Structural and enzymatic evidence for the methylation of the ACK1 tyrosine kinase by the histone lysine methyltransferase SETD2.

SETD2 (SET-domain containing protein 2) is a histone methyltransferase (HMT) of the SET family responsible for the trimethylation of K36 of histone H3, thus producing the epigenetic mark H3K36me3. Recent studies have shown that certain SET family HMTs, such as SMYD2, SMYD3 or SETDB1 can also methylate protein kinases and therefore be involved in signaling pathways. Here we provide structural and enzymatic evidence showing that SETD2 methylates the protein tyrosine kinase ACK1 in vitro. ACK1 is recognized as a major integrator of signaling from various receptor tyrosine kinases. Using ACK1 peptides and recombinant proteins, we show that SETD2 methylates the K514 residue of ACK1 generating K514 mono, di or tri-methylation. Interestingly, K514 is found in a "H3K36-like" motif of ACK1 which is known to be post-translationally modified and to be involved in protein-protein interaction. The crystal structure of SETD2 catalytic domain in complex with an ACK1 peptide further provides the structural basis for the methylation of ACK1 K514 by SETD2. Our work therefore strongly suggests that ACK1 could be a novel non-histone substrate of SETD2 and further supports that SET HMTs, such as SETD2, could be involved in both epigenetic regulations and cell signaling.

HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia.

Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.

Applying landscape metrics to species distribution model predictions to characterize internal range structure and associated changes.

Distributional shifts in species ranges provide critical evidence of ecological responses to climate change. Assessments of climate-driven changes typically focus on broad-scale range shifts (e.g. poleward or upward), with ecological consequences at regional and local scales commonly overlooked. While these changes are informative for species presenting continuous geographic ranges, many species have discontinuous distributions-both natural (e.g. mountain or coastal species) or human-induced (e.g. species inhabiting fragmented landscapes)-where within-range changes can be significant. Here, we use an ecosystem engineer species (Sabellaria alveolata) with a naturally fragmented distribution as a case study to assess climate-driven changes in within-range occupancy across its entire global distribution. To this end, we applied landscape ecology metrics to outputs from species distribution modelling (SDM) in a novel unified framework. SDM predicted a 27.5% overall increase in the area of potentially suitable habitat under RCP 4.5 by 2050, which taken in isolation would have led to the classification of the species as a climate change winner. SDM further revealed that the latitudinal range is predicted to shrink because of decreased habitat suitability in the equatorward part of the range, not compensated by a poleward expansion. The use of landscape ecology metrics provided additional insights by identifying regions that are predicted to become increasingly fragmented in the future, potentially increasing extirpation risk by jeopardising metapopulation dynamics. This increased range fragmentation could have dramatic consequences for ecosystem structure and functioning. Importantly, the proposed framework-which brings together SDM and landscape metrics-can be widely used to study currently overlooked climate-driven changes in species internal range structure, without requiring detailed empirical knowledge of the modelled species. This approach represents an important advancement beyond predictive envelope approaches and could reveal itself as paramount for managers whose spatial scale of action usually ranges from local to regional.

Is Down syndrome a risk factor or contraindication for dental implants? A systematic review.

STATEMENT OF PROBLEM: Whether oral rehabilitation with dental implants in patients with Down syndrome leads to an increased complication rate is unclear. PURPOSE: The purpose of this systematic review was to determine the effectiveness of dental implants placed in patients with Down syndrome and whether the condition is a risk factor or contraindication for dental implant placement. MATERIAL AND METHODS: Searches were conducted in 6 databases, including the non-peer-reviewed literature, up to February 2021 by 2 independent reviewers according to established inclusion and exclusion criteria to answer this question: Is Down syndrome a risk factor or contraindication for oral rehabilitation with dental implants? RESULTS: A total of 655 studies were initially found in the databases. Five were included in this systematic review, all of which were observational studies. A total of 50 patients with 186 implants were evaluated, with a reported effectiveness of 79.1%. The risk of bias assessment determined that 3 of the 5 studies had a high risk of bias. CONCLUSIONS: Treatment with dental implants in patients with Down syndrome is a suitable option, but more complications are to be expected than with patients without this condition. Controlled studies with better methodological design and less risk of bias should be developed to improve the scientific evidence for the treatment of these patients.

