Are Rattus rattus fleas invasive? Evaluation of flea communities in invasive and native rodents in Chile.

Co-invasion, characterized by the simultaneous introduction of hosts and parasites with the latter establishing themselves in native hosts, is a phenomenon of ecological concern. Rattus rattus, a notorious invasive species, has driven the extinction and displacement of numerous avian and mammalian species and serves as a key vector for diseases affecting both humans and wildlife. Among the parasites hosted by R. rattus are fleas, which exhibit obligate parasitic behaviour, a generalist nature and high prevalence, increasing the likelihood of flea invasion. Simultaneously, invasive species can serve as hosts for native parasites, leading to potential amplification or dilution of parasite populations in the environment. In Chile, R. rattus has been present since the 17th century because of the arrival of the Spanish colonizers through the ports and has spread throughout urban, rural and wild Chilean territories. This study aims to evaluate whether co-invasion of native fleas of invasive rats occurs on native rodents in Chile and to determine whether black rats have acquired flea native to Chile during their invasion. For this, we captured 1132 rodents from 26 localities (20° S-53° S). Rattus rattus was found coexisting with 11 native rodent species and two species of introduced rodents. Among the native rodents, Abrothrix olivacea and Oligoryzomys longicaudatus exhibited more extensive sympatry with R. rattus. We identified 14 flea species associated with R. rattus, of which only three were native to rats: Xenopsylla cheopis, Leptopsylla segnis and Nosopsyllus fasciatus. These three species presented a higher parasite load in black rats compared to native fleas. Leptopsylla segnis and N. fasciatus were also found associated with native rodent species that cohabit with R. rattus. The remaining species associated with R. rattus were fleas of native rodents, although they were less abundant compared to those associated with native rodents, except for Neotyphloceras pardinasi and Sphinctopsylla ares. Although there has been evidence of flea transmission from rats to native species, the prevalence and abundance were relatively low. Therefore, it cannot be definitively concluded that these fleas have established themselves in native rodent populations, and hence, they cannot be classified as invasive fleas. This study underscores R. rattus' adaptability to diverse environmental and geographical conditions in Chile, including its capacity to acquire fleas from native rodents. This aspect has critical implications for public health, potentially facilitating the spread of pathogens across various habitats where these rats are found.

Occupational Therapy Practice in Schools: National Survey in Spain.

AIMS: Interdisciplinary collaboration between health and education professionals is one of the principles of inclusive education. This study aimed to describe the practices and service delivery by pediatric occupational therapists (OTs) in schools in Spain. METHODS: Data came from a convenience sample of pediatric OTs recruited through Spanish professional colleges and associations for a web-based survey, mixed-method research study. Thirty-five respondents were excluded because they didn't meet the eligibility criteria. Ninety-two responses were obtained for data analysis. Twenty-nine OTs (31.5%) work in schools (school-OTs), and sixty-three participants (68.5%) don't work there but collaborate with schools (non-school OTs). RESULTS: Participants support students with and without a medical diagnosis. Services provided by OTs external to the educational system are mainly funded by families or only partially covered. Findings show that most participants use standardized assessments and apply several intervention approaches. They believe there are barriers to the collaboration and implementation of occupational therapy services in schools. CONCLUSIONS: This preliminary study shows a need for changes in Spain's State and Regional Education legislation and provides recommendations to improve school service delivery. Pediatric OTs are encouraged to reflect on and identify opportunities for changes to enhance school-based occupational therapy practice in Spain.

DNMR measurements of an asymmetric odd liquid crystal dimer: determination of the intramolecular angle and the degree of order of the two rigid cores.

