Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research.

The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice.

The Proof-of-Concept of MBA121, a Tacrine-Ferulic Acid Hybrid, for Alzheimer's Disease Therapy.

Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer's disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine-ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good ß-amyloid (Aß) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aß1-40, Aß1-42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aß plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.

A report on SARS-CoV-2 first wave in Ecuador: drug consumption dynamics.

Introduction: The first COVID-19 wave in Ecuador started in March 2020 and extended until November. Several types of drugs have been proposed as a potential treatment during this period, and some affected people have self-medicated. Method: A retrospective study was conducted with 10,175 individuals who underwent RT-PCR tests for SARS-CoV-2 from July to November 2020. We compared the number of positive and negative cases in Ecuador with symptoms and drug consumption. The Chi-square test of independence compared clinical and demographic data and PCR test results. Odds ratios analyzed drug consumption dynamics. Results: Of 10,175 cases, 570 were positive for COVID-19, while 9,605 were negative. In positive cases, there was no association between the RT-PCR result and sex, age, or comorbidities. When considering demographic data, Cotopaxi and Napo had the highest rates of positive cases (25.7% and 18.8%, respectively). Manabí, Santa Elena, and Guayas regions had fewer than 10% positive cases. The Drug consumption dynamic analysis showed that negative COVID-19 cases presented higher drug consumption than positive cases. In both groups, the most consumed medication was acetaminophen. Acetaminophen and Antihistamines had higher odds of consumption in positive PCR cases than in negative. Symptoms like fever and cough were more related to positive RT-PCR results. Conclusion: The first COVID-19 wave in Ecuador has affected the provinces differently. At a national level, the consumption of drugs has been highly associated with self-medication.

Preclinical examination of early-onset thalamic-cortical seizures after hemispheric stroke.

OBJECTIVE: Ischemic stroke is one of the main causes of death and disability worldwide and currently has limited treatment options. Electroencephalography (EEG) signals are significantly affected in stroke patients during the acute stage. In this study, we preclinically characterized the brain electrical rhythms and seizure activity during the hyperacute and late acute phases in a hemispheric stroke model with no reperfusion. METHODS: EEG signals and seizures were studied in a model of hemispheric infarction induced by permanent occlusion of the middle cerebral artery (pMCAO), which mimics the clinical condition of stroke patients with permanent ischemia. Electrical brain activity was also examined using a photothrombotic (PT) stroke model. In the PT model, we induced a similar (PT group-1) or smaller (PT group-2) cortical lesion than in the pMCAO model. For all models, we used a nonconsanguineous mouse strain that mimics human diversity and genetic variation. RESULTS: The pMCAO hemispheric stroke model exhibited thalamic-origin nonconvulsive seizures during the hyperacute stage that propagated to the thalamus and cortex. The seizures were also accompanied by progressive slowing of the EEG signal during the acute phase, with elevated delta/theta, delta/alpha, and delta/beta ratios. Cortical seizures were also confirmed in the PT stroke model of similar lesions as in the pMCAO model, but not in the PT model of smaller injuries. SIGNIFICANCE: In the clinically relevant pMCAO model, poststroke seizures and EEG abnormalities were inferred from recordings of the contralateral hemisphere (noninfarcted hemisphere), emphasizing the reciprocity of interhemispheric connections and that injuries affecting one hemisphere had consequences for the other. Our results recapitulate many of the EEG signal hallmarks seen in stroke patients, thereby validating this specific mouse model for the examination of the mechanistic aspects of brain function and for the exploration of the reversion or suppression of EEG abnormalities in response to neuroprotective and anti-epileptic therapies.

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 µmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

Hydrochemistry and stable isotopes revealed focused and diffuse recharge processes in the Sonora River basin, Mexico.

A hydro-geochemical characterization was conducted in the northern part of the Sonora River basin, covering an area of 9400 km2. Equipotential lines indicated that groundwater circulation coincided with the surface water flow direction. Based on the groundwater temperature measured (on average ∼21 °C), only one spring exhibited thermalism (51 °C). Electrical conductivity (160-1750 µS/cm), chloride and nitrate concentrations (>10 and >45 mg/L) imply highly ionized water and anthropogenic pollution. In the river network, δ18O values revealed a clear modern meteoric origin. Focused recharge occurred mainly from the riverbeds during the rainy season. During the dry season, diffuse recharge was characterized by complex return flows from irrigation, urban, agricultural, mining, and livestock. Drilled wells (>50 m) exhibited a strong meteoric origin from higher elevations during the rainy season with minimal hydrochemical anomalies. Our results contribute to the knowledge of mountain-front and mountain-block recharge processes in a semi-arid and human-altered landscape in northern Mexico, historically characterized by limited hydrogeological data.