What is the Effectiveness of Premaxilla Surgical Repositioning and its Stabilization Methods in Mixed Dentition Patients With Bilateral Cleft Lip and Palate?

OBJECTIVE: Verify the effectiveness of surgical repositioning of the premaxilla and its stabilization methods in patients with bilateral cleft lip and palate during mixed dentition. DESIGN: Systematic review. MATERIAL AND METHODS: The search was conducted in 7 databases (eg, Medline via PubMed; Scopus; Central Cochrane; LILACS; Embase, Web of Science; and Sigle via OpenGrey until August 2021), using the descriptors "premaxilla", "cleft Palate", and "bone transplantation". INCLUSION CRITERIA: Clinical trials and observational studies that have patients with bilateral cleft who had a need for superior/posterior repositioning of the premaxilla on mixed dentition; Studies in any language was evaluted whitout time restriction of publication. RESULTS: From 5572 records, 6 studies were included in the review with a total sample of 212 patients. Regarding the type of stabilization used in the premaxilla, the hybrid method (rigid and complementary semi-rigid stabilization) predominated, being observed in 184 patients (86.8%). A total of 17 failures were identified related to the surgical repositioning of the premaxilla, corresponding to 8% of the total number of surgeries. A meta-analysis of prevalence was performed, only with the retrospective studies. It was observed that the effectiveness rate of premaxilla repositioning was 92%, with a CI between 0.04 and 0.13, with all included studies showing a similar failure rate (0.08-0.09). The included studies also showed great homogeneity in this analysis (I2 = 0%; P = .75). CONCLUSION: Although there are several alternatives and techniques for repositioning and stabilizing the premaxilla, the statistical result did not differ between the different techniques.

Systemic inflammatory syndrome in children with FARSA deficiency.

Variants in aminoacyl-tRNA synthetases (ARSs) genes are associated to a broad spectrum of human inherited diseases. Patients with defective PheRS, encoded by FARSA and FARSB, display brain abnormalities, interstitial lung disease and facial dysmorphism. We investigated four children from two unrelated consanguineous families carrying two missense homozygous variants in FARSA with significantly reduced PheRS-mediated aminoacylation activity. In addition to the core ARS-phenotype, all patients showed an inflammatory profile associated with autoimmunity and interferon score, a clinical feature not ascribed to PheRS-deficient patients to date. JAK inhibition improved lung disease in one patient. Our findings expand the genetic and clinical spectrum of FARSA-related disease.

Determination of preclinical safety of oil obtained from Pachira aquatica Aublet (Malvaceae) seeds: histopathological, biochemical, hematological, and genetic toxicity studies in rats.

Pachira aquatica is a species used for medicinal and food purposes and has numerous phytochemicals that may have systemic toxic effects and damage to genetic material. This study aimed to evaluate acute and short-term oral toxicity, as well as genotoxic and clastogenic effects of oil extracted from P. aquatica (PASO) seeds in rats and Drosophila melanogaster. The results obtained with biochemical and hematological analyses did not show significant changes in any evaluated parameters when compared with reference values for the species used in the study. Data from the histopathological analysis corroborated results found in this study. These findings indicate low acute and short-term toxicity following oral PASO exposure in rats under the experimental conditions tested. Tests performed in rats showed that PASO did not present significant genotoxic or clastogenic effects on the cells analyzed with the three doses tested. Treatment with PASO in the offspring of HB crossing, which showed high cytochrome P450 levels, did not exhibit genotoxic activity, as demonstrated by the SMART test. These results suggest that products from the hepatic oil metabolism did not show genotoxicity under the conditions tested. Together, the results indicate that, under the experimental conditions tested, PASO is safe for repeated intake. As PASO exhibited low potential to cause harmful effects on living organisms, our study encourages further research aimed at assessing its pharmacological activity, since it is a widely consumed plant.

Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives.

Phosphorylation is an essential process in biological events and is considered critical for biological functions. In tissues, protein phosphorylation mainly occurs on tyrosine (Tyr), serine (Ser) and threonine (Thr) residues. The balance between phosphorylation and dephosphorylation is under the control of two super enzyme families, protein kinases (PKs) and protein phosphatases (PPs), respectively. Although there are many selective and effective drugs targeting phosphokinases, developing drugs targeting phosphatases is challenging. PTP1B, one of the most central protein tyrosine phosphatases (PTPs), is a key player in several human diseases and disorders, such as diabetes, obesity, and hematopoietic malignancies, through modulation of different signaling pathways. However, due to high conservation among PTPs, most PTP1B inhibitors lack specificity, raising the need to develop new strategies targeting this enzyme. In this mini-review, we summarize three classes of PTP1B inhibitors with different mechanisms: (1) targeting multiple aryl-phosphorylation sites including the catalytic site of PTP1B; (2) targeting allosteric sites of PTP1B; (3) targeting specific mRNA sequence of PTP1B. All three types of PTP1B inhibitors present good specificity over other PTPs and are promising for the development of efficient small molecules targeting this enzyme.

