Synthesis, antimycobacterial and cytotoxic activity of α,ß-unsaturated amides and 2,4-disubstituted oxazoline derivatives.

The synthesis of six α,ß,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8µM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4µM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,ß-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30µg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.

The geospatial relationship of geologic strata, geological fractures, and land use attained by a time-series aridity index in a semiarid region.

In a vast semiarid region of the Baja California Peninsula, remote sensing and GIS techniques were applied to moderate resolution images of Landsat 5 TM to explore the geospatial correlation among the grid aridity index (AI), shapefiles of geologic strata, land use, and geological fractures. A dataset of randomized sample points in a time-series of one hydrologic year along with vector file GIS delineated geologic fractures-including the area between their left/right parallel buffer lines-was used as mask analysis. MANOVA results were significant (p < 0.05) for geologic strata, land use, and basin. Overall results reveal the effects of soil texture on water retention on deeper soil horizons and the rate of vertical motion of rainwater. Despite the fact that geologic fractures underlie a large number of biotic communities, in both latitude and longitude gradients of the peninsula, no statistical significance was observed among the fractures themselves or the areas between their parallel buffer lines. One pulse rainfall event was documented by the AI grid maps enabling a robust vegetative response in early summer to an abnormal amount of rain provided by tropical storm Julio. AI grids appear to be useful for characterizing an ecosystem's dynamism. New options are suggested for this research strategy by expanding the number of datasets and incorporating geographic exclusion areas.

Vegetation response to hydrologic and geomorphic factors in an arid region of the Baja California Peninsula.

Remotely sensed imageries were used to analyze the response of desert vegetation to physiographic factors and accumulated precipitation in drier and wetter years within a region of >16,500 km(2) sampled with 5,000 random pixels of 30 m. Vegetation development was indexed by the annual maximum values for greenness (SAVI) and canopy water content (NDII). Precipitation was interpolated from the 0.25° grid of the Tropical Rainfall Measurement Mission satellite-based estimates, showing a regional average of ∼55 mm in the wetter year. The vegetation indices were only weakly related to total precipitation, often in a negative sense. Terrain factors that most often affected the vegetation indices, in multiple regression models, were Topographic Wetness Index, elevation, and slope gradient; these often had different signs for SAVI and for NDII. Models for NDII on intrusive igneous rocks gave better results than on extrusive igneous rocks. The strongest patterns in vegetation development were the contrast among Pacific coast, Cordillera, and Gulf coast subregions and the generally stronger results for NDII than SAVI.

Bacteria as Nanoparticle Carriers for Immunotherapy in Oncology.

The use of nanocarriers to deliver antitumor agents to solid tumors must overcome biological barriers in order to provide effective clinical responses. Once within the tumor, a nanocarrier should navigate into a dense extracellular matrix, overcoming intratumoral pressure to push it out of the diseased tissue. In recent years, a paradigm change has been proposed, shifting the target of nanomedicine from the tumoral cells to the immune system, in order to exploit the natural ability of this system to capture and interact with nanometric moieties. Thus, nanocarriers have been engineered to interact with immune cells, with the aim of triggering specific antitumor responses. The use of bacteria as nanoparticle carriers has been proposed as a valuable strategy to improve both the accumulation of nanomedicines in solid tumors and their penetration into the malignancy. These microorganisms are capable of propelling themselves into biological environments and navigating through the tumor, guided by the presence of specific molecules secreted by the diseased tissue. These capacities, in addition to the natural immunogenic nature of bacteria, can be exploited to design more effective immunotherapies that yield potent synergistic effects to induce efficient and selective immune responses that lead to the complete eradication of the tumor.

Bacteria-Assisted Transport of Nanomaterials to Improve Drug Delivery in Cancer Therapy.

Currently, the design of nanomaterials for the treatment of different pathologies is presenting a major impact on biomedical research. Thanks to this, nanoparticles represent a successful strategy for the delivery of high amounts of drugs for the treatment of cancer. Different nanosystems have been designed to combat this pathology. However, the poor penetration of these nanomaterials into the tumor tissue prevents the drug from entering the inner regions of the tumor. Some bacterial strains have self-propulsion and guiding capacity thanks to their flagella. They also have a preference to accumulate in certain tumor regions due to the presence of different chemo-attractants factors. Bioconjugation reactions allow the binding of nanoparticles in living systems, such as cells or bacteria, in a simple way. Therefore, bacteria are being used as a transport vehicle for nanoparticles, facilitating their penetration and the subsequent release of the drug inside the tumor. This review would summarize the literature on the anchoring methods of diverse nanosystems in bacteria and, interestingly, their advantages and possible applications in cancer therapy.

Evaluation of the penetration process of fluorescent collagenase nanocapsules in a 3D collagen gel.

One of the major limitations of nanomedicine is the scarce penetration of nanoparticles in tumoral tissues. These constrains have been tried to be solved by different strategies, such as the employ of polyethyleneglycol (PEG) to avoid the opsonization or reducing the extracellular matrix (ECM) density. Our research group has developed some strategies to overcome these limitations such as the employ of pH-sensitive collagenase nanocapsules for the digestion of the collagen-rich extracellular matrix present in most of tumoral tissues. However, a deeper understanding of physicochemical kinetics involved in the nanocapsules degradation process is needed to understand the nanocapsule framework degradation process produced during the penetration in the tissue. For this, in this work it has been employed a double-fluorescent labelling strategy of the polymeric enzyme nanocapsule as a crucial chemical tool which allowed the analysis of nanocapsules and free collagenase during the diffusion process throughout a tumour-like collagen matrix. This extrinsic label strategy provides far greater advantages for observing biological processes. For the detection of enzyme, collagenase has been labelled with fluorescein Isothiocyanate (FITC), whereas the nanocapsule surface was labelled with rhodamine Isothiocyanate (RITC). Thus, it has been possible to monitor the hydrolysis of nanocapsules and their diffusion throughout a thick 3D Collagen gel during the time, obtaining a detailed temporal evaluation of the pH-sensitive collagenase nanocapsule behaviour. These collagenase nanocapsules displayed a high enzymatic activity in low concentrations at acidic pH, and their efficiency to penetrate into tissue models pave the way to a wide range of possible nanomedical applications, especially in cancer therapy.

