Skin cancer is one of the cancers that registers the highest number of new cases annually. Among all forms of skin cancer, melanoma is the most invasive and deadliest. The resistance of this form of ...cancer to conventional treatments has led to the employment of alternative/complementary therapeutic approaches. Photodynamic therapy (PDT) appears to be a promising alternative to overcome the resistance of melanoma to conventional therapies. PDT is a non-invasive therapeutic procedure in which highly reactive oxygen species (ROS) are generated upon excitation of a photosensitizer (PS) when subjected to visible light of an adequate wavelength, resulting in the death of cancer cells. In this work, inspired by the efficacy of tetrapyrrolic macrocycles to act as PS against tumor cells, we report the photophysical characterization and biological assays of isobacteriochlorins and their corresponding chlorins and porphyrins against melanoma cancer cells through a photodynamic process. The non-tumoral L929 fibroblast murine cell line was used as the control. The results show that the choice of adequate tetrapyrrolic macrocycle-based PS can be modulated to improve the performance of PDT.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
12.
The Afterglow and Kilonova of the Short GRB 160821B Troja, E.; Castro-Tirado, A. J.; Gonzalez, J Becerra ...
Monthly notices of the Royal Astronomical Society,
08/2019, Volume:
489, Issue:
2
Journal Article
Peer reviewed
Open access
GRB 160821B is a short duration gamma-ray burst (GRB) detected and localized by the Neil Gehrels Swift Observatory in the outskirts of a spiral galaxy at z = 0.1613, at a projected physical offset of ...16 kpc from the galaxy’s center. We present X-ray, optical/nIR, and radio observations of its counterpart and model them with two distinct components of emission: a standard afterglow, arising from the interaction of the relativistic jet with the surrounding medium, and a kilonova, powered by the radioactive decay of the sub-relativistic ejecta. Broadband modelling of the afterglow data reveals a weak reverse shock propagating backward into the jet, and a likely jet-break at 3.5 d. This is consistent with a structured jet seen slightly off-axis (θview ∼ θcore) while expanding into a low-density medium (n ≈ 10−3 cm−3). Analysis of the kilonova properties suggests a rapid evolution towards red colours, similar toAT2017gfo, and a low-nIR luminosity, possibly due to the presence of a long-lived neutron star. The global properties of the environment, the inferred low mass (Mej <~ 0.006 Msun) and velocities (vej >~ 0.05c) of lanthanide-rich ejecta are consistent with a binary neutron star merger progenitor.
Macamides, amides of fatty acids first isolated from maca (Lepidium meyenii) are potentially responsible for the reduction of ischemic injury in the stroke animal model followed by maca extract ...administration. This deduction comes from its ability to inhibit the fatty acid amide hydrolase activity, an enzyme related to the endocannabinoid anandamide hydrolysis. However, no study about the effects of isolated macamides on in-vivo models has been published yet. Our objective was to evaluate the effect of a 10-day 30 mg/kg i.p. MCH1 administration, the macamide with the higher FAAH inhibition capability, on the neurological recovery and brain infarction area of Sprague-Dawley rats exposed to the transient middle cerebral artery occlusion (MCAO) model. Our results showed that the group receiving MCH1 for 10 days did not improve Garcia’s neurological score compared to receiving the vehicle only. Likewise, the MCH1 group did not improve their sensorimotor dysfunction as indicated by the latency to detect and remove the tape from the contralateral forepaw in the adhesive removal test, and a similar number of errors with the contralateral forepaw in the foot fault test compared to the vehicle group at the 10th day. Evaluation of the spatial memory and learning using the Barnes test showed longer latency to reach the escape box in the Vehicle and MCH1 groups compared to the control group (no MCAO) only in the retrieval test, while no effect of MCAO procedure or MCH1 administration was observed in the reversal learning test. Despite the lack of behavioral effect of MCH1, analysis of the infarcted areas in the brain using the 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining method in the seven consecutive coronal sections revealed that the infarcted area in the first (bregma + 4.2 mm) and fifth (bregma −3.8 mm) coronal sections of the MCAO + MCH1 group remained similar to the Control group. These results provide evidence that MCH1 can limit damage from ischemic stroke, although it is not reflected in neurological or sensorimotor behavior and spatial learning and memory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The stability of probiotic yogurts added with glucose oxidase and packaged in different plastic packaging systems that present different oxygen permeability transfer rates (0.09, 0.2, 0.39 and ...0.75mLO2/day) was evaluated during 28days of refrigerated storage. Probiotic stirred yogurts were submitted to physicochemical (pH, proteolytic activity, dissolved oxygen) and microbiological analyses (yogurt bacteria, Lactobacillus acidophilus and Bifidobacterium longum) as well as the content of organic acids (lactic and acetic acid) and aroma compound (diacetyl and acetaldehyde) were assessed. Overall, yogurts packaged in plastic containers with lower oxygen permeability rates showed a higher extent of post-acidification, proteolysis and organic acid production. Additionally, these samples also presented a lower content of dissolved oxygen and a lower decrease of the probiotic bacteria count. No influence on the production of aroma compounds was observed. Our results suggest that the use of packaging systems with different oxygen permeability rates coupled with the addition of glucose oxidase presented an interesting technological option to minimize the oxidative stress in probiotic yogurts.
