. High-energy neutrinos can be produced when ultra-relativistic cosmic-ray protons or nuclei interact with other matter or photons, and their observation could be a signature of these processes. Here we report an exceptionally high-energy event observed by KM3NeT, the deep-sea neutrino telescope in the Mediterranean Sea 4 , which we associate with a cosmic neutrino detection. We detect a muon with an estimated energy of 12 0 − 60 + 110 petaelectronvolts (PeV). In light of its enormous energy and near-horizontal direction, the muon most probably originated from the interaction of a neutrino of even higher energy in the vicinity of the detector. The cosmic neutrino energy spectrum measured up to now 5 , 6 – 7 falls steeply with energy. However, the energy of this event is much larger than that of any neutrino detected so far. This suggests that the neutrino may have originated in a different cosmic accelerator than the lower-energy neutrinos, or this may be the first detection of a cosmogenic neutrino 8 , resulting from the interactions of ultra-high-energy cosmic rays with background photons in the Universe. A very high-energy muon observed by the KM3NeT experiment in the Mediterranean Sea is evidence for the interaction of an exceptionally high-energy neutrino of cosmic origin.  

Odor attraction in walking Drosophila melanogaster is commonly used to relate neural function to behavior, but the algorithms underlying attraction are unclear. Here, we develop a high-throughput assay to measure olfactory behavior in response to well-controlled sensory stimuli. We show that odor evokes two behaviors: an upwind run during odor (ON response), and a local search at odor offset (OFF response). Wind orientation requires antennal mechanoreceptors, but search is driven solely by odor. Using dynamic odor stimuli, we measure the dependence of these two behaviors on odor intensity and history. Based on these data, we develop a navigation model that recapitulates the behavior of flies in our apparatus, and generates realistic trajectories when run in a turbulent boundary layer plume. The ability to parse olfactory navigation into quantifiable elementary sensori-motor transformations provides a foundation for dissecting neural circuits that govern olfactory behavior. All kinds of animals use their sense of smell to find things. Doing this is difficult because odors in air travel as plumes, which meander downwind and break apart. Scientists are interested in learning the rules that animals use to decipher these odor signals and trace them back to their source. For example, do animals use patterns of timing in the odor, differences between smell at the two nostrils, or the direction of the wind? Scientists would also like to know how animal’s brain circuits decipher this information. Tiny fruit flies make a good model for studying the way animals detect odors because scientists have already learned a great deal about how their brains work. There are also many tools available to help scientists study the brain circuits of fruit flies. Now, Álvarez-Salvado et al. show that fruit flies use multiple senses to track odors to their source. In the experiments, fruit flies that were blind and could not fly were placed in tiny wind tunnels and their behavior in response to a smell or no smell in the tunnel was carefully documented. When the flies detected an odor, they turned to face the wind using their antennae to detect wind direction and run toward it. When flies lost track of an odor they began to search for it at the spot where they last smelled it. Next, Álvarez-Salvado et al. created a computer model that recreated the flies’ behavior and was able to find the odor source as well as real flies. The model added together these basic behaviors to successfully recreate the flies’ odor-search strategy. Other animals are often better than humans at finding odor sources. As a result, people use pigs to find truffles and dogs to find lost hikers. The computer model Álvarez-Salvado et al. developed might help design robots that can search for truffles, hikers, or landmines, without risking the lives of animals. It might also be useful for designing autonomous vehicles that must respond to many types of information in changing environments to make decisions.

Physical activity (PA) is a key strategy for improving symptoms in people with rheumatic and musculoskeletal diseases (RMDs). The aim of this study was to investigate and rank the importance of known barriers and facilitators for engaging in PA, from the perspective of people living with RMD. Five hundred thirty-three people with RMD responded to a survey (nine questions) disseminated by the People with Arthritis and Rheumatism (PARE) network of the European Alliance of Associations for Rheumatology (EULAR). The survey required participants to rank — based on their perceived importance — known PA barriers and facilitators from the literature, and specifically RMD symptoms as well as healthcare and community factors that may affect PA participation. Of the participants, 58% reported rheumatoid arthritis as their primary diagnosis, 89% were female, and 59% were between 51 and 70 years of age. Overall, participants reported fatigue (61.4%), pain (53.6%) and painful/swollen joints (50.6%) as the highest ranked barriers for engaging in PA. Conversely, less fatigue (66.8%) and pain (63.6%), and being able to do daily activities more easy (56.3%) were identified as the most important facilitators to PA. Three literature identified PA barriers, i.e., general health (78.8%), fitness (75.3%) and mental health (68.1%), were also ranked as being the most important for PA engagement. Symptoms of RMDs, such as pain and fatigue, seem to be considered the predominant barriers to PA by people with RMD; the same barriers are also the ones that they want to improve through increasing PA, suggesting a bi-directional relationship between these factors. Key Points• Symptoms of rheumatic and musculoskeletal disease (RMD) are the predominant barriers for lack of physical activity engagement.• RMD symptoms are the factors that people with RMDs want to improve when engaging in PA.• The barriers that stop people living with RMDs to do more PA are the ones that can be significantly improved through PA engagement.

