Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53-/-. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo

Organelle tethering, pore formation and SNARE compensation in the late endocytic pathway

To provide insights into the kiss-and-run and full fusion events resulting in endocytic delivery to lysosomes, we investigated conditions causing increased tethering and pore formation between late endocytic organelles in HeLa cells. Knockout of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) VAMP7 and VAMP8 showed, by electron microscopy, the accumulation of tethered lysosome-associated membrane protein (LAMP)-carrier vesicles around multivesicular bodies, as well as the appearance of ‘hourglass’ profiles of late endocytic organelles attached by filamentous tethers, but did not prevent endocytic delivery to lysosomal hydrolases. Subsequent depletion of the SNARE YKT6 reduced this delivery, consistent with it compensating for the absence of VAMP7 and VAMP8. We also investigated filamentous tethering between multivesicular bodies and enlarged endolysosomes following depletion of charged multi-vesicular body protein 6 (CHMP6), and provide the first evidence that pore formation commences at the edge of tether arrays, with pore expansion required for full membrane fusion

Helical distribution of the bacterial chemoreceptor via colocalization with the Sec protein translocation machinery

In Escherichia coli, chemoreceptor clustering at a cell pole seems critical for signal amplification and adaptation. However, little is known about the mechanism of localization itself. Here we examined whether the aspartate chemoreceptor (Tar) is inserted directly into the polar membrane by using its fusion to green fluorescent protein (GFP). After induction of Tar–GFP, fluorescent spots first appeared in lateral membrane regions, and later cell poles became predominantly fluorescent. Unexpectedly, Tar–GFP showed a helical arrangement in lateral regions, which was more apparent when a Tar–GFP derivative with two cysteine residues in the periplasmic domain was cross-linked to form higher oligomers. Moreover, similar distribution was observed even when the cytoplasmic domain of the double cysteine Tar–GFP mutant was replaced by that of the kinase EnvZ, which does not localize to a pole. Observation of GFP–SecE and a translocation-defective MalE–GFP mutant, as well as indirect immunofluorescence microscopy on SecG, suggested that the general protein translocation machinery (Sec) itself is arranged into a helical array, with which Tar is transiently associated. The Sec coil appeared distinct from the MreB coil, an actin-like cytoskeleton. These findings will shed new light on the mechanisms underlying spatial organization of membrane proteins in E. coli

Magnetization steps in a diluted Heisenberg antiferromagnetic chain: Theory and experiments on TMMC:Cd

A theory for the equilibrium low-temperature magnetization M of a diluted Heisenberg antiferromagnetic chain is presented. The magnetization curve, M versus B, is calculated using the exact contributions of finite chains with 1 to 5 spins, and the "rise and ramp approximation" for longer chains. Some non-equilibrium effects that occur in a rapidly changing B, are also considered. Specific non-equilibrium models based on earlier treatments of the phonon bottleneck, and of spin flips associated with cross relaxation and with level crossings, are discussed. Magnetization data on powders of TMMC diluted with cadmium [i.e., (CH_3)_4NMn_xCd_(1-x)Cl_3, with 0.16<=x<=0.50 were measured at 0.55 K in 18 T superconducting magnets. The field B_1 at the first MST from pairs is used to determine the NN exchange constant, J, which changes from -5.9 K to -6.5 K as x increases from 0.16 to 0.50. The magnetization curves obtained in the superconducting magnets are compared with simulations based on the equilibrium theory. Data for the differential susceptibility, dM/dB, were taken in pulsed magnetic fields (7.4 ms duration) up to 50 T, with the powder samples in a 1.5 K liquid-helium bath. Non-equilibrium effects, which became more severe as x decreased, were observed. The non-equilibrium effects are tentatively interpreted using the "Inadequate Heat Flow Scenario," or to cross-relaxation, and crossings of energy levels, including those of excited states.Comment: 16 pages, 14 figure

Constraints on accelerating universe using ESSENCE and Gold supernovae data combined with other cosmological probes