► Probiotic yogurts with glucose oxidase packaged in plastic materials. ► Post-acidification, proteolysis and organic acids production improved. ► Probiotic bacteria counts and aroma compound with few alterations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The active pharmaceutical ingredient (API) is a drug product's biologically active chemical substance that produces the desired therapeutic effects. Most APIs are small organic molecules commercially ...available as a crystalline solid phase. Crystalline drugs are preferred in oral dosage formulations for their high purity and stability. However, some commercial drugs have low aqueous solubility, reducing their bioavailability and requiring high doses of API. Thus, discovering/investigating solid crystalline forms or controlling/designing more soluble forms with optimized pharmaceutical properties can be challenging or suitable for the pharmaceutical industry and academia. In this sense, the present work proposes a new physicochemical approach consisting of the average framework energy (
E&cmb.a.line;
framework
) which is the average intermolecular interaction in crystalline solids to predict the modification of API solubility in new solid forms. This way, it was possible to correlate the intermolecular interactions of a given crystalline solid-state with its respective aqueous solubility. Overall, 60 crystalline forms are involved in this investigation derived from 25 distinct APIs. The results indicate that the average energy framework calculated and the aqueous solubility display a linear upward trend in the distribution of points, meaning that the greater the solubility, the lower the interaction energy. Such an approach is more evident in box plot-based drugs grouped by solubility range indicating a handy predictive model for drug solubility estimation based exclusively on energy framework features.
Crystal structures with lower interaction energy tend to present higher aqueous solubility.
Hemodynamic factors are thought to be implicated in the progression and rupture of intracranial aneurysms. Current efforts aim to study the possible associations of hemodynamic characteristics such ...as complexity and stability of intra-aneurysmal flow patterns, size and location of the region of flow impingement with the clinical history of aneurysmal rupture. However, there are no reliable methods for measuring blood flow patterns in vivo. In this paper, an efficient methodology for patient-specific modeling and characterization of the hemodynamics in cerebral aneurysms from medical images is described. A sensitivity analysis of the hemodynamic characteristics with respect to variations of several variables over the expected physiologic range of conditions is also presented. This sensitivity analysis shows that although changes in the velocity fields can be observed, the characterization of the intra-aneurysmal flow patterns is not altered when the mean input flow, the flow division, the viscosity model, or mesh resolution are changed. It was also found that the variable that has the greater impact on the computed flow fields is the geometry of the vascular structures. We conclude that with the proposed modeling pipeline clinical studies involving large numbers cerebral aneurysms are feasible.
Context: Heterozygous, de novo mutations in the transcription factor SOX2 are associated with bilateral anophthalmia or severe microphthalmia and hypopituitarism. Variable additional abnormalities ...include defects of the corpus callosum and hippocampus.
Objective: We have ascertained a further three patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2. To provide further evidence of a direct role for SOX2 in hypothalamo-pituitary development, we have studied the expression of the gene in human embryonic tissues.
Results: All three patients harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (c.70_89del), and a novel nonsense mutation (p.Q61X) within the DNA binding domain that results in impaired transactivation. We also show that human SOX2 can inhibit β-catenin-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress efficiently this activity. Furthermore, we show that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as Rathke’s pouch, the developing anterior pituitary, and the eye.
Conclusions: Patients with SOX2 mutations often manifest the unusual phenotype of hypogonadotropic hypogonadism, with sparing of other pituitary hormones despite anterior pituitary hypoplasia. SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals. Given the critical role of Wnt-signaling in the development of most of these tissues, our data suggest that a failure to repress the Wnt-β-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.
