Tuning the endocytosis mechanism of Zr-based metal−organic frameworks through linker functionalization

A critical bottleneck for the use of metal-organic frameworks (MOFs) as drug delivery systems has been allowing them to reach their intracellular targets without being degraded in the acidic environment of the lysosomes. Cells take up particles by endocytosis through multiple biochemical pathways, and the fate of these particles depends on these routes of entry. Here, we show the effect of functional group incorporation into a series of Zr-based MOFs on their endocytosis mechanisms, allowing us to design an effi-cient drug delivery system. In particular, naphthalene-2,6-dicarboxylic acid and 4,4'-biphenyldicarboxylic acid ligands promote entry through the caveolin-pathway, allowing the particles to avoid lysosomal degradation and be delivered into the cytosol, en-hancing their therapeutic activity when loaded with drugs

LOS PEROMYSCUS (RODENTIA: MURIDAE) EN LA COLECCIÓN DE MAMÍFEROS DE LA UNIVERSIDAD AUTÓNOMA METROPOLITANA-UNIDAD IZTAPALAPA (UAMI)

We examined the 3704 specimens of rodents of the genera Habromys, Osgoodomys and Peromyscus, except those from the Mexican State of Tlaxcala. Mostly of them are from localities of the Mexican Transvolcanic Belt. We also include those specimens from marginal or occasional fieldwork in different parts of the country, as well as those given or permanent deposit in the Mammal Collection of UAMI. All of them belong to the following species Habromys lophurus, Osgoodomys banderanus, Peromyscus aztecus, P. beatae, P. bullatus, P. difficilis, P. eremicus, P. furvus, P. gratus, P. guatemalensis, P. hylocetes, P. leucopus, P. levipes, P. maniculatus, P. megalops, P. melanocarpus, P. melanophrys, P. melanotis, P. mexicanus, P. ochraventer, P. perfulvus, P. simulus, P. spicilegus, P. yucatanicus, and P. zarhynchus.Se examinaron 3704 ejemplares de ratones de los géneros Habromys, Osgoodomys y Peromyscus, excepto los de Tlaxcala. La mayoría de los ejemplares proceden de localidades del Eje Volcánico Transversal, aunque también se incluyen los de capturas marginales en otras regiones del país, así como los donados o que en calidad de depósito permanente se albergan en la Colección. Por lo anterior, se consignan ejemplares de las especies Habromys lophurus, Osgoodomys banderanus, Peromyscus aztecus, P. beatae, P. bullatus, P. difficilis, P. eremicus, P. furvus, P. gratus, P. guatemalensis, P. hylocetes, P. leucopus, P. levipes, P. maniculatus, P. megalops, P. melanocarpus, P. melanophrys, P. melanotis, P. mexicanus, P. ochraventer, P. perfulvus, P. simulus, P. spicilegus, P. yucatanicus y P. zarhynchus

Surface-functionalisation of Zr-Fumarate MOF for selective cytotoxicity and immune system compatibility in nanoscale drug delivery

Metal-organic frameworks (MOFs), network structures wherein metal ions or clusters link organic ligands into porous materials, are being actively researched as nanoscale drug delivery devices (DDSs) as they offer tuneable structures with high cargo loading that can easily be further functionalized for targeting and enhanced physiological stability. The excellent biocompatibility of Zr has meant that its MOFs are amongst the most studied to date, in particular the archetypal Zr terephthalate UiO-66. In contrast, the isoreticular analogue linked by fumarate (Zr-fum) has received little attention, despite the endogenous linker being part of the Krebs cycle. Herein, we report a comprehensive study of Zr-fum in the context of drug delivery. Reducing particle size is shown to increase uptake by cancer cells while reducing internalisation by macrophages, immune system cells that remove foreign objects from the bloodstream. Zr-fum is compatible with defect-loading of the drug dichloroacetate, as well as surface modification during synthesis, through coordination modulation, and postsynthetically. DCA-loaded, PEGylated Zr-fum shows selective in vitro cytotoxicity towards HeLa and MCF-7 cancer cells, likely as a consequence of its enhanced caveolae-mediated endocytosis compared to uncoated precursors, and it is well tolerated by HEK293 kidney cells, J774 macrophages, and human peripheral blood lymphocytes. Compared to UiO-66, Zr-fum is more efficient at transporting the drug mimic calcein into HeLa cells, and DCA-loaded, PEGylated Zr-fum is more effective at reducing HeLa and MCF-7 cell proliferation than the analogous UiO-66 sample. In vitro examination of immune system response shows Zr-fum samples induce less reactive oxygen species than UiO-66 analogues, possibly as a consequence of the linker being endogenous, and do not activate the C3 and C4 complement cascade pathways, suggesting that Zr-fum can avoid phagocytic activation. The results show that Zr-fum is an attractive alternative to UiO-66 for nanoscale drug delivery, and that a wide range of in vitro experiments are available to greatly inform the design of DDSs prior to early stage animal studies

