Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Astrocyte structural heterogeneity in the mouse hippocampus.

Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic transmission, the sum of which results in behavior modulation. These interactions are possible due to their complex morphology, composed of a tree-like structure of processes to cover defined territories ramifying in a mesh-like system of fine leaflets unresolved by conventional optic microscopy. While recent reports devoted more attention to leaflets and their dynamic interactions with synapses, our knowledge about the tree-like "backbone" structure in physiological conditions is incomplete. Recent transcriptomic studies described astrocyte molecular diversity, suggesting structural heterogeneity in regions such as the hippocampus, which is crucial for cognitive and emotional behaviors. In this study, we carried out the structural analysis of astrocytes across the hippocampal subfields of Cornu Ammonis area 1 (CA1) and dentate gyrus in the dorsoventral axis. We found that astrocytes display heterogeneity across the hippocampal subfields, which is conserved along the dorsoventral axis. We further found that astrocytes appear to contribute in an exocytosis-dependent manner to a signaling loop that maintains the backbone structure. These findings reveal astrocyte heterogeneity in the hippocampus, which appears to follow layer-specific cues and depend on the neuro-glial environment.

A retrospective study in tumour characteristics and clinical outcomes of overweight and obese women with breast cancer.

INTRODUCTION: Obesity and breast cancer are two major pathologies closely associated with increasing incidence and mortality rates, especially amongst women. The association between both diseases have been thoroughly discussed but much is still to uncover. AIM: The aim of this study is to analyse tumour characteristics and clinical outcomes of overweight and obese women to disclosure potential associations and better understand the impact of obesity in breast cancer. MATERIALS AND METHODS: Clinicopathological information of 2246 women were extracted from the institutional database of comprehensive cancer centre in Portugal diagnosed between 2012 and 2016. Women were stratified according to body mass index as normal, overweight, and obese. Patients' demographic information and tumour features (age, family history, topographic localization, laterality, histological type, and receptor status) were taken as independent variables and overall survival, tumour stage, differentiation grade and bilaterality were considered clinical outcomes. RESULTS: The main results reveal that overweight and obesity are predominantly associated with worse outcomes in breast cancer patients. Obese patients present larger (p-value: 0.002; OR 1.422; 95% CI 1.134-1.783) and more poorly differentiated tumours (p-value: 0.002; OR 1.480; 95% CI 1.154-1.898) and tend to have lower overall survival although without statistical significance (p-value: 0.117; OR 1.309; 95% CI 0.934-1.833). Overweighted women are more likely to have bilateral breast cancer (p-value: 0.017; OR 3.076; 95% CI 1.225-7.722) than obese women. The results also reveal that overweight women present less distant metastasis (p-value: 0.024; OR 0.525; 95%CI 0.299-0.920). Topographic localization and laterality did not achieve statistical significance.

Clinical and functional correlates of parkinsonism in a population-based sample of individuals aged 75 + : the Pietà study.

BACKGROUND: Parkinsonism is strongly associated with ageing, and many studies have suggested that parkinsonian signs may affect up to half of older adults and is associated with a wide range of adverse health outcomes. We compared clinical and functional characteristics of oldest-old community-dwelling individuals with parkinsonism (parkinsonian group [PG]) to individuals without parkinsonism (non-parkinsonian group [NPG]. METHODS: The Pietà study is a population-based study conducted in Caeté, southeast Brazil, involving 607 individuals aged 75 + years submitted to an extensive clinical evaluation. A subset of 65 PG individuals (61.5% women, median age of 82 years) was compared to 542 NPG individuals (64.8% women, median age of 80 years). RESULTS: PG individuals had significantly more functional impairment, clinical comorbidities (including number of falls, loss of bladder control and dysphagia) and major depression. Multivariate analysis revealed that older age, higher UPDRSm scores, lower category fluency test (animals/minute) and delayed recall memory scores were associated with PG. This group was also more cognitively impaired, with lower performance than NPG individuals in the Mini-Mental State Examination, category fluency test (animals/minute), clock drawing and in delayed recall (p < 0.001 for all tests). UPDRSm scores were the most contributing factor to cognition that independently explained variability in functionality of the entire sample. CONCLUSION: Individuals aged 75 + years with parkinsonism were significantly more clinically and functionally impaired in this population-based sample. Cognitive dysfunction explained most of the loss of functionality in these patients. UPDRS-m scores contributed independently to explain variability in functionality in the whole sample.

