Modulating anti-inflammatory and anticancer properties by designing a family of metal-complexes based on 5-nitropicolinic acid.

A new family of six complexes based on 5-nitropicolinic acid (5-npic) and transition metals has been obtained: [M(5-npic)2]n (MII = Mn (1) and Cd (2)), [Cu(5-npic)2]n (3), and [M(5-npic)2(H2O)2] (MII = Co (4), Ni (5), and Zn (6)), which display 1D, 2D, and mononuclear structures, respectively, thanks to different coordination modes of 5-npic. After their physicochemical characterization by single-crystal X-ray diffraction (SCXRD), elemental analyses (EA), and spectroscopic techniques, quantum chemical calculations using Time-Dependent Density Functional Theory (TD-DFT) were performed to further study the luminescence properties of compounds 2 and 6. The potential anticancer activity of all complexes was tested against three tumor cell lines, B16-F10, HT29, and HepG2, which are models widely used for studying melanoma, colon cancer, and liver cancer, respectively. The best results were found for compounds 2 and 4 against B16-F10 (IC50 = 26.94 and 45.10 µg mL-1, respectively). In addition, anti-inflammatory studies using RAW 264.7 cells exhibited promising activity for 2, 3, and 6 (IC50 NO = 5.38, 24.10, and 17.63 µg mL-1, respectively). This multidisciplinary study points to complex 2, based on CdII, as a promising anticancer and anti-inflammatory material.

A systematic comparison of deep learning methods for Gleason grading and scoring.

Prostate cancer is the second most frequent cancer in men worldwide after lung cancer. Its diagnosis is based on the identification of the Gleason score that evaluates the abnormality of cells in glands through the analysis of the different Gleason patterns within tissue samples. The recent advancements in computational pathology, a domain aiming at developing algorithms to automatically analyze digitized histopathology images, lead to a large variety and availability of datasets and algorithms for Gleason grading and scoring. However, there is no clear consensus on which methods are best suited for each problem in relation to the characteristics of data and labels. This paper provides a systematic comparison on nine datasets with state-of-the-art training approaches for deep neural networks (including fully-supervised learning, weakly-supervised learning, semi-supervised learning, Additive-MIL, Attention-Based MIL, Dual-Stream MIL, TransMIL and CLAM) applied to Gleason grading and scoring tasks. The nine datasets are collected from pathology institutes and openly accessible repositories. The results show that the best methods for Gleason grading and Gleason scoring tasks are fully supervised learning and CLAM, respectively, guiding researchers to the best practice to adopt depending on the task to solve and the labels that are available.

Comparative 3D genome analysis between neural retina and retinal pigment epithelium reveals differential cis-regulatory interactions at retinal disease loci.

BACKGROUND: Vision depends on the interplay between photoreceptor cells of the neural retina and the underlying retinal pigment epithelium (RPE). Most genes involved in inherited retinal diseases display specific spatiotemporal expression within these interconnected retinal components through the local recruitment of cis-regulatory elements (CREs) in 3D nuclear space. RESULTS: To understand the role of differential chromatin architecture in establishing tissue-specific expression at inherited retinal disease loci, we mapped genome-wide chromatin interactions using in situ Hi-C and H3K4me3 HiChIP on neural retina and RPE/choroid from human adult donor eyes. We observed chromatin looping between active promoters and 32,425 and 8060 candidate CREs in the neural retina and RPE/choroid, respectively. A comparative 3D genome analysis between these two retinal tissues revealed that 56% of 290 known inherited retinal disease genes were marked by differential chromatin interactions. One of these was ABCA4, which is implicated in the most common autosomal recessive inherited retinal disease. We zoomed in on retina- and RPE-specific cis-regulatory interactions at the ABCA4 locus using high-resolution UMI-4C. Integration with bulk and single-cell epigenomic datasets and in vivo enhancer assays in zebrafish revealed tissue-specific CREs interacting with ABCA4. CONCLUSIONS: Through comparative 3D genome mapping, based on genome-wide, promoter-centric, and locus-specific assays of human neural retina and RPE, we have shown that gene regulation at key inherited retinal disease loci is likely mediated by tissue-specific chromatin interactions. These findings do not only provide insight into tissue-specific regulatory landscapes at retinal disease loci, but also delineate the search space for non-coding genomic variation underlying unsolved inherited retinal diseases.

