160 research outputs found
The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk
Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1
Flavor conversion of cosmic neutrinos from hidden jets
High energy cosmic neutrino fluxes can be produced inside relativistic jets
under the envelopes of collapsing stars. In the energy range E ~ (0.3 - 1e5)
GeV, flavor conversion of these neutrinos is modified by various matter effects
inside the star and the Earth. We present a comprehensive (both analytic and
numerical) description of the flavor conversion of these neutrinos which
includes: (i) oscillations inside jets, (ii) flavor-to-mass state transitions
in an envelope, (iii) loss of coherence on the way to observer, and (iv)
oscillations of the mass states inside the Earth. We show that conversion has
several new features which are not realized in other objects, in particular
interference effects ("L- and H- wiggles") induced by the adiabaticity
violation. The neutrino-neutrino scattering inside jet and inelastic neutrino
interactions in the envelope may produce some additional features at E > 1e4
GeV. We study dependence of the probabilities and flavor ratios in the
matter-affected region on angles theta13 and theta23, on the CP-phase delta, as
well as on the initial flavor content and density profile of the star. We show
that measurements of the energy dependence of the flavor ratios will, in
principle, allow to determine independently the neutrino and astrophysical
parameters.Comment: 56 pages, 19 figures. Minor changes. Accepted by JHEP
Novel insights into host-fungal pathogen interactions derived from live-cell imaging
Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007β2013 grant agreement HEALTH-F2-2010-260338βALLFUN to NARG.Peer reviewedPublisher PD
Multiphoton Quantum Optics and Quantum State Engineering
We present a review of theoretical and experimental aspects of multiphoton
quantum optics. Multiphoton processes occur and are important for many aspects
of matter-radiation interactions that include the efficient ionization of atoms
and molecules, and, more generally, atomic transition mechanisms;
system-environment couplings and dissipative quantum dynamics; laser physics,
optical parametric processes, and interferometry. A single review cannot
account for all aspects of such an enormously vast subject. Here we choose to
concentrate our attention on parametric processes in nonlinear media, with
special emphasis on the engineering of nonclassical states of photons and
atoms. We present a detailed analysis of the methods and techniques for the
production of genuinely quantum multiphoton processes in nonlinear media, and
the corresponding models of multiphoton effective interactions. We review
existing proposals for the classification, engineering, and manipulation of
nonclassical states, including Fock states, macroscopic superposition states,
and multiphoton generalized coherent states. We introduce and discuss the
structure of canonical multiphoton quantum optics and the associated one- and
two-mode canonical multiphoton squeezed states. This framework provides a
consistent multiphoton generalization of two-photon quantum optics and a
consistent Hamiltonian description of multiphoton processes associated to
higher-order nonlinearities. Finally, we discuss very recent advances that by
combining linear and nonlinear optical devices allow to realize multiphoton
entangled states of the electromnagnetic field, that are relevant for
applications to efficient quantum computation, quantum teleportation, and
related problems in quantum communication and information.Comment: 198 pages, 36 eps figure
A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population
<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have assessed the prevalence of germline mutations in <it>BRCA1 </it>and <it>BRCA2 </it>genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of <it>BRCA1-2 </it>mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of <it>BRCA1-2 </it>germline mutations was also evaluated.</p> <p>Methods</p> <p>Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for <it>BRCA1-2 </it>mutations by DHPLC analysis and DNA sequencing. Association of <it>BRCA1 </it>and <it>BRCA2 </it>mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.</p> <p>Results and Conclusion</p> <p>Overall, 8 <it>BRCA1 </it>and 5 <it>BRCA2 </it>deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in <it>BRCA2 </it>gene. The geographical distribution of <it>BRCA1-2 </it>mutations was related to three specific large areas of Sardinia, reflecting its ancient history: <it>a</it>) the Northern area, linguistically different from the rest of the island (where a <it>BRCA2 c.8764_8765delAG </it>mutation with founder effect was predominant); <it>b</it>) the Middle area, land of the ancient Sardinian population (where <it>BRCA2 </it>mutations are still more common than <it>BRCA1 </it>mutations); and <it>c</it>) the South-Western area, with many Phoenician and Carthaginian locations (where <it>BRCA1 </it>mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of <it>BRCA1-2 </it>germline mutations.</p
Temporal context and conditional associative learning
<p>Abstract</p> <p>Background</p> <p>We investigated how temporal context affects the learning of arbitrary visuo-motor associations. Human observers viewed highly distinguishable, fractal objects and learned to choose for each object the one motor response (of four) that was rewarded. Some objects were consistently preceded by specific other objects, while other objects lacked this task-irrelevant but predictive context.</p> <p>Results</p> <p>The results of five experiments showed that predictive context consistently and significantly accelerated associative learning. A simple model of reinforcement learning, in which three successive objects informed response selection, reproduced our behavioral results.</p> <p>Conclusions</p> <p>Our results imply that not just the representation of a current event, but also the representations of past events, are reinforced during conditional associative learning. In addition, these findings are broadly consistent with the prediction of attractor network models of associative learning and their prophecy of a persistent representation of past objects.</p
Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats
Rationale Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific
neuronal processes underlying impulsive behavior is as yet lacking.
Objectives As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further
elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior.
Materials and methods The effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior,
namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm,
and response inhibition in a stop-signal paradigm.
Results In the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore,
SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters.
The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors
of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive
choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response
inhibition but did not change impulsive choice.
Conclusions The present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides
further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated
Prospective research on musculoskeletal disorders in office workers (PROMO): study protocol
BACKGROUND: This article describes the background and study design of the PROMO study (Prospective Research on Musculoskeletal disorders in Office workers). Few longitudinal studies have been performed to investigate the risk factors responsible for the incidence of hand, arm, shoulder and neck symptoms among office workers, given the observation that a large group of office workers might be at risk worldwide. Therefore, the PROMO study was designed. The main aim is to quantify the contribution of exposure to occupational computer use to the incidence of hand, arm, shoulder and neck symptoms. The results of this study might lead to more effective and/or cost-efficient preventive interventions among office workers. METHODS/DESIGN: A prospective cohort study is conducted, with a follow-up of 24 months. In total, 1821 participants filled out the first questionnaire (response rate of 74%). Data on exposure and outcome is collected using web-based self-reports. Outcome assessment takes place every three months during the follow-up period. Data on computer use are collected at baseline and continuously during follow-up using a software program. DISCUSSION: The advantages of the PROMO study include the long follow-up period, the repeated measurement of both exposure and outcome, and the objective measurement of the duration of computer use. In the PROMO study, hypotheses stemming from lab-based and field-based research will be investigated
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