In this work, we present a Deuteron Nuclear Magnetic Resonance (DNMR) study of the non-symmetric odd liquid crystal dimer α-(4-cyanobiphenyl-4'-yloxy)-ω-(1-pyrenimine-benzylidene-4'-oxy) heptane (CBO7O.Py), formed by a pro-mesogenic cyanobiphenyl unit and a bulky pyrene-containing unit, linked via alkoxy flexible chain. We have synthesized two partially deuterated samples: one with the deuterium atoms in the cyanobiphenyl moiety (dCBO7O.Py) and the other one with the deuterium atoms in the pyrenimine-benzylidene unit (CBO7O.dPy). We have performed angular distribution analysis in the SmA glassy state, obtaining the degree of order of both rigid cores and an estimation of the internal molecular angle between both structures. With the results from the angular study, we have been able to determine the degree of order of both rigid units in either the N phase and the SmA phase, far enough from the glass transition. Both rigid cores have the same degree of order close to the nematic-isotropic phase transition, but as the compound is cooled down, the degree of order of the cyanobiphenyl moiety is clearly higher than that of the pyrene-containing unit. The critical behaviour of the order parameter of the pyrene-containing moiety is consistent with the fact that, for CBO7O.Py, the N-I phase transition is tricritical, which seems to indicate that the uniaxial order parameter of the dimer is dominated by the degree of order of the pyrene-containing core.

PRGF Membrane with Tailored Optical Properties Preserves the Cytoprotective Effect of Plasma Rich in Growth Factors: In Vitro Model of Retinal Pigment Epithelial Cells.

The present study evaluates the ability of a novel plasma rich in growth factors (PRGF) membrane with improved optical properties to reduce oxidative stress in retinal pigment epithelial cells (ARPE-19 cells) exposed to blue light. PRGF was obtained from three healthy donors and divided into four main groups: (i) PRGF membrane (M-PRGF), (ii) PRGF supernatant (S-PRGF), (iii) platelet-poor plasma (PPP) membrane diluted 50% with S-PRGF (M-PPP 50%), and (iv) M-PPP 50% supernatant (S-PPP 50%). ARPE-19 cells were exposed to blue light and then incubated with the different PRGF-derived formulations or control for 24 and 48 h under blue light exposure. Mitochondrial and cell viability, reactive oxygen species (ROS) production, and heme oxygenase-1 (HO-1) and ZO-1 expression were evaluated. Mitochondrial viability and cell survival were significantly increased after treatment with the different PRGF-derived formulations. ROS synthesis and HO-1 expression were significantly reduced after cell treatment with any of the PRGF-derived formulations. Furthermore, the different PRGF-derived formulations significantly increased ZO-1 expression in ARPE-19 exposed to blue light. The new PRGF membrane with improved optical properties and its supernatant (M-PPP 50% and S-PPP 50%) protected and reversed blue light-induced oxidative stress in ARPE-19 cells at levels like those of a natural PRGF membrane and its supernatant.

Novel Vector of Scrub Typhus in Sub-Antarctic Chile: Evidence From Human Exposure.

The exposure of a research team to chigger mites in southern Chile allowed the first identification of a trombiculid species as vector and reservoir of scrub typhus outside the tsutsugamushi triangle, providing unique insights into the ecology and transmission of this recently discovered rickettsial infection in South America.

PAR4 activation involves extracellular loop 3 and transmembrane residue Thr153.

Protease-activated receptor 4 (PAR4) mediates sustained thrombin signaling in platelets and is required for a stable thrombus. PAR4 is activated by proteolysis of the N terminus to expose a tethered ligand. The structural basis for PAR4 activation and the location of its ligand binding site (LBS) are unknown. Using hydrogen/deuterium exchange (H/D exchange), computational modeling, and signaling studies, we determined the molecular mechanism for tethered ligand-mediated PAR4 activation. H/D exchange identified that the LBS is composed of transmembrane 3 (TM3) domain and TM7. Unbiased computational modeling further predicted an interaction between Gly48 from the tethered ligand and Thr153 from the LBS. Mutating Thr153 significantly decreased PAR4 signaling. H/D exchange and modeling also showed that extracellular loop 3 (ECL3) serves as a gatekeeper for the interaction between the tethered ligand and LBS. A naturally occurring sequence variant (P310L, rs2227376) and 2 experimental mutations (S311A and P312L) determined that the rigidity conferred by prolines in ECL3 are essential for PAR4 activation. Finally, we examined the role of the polymorphism at position 310 in venous thromboembolism (VTE) using the International Network Against Venous Thrombosis (INVENT) consortium multi-ancestry genome-wide association study (GWAS) meta-analysis. Individuals with the PAR4 Leu310 allele had a 15% reduction in relative risk for VTE (odds ratio, 0.85; 95% confidence interval, 0.77-0.94) compared with the Pro310 allele. These data are consistent with our H/D exchange, molecular modeling, and signaling studies. In conclusion, we have uncovered the structural basis for PAR4 activation and identified a previously unrecognized role for PAR4 in VTE.

