The rockefeller university

The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNA(hi) EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.

Background: In a previously conducted Health Impact Assessment of a well-water dependent southwest community, arsenic (As) levels greater than the EPA Maximum Contaminant Level (10 mu g/L) were identified in home water samples. The goals of this study were to test whether children from the previously studied well-water dependent community (Community 1) had higher blood As levels than children from a demographically similar and geographically nearby community dependent on a municipal water supply (Community 2); to test whether home water As levels predicted child As blood levels; and to examine how child As blood levels changed over time. Methods: This was an observational study of 252 children aged 4 to 12 years from two communities. Children were recruited through elementary schools and tested during the school day; 204 children participated in follow-up testing. Home water samples were collected according to U.S. Environmental Protection agency recommended procedures. Child heavy metal blood levels and home water sample heavy metal levels were analyzed using inductively coupled plasma mass spectrometry. General linear regression analysis was used to test the influence of community on child As levels, and to examine the contribution of home water As levels to child blood As levels. Results: Arsenic was detectable in all children tested. Blood levels ranged from 0.09-2.61 mu g/dL; approximately 31% of children tested at Time I (79/252) had blood As values above the current acceptable limit (1.2 mu g/dL). Approximately 8% of household water samples (6/76) had As levels higher than 10 mu g/L. Community did not predict child blood As levels; seasonal effects differed by Community. At Time II, child blood As levels were higher in Community 2 than in Community 1. Conclusion: A large proportion of children in the communities tested had As exposure. Home water As levels did not predict child blood As levels. Fluctuating child blood As levels by season and over time suggested the contribution of multiple factors and the need for further studies.

Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2(+)) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2(+) neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2(+) PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.

The phenylalanine-glycine-repeat nucleoporins (FG-Nups), which occupy the lumen of the nuclear pore complex (NPC), are critical for transport between the nucleus and cytosol. Although NPCs differ in composition across species, they are largely conserved in organization and function. Transport through the pore is on the millisecond timescale. Here, to explore the dynamics of nucleoporins on this timescale, we use coarse-grained computational simulations. These simulations generate predictions that can be experimentally tested to distinguish between proposed mechanisms of transport. Our model reflects the conserved structure of the NPC, in which FG-Nup filaments extend into the lumen and anchor along the interior of the channel. The lengths of the filaments in our model are based on the known characteristics of yeast FG-Nups. The FG-repeat sites also bind to each other, and we vary this association over several orders of magnitude and run 100-ms simulations for each value. The autocorrelation functions of the orientation of the simulated FG-Nups are compared with in vivo anisotropy data. We observe that FG-Nups reptate back and forth through the NPC at timescales commensurate with experimental measurements of the speed of cargo transport through the NPC. Our results are consistent with models of transport where FG-Nup filaments are free to move across the central channel of the NPC, possibly informing how cargo might transverse the NPC.

Two interesting unanswered questions are the extent to which both the broad patterns and genetic details of adaptive divergence are repeatable across species, and the timescales over which parallel adaptation may be observed. Drosophila melanogaster is a key model system for population and evolutionary genomics. Findings from genetics and genomics suggest that recent adaptation to latitudinal environmental variation (on the timescale of hundreds or thousands of years) associated with Out-of-Africa colonization plays an important role in maintaining biological variation in the species. Additionally, studies of interspecific differences between D. melanogaster and its sister species D. simulans have revealed that a substantial proportion of proteins and amino acid residues exhibit adaptive divergence on a roughly few million years long timescale. Here we use population genomic approaches to attack the problem of parallelism between D. melanogaster and a highly diverged conger, D. hydei, on two timescales. D. hydei, a member of the repleta group of Drosophila, is similar to D. melanogaster, in that it too appears to be a recently cosmopolitan species and recent colonizer of high latitude environments. We observed parallelism both for genes exhibiting latitudinal allele frequency differentiation within species and for genes exhibiting recurrent adaptive protein divergence between species. Greater parallelism was observed for longterm adaptive protein evolution and this parallelism includes not only the specific genes/proteins that exhibit adaptive evolution, but extends even to the magnitudes of the selective effects on interspecific protein differences. Thus, despite the roughly 50 million years of time separating D. melanogaster and D. hydei, and despite their considerably divergent biology, they exhibit substantial parallelism, suggesting the existence of a fundamental predictability of adaptive evolution in the genus.