Seasonal occurrence and individual variability of bull sharks, Carcharhinus leucas, in a marine reserve of the southwestern Gulf of California.

Background: Studying how the bull sharks aggregate and how they can be driven by life history traits such as reproduction, prey availability, predator avoidance and social interaction in a National Park such as Cabo Pulmo, is key to understand and protect the species. Methods: The occurrence variability of 32 bull sharks tracked with passive acoustic telemetry were investigated via a hierarchical logistic regression model, with inference conducted in a Bayesian framework, comparing sex, and their response to temperature and chlorophyll. Results: Based on the fitted model, occurrence probability varied by sex and length. Juvenile females had the highest values, whereas adult males the lowest. A strong seasonality or day of the year was recorded, where sharks were generally absent during September-November. However, some sharks did not show the common pattern, being detected just for a short period. This is one of the first studies where the Bayesian framework is used to study passive acoustic telemetry proving the potential to be used in further studies.

Designing Antitrypanosomal and Antileishmanial BODIPY Derivatives: A Computational and In Vitro Assessment.

Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 µM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 µM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.

Function and expression of N-acetyltransferases 1 and 2 are altered in lymphocytes in type 2 diabetes and obesity.

The cytosolic enzymes N-Acetyl Transferases 1 and 2 (NATs) transfer an acetyl group from acetyl-CoA to a xenobiotic substrate. NATs are regulated at the genetic and epigenetic levels by deacetylase enzymes such as sirtuins. The enzymatic expression of NAT1, NAT2, and SIRT1 was evaluated by flow cytometry, as well as the enzymatic activity of NATs by cell culture and HPLC analysis. Six SNPs were determined through genotyping. T2D patients (n = 29) and healthy subjects (n = 25) with a median age of 57 and 50, respectively, were recruited. An increased enzyme expression and a diminished NAT2 enzymatic activity were found in cells of T2D patients compared to the control group, while NAT1 was negatively correlated with body fat percentage and BMI. In contrast, Sirtuin inhibition increased NAT2 activity, while Sirtuin agonism decreased its activity in both groups. The analysis of NAT2 SNPs showed a higher frequency of rapid acetylation haplotypes in T2D patients compared to the control group, possibly associated as a risk factor for diabetes. The enzymatic expression of CD3+NAT2+ cells was higher in the rapid acetylators group compared to the slow acetylators group. The levels and activity of NAT1 were associated with total cholesterol and triglycerides. Meanwhile, CD3+NAT2+ cells and NAT2 activity levels were associated with HbA1c and glucose levels. The results indicate that NAT2 could be involved in metabolic processes related to the development of T2D, due to its association with glucose levels, HbA1c, and the altered SIRT-NAT axis. NAT1 may be involved with dyslipidaemias in people who are overweight or obese.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Reversible S-nitrosylation of bZIP67 by peroxiredoxin IIE activity and nitro-fatty acids regulates the plant lipid profile.

Nitric oxide (NO) is a gasotransmitter required in a broad range of mechanisms controlling plant development and stress conditions. However, little is known about the specific role of this signaling molecule during lipid storage in the seeds. Here, we show that NO is accumulated in developing embryos and regulates the fatty acid profile through the stabilization of the basic/leucine zipper transcription factor bZIP67. NO and nitro-linolenic acid target and accumulate bZIP67 to induce the downstream expression of FAD3 desaturase, which is misregulated in a non-nitrosylable version of the protein. Moreover, the post-translational modification of bZIP67 is reversible by the trans-denitrosylation activity of peroxiredoxin IIE and defines a feedback mechanism for bZIP67 redox regulation. These findings provide a molecular framework to control the seed fatty acid profile caused by NO, and evidence of the in vivo functionality of nitro-fatty acids during plant developmental signaling.

miR-21, miR-221, miR-29 and miR-34 are distinguishable molecular features of a metabolically unhealthy phenotype in young adults.