A Hybrid-Telerehabilitation Versus a Conventional Program for Urinary Incontinence: a Randomized Trial during COVID-19 Pandemic.

INTRODUCTION AND HYPOTHESIS: This study aimed to compare the effectiveness of a hybrid telerehabilitation program with a traditional face to face model in women with stress urinary incontinence (SUI) and mixed incontinence (MUI) with a predominance of SUI. The authors hypothesized that home pelvic floor muscle training (PFMT) would have a similar benefit to outpatient PFMT. METHODS: Parallel randomized controlled trial including 58 patients consecutively admitted to a tertiary academic hospital for pelvic floor rehabilitation consultation from 1 January to 30 April 2021 for conservative treatment of UI. Participants randomized to the intervention were submitted to a 12-week PFMT program: (1) a hybrid telerehabilitation program of two individual face-to-face sessions followed by 2-weekly sessions of video-telerehabilitation with a follow-up by a specialized physiotherapist, including one individual face-to-face session at 8 weeks; (2) a re-evaluation teleconsultation at 6 and 16 weeks; (3) a face-to-face consultation at 12 weeks. The control group had two initial individual sessions followed by twice-weekly group classes, and consultations were face to face. The primary outcome measure (at baseline and 12 weeks) was UI-related quality of life using the Portuguese Version of the King's Health Questionnaire. RESULTS: At baseline the intervention (n = 18) and control (n = 17) groups were similar. UI-related quality of life significantly improved in both the intervention and control groups betweenbaseline (T0) and the end of the 12-week PFMT program (T12) (p = 0.002, p < 0.001, respectively), although the magnitude of the improvement was not significantly different between groups (-10.0 vs. -9.5 points, p = 0.918, respectively). CONCLUSION: This hybrid telerehabilitation protocol showed effectiveness comparable to the traditional model in improving UI-related quality of life. Trial registration at www. CLINICALTRIALS: gov , no. NCT05114395.

A plant-specific syntaxin-6 protein contributes to the intracytoplasmic route for the begomovirus CabLCV.

Because of limited free diffusion in the cytoplasm, viruses must use active transport mechanisms to move intracellularly. Nevertheless, how the plant single-stranded DNA begomoviruses hijack the host intracytoplasmic transport machinery to move from the nucleus to the plasmodesmata remains enigmatic. Here, we identified nuclear shuttle protein (NSP)-interacting proteins from Arabidopsis (Arabidopsis thaliana) by probing a protein microarray and demonstrated that the cabbage leaf curl virus NSP, a facilitator of the nucleocytoplasmic trafficking of viral (v)DNA, interacts in planta with an endosomal vesicle-localized, plant-specific syntaxin-6 protein, designated NSP-interacting syntaxin domain-containing protein (NISP). NISP displays a proviral function, unlike the syntaxin-6 paralog AT2G18860 that failed to interact with NSP. Consistent with these findings, nisp-1 mutant plants were less susceptible to begomovirus infection, a phenotype reversed by NISP complementation. NISP-overexpressing lines accumulated higher levels of vDNA than wild-type. Furthermore, NISP interacted with an NSP-interacting GTPase (NIG) involved in NSP-vDNA nucleocytoplasmic translocation. The NISP-NIG interaction was enhanced by NSP. We also showed that endosomal NISP associates with vDNA. NISP may function as a docking site for recruiting NIG and NSP into endosomes, providing a mechanism for the intracytoplasmic translocation of the NSP-vDNA complex toward and from the cell periphery.

Applying Different Strategies of Task Constraint Manipulation in Small-Sided and Conditioned Games: How Do They Impact Physical and Tactical Demands?