Foraging networks and social tolerance in a cooperatively breeding primate (Callithrix jacchus).

Within-group competition over food resources can be a major cost of social living. In the wild, foragers are confronted with social (e.g. hierarchical rank) and ecological (e.g. food availability and distribution) challenges that affect their foraging decisions and feeding success. Exhibiting prosocial behaviours, such as tolerance at feeding sites, can benefit group members by developing affiliative social relationships, enhancing access to resources and maximizing fitness. We examined social tolerance at feeding sites in Callithrix jacchus, a cooperatively breeding primate species. We investigated the set of social (rank, age and sex) and ecological (food availability) factors that influence the structure and dynamics of within-group foraging association networks. We designed and conducted an experimental field study of four wild groups of common marmosets in which we controlled food distribution (concentrated or scattered) and productivity (high, medium or low food rewards). Then, we used social network analyses to assess the number and strength of foraging associations among group members, their effects on individual food consumption, and whether recent experiences with conspecifics during foraging affected subsequent associations. Overall, common marmoset foraging association networks were cohesive, as group members jointly occupied feeding sites. The number and strength of associations varied depending on the ecological context. Associations were stronger during conditions in which food was concentrated at a single site. Individuals obtained greater access to food resources when sharing a feeding site with conspecifics, but once a food item was obtained, the forager moved to a nearby tree and consumed it away from others. Additionally, the strength of previous foraging associations and subsequent levels of social tolerance at feeding sites were positively related, a relationship compatible with the ability of memorizing associations over time and recalling the information in future decision-making. In sum, marmosets adjusted their partner choices and the strength of foraging associations in response to food availability. They exhibited increased social tolerance at feeding sites during conditions in which opportunities for contest competition were expected to be greatest. These cooperative breeding primates appear to mutually benefit by maintaining cohesive and strong affiliative relationships, and by increasing opportunities for coordinated behaviour and offspring survival.

A competição por recursos alimentares dentro do grupo pode ser um grande custo da vida social. Na natureza, os forrageadores são confrontados com desafios sociais (e.g. posição hierárquica) e ecológicos (e.g. disponibilidade e distribuição de alimentos) que afetam suas decisões de forrageio e seu sucesso alimentar. Exibir comportamentos pró-sociais, como tolerância em sítios de alimentação, pode beneficiar os membros do grupo, desenvolvendo relações sociais afiliativas, melhorando o acesso aos recursos e maximizando sua aptidão evolutiva. Examinamos a tolerância social de um primata com reprodução cooperativa (Callithrix jacchus) em sítios de alimentação. Investigamos a influência de um conjunto de fatores sociais (hierarquia, idade, sexo) e ecológicos (disponibilidade de alimento) na estrutura e dinâmica das redes de associação de forrageio dentro do grupo social. Planejamos e conduzimos um experimento de campo com quatro grupos de saguis-comuns de vida livre, no qual controlamos a distribuição (concentrada e dispersa) e a produtividade de alimento (altas, médias ou baixas recompensas). Usamos análise de redes sociais para avaliar o número e a força das associações de forrageio entre os membros do grupo, seu efeito no consumo individual de alimento, e se experiências recentes de forrageio entre coespecíficos afetam associações subsequentes. Em geral, as redes de associação de forrageio dos saguis foram coesas e os membros de cada grupo ocuparam sítios de alimentação em conjunto. O número e a força das associações variaram dependendo do contexto ecológico. As associações foram mais fortes durante as condições em que o alimento se encontrava concentrado em um sítio. Os indivíduos obtiveram maior acesso aos recursos quando compartilharam o sítio de alimentação com coespecíficos, e uma vez que o item alimentar era obtido, o forrageador o consumia em uma árvore próxima, longe dos outros. Além disso, a força das associações recentes e os níveis subsequentes de tolerância social em sítios de alimentação foram positivamente relacionados, compatível com a capacidade de memorizar associações ao longo do tempo e relembrá-las em tomadas de decisão futuras. Em conclusão, os saguis ajustaram suas escolhas de parceiros e a força das associações de forrageio em resposta à disponibilidade de alimento. Eles exibiram uma maior tolerância social em sítios de alimentação durante as condições em que se esperava que as oportunidades de competição direta fossem maiores. Estes primatas com reprodução cooperativa parecem se beneficiar mutuamente ao manterem relações afiliativas coesas e fortes, as quais aumentam as oportunidades para comportamentos coordenados e a sobrevivência da prole.