Discrepancies between the measurement of body mass index (BMI) and metabolic health status have been described for the onset of metabolic diseases. Studying novel biomarkers, some of which are associated with metabolic syndrome, can help us to understand the differences between metabolic health (MetH) and BMI. A group of 1469 young adults with pre-specified anthropometric and blood biochemical parameters were selected. Of these, 80 subjects were included in the downstream analysis that considered their BMI and MetH parameters for selection as follows: norm weight metabolically healthy (MHNW) or metabolically unhealthy (MUNW); overweight/obese metabolically healthy (MHOW) or metabolically unhealthy (MUOW). Our results showed for the first time the differences when the MetH status and the BMI are considered as global MetH statures. First, all the evaluated miRNAs presented a higher expression in the metabolically unhealthy group than the metabolically healthy group. The higher levels of leptin, IL-1b, IL-8, IL-17A, miR-221, miR-21, and miR-29 are directly associated with metabolic unhealthy and OW/OB phenotypes (MUOW group). In contrast, high levels of miR34 were detected only in the MUNW group. We found differences in the SIRT1-PGC1α pathway with increased levels of SIRT1+ cells and diminished mRNA levels of PGCa in the metabolically unhealthy compared to metabolically healthy subjects. Our results demonstrate that even when metabolic diseases are not apparent in young adult populations, MetH and BMI have a distinguishable phenotype print that signals the potential to develop major metabolic diseases.

Citizen science and social innovation as citizen empowerment tools to address urban health challenges: The case of the urban health citizen laboratory in Barcelona, Spain.

Urban health faces significant challenges due to the rapid growth of cities and the concentration of population in urban settings that have a strong impact on people's health. The approach to characterize and address these challenges requires increased societal involvement and interdisciplinary solutions to ensure their effectiveness and democratic nature. With this purpose, it is necessary to explore methodologies for citizen participation that foster a critical understanding of the environment and promote their active role in generating scientific knowledge and change. This article describes the creation of a collaborative space for experimentation and learning that, through the intersection of citizen science and social innovation, aims to engage citizens in the research and diagnosis of their local environment, as well as in the design and implementation of local solutions, while raising awareness about the main challenges to urban health. Through a collaborative and participatory framework, the community identified relevant challenges to urban health they wanted to investigate, co-designed and developed the methodology for data collection and analysis, and ultimately, they devised, designed, and implemented innovative solutions based on the scientific evidence obtained. The framework and results of this project hold potential interest for the scientific community, facilities, institutions, and society by offering an innovative and participatory approach to addressing the present and future urban health challenges.

Quality of Recovery After Unplanned and Planned Cesarean Deliveries: A Prospective Observational Study Using the Obstetric Quality of Recovery-10 Tool.

BACKGROUND: There is a paucity of literature examining the differences between patient-reported outcome measures after planned and unplanned cesarean delivery using a validated quality of recovery tool. The Obstetric Quality of Recovery-10 (ObsQoR-10) scoring tool has been validated to quantify functional recovery after cesarean delivery. We aimed to use the ObsQoR-10 to compare the postoperative recovery characteristics of patients undergoing planned and unplanned cesarean deliveries. METHODS: We conducted a prospective single-center observational study. Patients undergoing planned and unplanned cesarean deliveries under neuraxial anesthesia were asked to complete the ObsQoR-10 questionnaire 24 hours, 48 hours, and 1 week postpartum. We collected information on total in-hospital postoperative opioid consumption and patients´ perception of readiness for discharge at 24 and 48 hours postpartum. Additionally, patient characteristics were collected to assess their correlation with our findings. RESULTS: We included 112 patients (56 in each group). No statistical differences in ObsQoR-10 scores at 24 hours, 48 hours, and 1 week postpartum were observed between the planned and unplanned cesarean deliveries. Additionally, there was no difference between the groups in patients' perception of readiness for hospital discharge at 24 and 48 hours and opioid consumption in the first 2 days after surgery. Most patients in both groups did not think they would be ready for discharge at 24 hours postpartum. Analysis of the individual components of ObsQoR-10 at 24 hours showed a difference in the responses assessing the severity of shivering (higher in unplanned cesarean deliveries) and the ability to look after personal hygiene (lower in unplanned cesarean deliveries). CONCLUSIONS: As assessed by the ObsQoR-10, no significant difference in the quality of recovery was observed between patients undergoing planned and unplanned cesarean delivery.