This study aimed to investigate how different strategies of task constraint manipulation impact physical and tactical demands in small-sided and conditioned games (SSCG). Ten recreational U-17 soccer players participated in this study (16.89 ± 0.11 years). We used different strategies of task manipulation to design two 4 vs. 4 SSCG: Structural SSCG and Functional SSCG. In Structural SSCG, pitch format and goal sizes were manipulated, while in Functional SSCG, players were allowed to kick the ball twice and at least 5 passes to shoot at the opponent's goal. Players participated in four Structural and Functional SSCG, of five minutes duration with a two-minute interval in between. Players' physical performance and tactical behavior were assessed using the WIMU PROTM inertial device. Structural SSCG stimulated players to cover more distance in sprinting (p = 0.003) and high-speed running (p < 0.001). Regarding tactical behavior, Structural SSCG stimulated players to explore game space better (p < 0.001). Moreover, Functional SSCG stimulated players to be closer to the ball, decreasing the effective playing space (p = 0.008). We conclude that these strategies of task constraint manipulation impact physical and tactical demands of the game.

The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome.

Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R+/+ and P2X7R-/- mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R+/+ mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. Results: The P2X7R+/+ mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R-/- and the P2X7R+/+ mice treated with A740003. The P2X7R+/+ mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of NLRP3 and NLRP12 genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R-/- and P2X7R+/+-induced mice, partially reversed by the A740003 treatment. Conclusions: Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development.

Survival Impact and Cost-Effectiveness of a Multidisciplinary Tumor Board for Breast Cancer in Mozambique, Sub-Saharan Africa.

BACKGROUND: Despite the international endorsement of multidisciplinary tumor boards (MTBs) for breast cancer care, implementation is suboptimal worldwide, and evidence regarding their effectiveness in developing countries is lacking. We assessed the impact on survival and the cost-effectiveness of implementing an MTB in Mozambique, sub-Saharan Africa. MATERIALS AND METHODS: This prospective cohort study included 205 patients with breast cancer diagnosed between January 2015 and August 2017 (98 before and 107 after MTB implementation), followed to November 2019. Pre- and post-MTB implementation subcohorts were compared for clinical characteristics, treatments, and overall survival. We used hazard ratios and 95% confidence intervals (CI), computed by Cox proportional hazards regression. The impact of MTB implementation on the cost per quality-adjusted life year (QALY) was estimated from the provider perspective. RESULTS: We found no significant differences between pre- and post-MTB subcohorts regarding clinical characteristics or treatments received. Among patients with early breast cancer (stage 0-III; n = 163), the 3-year overall survival was 48.0% (95% CI, 35.9-59.1) in the pre-MTB and 73.0% (95% CI, 61.3-81.6) in the post-MTB subcohort; adjusted hazard ratio, 0.47 (95% CI, 0.27-0.81). The absolute 3-year mean cost increase was $119.83 per patient, and the incremental cost-effectiveness ratio was $802.96 per QALY, corresponding to 1.6 times the gross domestic product of Mozambique. CONCLUSION: The implementation of a MTB in Mozambique led to a 53% mortality decrease among patients with early breast cancer, and it was cost-effective. These findings highlight the feasibility of implementing this strategy and the need for scaling-up MTBs in developing countries, as a way to improve patient outcomes. IMPLICATIONS FOR PRACTICE: Currently, more than half of the deaths from breast cancer in the world occur in developing countries. Strategies that optimize care and that are adjusted for available resources are needed to improve the outcomes of patients with breast cancer in these regions. The discussion of cases at multidisciplinary tumor boards (MTBs) may improve survival outcomes, but implementation is suboptimal worldwide, and evidence regarding their effectiveness in developing countries is lacking. This study evaluated the impact of implementing an MTB on the care and survival of patients with breast cancer in Mozambique, sub-Saharan Africa and its cost-effectiveness in this low-income setting.

Effect of the Interfacial Tension on Droplet Association in Aqueous Multiphase Systems.