Self-medication in nonhuman primates: A systematic evaluation of the possible function of the use of medicinal plants.

Animal self-medication is thought to provide an adaptive advantage, as species would actively respond to a disease state or homeostatic imbalances. In wild nonhuman primates, it is challenging to differentiate plant use as part of the diet or as medication, especially because self-medication can be preventive or therapeutic. Here, we aimed to compile the available potential evidence on primate self-medication modes, investigating which proposed requirements are fulfilled for each plant species reported to date. We systematically reviewed the scientific literature on plant use for potential self-medication in wild nonhuman primates. To construct the extensive database, we extracted data on the primate species, study area, plant/plant's part used, the requirement(s) met for demonstrating self-medication modes, and self-medicative behavioral patterns. We also updated available information on plant's biological compounds and/or physical characteristics, pharmacological properties, and ethnomedical uses. We identified 575 plant species (135 families), used by 25 primate species (9 families). Plants were used by Old World monkeys (46.5%, n = 268 plant species), followed by apes (41%, n = 235), New World monkeys (13.4%, n = 77), and prosimians (1%, n = 6). We found three general types of self-medicative behaviors: ingestion (including, but not limited to, leaf-swallowing, seed-swallowing, and bitter pith chewing), topical (fur-rubbing), and nest fumigation. Plant uses were associated with antiparasitic, antibacterial, antimalarial, anti-inflammatory, insect repellent, among other properties. Self-medication is widespread in nonhuman primate species across Central and South America, Africa, Madagascar, and Asia. Long-term field research efforts and studies integrating different research sites and topics are urgent to advance our knowledge into the evolution of plant selection, medical traditions, and to bring insights into potentially novel medicinal plants and bioactive compounds to treat emergent or established primate and human diseases.

Temperature and exudativory as drivers of the marmoset (Callithrix spp.) daily activity period.

Primates are affected by fluctuations in ambient temperatures, mostly through thermoregulatory costs and changes in the availability of food. In the present study, we investigate whether the ambient temperature and proxies of food availability affect the activity period of marmosets (Callithrix spp.). We predicted that: (i) at colder sites, marmosets would spend more time at sleeping sites; (ii) midday resting bouts would be longer at hotter sites; (iii) the onset/cessation of activity and resting behavior at midday would be more closely related to temperature than food availability, and (iv) highly exudativorous groups would have higher total levels of resting. We compiled data on the onset and cessation of activity and the time spent resting at midday from seven marmoset studies from sites with a wide range of temperatures. We used generalized linear mixed models to verify the relationship between the dependent variables (lag between dawn and the onset of activities, lag between cessation of activities and dusk, and proportion of resting during midday) and the minimum and maximum temperatures at the respective study sites, together with proxies of food availability (exudativory rates, the amount of habitat available per individual, and net primary productivity) using each sample month as a sampling unit and the identity of the study as a categorical random factor. At colder sites and during colder months, the marmosets left sleeping trees later in the morning and ceased their activities earlier, while at hotter sites and during hotter months, they spent more time resting during midday. More exudativorous groups become active later in the morning, but also ceased their activities later. The abundance of food did not affect the timing of activities. We provide evidence that both low and high temperatures affect marmosets' activities, and that their activity period appears to be more influenced by the thermal environment than food availability.