Genetic risk score for insulin resistance based on gene variants associated to amino acid metabolism in young adults.

Circulating concentration of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine are increased in subjects with insulin resistance, which could in part be attributed to the presence of single nucleotide polymorphisms (SNPs) within genes associated with amino acid metabolism. Thus, the aim of this work was to develop a Genetic Risk Score (GRS) for insulin resistance in young adults based on SNPs present in genes related to amino acid metabolism. We performed a cross-sectional study that included 452 subjects over 18 years of age. Anthropometric, clinical, and biochemical parameters were assessed including measurement of serum amino acids by high performance liquid chromatography. Eighteen SNPs were genotyped by allelic discrimination. Of these, ten were found to be in Hardy-Weinberg equilibrium, and only four were used to construct the GRS through multiple linear regression modeling. The GRS was calculated using the number of risk alleles of the SNPs in HGD, PRODH, DLD and SLC7A9 genes. Subjects with high GRS (≥ 0.836) had higher levels of glucose, insulin, homeostatic model assessment- insulin resistance (HOMA-IR), total cholesterol and triglycerides, and lower levels of arginine than subjects with low GRS (p < 0.05). The application of a GRS based on variants within genes associated to amino acid metabolism may be useful for the early identification of subjects at increased risk of insulin resistance.

Effect of heat stress during the dry period on milk yield and reproductive performance of Holstein cows.

This study aimed to determine the influence of heat stress during the dry period on milk yield and reproductive performance of Holstein cows in a hot environment. Breeding and milk production records of cows, as well as meteorological data between 2017 and 2020 from a commercial dairy herd (n = 12,102 lactations), were used to determine the relationship between climatic conditions during the dry period (average of the temperature-humidity index (THI) at the beginning, middle, and end of the dry period) and reproductive efficiency and milk yield traits. THI was divided into < 70 (no heat stress), 70-80 (moderate heat stress), and > 80 (severe heat stress). First-service pregnancy rate of cows decreased (P < 0.01) with increasing hyperthermia during the dry period (9.5, 7.3, and 3.4% for THI < 70, 70-80, and > 80, respectively). All-service pregnancy rate was highest (P < 0.01) for cows not undergoing heat stress during the dry period (60.2%) and lowest (42.6%) for cows with severe heat stress during the dry period. Cows not experiencing heat stress during the dry period required a mean ± SD of 5.6 ± 3.8 services per pregnancy compared with 6.5 ± 3.6 (P < 0.01) for cows subjected to THI > 80 during the dry period. Cows not suffering heat stress during the dry period produced more (P < 0.01) 305-day milk (10,926 ± 1206 kg) than cows subjected to moderate (10,799 ± 1254 kg) or severe (10,691 ± 1297 kg) heat stress during the dry period. Total milk yield did not differ (P > 0.10) between cows not undergoing heat stress (13,337 ± 3346 kg) and cows subjected to severe heat stress during the dry period (13,911 ± 4018 kg). It was concluded that environmental management of dry cows during hot months is warranted to maximize reproductive performance and milk yield in the following lactation.

Piceid Octanoate Protects Retinal Cells against Oxidative Damage by Regulating the Sirtuin 1/Poly-ADP-Ribose Polymerase 1 Axis In Vitro and in rd10 Mice.