Smell dysfunction is a common and underdiagnosed medical condition that can have serious consequences. It is also an early biomarker of neurodegenerative diseases, including Alzheimer's disease, where olfactory deficits precede detectable memory loss. Clinical tests that evaluate the sense of smell face two major challenges. First, human sensitivity to individual odorants varies significantly, so test results may be unreliable in people with low sensitivity to a test odorant but an otherwise normal sense of smell. Second, prior familiarity with odor stimuli can bias smell test performance. We have developed nonsemantic tests for olfactory sensitivity (SMELL-S) and olfactory resolution (SMELL-R) that use mixtures of odorants that have unfamiliar smells. The tests can be self-administered by healthy individuals with minimal training and show high test-retest reliability. Because SMELL-S uses odor mixtures rather than a single molecule, odor-specific insensitivity is averaged out, and the test accurately distinguished people with normal and dysfunctional smell. SMELL-R is a discrimination test in which the difference between two stimulus mixtures can be altered stepwise. This is an advance over current discrimination tests, which ask subjects to discriminate monomolecular odorants whose difference in odor cannot be quantified. SMELL-R showed significantly less bias in scores between North American and Taiwanese subjects than conventional semantically based smell tests that need to be adapted to different languages and cultures. Based on these proof-of-principle results in healthy individuals, we predict that SMELL-S and SMELL-R will be broadly effective in diagnosing smell dysfunction.

The differential production cross sections of B-+/- mesons are measured via the exclusive decay channels B-+/- -> J/psi K-+/- -> mu(+)mu K--(+/-) as a function of transverse momentum in pp and Pb-Pb collisions at a center-of-mass energy root s(NN) = 5.02 TeV per nucleon pair with the CMS detector at the LHC. The pp(Pb - Pb) data set used for this analysis corresponds to an integrated luminosity of 28.0 pb(-1) (351 mu b(-1)). The measurement is performed in the B-+/- meson transverse momentum range of 7 to 50 GeV/c, in the rapidity interval vertical bar y vertical bar < 2.4. In this kinematic range, a strong suppression of the production cross section by about a factor of 2 is observed in the Pb-Pb system in comparison to the expectation from pp reference data. These results are found to be roughly compatible with theoretical calculations incorporating beauty quark diffusion and energy loss in a quark-gluon plasma.

Background: Adolescence is the most vulnerable period, the period of greatest susceptibility to the development of addiction, for all those who are exposed to psychoactive substances. Despite a substantial experience of psychoactive usage prevention programmes (including educational work and even random urine tests), their success has so far been limited. Aims: To describe the results of educational and urine testing drug programmes among all the students and staff at in a private high school in order to identify and curtail drug use in its early stages and so save lives. Methods: During six years (April 2008 to April 2014) of studies in a private high school, urine samples for substance abuse (cannabinoids, cocaine, heroin, morphine, oxycontin, methadone, benzodiazepine, amphetamines, and ethanol) were collected and tested among all grades (9th-12th) and staff. The tests were done every few months in a random manner, and involved everyone. Positive tests were re-checked and were defined as positive if no medical prescriptions had been written. Results: During this period we performed 19 tests (about three per year) among all available students on each occasion (with numbers of participants ranging from 37 to 137). Reviewing all the 19 test times during the six years, only four students showed positive results for cannabinoids (two of them only once, the other two more than once). Conclusions: The programme results indicated minimum substance usage among adolescent children. Our finding was limited to a private high school with a selected population group, where all students and staff members agreed to participate in the programme when registering for admission to the school or, for staff members, when taking up employment. Based on our observational non-controlled study, future programmes, including controlled studies, can now be recommended.

Although bacterial bioactive metabolites have been one of the most prolific sources of lead structures for the development of small-molecule therapeutics, very little is known about the environmental factors associated with changes in secondary metabolism across natural environments. Large-scale sequencing of environmental microbiomes has the potential to shed light on the richness of bacterial biosynthetic diversity hidden in the environment, how it varies from one environment to the next, and what environmental factors correlate with changes in biosynthetic diversity. In this study, the sequencing of PCR amplicons generated using primers targeting either ketosynthase domains from polyketide biosynthesis or adenylation domains from nonribosomal peptide biosynthesis was used to assess biosynthetic domain composition and richness in soils collected across the Australian continent. Using environmental variables collected at each soil site, we looked for environmental factors that correlated with either high overall domain richness or changes in the domain composition. Among the environmental variables we measured, changes in biosynthetic domain composition correlate most closely with changes in latitude and to a lesser extent changes in pH. Although it is unclear at this time the exact mix of factors that may drive the relationship between biosynthetic domain composition and latitude, from a practical perspective the identification of a latitudinal basis for differences in soil metagenome biosynthetic domain compositions should help guide future natural product discovery efforts.

A measurement of the differential cross sections for a W boson produced in association with jets in the muon decay channel is presented. The measurement is based on 13 TeV proton-proton collision data corresponding to an integrated luminosity of 2.2 fb(-1), recorded by the CMS detector at the LHC. The cross sections are reported as functions of jet multiplicity, jet transverse momentum pT, jet rapidity, the scalar pT sum of the jets, and angular correlations between the muon and each jet for different jet multiplicities. The measured cross sections are in agreement with predictions that include multileg leading-order (LO) and next-to-LO matrix element calculations interfaced with parton showers, as well as a next-to-next-to-LO calculation for the W boson and one jet production.