Enhanced nitrogen and carbon removal in natural seawater by electrochemical enrichment in a bioelectrochemical reactor.

Municipal and industrial wastewater discharges in coastal and marine environments are of major concern due to their high carbon and nitrogen loads and the resulted phenomenon of eutrophication. Bioelectrochemical reactors (BERs) for simultaneous nitrogen and carbon removal have gained attention owing to their cost efficiency and versatility, as well as the possibility of electrochemical enrich specific groups. This study presented a scalable two-chamber BERs using graphite granules as electrode material. BERs were inoculated and operated for 37 days using natural seawater with high concentrations of ammonium and acetate. The BERs demonstrated a maximum current density of 0.9 A m-3 and removal rates of 7.5 mg NH4+-N L-1 d-1 and 99.5 mg L-1 d-1 for total organic carbon (TOC). Removals observed for NH4+-N and TOC were 96.2% and 68.7%, respectively. The results of nutrient removal (i.e., ammonium, nitrate, nitrite and TOC) and microbial characterization (i.e., next-generation sequencing of the 16S rRNA gene and fluorescence in situ hybridization) showed that BERs operated with a poised cathode at -260 mV (vs. Ag/AgCl) significantly enriched nitrifying microorganisms in the anode and denitrifying microorganisms and planctomycetes in the cathode. Interestingly, the electrochemical enrichment did not increase the total number of microorganisms in the formed biofilms but controlled their composition. Thus, this work shows the first successful attempt to electrochemically enrich marine nitrifying and denitrifying microorganisms and presents a technique to accelerate the start-up process of BERs to remove dissolved inorganic nitrogen and total organic carbon from seawater.

Apparent inhibition of induced plant volatiles by a fungal pathogen prevents airborne communication between potato plants.

Plant communication in response to insect herbivory has been increasingly studied, whereas that involving pathogen attack has received much less attention. We tested for communication between potato (Solanum tuberosum) plants in response to leaf infection by the fungal pathogen Sclerotinia sclerotiorum. To this end, we measured the total amount and composition of volatile organic compounds (VOCs) produced by control and infected emitter plants, as well as tested for induced resistance of receiver plants exposed to VOCs from emitters. We further tested for changes in the expression of defensive genes due to pathogen infection. Fungal infection did not significantly affect the total amount or composition of VOCs produced by emitter plants. Correspondingly, we found no evidence of higher resistance to the pathogen in receiver plants exposed to VOCs from infected emitters relative to control emitters. Molecular analyses indicated that pathogen infection drove a down-regulation of genes coding for VOC precursors, potentially explaining the absence of pathogen effects on VOC emissions and thus of communication. Overall, these results indicate no evidence of airborne communication between potato plants in response to fungal infection and point at pathogen inhibition of VOC emissions as a likely explanation for this result.

Fermented food consumption in wild nonhuman primates and its ecological drivers.

OBJECTIVES: Although fermented food use is ubiquitous in humans, the ecological and evolutionary factors contributing to its emergence are unclear. Here we investigated the ecological contexts surrounding the consumption of fruits in the late stages of fermentation by wild primates to provide insight into its adaptive function. We hypothesized that climate, socioecological traits, and habitat patch size would influence the occurrence of this behavior due to effects on the environmental prevalence of late-stage fermented foods, the ability of primates to detect them, and potential nutritional benefits. MATERIALS AND METHODS: We compiled data from field studies lasting at least 9 months to describe the contexts in which primates were observed consuming fruits in the late stages of fermentation. Using generalized linear mixed-effects models, we assessed the effects of 18 predictor variables on the occurrence of fermented food use in primates. RESULTS: Late-stage fermented foods were consumed by a wide taxonomic breadth of primates. However, they generally made up 0.01%-3% of the annual diet and were limited to a subset of fruit species, many of which are reported to have mechanical and chemical defenses against herbivores when not fermented. Additionally, late-stage fermented food consumption was best predicted by climate and habitat patch size. It was more likely to occur in larger habitat patches with lower annual mean rainfall and higher annual mean maximum temperatures. DISCUSSION: We posit that primates capitalize on the natural fermentation of some fruits as part of a nutritional strategy to maximize periods of fruit exploitation and/or access a wider range of plant species. We speculate that these factors contributed to the evolutionary emergence of the human propensity for fermented foods.

