Phylogenetic patterns of rarity in a regional species pool of tropical trees

Species rarity is often defined in terms of: local abundance, geographic range size and habitat breadth. It is thought that each of these rarity axes has distinct effects on extinction risk. Thus, understanding phylogenetic patterns of these three axes is of considerable interest because they provide insights into the extent to which rarity is phylogenetically conserved and, in turn, how extinction risk is distributed across phylogenies. Here I examine the extent to which the three axes of rarity show phylogenetic signal (the tendency of related species to resemble each other more than species drawn at random from the same phylogenetic tree), and phylogenetic conservatism (stronger phylogenetic clustering than expected from a Brownian motion model of evolution) across a regional pool of woody plants in the Madidi region of the tropical Andes of Bolivia. I measured local abundance, geographic range size, and habitat breadth for 806 species in 101 families occurring in a set of 48 1-ha tree plots, and for 1,739 species in 141 families occurring in a set of 442 0.1-ha tree plots. I used three approaches to describe phylogenetic patterns of rarity: 1) hierarchical variance partitioning across taxonomic levels, 2) Blomberg’s K statistic, and 3) disparity through time. I compared observed patterns described by these three approaches to patterns expected from a tip randomization null model that randomly assigns values of the axes of rarity to species. In addition, I compared observed patterns described by Blomberg’s K statistic and disparity through time to patterns expected from a Brownian motion model of evolution. The hierarchical variance partitioning analysis showed that the three axes of rarity display phylogenetic signal: species belonging to the same genus tended to be more similar than expected from the tip randomization null model. At deeper phylogenetic levels the axes of rarity exhibited little or no phylogenetic signal and did not display phylogenetic conservatism. These findings suggest that, given the currently changing environment of the Tropical Andes, extinction risk could be phylogenetically clustered because certain genera may contain an unusually high number of threatened species

Regional and Historical Influences on the Spatial Distribution of Neotropical Trees

At small spatial scales, the composition of species assemblages depends on local conditions and the dispersal of propagules from surrounding regions. In turn, processes taking place at broad temporal and spatial scales, including changes in regional physiography and climate, shape the species pools in these source regions. This dissertation seeks to understand the effects of regional and historical processes on the spatial distribution of Neotropical tree species. In chapter 1, I investigate regional enrichment of local species assemblages testing two hypothesis: i) local species assemblages are enriched by unfiltered species pools, which are composed of all species that can disperse to a locality, regardless of the suitability of the local environment; and ii) local species assemblages are enriched by filtered species pools, which are composed of all species that can disperse to a locality from similar environments. I found that unfiltered species pools enrich local species assemblages. In chapter 2, I explore two legacies of the Great American Biotic Interchange: i) a major contrast in plant family composition between lowland and montane tree floras, and ii) lowland floras form a nested gradient of species diversity from the Darien to the Tehuantepec region, whereas montane floras form a nested gradient in the opposite direction. I found marked differences in the representation of families between lowland and montane floras. However, lowland and montane floras do not exhibit the proposed nested gradients of diversity. In chapter 3, I focus on the effects of the Last Glacial Maximum on the distribution of palms across Neotropical lowland humid-to-superhumid forest. I explore the hypothesis of postglacial migration lags, which states that due to the effects of past glaciations species do not occupy all climatically suitable areas. I found that palm species had little opportunity to experience postglacial migration lags but, nonetheless, seem to exhibit such lags. This thesis illustrates how consideration of processes operating at different spatial scales in particular historical contexts contributes to our understanding of current patterns and dynamics of species distributions, providing a foundation for efforts directed at the conservation of biodiversity

Safe and Sound: Safe Space in Drama Therapy - A Heuristic Inquiry

This qualitative research paper uses a heuristic model of investigation (Moustakas, 2011) to focus on the process of a drama therapy student exploring the concept of safe space and its implications for potential therapeutic transformation. Within the therapeutic context, a safe space is defined as a free-from-harm environment between therapist and client where the latter can explore his/her inner conflicts with freedom; without fear of being judged or hurt in any way. In drama therapy, the safe space lies in the relationship between client and therapist, which is developed through play. The curiosity on the notion of safe space emerges from the student’s context of training as a drama therapist and her own encounter with the subject as a foreigner in Canada. This paper aims to tell the experience of the researcher examining in depth the idea of safe space through the literature and visiting several locations, in which she used art to respond to her living process