Biochemical, Enzymatic, and Computational Characterization of Recurrent Somatic Mutations of the Human Protein Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma.

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma.

Does the Muscle Action Duration Induce Different Regional Muscle Hypertrophy in Matched Resistance Training Protocols?

ABSTRACT: Diniz, RCR, Tourino, FD, Lacerda, LT, Martins-Costa, HC, Lanza, MB, Lima, FV, and Chagas, MH. Does the muscle action duration induce different regional muscle hypertrophy in matched resistance training protocols? J Strength Cond Res 36(9): 2371-2380, 2022-The manipulation of the muscle action duration (MAD) can influence the instantaneous torque along the range of motion, which can lead to adaptations of regional muscle hypertrophy. The aim of this study was to compare the effects of matched resistance training (RT) on the knee extension machine with different MAD in the cross-sectional area (CSA) responses within the quadriceps femoris (QF) and its muscles. Forty-four subjects were allocated into a control and 3 experimental groups. For a period of 10 weeks, subjects in the experimental groups performed the training protocols that were different only by the MAD: group 5c1e (5s concentric action [CON] and 1s eccentric action [ECC]; group 3c3e (3s CON and 3s ECC) and group 1c5e (1s CON and 5s ECC). Magnetic resonance imaging was performed (before and after the intervention) to determine the relative change (%) in CSA of the QF muscles along proximal (30%), middle (50%), and distal regions (70% distal of the femur). The change in CSA of the rectus femoris at the middle region are greater in 5c1e (6.8 ± 6.5%) and 1c5e (7.4 ± 6.0%) groups than 3c3e (3.4 ± 6.6%) and control groups (0.2 ± 1.8%). In addition, vastus lateralis at the distal region (5c1e = 15.9 ± 11.8%; 1c5e = 14.4 ± 10.0%) presenting greater increases in change of CSA than the others vastus only 5c1e (vastus lateralis [VI] = 5.0 ± 4.7%; vastus medialis [VM] = 4.2 ± 3.2%) and 1c5e groups (VI = 4.7 ± 3.6%; VM = 3.4 ± 3.1%). In conclusion, this study showed that matched RT protocols with different MAD resulted in different region-specific muscle hypertrophic across the individual muscles of QF.

Equalization of Training Protocols by Time Under Tension Determines the Magnitude of Changes in Strength and Muscular Hypertrophy.

ABSTRACT: Martins-Costa, HC, Lacerda, LT, Diniz, RCR, Lima, FV, Andrade, AGP, Peixoto, GH, Gomes, MC, Lanza, MB, Bemben, MG, and Chagas, MH. Equalization of training protocols by time under tension determines the magnitude of changes in strength and muscular hypertrophy. J Strength Cond Res 36(7): 1770-1780, 2022-The aim of this study was to investigate the effects of 2 training protocols equalized by tension (TUT) on maximal strength (1 repetition maximum [RM]), regional cross-sectional areas (proximal, middle, and distal), and total cross-sectional areas (sum of the regional cross-sectional areas) of the pectoralis major and triceps brachii muscles. Thirty-eight men untrained in resistance training participated in the study and were allocated under 3 conditions: Protocol 3s (n = 11; 12 repetitions; 3s repetition duration), Protocol 6s (n = 11; 6 repetitions; 6s repetition duration), and Control (n = 11; no training). Training protocols (10 weeks; bench press exercise) were equated for TUT (36 seconds per set), number of sets (3-4), intensity (50-55% of 1RM), and rest between sets (3 minutes). Analysis of variance was used to examine a percentage change in variables of interest across the 3 groups with an alpha level of 0.05 used to establish statistical significance. Protocols 3s and 6s showed no differences in the increase of total and regional muscle cross-sectional areas. There were no differences in regional hypertrophy of the pectoralis major muscle. In the triceps brachii muscle, the increase in distal cross-sectional area was greater when compared with the middle and proximal regions. Both experimental groups had similar increases in the 1RM test. In conclusion, training protocols with the same TUT promote similar strength gains and muscle hypertrophy. Moreover, considering that the protocols used different numbers of repetitions, the results indicate that training volumes cannot be considered separately from TUT when evaluating neuromuscular adaptations.

