Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination.

The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild-type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.

c-Kit Receptor Maintains Sensory Axon Innervation of the Skin through Src Family Kinases.

Peripheral somatosensory neurons innervate the skin and sense the environment. Whereas many studies focus on initial axon outgrowth and pathfinding, how signaling pathways contribute to maintenance of the established axon arbors and terminals within the skin is largely unknown. This question is particularly relevant to the many types of neuropathies that affect mature neuronal arbors. We show that a receptor tyrosine kinase (RTK), c-Kit, contributes to maintenance, but not initial development, of cutaneous axons in the larval zebrafish before sex determination. Downregulation of Kit signaling rapidly induced retraction of established axon terminals in the skin and a reduction in axonal density. Conversely, misexpression of c-Kit ligand in the skin in larval zebrafish induced increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon maintenance. We found Src family kinases (SFKs) act directly downstream to mediate Kit's role in regulating cutaneous axon density. Our data demonstrate a requirement for skin-to-axon signaling to maintain axonal networks and elucidate novel roles for Kit and SFK signaling in this context. This Kit-SFK signaling axis offers a potential pathway to therapeutically target in sensory neuropathies and to further explore in other neurobiological processes.SIGNIFICANCE STATEMENTThe skin is full of small nerve endings that sense different environmental stimuli. How these nerve endings grow and reach a specific area of the skin during development has been the focus of many studies. In contrast, the cellular and molecular mechanisms required to maintain the function and health of these structures is relatively unknown. We discovered that a specific receptor in sensory neurons, c-Kit, is required to maintain the density of nerve endings in the skin. Furthermore, we found that a molecular target of c-Kit, Src family kinases (SFKs), is necessary for this role. Thus, c-Kit/SFK signaling regulates density and maintenance of sensory nerve endings in the skin and may have important roles in neural disease and regeneration.

[Antibacterial activity of copper salts against microorganisms isolated from chronic infected wounds]. / Comportamiento antibacteriano de partículas de cobre frente a microorganismos obtenidos de úlceras crónicas infectadas y su relación con la resistencia a antimicrobianos de uso común.

BACKGROUND: The antimicrobial activity of copper (Cu+2) is recognized and used as an antimicrobial agent. AIM: To evaluate the antimicrobial activity of copper against microorganisms obtained from chronic cutaneous wound infections. MATERIAL AND METHODS: Five chemical products that contained copper particles in their composition were tested (zeolite, silica, acetate, nitrate and nanoparticle of copper). The antimicrobial activity against antibiotic resistant strains usually isolated from chronic cutaneous wound infections was determined for two of the products with better performance in copper release. RESULTS: The minimal inhibitory and minimal bactericidal concentrations of copper acetate and nitrate were similar, fluctuating between 400-2,000 µg/ml. CONCLUSIONS: The studied copper salts show great potential to be used to control both gram positive and gram negative, antibiotic resistant bacteria isolated from wound infections.

Evaluation of the impact of the intensive exploitation of groundwater and the mega-drought based on the hydrochemical and isotopic composition of the waters of the Chacabuco-Polpaico basin in central Chile.

A hydrogeochemical and isotopic study has been carried out to understand the hydrogeological functioning of a small alluvial aquifer in central Chile in a context of mega-drought and intensive exploitation of its waters. Additionally, two mine tailings dams from porphyry copper mining are situated in the area. The prolonged mega-drought, which has lasted for over thirteen years, has resulted in a significant decrease in rainfall recharge and a drop of up to 50 m in piezometric levels, although no serious groundwater contamination problems have yet been detected, except for a rise in nitrate contents (ranging between 23 and 45 mg/L NO3) attributed to return irrigation. Groundwaters are calcium-bicarbonate and calcium-sodium-bicarbonate in composition. The values of δ18O and δ2H of the alluvial aquifer indicate fractionation by evaporation that would be explained by the recirculation of water that occurs in the agricultural areas of the basin, where the excess irrigation water that go back to the aquifer presents fractionation by evaporation. The δ34S and δ18O of dissolved sulfate point to pyrite oxidation, which could be related to the pyrite present in the copper porphyry and recognized in the Andes Cordillera. The 87Sr/86Sr isotopic values of the alluvial aquifer waters are close to the isotopic fingerprint of the volcanic rocks of the Abanico Formation. However, the water from the wells located further downstream in the basin and close to the tailing dams show δ34S and δ18O of dissolved sulfate and 87Sr/86Sr consistent with Miocene intrusive mineralogies of the copper porphyry type. The groundwater chemistry does not show water seepage from the tailings dam. Therefore, a minor contribution of minerals related to the intrusive rocks is proposed, which would originate from the movement of fine particles by the wind from the dams to the valley floor. The 14C activities indicate that groundwater is recent.

Recharge and residence times of groundwater in hyper arid areas: The confined aquifer of Calama, Loa River Basin, Atacama Desert, Chile.