We use recently observed data: the 192 ESSENCE type Ia supernovae (SNe Ia), the 182 Gold SNe Ia, the 3-year WMAP, the SDSS baryon acoustic peak, the X-ray gas mass fraction in clusters and the observational $H(z)$ data to constrain models of the accelerating universe. Combining the 192 ESSENCE data with the observational $H(z)$ data to constrain a parameterized deceleration parameter, we obtain the best fit values of transition redshift and current deceleration parameter $z_{T}=0.632^{+0.256}_{-0.127}$, $q_{0}=-0.788^{+0.182}_{-0.182}$. Furthermore, using $\Lambda$CDM model and two model-independent equation of state of dark energy, we find that the combined constraint from the 192 ESSENCE data and other four cosmological observations gives smaller values of $\Omega_{0m}$ and $q_{0}$, but a larger value of $z_{T}$ than the combined constraint from the 182 Gold data with other four observations. Finally, according to the Akaike information criterion it is shown that the recently observed data equally supports three dark energy models: $\Lambda$CDM, $w_{de}(z)=w_{0}$ and $w_{de}(z)=w_{0}+w_{1}\ln(1+z)$.Comment: 18 pages, 8 figure

Searches for lepton number violating K+ decays

The NA62 experiment at CERN reports a search for the lepton number violating decays K+→π−e+e+ and K+→π−μ+μ+ using a data sample collected in 2017. No signals are observed, and upper limits on the branching fractions of these decays of 2.2 x 10^-10 and 4.2 x 10^-11 are obtained, respectively, at 90% confidence level. These upper limits improve on previously reported measurements by factors of 3 and 2, respectively

Search for heavy neutral lepton production in K+ decays to positrons

A search for heavy neutral lepton (N) production in K+→e+N decays using the data sample collected by the NA62 experiment at CERN in 2017-2018 is reported. Upper limits of the extended neutrino mixing matrix element |Ue4|^2 are established at the level of 10^−9 over most of the accessible heavy neutral lepton mass range 144-462 MeV/c^2, with the assumption that the lifetime exceeds 50 ns. These limits improve significantly upon those of previous production and decay searches. The |Ue4|^2 range favoured by Big Bang Nucleosynthesis is excluded up to a mass of about 340 MeV/c^2

The On-orbit Calibrations for the Fermi Large Area Telescope

The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope began its on--orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.Comment: 60 pages, 34 figures, submitted to Astroparticle Physic

Deliberação online em consultas públicas? O caso da assembleia legislativa de Minas Gerais

Este artigo busca analisar uma consulta pública online sobre reforma política promovida em 2011 pela Assembleia Legislativa de Minas Gerais. Embasado pela teoria deliberacionista, o estudo de 752 posts guiou-se pela discussão de seis tópicos: (1) inclusividade; (2) provimento de razões; (3) reciprocidade; (4) respeito mútuo; (5) orientação para o bem comum; e (6) articulação entre arenas. Os resultados indicam: (1) uma sobrerepresentação de participantes masculinos e oriundos da Região Metropolitana de Belo Horizonte, embora não tenha havido concentração de posts em alguns comentadores; (2) o predomínio de posts on topic e que apresentam justificativas para as posições advogadas; (3) índices muito baixos de reciprocidade entre posts e de uso de marcadores de interatividade; (4) graus muito elevados de respeito; (5) diferentes formas de ligação das justificativas a ideias de bem comum; (6) o baixo impacto decisório e a conexão com outras arenas da esfera pública, destacando-se a relação com uma matéria publicada em jornal de grande circulação. Os achados são ambivalentes para os defensores da deliberação, indicando baixa probabilidade de deliberação interna ao fórum, mas algum potencial deliberativo quando se adotam lentes mais amplas. Os cruzamentos entre variáveis sugerem que as pessoas tendem a prover mais justificativas em discussões mais controversas, embora tendam a dialogar menos nesses casos. Assim, a hipótese da preferência por conversas entre like-minded encontra respaldo nos dados analisados

Development of a new CEDAR for kaon identification at the NA62 experiment at CERN

The NA62 experiment at CERN utilises a differential Cherenkov counter with achromatic ring focus (CEDAR) for tagging kaons within an unseparated monochromatic beam of charged hadrons. The CEDAR-H detector was developed to minimise the amount of material in the path of the beam by using hydrogen gas as the radiator medium. The detector was shown to satisfy the kaon tagging requirements in a test-beam before installation and commissioning at the experiment. The CEDAR-H performance was measured using NA62 data collected in 2023