Novel phthalazin-1(2H)-one derivatives displaying a dithiocarbamate moiety as potential anticancer agents

Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6–8, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6–8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a–b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.Universidade de Vigo, Xunta de Galicia | Ref. ED431C 2022/20Universidade de Vigo, Xunta de Galicia | Ref. ED431G 2019/0

Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs

Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid receptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugsThis work was financially supported by the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: ED431B 2020/43), Centro Singular de Investigación de Galicia accreditation 2019–2022 (ED431G 2019/03), Ministerio de Ciencia e Innovación (PID2020-113430RB-I00) and the European Regional Development Fund (ERDF)S

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo e cacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H2O2), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activityFinancial support was received from FONDECYT (Research Grant N◦ 1161816) and FONDEQUIP program CONICYT EQM 160042, Czech Science Foundation (19-09086S) and Palacky University (IGA_PrF_2019_013) and Xunta de Galicia (ED431C 2018/21) and European Regional Development Fund (Project ENOCH, N◦ CZ.02.1.01/0.0/0.0/16_019/0000868)S

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

Abstract: The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I2 receptors (I2‐IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I2‐IR by developing structurally new molecules, in particular, a family of bicyclic α‐iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age‐related cognitive decline and the other for Alzheimer's disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME‐Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de‐risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson's disease (PD). B06 rescued the human dopaminergic cell line SH‐SY5Y from death after treatment with 6‐hydroxydopamine (6‐OHDA) and showed a crucial anti‐inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I2‐IR as a fresh approach for the therapy of ND

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depressionThis research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016), Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundação para a Ciência e Tecnologia (PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021). Financial support from the Xunta de Galicia (Centro de investigación de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund - ERDF), is also gratefully acknowledged. M.I.R.-F. acknowledges the economic support from the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grant PID2021-122650OB-I00) and from CSIC (PIE-202080E118)S

Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU : A multicentre retrospective cohort study

It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9-16] vs 14 [IQR 10-19]) and the organ failure assessment score (median SOFA 4 [3-6] vs 5 [3-7], p <0·001). The need of invasive mechanical ventilation was high (76·1%) during the whole study period. However, a significant increase in the use of high flow nasal cannula (48·7% vs 18·2%, p <0·001) was found in the second/third waves compared with the first surge. Significant changes on treatments prescribed were also observed, highlighting the remarkable increase on the use of corticosteroids to up to 95.9% in the second/third waves. A significant reduction on the use of tocilizumab was found during the study (first wave 28·9% vs second/third waves 6·2%, p <0·001), and a negligible administration of lopinavir/ritonavir, hydroxychloroquine, and interferon during the second/third waves compared with the first wave. Overall ICU mortality was 30·7% (n = 1166), without significant differences between study periods (first wave 31·7% vs second/third waves 28·8%, p = 0·06). No significant differences were found in ICU mortality between waves according to age subsets except for the subgroup of 61-75 years of age, in whom a reduced unadjusted ICU mortality was observed in the second/third waves (first 38·7% vs second/third 34·0%, p = 0·048). Non-survivors were older, with higher severity of the disease, had more comorbidities, and developed more complications. After adjusting for confounding factors through a multivariable analysis, no significant association was found between the COVID-19 waves and mortality (OR 0·81, 95% CI 0·64-1·03; p = 0·09). Ventilator-associated pneumonia rate increased significantly during the second/third waves and it was independently associated with ICU mortality (OR 1·48, 95% CI 1·19-1·85, p <0·001). Nevertheless, a significant reduction both in the ICU and hospital length of stay in survivors was observed during the second/third waves. Despite substantial changes on supportive care and management, we did not find significant improvement on case-fatality rates among critical COVID-19 pneumonia patients. Ricardo Barri Casanovas Foundation (RBCF2020) and SEMICYU