Groundwater recharge in hyper arid areas often depends on surface water infiltration and diffuse recharge of highly evaporated precipitation only contribute under favorable conditions. This happens in the Calama basin two-aquifer system, in the Central Andean area of northern Chile. A conceptual model of the groundwater system and its relationship with the Loa River is defined. We focus on the confined aquifer of the Calama basin, combining hydrodynamic, hydrogeochemical and isotopic methods. Radiocarbon (14C) activity data of dissolved inorganic carbon (DIC), in conjunction with chemical data, are applied to evaluate groundwater residence time within the confined aquifer. The Loa River recharges the Calama basin aquifers in its northeastern part, with water that has chemical and isotopic characteristics inherited from the arid environment and volcanic rocks in its upper basin. In the central and northeastern part of the confined aquifer, minor variations in chloride concentration suggest that the deep aquifer is well confined. The δ18O and δ2H values in groundwater of the confined aquifer show an increasing isotopic fractionation from the recharge area (around -10‰ δ18O) to those in the discharge area (between -8.5‰ and -8‰) in the southwestern part of the aquifer. The 14C activity continuously decreases down flow from the recharge by the Loa River. Adjusted DIC radiocarbon ages indicate a groundwater travel time between 1500 and 4000 years in the confined aquifer of Calama. Despite the limitations and uncertainties of radiocarbon in DIC to estimate groundwater transit times for the confined aquifer and considering complementary chemical and isotopic constraints, the DIC 14C provides acceptable values. The approach may be applicable in other confined aquifers in hyper-arid climates in which the formation of aquifer systems linked to river damming by geological action took place. This information is needed for sound management of the scarce groundwater resources.

Toward Tailor-Made Biocide Materials Based on Poly(propylene)/Copper Nanoparticles.

A set of poly(propylene) composites containing different amounts of copper nanoparticles (CNP) were prepared by the melt mixed method and their antimicrobial behavior was quantitatively studied. The time needed to reduce the bacteria to 50% dropped to half with only 1 v/v % of CNP, compared to the polymer without CNP. After 4 h, this composite killed more than 99.9% of the bacteria. The biocide kinetics can be controlled by the nanofiller content; composites with CNP concentrations higher than 10 v/v % eliminated 99% of the bacteria in less than 2 h. X-ray photoelectron spectroscopy did not detect CNP at the surface, therefore the biocide behavior was attributed to copper in the bulk of the composite.

In situ antimicrobial behavior of materials with copper-based additives in a hospital environment.

Copper and its alloys are effective antimicrobial surface materials in the laboratory and in clinical trials. Copper has been used in the healthcare setting to reduce environmental contamination, and thus prevent healthcare-associated infections, complementing traditional protocols. The addition of copper nanoparticles to polymer/plastic matrices can also produce antimicrobial materials, as confirmed under laboratory conditions. However, there is a lack of studies validating the antimicrobial effects of these nanocomposite materials in clinical trials. To satisfy this issue, plastic waiting room chairs with embedded metal copper nanoparticles, and metal hospital IV pools coated with an organic paint with nanostructured zeolite/copper particles were produced and tested in a hospital environment. These prototypes were sampled once weekly for 10 weeks and the viable microorganisms were analysed and compared with the copper-free materials. In the waiting rooms, chairs with copper reduced by around 73% the total viable microorganisms present, showing activity regardless of the microorganism tested. Although there were only low levels of microorganisms in the IV pools installed in operating rooms because of rigorous hygiene protocols, samples with copper presented lower total viable microorganisms than unfilled materials. Some results did not have statistical significance because of the low load of microorganisms; however, during at least three weeks the IV pools with copper had reduced levels of microorganisms by a statistically significant 50%. These findings show for the first time the feasibility of utilizing the antimicrobial property of copper by adding nanosized fillers to other materials in a hospital environment.

Comportamiento antibacteriano de partículas de cobre frente a microorganismos obtenidos de úlceras crónicas infectadas y su relación con la resistencia a antimicrobianos de uso común / Antibacterial activity of copper salts against microorganisms isolated from chronic infected wounds

Background: The antimicrobial activity of copper (Cu+2) is recognized and used as an antimicrobial agent. Aim: To evaluate the antimicrobial activity of copper against microorganisms obtained from chronic cutaneous wound infections. Material and Methods: Five chemical products that contained copper particles in their composition were tested (zeolite, silica, acetate, nitrate and nanoparticle of copper). The antimicrobial activity against antibiotic resistant strains usually isolated from chronic cutaneous wound infections was determined for two of the products with better performance in copper release. Results: The minimal inhibitory and minimal bactericidal concentrations of copper acetate and nitrate were similar, fluctuating between 400-2,000 µg/ml. Conclusions: The studied copper salts show great potential to be used to control both gram positive and gram negative, antibiotic resistant bacteria isolated from wound infections.