A bstract KM3NeT/ORCA is a next-generation neutrino telescope optimised for atmospheric neutrino oscillations studies. In this paper, the sensitivity of ORCA to the presence of a light sterile neutrino in a 3+1 model is presented. After three years of data taking, ORCA will be able to probe the active-sterile mixing angles θ 14 , θ 24 , θ 34 and the effective angle θ μe , over a broad range of mass squared difference ∆ m 41 2 ∼ [10 − 5 , 10] eV 2 , allowing to test the eV-mass sterile neutrino hypothesis as the origin of short baseline anomalies, as well as probing the hypothesis of a very light sterile neutrino, not yet constrained by cosmology. ORCA will be able to explore a relevant fraction of the parameter space not yet reached by present measurements.

Objectives: We examined how opposing running slopes can modulate interval training effects on aerobic performance and reduction–oxidation (REDOX) determinants. Methods: Fourteen physically active volunteers, assigned to either the Uphill group (UG) or the Downhill group (DG), completed 16 workouts of ten 30-s runs, at either +10% or −10% grade, with a work-to-rest ratio of 1:2 at 90% of their Maximum Aerobic Speed (MAS) over 8 weeks. Maximal oxygen uptake (VO2max), MAS, Running Economy (RE), time to exhaustion at MAS (Tmax), respiratory exchange ratio (RER), and blood lactate at rest, 5th, and 10th runs were evaluated pre-, mid-, and post-training. Also, REDOX markers [Total Antioxidant Capacity (TAC), Protein Carbonyls (PCs) were assessed in blood samples taken at rest and 3 min post-exercise of the first and last workouts. Results: VO2max was unchanged in both groups; in the DG, MAS increased (from 14.2 ± 1.7 to 15.0 ± 1.5 km/h, d = 0.43), and post-training RER significantly increased (from 1.06 ± 0.07 to 1.12 ± 0.03). In the last training session, blood lactate levels increased in the UG (from 9.30 ± 2.69 mmοl/L to 13.34 ± 4.64 mmοl/L) but remained low and unchanged in DG (<2 mmοl/L). Post-training, resting TAC decreased in both groups, and the exercise-induced rise in PC levels was attenuated. Conclusions: Despite the brief intervention, VO2max levels were maintained in both groups, with divergent changes in metabolic, REDOX, and performance indicators; uphill HIIT may serve for enhancing lactate tolerance, while downhill intermittent running may improve running economy.

Background The role of omega-3 polyunsaturated fatty acids (n-3PUFA), and the potential impact of n-3PUFA supplementation, in the treatment and management of type 1 diabetes (T1D) remains unclear and controversial. Therefore, this study aimed to examine the efficacy of daily high-dose-bolus n-3PUFA supplementation on vascular health, glycaemic control, and metabolic parameters in subjects with T1D. Methods Twenty-seven adults with T1D were recruited to a 6-month randomised, double-blind, placebo-controlled trial. Subjects received either 3.3 g/day of encapsulated n-3PUFA or encapsulated 3.0 g/day corn oil placebo (PLA) for 6-months, with follow-up at 9-months after 3-month washout. Erythrocyte fatty acid composition was determined via gas chromatography. Endpoints included inflammation-associated endothelial biomarkers (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin, P-selectin, pentraxin-3, vascular endothelial growth factor [VEGF]), and their mediator tumor necrosis factor alpha [TNFα] analysed via immunoassay, vascular structure (carotid intima-media thickness [CIMT]) and function (brachial artery flow mediated dilation [FMD]) determined via ultrasound technique, blood pressure, glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial metabolism. Results Twenty subjects completed the trial in full. In the n-3PUFA group, the mean ± SD baseline n-3PUFA index of 4.93 ± 0.94% increased to 7.67 ± 1.86% ( P  < 0.001) after 3-months, and 8.29 ± 1.45% ( P  < 0.001) after 6-months. Total exposure to n-3PUFA over the 6-months (area under the curve) was 14.27 ± 3.05% per month under n-3PUFA, and 9.11 ± 2.74% per month under PLA ( P  < 0.001). VCAM-1, ICAM-1, E-selectin, P-selectin, pentraxin-3, VEGF, TNFα, CIMT, FMD, blood pressure, HbA1c, FPG, and postprandial metabolism did not differ between or within groups after treatment ( P  > 0.05). Conclusions This study indicates that daily high-dose-bolus of n-3PUFA supplementation for 6-months does not improve vascular health, glucose homeostasis, or metabolic parameters in subjects with T1D. The findings from this preliminary RCT do not support the use of therapeutic n-3PUFA supplementation in the treatment and management of T1D and its associated complications. Trial Registration ISRCTN, ISRCTN40811115. Registered 27 June 2017, http://www.isrctn.com/ISRCTN40811115 .

The clinical spectrum of adults with celiac disease in the United States, where the disease is considered rare, is not known. We sought this information by distributing a survey. A questionnaire was distributed by way of a celiac newsletter, directly to celiac support groups, and through the Internet. Respondents (1612) were from all United States except one. Seventy-five percent (1138) were biopsy proven. Women predominated (2.9:1). The majority of respondents were diagnosed in their fourth to sixth decades. Symptoms were present a mean of 11 yr before diagnosis. Diarrhea was present in 85%. Diagnosis was considered prompt by only 52% and 31% had consulted two or more gastroenterologists. Improved quality of life after diagnosis was reported by 77%. Those diagnosed at age ≥60 yr also reported improved quality of life. Five respondents had small intestinal malignancies (carcinoma 2, lymphoma 3) accounting for a relative risk of 300 (60–876) for the development of lymphoma and 67 (7–240) for adenocarcinoma. Patients with celiac disease in the United States have a long duration of symptoms and consider their diagnosis delayed. Improved quality of life after diagnosis is common. An increased risk of developing small intestine malignancies is present.