Aqueous multiphase systems (AMPS) were formed by mixtures of three or more incompatible water-soluble macromolecules. Droplets formed by different phases in the water-in-water emulsions were found to associate and their morphology was studied using confocal laser scanning microscopy. By analyzing the angles between different associated phases it was possible to determine the relative interfacial tensions between phases with respect to each other. In this manner, the relative interfacial tension of 15 different pairs of polymers solutions was determined. The effect of the total polymer concentration on the relative interfacial tensions was found to be small as long as mixing of the polymers in the phases was small. The effect of adding protein microgels was studied for systems where they adsorb at the interface between the phases. It is shown that protein microgels can in some cases stabilize associated droplets in suspension.

NIK1-mediated translation suppression functions as a plant antiviral immunity mechanism.

Plants and plant pathogens are subject to continuous co-evolutionary pressure for dominance, and the outcomes of these interactions can substantially impact agriculture and food security. In virus-plant interactions, one of the major mechanisms for plant antiviral immunity relies on RNA silencing, which is often suppressed by co-evolving virus suppressors, thus enhancing viral pathogenicity in susceptible hosts. In addition, plants use the nucleotide-binding and leucine-rich repeat (NB-LRR) domain-containing resistance proteins, which recognize viral effectors to activate effector-triggered immunity in a defence mechanism similar to that employed in non-viral infections. Unlike most eukaryotic organisms, plants are not known to activate mechanisms of host global translation suppression to fight viruses. Here we demonstrate in Arabidopsis that the constitutive activation of NIK1, a leucine-rich repeat receptor-like kinase (LRR-RLK) identified as a virulence target of the begomovirus nuclear shuttle protein (NSP), leads to global translation suppression and translocation of the downstream component RPL10 to the nucleus, where it interacts with a newly identified MYB-like protein, L10-INTERACTING MYB DOMAIN-CONTAINING PROTEIN (LIMYB), to downregulate translational machinery genes fully. LIMYB overexpression represses ribosomal protein genes at the transcriptional level, resulting in protein synthesis inhibition, decreased viral messenger RNA association with polysome fractions and enhanced tolerance to begomovirus. By contrast, the loss of LIMYB function releases the repression of translation-related genes and increases susceptibility to virus infection. Therefore, LIMYB links immune receptor LRR-RLK activation to global translation suppression as an antiviral immunity strategy in plants.

Diabetes and impaired fasting glucose in a population-based sample of individuals aged 75 + years: associations with cognition, major depressive disorder, functionality and quality of life-the Pietà study.

OBJECTIVES: To investigate the rates of diabetes mellitus (DM) and impaired fasting glucose (IFG) in a population-based sample of individuals aged 75 + years old and their associations with cognitive performance, depression, functionality, and quality of life (QoL). STUDY DESIGN: Overall, 350 people participated in the study. Assessments of cognition, mood, functionality and QoL were performed using the mini-mental state examination (MMSE), clock-drawing, category fluency tests, the Mini-International Neuropsychiatric Interview, Pfeffer's Functional Activities Questionnaire, and the WHO Quality of Life-Old (WHOQOL-OLD). RESULTS: IFG (ADA criteria) was identified in 42.1% of the sample, while the DM rate was 24.1%. Lack of knowledge of the DM diagnosis and lack of treatment occurred in 27% and 39% of the sample, respectively. Rates of dementia and depression, MMSE, category fluency scores, and previous cardiovascular events did not differ between the glycaemic groups. Individuals with DM performed worse on the clock-drawing test, functionality, and WHOQOL-OLD than the other participants. Individuals with IFG presented similar QoL and functionality when compared with the group without DM. CONCLUSIONS: IFG and DM were common in this population-based sample aged 75 + years old, as were inadequate diagnoses and treatments of DM. DM individuals presented poor performance in the executive function test, functionality, and QoL. Further studies are recommended to investigate the value of an IFG diagnosis among the most elderly population.

The influence of age, sex and education on the phenomenology of depressive symptoms in a population-based sample aged 75+ years with major depression: the Pietà Study.