Mobile application as a learning tool for improving dental students' knowledge regarding dental trauma.

INTRODUCTION: Current evidence suggests an important knowledge gain of health sciences' students and professionals with mobile devices (m-learning). This study aimed to verify whether different strategies of teaching (traditional lecture classroom, m-learning and association of both methods) would present greater efficacy in knowledge improvement regarding dental trauma in primary dentition. MATERIALS AND METHODS: An action research study using a participatory approach was conducted with 36 undergraduate Brazilian dental students. A structured questionnaire composed of six clinical cases of traumatic injuries was initially applied to all students (pre-test). Participants were then randomly distributed into three experimental groups: TC-students who had access exclusively to traditional lecture classroom; APP-access exclusively to the mobile application; and TC-APP-access to both approaches. The traditional and technological methods had evidence-based content and visual resources of the subject. After interventions, all students responded to the same previous questionnaire (post-test). Wilcoxon and Kruskal-Wallis tests were performed for statistical analysis. RESULTS: All tested groups obtained statistically significant improvement between their pre-test and post-test scores, for both diagnosis and treatment of dental trauma (p < .005). Nonetheless, no intergroup differences were observed amongst the scores of pre- and post-test for diagnosis (p = .159) and treatment (p = .206). CONCLUSION: All teaching approaches applied obtained similar knowledge improvement of undergraduate dental students regarding traumatic injuries in primary teeth.

Combined training is not superior to strength and aerobic training to mitigate cardiovascular risk in adult healthy men.

Although the beneficial effects of aerobic training on cardiovascular risk factors are evident, the potential beneficial effect of strength and combined training on these risk factors is controversial. This study aimed to evaluate the effect of aerobic and strength training programmes, performed alone or in combination, on cardiovascular risk factors in sedentary, apparently healthy and non-obese adult men. The study was conducted with 37 subjects who were randomly divided into the following groups: aerobic (AG), combined (ASG), strength (SG) and control (CG). The exercise programmes were performed three times a week and lasted approximately 50 minutes. Dietary intake, anthropometry, blood pressure, muscular strength, aerobic capacity, lipid profile and glycaemic control were assessed before and after 12 weeks of the intervention. One-way analysis of variation (ANOVA) for baseline, and ANOVA for repeated measures were used to assess differences between the initial and final time points of the four groups. Changes in blood pressure and glycaemic control were not significant in any of the groups. No differences were observed in LDL-C between training groups. HDL-C increased significantly only in the AG. In conclusion, if minimal changes in the lipid profile are needed, an aerobic training programme can provide possible benefits for HDL-C in apparently healthy and non-obese adult men.

The Benzene Hematotoxic and Reactive Metabolite 1,4-Benzoquinone Impairs the Activity of the Histone Methyltransferase SET Domain Containing 2 (SETD2) and Causes Aberrant Histone H3 Lysine 36 Trimethylation (H3K36me3).