Expression and Purification of Protease-Activated Receptor 4 (PAR4) and Analysis with Histidine Hydrogen-Deuterium Exchange.

Protease-activated receptors (PARs) are G-protein-coupled receptors that are activated by proteolysis of the N-terminus, which exposes a tethered ligand that interacts with the receptor. Numerous studies have focused on the signaling pathways mediated by PARs. However, the structural basis for initiation of these pathways is unknown. Here, we describe a strategy for the expression and purification of PAR4. This is the first PAR family member to be isolated without stabilizing modifications for biophysical studies. We monitored PAR4 activation with histidine hydrogen-deuterium exchange. PAR4 has nine histidines that are spaced throughout the protein, allowing a global view of solvent accessible and nonaccessible regions. Peptides containing each of the nine His residues were used to determine the t1/2 for each His residue in apo or thrombin-activated PAR4. The thrombin-cleaved PAR4 exhibited a 2-fold increase (p > 0.01) in t1/2 values observed for four histidine residues (His180, His229, His240, and His380), demonstrating that these regions have decreased solvent accessibility upon thrombin treatment. In agreement, thrombin-cleaved PAR4 also was resistant to thermolysin digestion. In contrast, the rate of thermolysin proteolysis following stimulation with the PAR4 activation peptide was the same as that of unstimulated PAR4. Further analysis showed the C-terminus is protected in thrombin-activated PAR4 compared to uncleaved or agonist peptide-treated PAR4. The studies described here are the first to examine the tethered ligand activation mechanism for a PAR family member biophysically and shed light on the overall conformational changes that follow activation of PARs by a protease.

Ferroelectric-Ferroelastic Phase Transition in a Nematic Liquid Crystal.

Ferroelectric ordering in liquids is a fundamental question of physics. Here, we show that ferroelectric ordering of the molecules causes the formation of recently reported splay nematic liquid-crystalline phase. As shown by dielectric spectroscopy, the transition between the uniaxial and the splay nematic phase has the characteristics of a ferroelectric phase transition, which drives an orientational ferroelastic transition via flexoelectric coupling. The polarity of the splay phase was proven by second harmonic generation imaging, which additionally allowed for determination of the splay modulation period to be of the order of 5-10 microns, also confirmed by polarized optical microscopy. The observations can be quantitatively described by a Landau-de Gennes type of macroscopic theory.

Plasma rich in growth factors reduces blue light-induced oxidative damage on retinal pigment epithelial cells and restores their homeostasis by modulating vascular endothelial growth factor and pigment epithelium-derived factor expression.

BACKGROUND: This study analysed the effectiveness of plasma rich in growth factors (PRGF) in reducing the oxidative stress induced by blue light exposition on retinal pigment epithelial (RPE) cells. METHODS: Blood from six healthy donors was collected to obtain the PRGF. Retinal pigment epithelium (ARPE-19) cells were exposed to blue light. Then, cells were incubated with PRGF or with control for 24 and 48 hours maintaining exposure to blue light. The cytoprotective effect of PRGF on ARPE cells was evaluated by measuring the cell viability, the reactive oxygen species (ROS) production and the expression of different proteins such as heme oxygenase 1 (HO-1), catalase (CAT), superoxide dismutase (SOD-1), apoptosis-inducing factor (AIF), pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF). RESULTS: The cell viability increased significantly at 24 and 48 hours after PRGF treatment compared to the control group. ROS synthesis was significantly reduced in PRGF-treated cells with respect to control. Furthermore, the levels of HO-1, SOD-1 and AIF were significantly reduced after PRGF treatment at both times of treatment. However, CAT levels were only significantly reduced after PRGF treatment at 48 hours. The high expression of VEGF by RPE cells exposed to blue light was only counterbalanced in the PRGF group by increasing the expression of PEDF in comparison to the control group. CONCLUSION: The present results show that PRGF treatment reduces the cytotoxic effects induced in RPE cells exposed to an oxidative stress environment. Furthermore, PRGF treatment preserves the mitochondrial activity and cell viability of RPE cells subjected to an oxidative stress.