Nitrate isotopes (δ15N, δ18O) in precipitation: best practices from an international coordinated research project.

Stable isotope ratios of nitrogen and oxygen (15N/14N and 18O/16O) of nitrate (NO3-) are excellent tracers for developing systematic understanding of sources, conversions, and deposition of reactive atmospheric nitrogen (Nr) in the environment. Despite recent analytical advances, standardized sampling of NO3-) isotopes in precipitation is still lacking. To advance atmospheric studies on Nr species, we propose best-practice guidelines for accurate and precise sampling and analysis of NO3- isotopes in precipitation based on the experience obtained from an international research project coordinated by the International Atomic Energy Agency (IAEA). The precipitation sampling and preservation strategies yielded a good agreement between the NO3- concentrations measured at the laboratories of 16 countries and at the IAEA. Compared to conventional methods (e.g., bacterial denitrification), we confirmed the accurate performance of the lower cost Ti(III) reduction method for isotope analyses (15N and 18O) of NO3- in precipitation samples. These isotopic data depict different origins and oxidation pathways of inorganic nitrogen. This work emphasized the capability of NO3- isotopes to assess the origin and atmospheric oxidation of Nr and outlined a pathway to improve laboratory capability and expertise at a global scale. The incorporation of other isotopes like 17O in Nr is recommended in future studies.

Neuroprotective and antioxidant properties of new quinolylnitrones in in vitro and in vivo cerebral ischemia models.

Cerebral ischemia is a condition affecting an increasing number of people worldwide, and the main cause of disability. Current research focuses on the search for neuroprotective drugs for its treatment, based on the molecular targets involved in the ischemic cascade. Nitrones are potent antioxidant molecules that can reduce oxidative stress. Here we report the neuroprotective properties and the antioxidant power of the six new quinolylnitrones (QNs) 1-6 for their potential application in stroke therapy. QNs 1-4 are 2-chloro-8-hydroxy-substituted QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C3, whereas QN5 and QN6 are 8-hydroxy QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C2, respectively. In vitro neuroprotection studies using QNs 1-6 in an oxygen-glucose-deprivation model of cerebral ischemia, in human neuroblastoma cell cultures, indicate that all QNs have promising neuroprotective, anti-necrotic, anti-apoptotic, and anti-oxidant properties against experimental ischemia-reperfusion in neuronal cultures. QN6 stands out as the most balanced nitrone out of all tested QNs, as it strongly prevents decreased neuronal metabolic activity (EC50 = 3.97 ± 0.78 µM), as well as necrotic (EC50 = 3.79 ± 0.83 µM) and apoptotic cell death (EC50 = 3.99 ± 0.21 µM). QN6 showed high capacity to decrease superoxide production (EC50 = 3.94 ± 0.76 µM), similar to its parent molecule α-phenyl-tert-butyl nitrone (PBN) and the well-known anti-oxidant molecule N-acetyl-L-cysteine (NAC). Thus, QN6 demonstrated the highest antioxidant power out of the other tested QNs. Finally, in vivo treatment with QN6 in an experimental permanent stroke model elicited a significant reduction (75.21 ± 5.31%) of the volume size of brain lesion. Overall, QN6 is a potential agent for the therapy of cerebral ischemia that should be further investigated.

Trophic ecology of juvenile bull sharks (Carcharhinus leucas) in the Coyote estuary, Costa Rica.

Bull shark (Carcharhinus leucas) is a near-threatened elasmobranch species capable of moving between the fresh and salty waters of tropical and subtropical coastal areas, for which we still lack important ecological information. During their first years of life, bull sharks use estuarine systems as nursery areas, making them highly susceptible to environmental and anthropogenic pressures. We studied the trophic ecology of juveniles found in the Coyote estuary, a potential nursery area in Costa Rica, to understand the potential impact of further bull shark declines and gain knowledge that could aid in their conservation. We analysed the trophic ecology of juvenile bull sharks [81-103 cm total length (TL)] in the Coyote estuary, Costa Rica, using stable isotopes of δ15 N and δ13 C. Since one problem using this technique in juveniles is the confounding effect of the maternal signature, we sampled different tissues (muscle and plasma), verified the status of the shark's umbilical scar and identified the size at which the isotope signature is a result of the animal's current diet. The isotopic values of the muscle tissue reflected the maternal isotopic signature. In contrast, plasma values reflected the diet of juvenile bull sharks >95 cm TL and with a closed umbilical scar. Juvenile bull sharks fed primarily on teleost fishes of the order Anguilliformes and Siluriformes, and have a high trophic position (≥4.0) in the Coyote estuary. Our findings suggest that this estuary is an important feeding site for juvenile bull sharks of the Pacific of Costa Rica. Thus, the protection of essential habitats such as the Coyote estuary will benefit not only bull shark conservation, but also the conservation of an array of fish species that also use this habitat as a rookery, many of which are of commercial interest.

Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations.

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.

Conteo de carga viral en pacientes con VIH/SIDA usuarios de terapias alternativas o complementarias / Viral load count in patients with HIV/AIDS users of alternative and/or complementary therapies

Introducción: una alternativa para mitigar los efectos del virus de inmunodeficiencia humana (VIH) es la medicina complementaria, alternativa o integrativa (MCAI); sin embargo, esta puede tener una influencia negativa en los pacientes con VIH. Objetivo: estimar la relación entre la carga viral y el uso de MCAI en pacientes con VIH/SIDA. Metodología: estudio analítico con 232 pacientes de la clínica de VIH/SIDA de una unidad médica de segundo nivel de atención en Cancún, México. Previo consentimiento informado, a cada paciente se le aplicó un cuestionario para identificar el uso de la MCAI y simultáneamente se obtuvo el conteo de carga viral y el CD4 del expediente electrónico. Resultados: el 47.8% utilizaron herbolaria como tratamiento alternativo. No se encontró diferencia estadística entre la utilización de herbolaria y su conteo de carga viral (p > 0.646). La terapia cuerpo-mente, los suplementos vitamínicos, la homeopatía y la acupuntura se usaron del 5 al 24.6%, sin diferencia estadística (p > 0.05) entre los grupos. Por el contrario, el uso de sesiones de manipulación del cuerpo mostró diferencia en relación con quienes no las utilizaban (p < 0.05). Conclusiones: es importante que el profesional de la salud identifique los efectos adversos o benéficos de las terapias alternativas y complementarias, con la finalidad de orientar a sus pacientes y no afectar su tratamiento antirretroviral y, en consecuencia, su conteo de carga viral.

Introduction: An alternative to mitigate the effects of human immunodeficiency virus (HIV) is the complementary and alternative medicine (CAM); however, this could have a negative influence in patients with HIV. Objective: To estimate the relationship between viral load and the use of CAM in patients with HIV/AIDS. Method: Analytical study with 232 patients from the HIV/AIDS Clinic of a second-level healthcare unit in Cancun, Mexico. With prior informed consent, a questionnaire was administered to each patient to identify the use of CAM, and, simultaneously, the viral load and CD4 counts were obtained from their electronic file. Results: 47.8% used herbal medicine as an alternative treatment. No statistical difference was found between the use of herbal products and their viral load (p > 0.646). Body-mind therapy, vitamin supplements, homeopathy and acupuncture were used from 5 to 24.6% without statistical difference (p > 0.05) among groups. However, the use of massage therapy showed a difference in relation to those who did not use it (p < 0.05). Conclusions: It is important that health professionals identify the adverse or beneficial effects of alternative and complementary therapies, so that they can guide their patients and not affect their antiretroviral treatment and, consequently, their viral load.

Isotopic composition and major ion concentrations of national and international bottled waters in Costa Rica.

Global bottled water consumption has largely increased (14.35 billion gallons in 2020) [1], [2], [3], [4], [5] during the last decade since consumers are demanding healthier and safer forms of rehydration. Bottled water sources are normally labeled as mountainous and pristine mineral springs (fed by rainfall and snow/glacier melting processes), deep groundwater wells or industrial purified water. The advent of numerous international and national-based bottled water brands has simultaneously raised a worldwide awareness related to the water source and chemical content traceability [6]. Here, we present the first database of stable isotope compositions and reported chemical concentrations from imported and national-based bottled waters in Costa Rica. In total, 45 bottled waters produced in Costa Rica and 31 imported from USA, Europe, Oceania, and other countries of Central America were analyzed for δ18O, δ2H, and d-excess. Chemical compositions were obtained from available bottle labels. National-based bottle waters ranged from -2.47‰ to -10.65‰ in δ18O and from -10.4‰ to -78.0‰ in δ2H, while d-excess varied from +4.2‰ up to +17.0‰. International bottle waters ranged between -2.21‰ and -11.03‰ in δ18O and from -11.3‰ up to -76.0‰ in δ2H, while d-excess varied from +5.0‰ up to +19.1‰. In Costa Rica, only 19% of the brands reported chemical parameters such as Na+, K+, Ca+2, Mg+2, F-, Cl-, NO3 -, SO4 -2, CO3 -2, SiO2, dry residue, and pH; whereas 27% of the international products reported similar parameters. The absence of specific geographic coordinates or water source origin limited a spatial analysis to validate bottled water isotope compositions versus available isoscapes in Costa Rica [7]. This database highlights the potential and relevance of the use of water stable isotope compositions to improve the traceability of bottled water sources and the urgent need of more robust legislation in order to provide detailed information (i.e., water source, chemical composition, purification processes) to the final consumers.