Human SETD2 is the unique histone methyltransferase that generates H3K36 trimethylation (H3K36me3), an epigenetic mark that plays a key role in normal hematopoiesis. Interestingly, recurrent inactivating mutations of SETD2 and aberrant H3K36me3 are increasingly reported to be involved in hematopoietic malignancies. Benzene (BZ) is a ubiquitous environmental pollutant and carcinogen that causes leukemia. The leukemogenic properties of BZ depend on its biotransformation in the bone marrow into oxidative metabolites, in particular 1,4-benzoquinone (BQ). This hematotoxic metabolite can form DNA and protein adducts that result in the damage and the alteration of cellular processes. Recent studies suggest that BZ-dependent leukemogenesis could depend on epigenetic perturbations, notably aberrant histone methylation. We investigated whether H3K36 trimethylation by SETD2 could be impacted by BZ and its hematotoxic metabolites. Herein, we show that BQ, the major leukemogenic metabolite of BZ, inhibits irreversibly the human histone methyltransferase SETD2, resulting in decreased H3K36me3. Our mechanistic studies further indicate that the BQ-dependent inactivation of SETD2 is due to covalent binding of BQ to reactive Zn-finger cysteines within the catalytic domain of the enzyme. The formation of these quinoprotein adducts results in loss of enzyme activity and protein crosslinks/oligomers. Experiments conducted in hematopoietic cells confirm that exposure to BQ results in the formation of SETD2 crosslinks/oligomers and concomitant loss of H3K36me3 in cells. Taken together, our data indicate that BQ, a major hematotoxic metabolite of BZ, could contribute to BZ-dependent leukemogenesis by perturbing the functions of SETD2, a histone lysine methyltransferase of hematopoietic relevance. SIGNIFICANCE STATEMENT: Benzoquinone is a major leukemogenic metabolite of benzene. Dysregulation of histone methyltransferase is involved in hematopoietic malignancies. This study found that benzoquinone irreversibly impairs SET domain containing 2, a histone H3K36 methyltransferase that plays a key role in hematopoiesis. Benzoquinone forms covalent adducts on Zn-finger cysteines within the catalytic site, leading to loss of activity, protein crosslinks/oligomers, and concomitant decrease of H3K36me3 histone mark. These data provide evidence that a leukemogenic metabolite of benzene can impair a key epigenetic enzyme.

Oxidative stress activates red cell adhesion to laminin in sickle cell disease.

Vaso-occlusive crises are the hallmark of sickle cell disease (SCD). They are believed to occur in two steps, starting with adhesion of deformable low-dense red blood cells (RBCs), or other blood cells such as neutrophils, to the wall of post-capillary venules, followed by trapping of the denser RBCs or leukocytes in the areas of adhesion because of reduced effective lumen-diameter. In SCD, RBCs are heterogeneous in terms of density, shape, deformability and surface proteins, which accounts for the differences observed in their adhesion and resistance to shear stress. Sickle RBCs exhibit abnormal adhesion to laminin mediated by Lu/BCAM protein at their surface. This adhesion is triggered by Lu/BCAM phosphorylation in reticulocytes but such phosphorylation does not occur in mature dense RBCs despite firm adhesion to laminin. In this study, we investigated the adhesive properties of sickle RBC subpopulations and addressed the molecular mechanism responsible for the increased adhesion of dense RBCs to laminin in the absence of Lu/BCAM phosphorylation. We provide evidence for the implication of oxidative stress in post-translational modifications of Lu/BCAM that impact its distribution and cis-interaction with glycophorin C at the cell surface activating its adhesive function in sickle dense RBCs.

Resistance training intervention performed with different muscle action durations influences the maximal dynamic strength without promoting joint-angle specific strength gains.

The present study investigated the effect of 10-week matched (range of motion, volume, intensity, rest, and repetition duration) training protocols with varying muscle action duration (MAD) on maximal voluntary isometric contraction (MVIC) test at eight different knee angles and one-repetition maximum (1RM) test after in seated knee extensor machine. Forty women were allocated into one control and three training groups with varying MAD: 5C1E (5s concentric action [CON] and 1s eccentric action [ECC]), 3C3E (3s CON and 3s ECC), and 1C5E (1s CON and 5s ECC). All training groups (5C1E, 3C3E, and 1C5E) showed a greater relative response in 1RM performance than the control group (0.1 ± 3.5%, p ≤ 0.05). The 1C5E group presented greater relative increases in the 1RM performance (22.1 ± 11.6%) compared to 5C1E (13.6 ± 9.2%; p ≤ 0.05) and 3C3E (14.1 ± 5.5%, p ≤ 0.05) groups. The training groups increased the MVIC performance more than the control group (p ≤ 0.05), although there were no significant differences between the training groups. This study demonstrated that isoinertial resistance training protocols with shorter CON MAD showed greater maximum dynamic strength performance response than matched training protocols with other MAD configurations. However, the configuration of MAD did not induce angle-specificity to increase the maximum isometric strength.

Transcriptomic response of the intertidal limpet Patella vulgata to temperature extremes.