UVA-Degradable Collagenase Nanocapsules as a Potential Treatment for Fibrotic Diseases.

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.

Bacteria as Nanoparticles Carrier for Enhancing Penetration in a Tumoral Matrix Model.

One of the major concerns in the application of nanocarriers in oncology is their scarce penetration capacity in tumoral tissues, which drastically compromises the effctivity. Living organisms as cells and bacteria present the capacity to navigate autonomously following chemical gradients being able to penetrate deeply into dense tissues. In the recent years, the possibility to employ these organisms for the transportation of therapeutic agents and nanocarriers attached on their membrane or engulfed in their inner space have received huge attention. Herein, based on this principle, a new approach to deliver drug loaded nanoparticles achieving high penetration in tumoral matrices is presented. In this case, Escherichia coli (E. coli) bacteria wall is decorated with azide groups, whereas alkyne-strained groups are incorporated on the surface of mesoporous silica nanoparticles loaded with a potent cytotoxic compound, doxorubicin. Both functional groups form stable triazole bonds by click-type reaction allowing the covalent grafting of nanoparticles on living bacteria. Thus, the motility and penetration capacity of bacteria, which carried nanoparticles are evaluated in a 3D tumoral matrix model composed by a dense collagen extracellular matrix with HT1080 human fibrosarcome cells embedded. The results confirmed that bacteria are able to transport the nanoparticles crossing a thick collagen layer being able to destroy almost 80% of the tumoral cells located underneath. These findings envision a powerful strategy in nanomedicine applied for cancer treatment by allowing a homogeneous distribution of therapeutic agents in the malignancy.

Role of short-term dispersal on the dynamics of Zika virus in an extreme idealized environment.

In November 2015, El Salvador reported their first case of Zika virus (ZIKV) infection, an event followed by an explosive outbreak that generated over 6000 suspected cases in a period of two months. National agencies began implementing control measures that included vector control and recommending an increased use of repellents. Further, in response to the alarming and growing number of microcephaly cases in Brazil, the importance of avoiding pregnancies for two years was stressed. In this paper, we explore the role of mobility within communities characterized by extreme poverty, crime and violence. Specifically, the role of short term mobility between two idealized interconnected highly distinct communities is explored in the context of ZIKV outbreaks. We make use of a Lagrangian modeling approach within a two-patch setting in order to highlight the possible effects that short-term mobility, within highly distinct environments, may have on the dynamics of ZIKV outbreak when the overall goal is to reduce the number of cases not just in the most affluent areas but everywhere. Outcomes depend on existing mobility patterns, levels of disease risk, and the ability of federal or state public health services to invest in resource limited areas, particularly in those where violence is systemic. The results of simulations in highly polarized and simplified scenarios are used to assess the role of mobility. It quickly became evident that matching observed patterns of ZIKV outbreaks could not be captured without incorporating increasing levels of heterogeneity. The number of distinct patches and variations on patch connectivity structure required to match ZIKV patterns could not be met within the highly aggregated model that is used in the simulations.

Mass Media and the Contagion of Fear: The Case of Ebola in America.

BACKGROUND: In the weeks following the first imported case of Ebola in the U. S. on September 29, 2014, coverage of the very limited outbreak dominated the news media, in a manner quite disproportionate to the actual threat to national public health; by the end of October, 2014, there were only four laboratory confirmed cases of Ebola in the entire nation. Public interest in these events was high, as reflected in the millions of Ebola-related Internet searches and tweets performed in the month following the first confirmed case. Use of trending Internet searches and tweets has been proposed in the past for real-time prediction of outbreaks (a field referred to as "digital epidemiology"), but accounting for the biases of public panic has been problematic. In the case of the limited U. S. Ebola outbreak, we know that the Ebola-related searches and tweets originating the U. S. during the outbreak were due only to public interest or panic, providing an unprecedented means to determine how these dynamics affect such data, and how news media may be driving these trends. METHODOLOGY: We examine daily Ebola-related Internet search and Twitter data in the U. S. during the six week period ending Oct 31, 2014. TV news coverage data were obtained from the daily number of Ebola-related news videos appearing on two major news networks. We fit the parameters of a mathematical contagion model to the data to determine if the news coverage was a significant factor in the temporal patterns in Ebola-related Internet and Twitter data. CONCLUSIONS: We find significant evidence of contagion, with each Ebola-related news video inspiring tens of thousands of Ebola-related tweets and Internet searches. Between 65% to 76% of the variance in all samples is described by the news media contagion model.

In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis.

The in vitro activities of DA-7157, a novel oxazolidinone, against clinical isolates of Nocardia brasiliensis and Mycobacterium tuberculosis were determined. Equal MIC(50)s and MIC(90)s (0.25 and 0.5 microg/ml, respectively) were found for susceptible and multidrug-resistant isolates of M. tuberculosis. The N. brasiliensis isolates showed an MIC(90) of 1 microg/ml and an MIC(50) of 1 microg/ml. The DA-7157 prodrug, DA-7218, exhibited similar MICs for M. tuberculosis but fivefold-higher MICs for N. brasiliensis.