Plasma Rich in Growth Factors Enhances Cell Survival after in Situ Retinal Degeneration.

PURPOSE: The purpose of this study was to examine the effect of plasma rich in growth factors (PRGFs) under blue light conditions in an in vivo model of retinal degeneration. METHODS: Male Wistar rats were exposed to dark/blue light conditions for 9 days. On day 7, right eyes were injected with saline and left eyes with PRGF. Electroretinography (ERG) and intraocular pressure (IoP) measurements were performed before and after the experiment. After sacrifice, retinal samples were collected. Hematoxylin and eosin staining was performed to analyze the structure of retinal sections. Immunofluorescence for brain-specific homeobox/POU domain protein 3A (Brn3a), choline acetyltransferase (ChAT), rhodopsin, heme oxygenase-1 (HO-1), and glial fibrillary acidic protein (GFAP) was performed to study the retinal conditions. RESULTS: Retinal signaling measured by ERG was reduced by blue light and recovered with PRGF; however, IoP measurements did not show significant differences among treatments. Blue light reduced the expression for Brn3a, ChAT, and rhodopsin. Treatment with PRGF showed a recovery in their expressions. HO-1 and GFAP results showed that blue light increased their expression but the use of PRGF reduced the effect of light. CONCLUSIONS: Blue light causes retinal degeneration. PRGF mitigated the injury, restoring the functionality of these cells and maintaining the tissue integrity.

Antioxidant Role of PRGF on RPE Cells after Blue Light Insult as a Therapy for Neurodegenerative Diseases.

Oxidative stress has a strong impact on the development of retinal diseases such as age-related macular degeneration (AMD). Plasma rich in growth factors (PRGF) is a novel therapeutic approach in ophthalmological pathologies. The aim of this study was to analyze the antioxidant effect of PRGF in retinal epithelial cells (EPR) in in vitro and ex vivo retinal phototoxicity models. In vitro analyses were performed on ARPE19 human cell line. Viability and mitochondrial status were assessed in order to test the primary effects of PRGF. GSH level, and protein and gene expression of the main antioxidant pathway (Keap1, Nrf2, GCL, HO-1, and NQO1) were also studied. Ex vivo analyses were performed on rat RPE, and HO-1 and Nrf2 gene and protein expression were evaluated. The results show that PRGF reduces light insult by stimulating the cell response against oxidative damage and modulates the antioxidant pathway. We conclude that PRGF's protective effect could prove useful as a new therapy for treating neurodegenerative disorders such as AMD.

Morphometric variation of Androlaelaps fahrenholzi (Mesostigmata: Laelapidae) associated with three Sigmodontinae (Rodentia: Cricetidae) from the north of Chile.

Androlaelaps fahrenholzi is a mite with a large distribution and associated with a wide range of hosts. To assess morphometric variation of A. fahrenholzi associated with different host species (Phyllotis xanthopygus and Akodon albiventer, both from Putre, Chile) and localities (Las Chinchillas National Reserve, Fray Jorge National Park, and Llanos de Challe National Park, all in Chile and all from the host Phyllotis darwini), 41 morphological characters of each specimen were measured, and principal component analysis and discriminant analysis were used. Both analyses showed two groups separated for species of rodents. Mites associated with P. xanthopygus are smaller than those of A. albiventer. The analysis by location indicates two groups: group 1 comprises all mites collected from Fray Jorge National Park and Las Chinchillas National Reserve, and group 2 comprises only mites from Llanos de Challe National Park. These results indicate that A. fahrenholzi population can vary between hosts and geographical areas. Molecular analysis would be necessary to validate these results and determine whether they are subspecies or different species.