Stable isotopic characterization of nitrate wet deposition in the tropical urban atmosphere of Costa Rica.

Increasing energy consumption and food production worldwide results in anthropogenic emissions of reactive nitrogen into the atmosphere. To date, however, little information is available on tropical urban environments where inorganic nitrogen is vastly transported and deposited through precipitation on terrestrial and aquatic ecosystems. To fill this gap, we present compositions of water stable isotopes in precipitation and atmospheric nitrate (δ18O-H2O, δ2H-H2O, δ15N-NO3-, and δ18O-NO3-) collected daily between August 2018 and November 2019 in a tropical urban atmosphere of central Costa Rica. Rainfall generation processes (convective and stratiform rainfall fractions) were identified using stable isotopes in precipitation coupled with air mass back trajectory analysis. A Bayesian isotope mixing model using δ15N-NO3- compositions and corrected for potential 15N fractionation effects revealed the contribution of lightning (25.9 ± 7.1%), biomass burning (21.8 ± 6.6%), gasoline (19.1 ± 6.4%), diesel (18.4 ± 6.0%), and soil biogenic emissions (15.0 ± 2.6%) to nitrate wet deposition. δ18O-NO3- values reflect the oxidation of NOx sources via the ·OH + RO2 pathways. These findings provide necessary baseline information about the combination of water and nitrogen stable isotopes with atmospheric chemistry and hydrometeorological techniques to better understand wet deposition processes and to characterize the origin and magnitude of inorganic nitrogen loadings in tropical regions.

Stable isotopes reveal groundwater to river connectivity in a mesoscale subtropical watershed.

The Corumbataí River basin (São Paulo, Brazil) has a critical situation regarding water availability due to the intensive use to support agriculture and urbanization, requiring scientific information to face water demand. The aim of this study is to present a hydrological characterization based on the analysis of seasonal isotope variations (rainfall, groundwater, and surface water) and hydrometric data. Results indicate that baseflow contribution varies from 50 % to 70 % of the total flow, and water isotopic composition denotes a seasonal regime marked by the mixing of surface and groundwater in the wet period and groundwater discharge during the dry season. The results presented indicated the strong seasonal connection between atmospheric inputs and water movement across the basin, which poses an urgent need to diversify monitoring methods and create feasible regional and political regulations to control the effects on basin water resilience in the face of climate change and growing demand.

Hydrological dataset of a sub-humid continental plain basin (Buenos Aires, Argentina).

The Chaco-Pampean Plain (Argentina) is the strongest economic region and the most inhabited in the country, comprising approximately 66% of the country's population (26,500 million) [1]. In this region, surface slopes are very low (<0.1%) and due to the current climatological features, floods and droughts alternate over time. Salinity and alkalinity of water and soil increase towards the flattest sector of the basin, as well as the contents of arsenic and fluoride, which restrict their human use. Worldwide, population growth and global warming, in addition to political decisions, are leading to abrupt land use changes. Under this premise, identifying and quantifying the hydrological processes that control water quantity and its chemical quality become an imperative task [2]. This data article provides a long-term hydrological dataset from a sector of the Chaco-Pampean Plain, the Del Azul creek basin. Hydrological data such as flow rates and piezometric levels, and physical-chemical (i.e., major and minor solutes, and trace elements) and isotopic (δ18O, δ2H; and d-excess) data from rainwater, surface (creek and wetland) and groundwater (at two depths) are available. Rainwater samples are derived from three precipitation collectors installed at different altitudes (monitoring period: 2010-2019; n = 57). Surface water samples were collected at three sampling sites located along the Del Azul Creek and six wetlands (monitoring period: 2018-2019; n = 12). Groundwater samples were collected from 17 piezometers with depths ranging between 3 and 10 m, and from 12 piezometers of 30 m depth, all located throughout the entire basin (monitoring period: 2018-2019; n = 115). Sampling campaigns were performed during the austral dry (summer) and wet (spring) seasons. This dataset provides useful information to understand a) how water moves from recharge to discharge areas, b) how water acquires salinity, and c) how particular solutes of concern, such as arsenic and fluoride, are distributed in space and time across in an extensive plain.