Retinitis pigmentosa is a common cause of inherited blindness in adults, which in many cases is associated with an increase in the formation of reactive oxygen species (ROS) that induces DNA damage, triggering Poly-ADP-Ribose Polymerase 1 (PARP1) activation and leading to parthanatos-mediated cell death. Previous studies have shown that resveratrol (RSV) is a promising molecule that can mitigate PARP1 overactivity, but its low bioavailability is a limitation for medical use. This study examined the impact of a synthesized new acylated RSV prodrug, piceid octanoate (PIC-OCT), in the 661W cell line against H2O2 oxidative stress and in rd10 mice. PIC-OCT possesses a better ADME profile than RSV. In response to H2O2, 661W cells pretreated with PIC-OCT preserved cell viability in more than 38% of cells by significantly promoting SIRT1 nuclear translocation, preserving NAD+/NADH ratio, and suppressing intracellular ROS formation. These effects result from expressing antioxidant genes, maintaining mitochondrial function, reducing PARP1 nuclear expression, and preventing AIF nuclear translocation. In rd10 mice, PIC-OCT inhibited PAR-polymer formation, increased SIRT1 expression, significantly reduced TUNEL-positive cells in the retinal outer nuclear layer, preserved ERGs, and enhanced light chamber activity (all p values < 0.05). Our findings corroborate that PIC-OCT protects photoreceptors by modulating the SIRT1/PARP1 axis in models of retinal degeneration.

Guided Imagery for Symptom Management of Patients with Life-Limiting Illnesses: A Systematic Review of Randomized Controlled Trials.

Background: Patients with life-limiting illnesses receiving palliative care have a high symptom burden that can be challenging to manage. Guided imagery (GI), a complementary and integrative therapy in which patients are induced to picture mental images with sensory components, has proven in quasi-experimental studies to be effective as a complementary therapy for symptom management. Objective: To systematically review randomized controlled trials that report evidence of guided imagery for symptom management in patients with life-limiting illnesses. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed for this review and the search strategy was applied in Medline, CINHAL, and Web of Science. The quality of articles was evaluated using the Cochrane Collaboration's Risk-of-Bias Tool 2 (RoB 2). The results are presented using the Guidance on the Conduct of Narrative Synthesis in Systematic Reviews. Results: A total of 8822 studies were initially identified through the search strategy, but after applying exclusion criteria, 14 randomized controlled trials were included in this review. The quality assessment revealed that four studies had a high risk of bias, nine had some concerns, and one had a low risk of bias. Out of the 14 studies, 6 evaluated oncological diagnosis, while the remaining 8 focused on nononcological diagnoses across 6 different diseases. GI was found to be effective in managing symptoms in 10 out of the 14 studies. Regardless of the disease stage, patients who received guided imagery experienced relief from anxiety, depression, pain, sleep disturbances, and fatigue. Conclusion: GI therapy has shown promising results regarding symptom management in palliative care patients with life-limiting illnesses at different stages.

A yeast-based high-throughput screen identifies inhibitors of trypanosomatid HRG heme transporters with potent leishmanicidal and trypanocidal activity.

OBJECTIVES: New drugs are required to treat neglected diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi. An Achilles' heel of these parasites is their heme auxotrophy; they have an absolute dependence on scavenging this molecule from the host, and trypanosomatid HRG heme transporters (TrypHRG) play an important role in this process. As these proteins are essential for the parasites and have low similarity with their human orthologue, they have been proposed as attractive therapeutic targets. Here, we have developed two yeast-based assays that allow an inexpensive high-throughput screening of TrypHRG inhibitors within a cellular context. METHODS: We first assessed that Leishmania major, Leishmania donovani and T. brucei HRG proteins were heterologously expressed in the digestive vacuole membrane of a mutant heme auxotrophic yeast strain. Here, TrypHRG imports hemoglobinderived heme into the cytosol, allowing mutant yeast to grow in the presence of low hemoglobin concentrations and promoting the activity of hemeproteins such as catalase, which was used as a reporter of cytosolic heme levels. RESULTS: In the presence of a TrypHRG inhibitor, both catalase activity (test 1) and yeast growth (test 2) were diminished, being easily monitored. The assays were then tested on a pilot scale for HTS purposes using a collection of repurposing drugs and food antioxidants. Some of the TrypHRG inhibitors identified in yeast presented strong trypanocidal and leishmanicidal activity in the submicromolar range, proving the potential of this approach. CONCLUSIONS: Cumulatively, it was shown that the inhibition bioassays developed were robust and applicable to large-scale HTS.