OBJECTIVES: Late-life depression (LLD) is the most common mental disorder among the elderly, but its clinical features remain unclear, especially among older adults. We sought to investigate if age, sex and education could influence the severity or frequency of LLD symptoms. METHODS: We evaluated 639 community-dwelling individuals aged 75+ years in Caeté (MG), Brazil. We used the Mini International Neuropsychiatric Interview to diagnose major depression according to DSM-IV criteria and the GDS-15 to measure depression severity. RESULTS: Excluding 174 individuals diagnosed with dementia, 54 (11.6%) of the remaining 457 individuals were diagnosed with LLD; 77.8% of which were female. On average, these participants were aged 81.0 ± 4.8 years and had 2.7 ± 3.3 years of schooling. Symptom severity was not influenced by sociodemographic variables. Death/suicidal ideation was more frequent among men, while psychomotor disturbance was more present in women (p = 0.04 and p = 0.042). More educated individuals (≥ 4 years) also reported a higher frequency of psychomotor disturbance (p = 0.039). CONCLUSIONS: Severity of depressive episode was not influenced by sociodemographic variables. Sex and educational level had a significant impact on symptom profiles.

The genomic context of retrocopies increases their chance of functional relevancy in mammals.

Described as "junk" DNA, pseudogenes are dead structures of previously active genes present in genomes. Pseudogenes are categorized into two main classes: processed pseudogenes, formed through retrotransposition, and non-processed pseudogenes, typically originated from gene decay following duplication events. The term "processed pseudogene" has changed to "retrocopy" since they are likely to evolve new functional roles and became a retrogene. Here, we surveyed 38,080 retrocopies from chimpanzee, dog, human, mouse, and rat genomes to assess their potential adaptive value. The retrocopies inserted in the same chromosome of the parental gene have higher chances of remain potentially "active" (absence of premature stop codons and frameshifts) (~26.1%), while those placed into a different chromosome have a twofold decrease chance of continuing potentially "active" (~7.52%). The genomic context of their placement seems associated with their expression. Retrocopies placed in intragenic regions and the same sense of the "host" gene have higher chances of being expressed relative to other genomic contexts. The proximity of retrocopies to their parental gene is associated with a lower decay rate, and their location likely influence their expression. Thus, despite their unclear role, retrocopies are probably involved in adaptive processes. Our results evidence natural selection acting in retrocopies.

Evolutionary genomics of mammalian lung cancer genes reveals signatures of positive selection in APC, RB1 and TP53.

Lung cancer is the type of cancer causing most deaths in humans, with 234,030 new cases of lung cancer diagnosed in the United States in 2018. Recently, Tumor suppressor genes (TSGs) or the control of its pathway became promising drug targets for cancer therapy. A diverse group of TSGs is involved in progression and metastasis of lung cancer. Here, we surveyed nine highly significant mutated genes in 20 mammalian genomes to assess signatures of adaptive evolution using maximum likelihood approaches. We found that three genes (APC, RB1, and TP53) are under strong positive selection, influencing amino acids located in functionally important protein domains, such as three sites in APC found in the APC_N_CC domain, which is responsible for the binding to beta-catenin armadillo repeats that regulate beta-catenin level (beta-catenin is a transcription factor and its misregulation lead to malignant transformation of normal cells). Such sites substitutions mostly increase the stability of the domain. Moreover, substitution of some other sites found in important motifs, such as codon 47 (proline-directed kinase motif) in TP53, modify the phosphorylation activity of TP53 playing a key role in cancer risk. Our findings will open recommendation to drug targeting sites and will foster further research to understand better these proteins function.

The role of nanohydroxyapatite on the morphological, physical, and biological properties of chitosan nanofibers.

OBJECTIVES: This study aimed to evaluate the effects of nanohydroxyapatite (nHAp) particles on the morphological, chemical, physical, and biological properties of chitosan electrospun nanofibers. MATERIALS AND METHODS: nHAp particles with a 1.67 Ca/P ratio were synthesized via the aqueous precipitation method, incorporated into chitosan polymer solution (0.5 wt%), and electrospun into nHAp-loaded fibers (ChHa fibers). Neat chitosan fibers (nHAp-free, Ch fibers) were used as the control. The electrospun fiber mats were characterized using morphological, topographical, chemical, thermal, and a range of biological (antibacterial, antibiofilm, cell viability, and alkaline phosphatase [ALP] activity) analyses. Data were analyzed using ANOVA and Tukey's test (α = 0.05). RESULTS: ChHa fibers demonstrated a bead-like morphology, with thinner (331 ± 110 nm) and smoother (Ra = 2.9 ± 0.3 µm) distribution as compared to the control fibers. Despite showing similar cell viability and ALP activity to Ch fibers, the ChHa fibers demonstrated greater antibacterial potential against most tested bacteria (except for P. intermedia), and higher antibiofilm activity against P. gingivalis biofilm. CONCLUSIONS: The incorporation of nHAp particles did not jeopardize the overall morphology, topography, physical, and biological characteristics of the chitosan nanofibers. CLINICAL RELEVANCE: The combination of nHAp particles with chitosan can be used to engineer bioactive, electrospun composite nanofibers with potential applications in regenerative dentistry.

Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells.

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

Ultrasonication Improves Solid Phase Synthesis of Peptides Specific for Fibroblast Growth Factor Receptor and for the Protein-Protein Interface RANK-TRAF6.

Considering our interest in the use of peptides as potential target-specific drugs or as delivery vectors of metallodrugs for various biomedical applications, it is crucial to explore improved synthetic methodologies to accomplish the highest peptide crude purity in the shortest time possible. Therefore, we compared "classical" fluorenylmethoxycarbonyl (Fmoc)-solid phase peptide synthesis (SPPS) with ultrasound(US)-assisted SPPS based on the preparation of three peptides, namely the fibroblast growth factor receptor 3(FGFR3)-specific peptide Pep1 (VSPPLTLGQLLS-NH2) and the novel peptides Pep2 (RQMATADEA-NH2) and Pep3 (AAVALLPAVLLALLAPRQMATADEA-NH2), which are being developed aimed at interfering with the intracellular protein-protein interaction(PPI) RANK-TRAF6. Our results demonstrated that US-assisted SPPS led to a 14-fold (Pep1) and 4-fold time reduction (Pep2) in peptide assembly compared to the "classical" method. Interestingly, US-assisted SPPS yielded Pep1 in higher purity (82%) than the "classical" SPPS (73%). The significant time reduction combined with high crude peptide purity attained prompted use to apply US-assisted SPPS to the large peptide Pep3, which displays a high number of hydrophobic amino acids and homooligo-sequences. Remarkably, the synthesis of this 25-mer peptide was attained during a "working day" (347 min) in moderate purity (approx. 49%). In conclusion, we have reinforced the importance of using US-SPPS towards facilitating the production of peptides in shorter time with increased efficacy in moderate to high crude purity. This is of special importance for long peptides such as the case of Pep3.

Measuring phylogenetic signal between categorical traits and phylogenies.

MOTIVATION: Determining whether a trait and phylogeny share some degree of phylogenetic signal is a flagship goal in evolutionary biology. Signatures of phylogenetic signal can assist the resolution of a broad range of evolutionary questions regarding the tempo and mode of phenotypic evolution. However, despite the considerable number of strategies to measure it, few and limited approaches exist for categorical traits. Here, we used the concept of Shannon entropy and propose the δ statistic for evaluating the degree of phylogenetic signal between a phylogeny and categorical traits. RESULTS: We validated δ as a measure of phylogenetic signal: the higher the δ-value the higher the degree of phylogenetic signal between a given tree and a trait. Based on simulated data we proposed a threshold-based classification test to pinpoint cases of phylogenetic signal. The assessment of the test's specificity and sensitivity suggested that the δ approach should only be applied to 20 or more species. We have further tested the performance of δ in scenarios of branch length and topology uncertainty, unbiased and biased trait evolution and trait saturation. Our results showed that δ may be applied in a wide range of phylogenetic contexts. Finally, we investigated our method in 14 360 mammalian gene trees and found that olfactory receptor genes are significantly associated with the mammalian activity patterns, a result that is congruent with expectations and experiments from the literature. Our application shows that δ can successfully detect molecular signatures of phenotypic evolution. We conclude that δ represents a useful measure of phylogenetic signal since many phenotypes can only be measured in categories. AVAILABILITY AND IMPLEMENTATION: https://github.com/mrborges23/delta_statistic. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.