Inhibition of the histone demethylase, KDM5B, directly induces re-expression of tumor suppressor protein HEXIM1 in cancer cells.

BACKGROUND: The tumor suppressor actions of hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) in the breast, prostate, melanomas, and AML have been reported by our group and others. Increased HEXIM1 expression caused differentiation and inhibited proliferation and metastasis of cancer cells. Historically, HEXIM1 has been experimentally induced with the hybrid polar compound HMBA, but HMBA is a poor clinical candidate due to lack of a known target, poor pharmacological properties, and unfavorable ADMETox characteristics. Thus, HEXIM1 induction is an intriguing therapeutic approach to cancer treatment, but requires better chemical tools than HMBA. METHODS: We identified and verified KDM5B as a target of HEXIM1 inducers using a chemical proteomics approach, biotin-NeutrAvidin pull-down assays, surface plasmon resonance, and molecular docking. The regulation of HEXIM1 by KDM5B and KDM5B inhibitors was assessed using chromatin immunoprecipitation assays, RT-PCR, western blotting, and depletion of KDM5B with shRNAs. The regulation of breast cancer cell phenotype by KDM5B inhibitors was assessed using western blots, differentiation assays, proliferation assays, and a mouse model of breast cancer metastasis. The relative role of HEXIM1 in the action of KDM5B inhibitors was determined by depleting HEXIM1 using shRNAs followed by western blots, differentiation assays, and proliferation assays. RESULTS: We have identified a highly druggable target, KDM5B, which is inhibited by small molecule inducers of HEXIM1. RNAi knockdown of KDM5B induced HEXIM1 expression, thus validating the specific negative regulation of tumor suppressor HEXIM1 by the H3K4me3/2 demethylase KDM5B. Known inhibitors of KDM5B were also able to induce HEXIM1 expression, inhibit cell proliferation, induce differentiation, potentiate sensitivity to cancer chemotherapy, and inhibit breast tumor metastasis. CONCLUSION: HMBA and 4a1 induce HEXIM1 expression by inhibiting KDM5B. Upregulation of HEXIM1 expression levels plays a critical role in the inhibition of proliferation of breast cancer cells using KDM5B inhibitors. Based on the novel molecular scaffolds that we identified which more potently induced HEXIM1 expression and data in support that KDM5B is a target of these compounds, we have opened up new lead discovery and optimization directions.

Exosome-mimetic nanoplatforms for targeted cancer drug delivery.

BACKGROUND: Lack of effective tumor-specific delivery systems remains an unmet clinical challenge for successful translation of innovative therapies, such as, therapeutic oligonucleotides. In the past decade, exosomes have been suggested to be ideal drug delivery systems with application in a broad range of pathologies including cancer, due to their organotropic properties. Tumor-derived exosomes, having tumor-homing properties, can efficiently reach cancer cells and therefore behave as carriers for improved drug delivery to the primary tumor and metastases. However, due to their complex composition, and still undefined biological functions, safety concerns arise hampering their translation to the clinics. RESULTS: We propose here the development of exosome-mimetic nanosystems (EMNs) that simulate natural tumor-derived exosomes with respect to their structure and functionality, but with a controlled composition, for the targeted delivery of therapeutic oligonucleotides to lung adenocarcinoma cells (microRNA-145 mimics). Making use of the well-known liposome technology, EMNs can be engineered, loaded with the therapeutic compounds, and tailored with specific proteins (integrin α6ß4) providing them organotropic properties. EMNs show great similarities to natural exosomes with respect to their physicochemical properties, drug loading capacity, and ability to interact with the cancer target cells in vitro and in vivo, but are easier to manufacture, can be produced at high yields, and are safer by definition. CONCLUSIONS: We have designed a multifunctional nanoplatform mimicking exosomes, EMNs, and proved their potential to reach cancer cells with a similar efficient that tumor-derived exosomes but providing important advantages in terms of production methodology and regulations. Additionally, EMNs are highly versatile systems that can be tunable for a broader range of applications.