Global warming is challenging wild species in land and water. In the intertidal zone, species are already living at their thermal limits, being vulnerable even to small increases in maximum habitat temperatures. Knowledge of the mechanisms by which many intertidal zone species cope with elevated temperatures is limited. We analysed the molecular thermal stress response of the limpet Patella vulgata under slight and frequent (one-day), and extreme and rare (three-day) warming events. Using RNA-seq to assess differential gene expression among treatments, differing molecular responses were obtained in the two treatments, with more changes in gene expression after the three-day event; with one-third of the differentially expressed transcripts being down-regulated. However, across treatments we observed shifts in gene expression for common aspects of the heat stress response including intra-cellular communication, protein chaperoning, proteolysis and cell cycle arrest. Of the 71,675 transcripts obtained, only 259 were differentially expressed after both heating events. From these, 218 defined the core group (i.e. genes induced by thermal stress with similar expression patterns irrespective of the magnitude of the warming event). The core group was composed of already well-studied genes in heat stress responses in intertidal organisms (e.g. heat shock proteins), but also genes from less explored metabolic pathways, e.g. the ubiquitin system, which were also fundamental regardless of the magnitude of the imposed warming. Moreover, we have also identified 41 signaling genes (i.e. a set of genes responding to both events and with expression patterns specific to the intensity of thermal stress), principally including genes involved in the maintenance of extracellular structure that have previously not been identified as part of the response to thermal stress in intertidal zone organisms. These signaling genes will be useful heat stress molecular biomarkers for monitoring heat stress in natural populations.

Antineoplastics Encapsulated in Nanostructured Lipid Carriers.

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.

Understanding the Impact of Walkability, Population Density, and Population Size on COVID-19 Spread: A Pilot Study of the Early Contagion in the United States.

The novel coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global event that has been challenging governments, health systems, and communities worldwide. Available data from the first months indicated varying patterns of the spread of COVID-19 within American cities, when the spread was faster in high-density and walkable cities such as New York than in low-density and car-oriented cities such as Los Angeles. Subsequent containment efforts, underlying population characteristics, variants, and other factors likely affected the spread significantly. However, this work investigates the hypothesis that urban configuration and associated spatial use patterns directly impact how the disease spreads and infects a population. It follows work that has shown how the spatial configuration of urban spaces impacts the social behavior of people moving through those spaces. It addresses the first 60 days of contagion (before containment measures were widely adopted and had time to affect spread) in 93 urban counties in the United States, considering population size, population density, walkability, here evaluated through walkscore, an indicator that measures the density of amenities, and, therefore, opportunities for population mixing, and the number of confirmed cases and deaths. Our findings indicate correlations between walkability, population density, and COVID-19 spreading patterns but no clear correlation between population size and the number of cases or deaths per 100 k habitants. Although virus spread beyond these initial cases may provide additional data for analysis, this study is an initial step in understanding the relationship between COVID-19 and urban configuration.

Benzoquinone, a leukemogenic metabolite of benzene, catalytically inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling.

Protein tyrosine phosphatase, nonreceptor type 2 (PTPN2) is mainly expressed in hematopoietic cells, where it negatively regulates growth factor and cytokine signaling. PTPN2 is an important regulator of hematopoiesis and immune/inflammatory responses, as evidenced by loss-of-function mutations of PTPN2 in leukemia and lymphoma and knockout mice studies. Benzene is an environmental chemical that causes hematological malignancies, and its hematotoxicity arises from its bioactivation in the bone marrow to electrophilic metabolites, notably 1,4-benzoquinone, a major hematotoxic benzene metabolite. Although the molecular bases for benzene-induced leukemia are not well-understood, it has been suggested that benzene metabolites alter topoisomerases II function and thereby significantly contribute to leukemogenesis. However, several studies indicate that benzene and its hematotoxic metabolites may also promote the leukemogenic process by reacting with other targets and pathways. Interestingly, alterations of cell-signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), have been proposed to contribute to benzene-induced malignant blood diseases. We show here that 1,4-benzoquinone directly impairs PTPN2 activity. Mechanistic and kinetic experiments with purified human PTPN2 indicated that this impairment results from the irreversible formation (kinact = 645 m-1·s-1) of a covalent 1,4-benzoquinone adduct at the catalytic cysteine residue of the enzyme. Accordingly, cell experiments revealed that 1,4-benzoquinone exposure irreversibly inhibits cellular PTPN2 and concomitantly increases tyrosine phosphorylation of STAT1 and expression of STAT1-regulated genes. Our results provide molecular and cellular evidence that 1,4-benzoquinone covalently modifies key signaling enzymes, implicating it in benzene-induced malignant blood diseases.