The post-functionalization of 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide, known as a highly efficient photosensitizer (PS) for antimicrobial photodynamic therapy ...(aPDT), in the presence of 3- or 4-mercaptobenzoic acid, afforded two new tricationic porphyrins with adequate carboxylic pending groups to be immobilized on chitosan or titanium oxide. The structural characterization of the newly obtained materials confirmed the success of the porphyrin immobilization on the solid supports. The photophysical properties and the antimicrobial photodynamic efficacy of the non-immobilized porphyrins and of the new conjugates were evaluated. The results showed that the position of the carboxyl group in the mercapto units or the absence of these substituents in the porphyrin core could modulate the action of the photosensitizer towards the bioluminescent Gram-negative
bacterium. The antimicrobial activity was also influenced by the interaction between the photosensitizer and the type of support (chitosan or titanium dioxide). The new cationic porphyrins and some of the materials were shown to be very stable in PBS and effective in the photoinactivation of
bacterium. The physicochemical properties of TiO
allowed the interaction of the PS with its surface, increasing the absorption profile of TiO
, which enables the use of visible light, inactivating the bacteria more efficiently than the corresponding PS immobilized on chitosan.
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Spalt-like proteins are Zinc finger transcription factors from Caenorhabditis elegans to vertebrates, with critical roles in development. In vertebrates, four paralogues have been identified ...(SALL1-4), and SALL2 is the family's most dissimilar member. SALL2 is required during brain and eye development. It is downregulated in cancer and acts as a tumor suppressor, promoting cell cycle arrest and cell death. Despite its critical functions, information about SALL2 regulation is scarce. Public data indicate that SALL2 is ubiquitinated and phosphorylated in several residues along the protein, but the mechanisms, biological consequences, and enzymes responsible for these modifications remain unknown. Bioinformatic analyses identified several putative phosphorylation sites for Casein Kinase II (CK2) located within a highly conserved C-terminal PEST degradation motif of SALL2. CK2 is a serine/threonine kinase that promotes cell proliferation and survival and is often hyperactivated in cancer. We demonstrated that CK2 phosphorylates SALL2 residues S763, T778, S802, and S806 and promotes SALL2 degradation by the proteasome. Accordingly, pharmacological inhibition of CK2 with Silmitasertib (CX-4945) restored endogenous SALL2 protein levels in SALL2-deficient breast MDA-MB-231, lung H1299, and colon SW480 cancer cells. Silmitasertib induced a methuosis-like phenotype and cell death in SW480 cells. However, the phenotype was significantly attenuated in CRISPr/Cas9-mediated SALL2 knockout SW480 cells. Similarly, Sall2-deficient tumor organoids were more resistant to Silmitasertib-induced cell death, confirming that SALL2 sensitizes cancer cells to CK2 inhibition. We identified a novel CK2-dependent mechanism for SALL2 regulation and provided new insights into the interplay between these two proteins and their role in cell survival and proliferation.
ABSTRACT
We present and perform a detailed analysis of multiwavelength observations of GRB 140102A, an optical bright GRB with an observed reverse shock (RS) signature. Observations of this GRB were ...acquired with the BOOTES-4 robotic telescope, the Fermi, and the Swift missions. Time-resolved spectroscopy of the prompt emission shows that changes to the peak energy (Ep) tracks intensity and the low-energy spectral index seems to follow the intensity for the first episode, whereas this tracking behaviour is less clear during the second episode. The fit to the afterglow light curves shows that the early optical afterglow can be described with RS emission and is consistent with the thin shell scenario of the constant ambient medium. The late time afterglow decay is also consistent with the prediction of the external forward shock model. We determine the properties of the shocks, Lorentz factor, magnetization parameters, and ambient density of GRB 140102A, and compare these parameters with another 12 GRBs, consistent with having RS produced by thin shells in an interstellar medium like medium. The value of the magnetization parameter (RB ≈ 18) indicates a moderately magnetized baryonic dominant jet composition for GRB 140102A. We also report the host galaxy photometric observations of GRB 140102A obtained with 10.4 m GTC, 3.5 m Calar Alto Astronomical Observatory, and 3.6 m Devasthal optical telescope and find the host (photo z = $2.8^{+0.7}_{-0.9}$) to be a high-mass, star-forming galaxy with a star formation rate of $20 \pm 10 {\rm ~M_{\odot }}\, \rm yr^{-1}$.
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