A Late Pleistocene hominin footprint site on the North African coast of Morocco.

Footprints represent a relevant vestige providing direct information on the biology, locomotion, and behaviour of the individuals who left them. However, the spatiotemporal distribution of hominin footprints is heterogeneous, particularly in North Africa, where no footprint sites were known before the Holocene. This region is important in the evolution of hominins. It notably includes the earliest currently known Homo sapiens (Jebel Irhoud) and the oldest and richest African Middle Stone Age hominin sites. In this fragmented ichnological record, we report the discovery of 85 human footprints on a Late Pleistocene now indurated beach surface of about 2800 m2 at Larache (Northwest coast of Morocco). The wide range of sizes of the footprints suggests that several individuals from different age groups made the tracks while moving landward and seaward across a semi-dissipative bar-trough sandy beach foreshore. A geological investigation and an optically stimulated luminescence dating of a rock sample extracted from the tracksite places this hominin footprint surface at 90.3 ± 7.6 ka (MIS 5, Late Pleistocene). The Larache footprints are, therefore, the oldest attributed to Homo sapiens in Northern Africa and the Southern Mediterranean.

Cortistatin as a Novel Multimodal Therapy for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a complex disorder characterized by the impairment of the dopaminergic nigrostriatal system. PD has duplicated its global burden in the last few years, becoming the leading neurological disability worldwide. Therefore, there is an urgent need to develop innovative approaches that target multifactorial underlying causes to potentially prevent or limit disease progression. Accumulating evidence suggests that neuroinflammatory responses may play a pivotal role in the neurodegenerative processes that occur during the development of PD. Cortistatin is a neuropeptide that has shown potent anti-inflammatory and immunoregulatory effects in preclinical models of autoimmune and neuroinflammatory disorders. The goal of this study was to explore the therapeutic potential of cortistatin in a well-established preclinical mouse model of PD induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). We observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons in the substantia nigra and their connections to the striatum. Consequently, cortistatin administration improved the locomotor activity of animals intoxicated with MPTP. In addition, cortistatin diminished the presence and activation of glial cells in the affected brain regions of MPTP-treated mice, reduced the production of immune mediators, and promoted the expression of neurotrophic factors in the striatum. In an in vitro model of PD, treatment with cortistatin also demonstrated a reduction in the cell death of dopaminergic neurons that were exposed to the neurotoxin. Taken together, these findings suggest that cortistatin could emerge as a promising new therapeutic agent that combines anti-inflammatory and neuroprotective properties to regulate the progression of PD at multiple levels.

Bird species responses to rangeland management in relation to their traits: Rio de la Plata Grasslands as a case study.

Areas used for livestock production and dominated by native grasses represent a unique opportunity to reconcile biodiversity conservation and livestock production. However, limited knowledge of individual species' responses to rangeland management restricts our capacity to design grazing practices that favor endangered species and other priority birds. In this work, we applied Hierarchical Modelling of Species Communities (HMSC) to study individual species responses, as well as the influence of traits on such responses, to variables related to rangeland management using birds of the Rio de la Plata Grasslands as a case study. Based on presence-absence data collected in 454 paddocks across 46 ranches we inferred the response of 69 species considering imperfect detection. This degree of detail fills a major gap in rangeland management, as species-level responses can be used to achieve targeted conservation goals other than maximizing richness or abundance. We found that artificial pastures had an overall negative impact on many bird species, whereas the presence of tussocks had a positive effect, including all threatened species. Grassland specialists were in general sensitive to grass height and tended to respond positively to tussocks but negatively to tree cover. Controlling grass height via adjustments in stocking rate can be a useful tool to favor grassland specialists. To favor a wide range of bird species in ranches, a mosaic of short and tall native grasslands with patches of tussocks and trees is desirable. We also found that species-specific responses were modulated by their traits: small-sized birds responded positively to tussocks and tree cover while large species responded negatively to increasing grass height. Ground foragers preferred short grass while birds that scarcely use this stratum were not affected by grass height. Results on the influence of traits on bird responses are an important novelty in relation to previous work in rangelands and potentially increase our predicting capacity and model transferability across grassland regions.