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models.

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1'Z)-1,1'-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC50 = 1.24 ± 0.39 µM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke.

Isotope composition of carbon dioxide and methane in a tropical urban atmosphere.

This work presents a weekly carbon isotope composition analysis (June 2017-January 2018) of carbon dioxide (CO2) and methane (CH4) in a tropical urban atmosphere (Central Valley, Costa Rica). δ13C values of CO2 and CH4 ranged from -12.2 to -5.9 ‰, and from -51.6 to -46.3 ‰, respectively. Mixing ratios of CO2 and CH4 varied from 384.2 to 528.5 ppmv, and from 1.860 to 2.613 ppmv, respectively. δ13C spatial variation and mixing ratios of CO2 and CH4 were influenced by the atmospheric stability and air circulation patterns in the metropolitan area. Low δ13C values and large mixing ratios were observed in the southwestern area of the valley during the rainiest period (September-November). Preliminary linear relationships between reciprocal CO2 mixing ratios and δ13C values indicate that CO2 emissions in the Central Valley are probably related to respiration processes and fossil fuel combustion, although CO2 enriched in 13C from volcanic degassing was also detected. Under stable atmospheric conditions, CH4 data seems to reflect the influence of emissions near the sampling sites. These preliminary results based on the carbon isotope technique demonstrate potential for carrying out atmospheric studies at tropical urban locations with different terrain characteristics and atmospheric mixing conditions.

From mountains to cities: a novel isotope hydrological assessment of a tropical water distribution system.

Water use by anthropogenic activities in the face of climate change invokes a better understanding of headwater sources and lowland urban water allocations. Here, we constrained a Bayesian mixing model with stable isotope data (2018-2019) in rainfall (N = 704), spring water (N = 96), and surface water (N = 94) with seasonal isotope sampling (wet and dry seasons) of an urban aqueduct (N = 215) in the Central Valley of Costa Rica. Low δ 18O rainfall compositions corresponded to the western boundary of the study area, whereas high values were reported to the northeastern limit, reflecting the influence of moisture transport from the Caribbean domain coupled with strong orographic effects over the Pacific slope. The latter is well-depicted in the relative rainfall contributions (west versus east) in two headwater systems: (a) spring (68.7 ± 3.4 %, west domain) and (b) stream (55.8 ± 3.9 %, east domain). The aqueduct exhibited a spatial predominance of spring water and surface water during a normal wet season (78.7 %), whereas deep groundwater and spring water were fundamental sources for the aqueduct in the dry season (69.4 %). Our tracer-based methodology can help improve aqueduct management practices in changing climate, including optimal water allocation and reduced evaporative losses in the dry season.

Biomaterials to Neuroprotect the Stroke Brain: A Large Opportunity for Narrow Time Windows.

Ischemic stroke represents one of the most prevalent pathologies in humans and is a leading cause of death and disability. Anti-thrombolytic therapy with tissue plasminogen activator (t-PA) and surgical thrombectomy are the primary treatments to recanalize occluded vessels and normalize the blood flow in ischemic and peri-ischemic regions. A large majority of stroke patients are refractory to treatment or are not eligible due to the narrow time window of therapeutic efficacy. In recent decades, we have significantly increased our knowledge of the molecular and cellular mechanisms that inexorably lead to progressive damage in infarcted and peri-lesional brain areas. As a result, promising neuroprotective targets have been identified and exploited in several stroke models. However, these considerable advances have been unsuccessful in clinical contexts. This lack of clinical translatability and the emerging use of biomaterials in different biomedical disciplines have contributed to developing a new class of biomaterial-based systems for the better control of drug delivery in cerebral disorders. These systems are based on specific polymer formulations structured in nanoparticles and hydrogels that can be administered through different routes and, in general, bring the concentrations of drugs to therapeutic levels for prolonged times. In this review, we first provide the general context of the molecular and cellular mechanisms impaired by cerebral ischemia, highlighting the role of excitotoxicity, inflammation, oxidative stress, and depolarization waves as the main pathways and targets to promote neuroprotection avoiding neuronal dysfunction. In the second part, we discuss the versatile role played by distinct biomaterials and formats to support the sustained administration of particular compounds to neuroprotect the cerebral tissue at risk of damage.