The effect of reverse current on the dark properties of photovoltaic solar modules

AbstractForward and reverse dark current-voltage (I-V) and capacitance-voltage (C-V) characteristics of commercial amorphous silicon solar modules, were measured in order to study their performance under the influence of induced reverse currents. Maximum module surface temperatures were directly related to each value of the induced reverse current and in to the amount of current leakage respectively. Microscopic changes as a result of hot spots defects and overheating of the solar module, linked to reverse current effects, were also documented and discussed. Experimental evidence showed that different levels of reverse currents are confirmed to be a major degrading factor affecting the performance, efficiency, and power of solar modules

A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways.

<b>Purpose:</b> Because of emergence of resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), no targeted treatments are available for patients with lung cancer who lose sensitivity due to new mutations or bypass mechanisms. We examined in animals and <i>in vitro</i> an alternative therapeutic approach making use of antibodies. <b>Experimental Design:</b> An osimertinib-sensitive animal model of lung cancer, which rapidly develops drug resistance, has been employed. To overcome compensatory hyperactivation of ERK, which we previously reported, an anti-EGFR antibody (cetuximab) was combined with other antibodies, as well as with a subtherapeutic dose of osimertinib, and cancer cell apoptosis was assayed. <b>Results:</b> Our animal studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 mAb), and osimertinib (low dose), as an effective and long-lasting treatment that is able to prevent onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and for prevention of relapses. Studies employing cultured cells and analyses of tumor extracts indicated that the combination of two mAbs and a subtherapeutic TKI dose sorted EGFR and HER2 for degradation; cooperatively enhanced apoptosis; inhibited activation of ERK; and reduced abundance of several bypass proteins, namely MET, AXL, and HER3. <b>Conclusions:</b> Our <i>in vitro</i> assays and animal studies identified an effective combination of clinically approved drugs that might overcome resistance to irreversible TKIs in clinical settings. The results we present attribute the long-lasting effect of the drug combination to simultaneous blockade of several well-characterized mechanisms of drug resistance. <i>Clin Cancer Res; 24(22); 5610-21. ©2018 AACR</i> <i>See related commentary by Fan and Yu, p. 5499</i>

Effect of chitosan essential oil films on the storage-keeping quality of pork meat products

Edible films based on chitosan were prepared, with and without basil or thyme essential oils, with the aim of assessing their protective ability against lipid oxidation and their antimicrobial activity. Chitosan films had good oxygenbarrier properties, which were worsened by essential oil addition, especially when the film equilibrium moisture content increased. Due to the oxygen-barrier effect, all the films effectively protected pork fat from oxidation, in comparison to unprotected samples. In spite of the worsening of the oxygen-barrier properties, the films with essential oils were more effective than those of pure chitosan, which points to the chemical action of specific antioxidant compounds of the oils. Films were effective to control microbial growth in minced pork meat, although the incorporation of essential oils did not improve their antimicrobial activity. 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Short-Term Memory Maintenance of Object Locations during Active Navigation: Which Working Memory Subsystem Is Essential?

The goal of the present study was to examine the extent to which working memory supports the maintenance of object locations during active spatial navigation. Participants were required to navigate a virtual environment and to encode the location of a target object. In the subsequent maintenance period they performed one of three secondary tasks that were designed to selectively load visual, verbal or spatial working memory subsystems. Thereafter participants re-entered the environment and navigated back to the remembered location of the target. We found that while navigation performance in participants with high navigational ability was impaired only by the spatial secondary task, navigation performance in participants with poor navigational ability was impaired equally by spatial and verbal secondary tasks. The visual secondary task had no effect on navigation performance. Our results extend current knowledge by showing that the differential engagement of working memory subsystems is determined by navigational ability

Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study

22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the neurobiological substrate underlying these deficits is poorly understood. We investigated brain function during a visuospatial working memory (SWM) task in eight children with 22q11DS and 13 healthy controls, using fMRI. Both groups showed task-related activation in dorsolateral prefrontal cortex (DLPFC) and bilateral parietal association cortices. Controls activated parietal and occipital regions significantly more than those with 22q11DS but there was no significant between-group difference in DLPFC. In addition, while controls had a significant age-related increase in the activation of posterior brain regions and an age-related decrease in anterior regions, the 22q11DS children showed the opposite pattern. Genetically determined differences in the development of specific brain systems may underpin the cognitive deficits in 22q11DS, and may contribute to the later development of neuropsychiatric disorders

Progress and Research Needs of Plant Biomass Degradation by Basidiomycete Fungi

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