Benzofurans as Acetylcholinesterase Inhibitors for Treating Alzheimer's Disease: Synthesis, in†vitro Testing, and in†silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by a progressive decline in cholinergic neurotransmission. During the development of AD, acetylcholinesterase (AChE) binds to ß-amyloid peptides to form amyloid fibrils, which aggregate into plaque deposits. Meanwhile, tau proteins are hyperphosphorylated, forming neurofibrillary tangles (NFTs) that aggregate into inclusions. These complexes are cytotoxic for the brain, causing impairment of memory, attention, and cognition. AChE inhibitors are the main treatment for AD, but their effect is only palliative. This study aimed to design and synthesize novel benzofuran derivatives and evaluate their inhibition of AChE in vitro and in silico. Results: The seven synthesized benzofuran derivatives inhibited AChE in vitro. Benzofurans hydroxy ester 4, amino ester 5, and amido ester (±)-7 had the lowest inhibition constant (Ki) values and displayed good affinity for EeAChE in molecular docking. Six derivatives showed competitive inhibition, while the best compound (5: Ki=36.53 µM) exhibited uncompetitive inhibition. The amino, hydroxyl, amide, and ester groups of the ligands favored interaction with the enzyme by hydrogen bonds. Conclusion: Three benzofurans were promising AChE inhibitors with excellent Ki values. In future research on their their application to AD, 5 will be considered as the base structure.

Bioenergetic status of swordfish (Xiphias gladius) during the El Niño Southern Oscillation (ENSO) in the Southeast Pacific Ocean: An interannual scale.

The bioenergetic status of fishes has been used to study their physiological responses to temporal changes at interannual scales. We evaluated the physiological responses of swordfish at an interannual scale from the El Niño Southern Oscillation (ENSO): warm phase "El Niño" in 2015 to the cold phase "La Niña" in 2017 and under neutral conditions as well in 2019. Herein, muscle samples from females and males were analyzed to evaluate the bioenergetic status from their biochemical constituents (L: lipids, P: proteins and G: glucose, E: total energy, and FAs: fatty acid profile), elemental composition (C: carbon, N: nitrogen, H: hydrogen), and nutritional indices (L:P, C:N, DHA/C18:1n-3, DHA/C16:0 and ω3/ω6 FAs). The physiological response of swordfish showed an interaction between the year and sex. Herein, the L and E showed similar trends, with the lowest female values found in 2015 and the highest in 2019. Contrary, males showed their highest values in 2015 and lowest in 2019. FA profile differed among years and highlighted significant differences between females and males in 2019. Although the female L:P and C:N ratios were lower in 2015 than in 2017, a decreasing trend in these ratios was found from 2017 to 2019. Moreover, DHA/C18:1n-3, DHA/C16:0 and ω3/ω6 showed higher ratios in females than males in 2019. Our results coincide with the beginning of the ENSO phases; it is therefore likely that the swordfish diet changed in response to the disturbances in environmental conditions. Furthermore, the degree of individual dietary specialization found under the neutral conditions could indicate differences in the feeding behaviors of males vs. females, which may be an adaptive strategy in this species. These findings will aid in understanding the bioenergetic status of swordfish under different climatic scenarios and the current global warming, providing relevant information for the management of this resource.

In silico identification of a biarylamine acting as agonist at human ß3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism.

Human ß3-adrenoceptor (ß3AR) agonists were considered potential agents for the treatment of metabolic disorders. However, compounds tested as ß3AR ligands have shown marked differences in pharmacological profile in rodent and human species, although these compounds remain attractive as they were successfully repurposed for the therapy of urinary incontinence. In this work, some biarylamine compounds were designed and tested in silico as potential ß3AR agonists on 3-D models of mouse or human ß3ARs. Based on the theoretical results, we identified, synthesized and tested a biarylamine compound (polibegron). In CHO-K1 cells expressing the human ß3AR, polibegron and the ß3AR agonist BRL 37344 were partial agonists for stimulating cAMP accumulation (50 and 57% of the response to isoproterenol, respectively). The potency of polibegron was 1.71- and 4.5-fold higher than that of isoproterenol and BRL37344, respectively. These results indicate that polibegron acts as a potent, but partial, agonist at human ß3ARs. In C57BL/6N mice with obesity induced by a high-fat diet, similar effects of the equimolar intraperitoneal administration of polibegron and BRL37344 were observed on weight, visceral fat and plasma levels of glucose, cholesterol and triglycerides. Similarities and differences between species related to ligand-receptor interactions can be useful for drug designing.

PI3K-C2ß limits mTORC1 signaling and angiogenic growth.

Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2ß is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2ß was a critical regulator of blood vessel growth by restricting endothelial mTORC1 signaling. Mice expressing a kinase-inactive form of PI3K-C2ß displayed enlarged blood vessels without corresponding changes in endothelial cell proliferation or migration. Instead, inactivation of PI3K-C2ß resulted in an increase in the size of endothelial cells, particularly in the sprouting zone of angiogenesis. Mechanistically, we showed that the aberrantly large size of PI3K-C2ß mutant endothelial cells was caused by mTORC1 activation, which sustained growth in these cells. Consistently, pharmacological inhibition of mTORC1 with rapamycin normalized vascular morphogenesis in PI3K-C2ß mutant mice. Together, these results identify PI3K-C2ß as a crucial determinant of endothelial signaling and illustrate the importance of mTORC1 regulation during angiogenic growth.

Development of a bicistronic anti-CD19/CD20 CAR construct including abrogation of unexpected nucleic acid sequence deletions.

To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct encoding an anti-CD19 CAR and an anti-CD20 CAR. We detected deletions from the expected bicistronic construct sequence in a minority of transcripts by mRNA sequencing. Loss of bicistronic construct transgene DNA was also detected. Deletions of sequence were present at much higher frequencies in transduced T cell mRNA versus gamma-retroviral vector RNA. We concluded that these deletions were caused by intramolecular template switching of the reverse transcriptase enzyme during reverse transcription of gamma-retroviral vector RNA into transgene DNA of transduced T cells. Intramolecular template switching was driven by repeated regions of highly similar nucleic acid sequence within CAR sequences. We optimized the sequence of the bicistronic CAR construct to reduce repeated regions of highly similar sequences. This optimization nearly eliminated sequence deletions. This work shows that repeated regions of highly similar nucleic acid sequence must be avoided in complex CAR constructs. We further optimized the bicistronic construct by lengthening the linker of the anti-CD20 single-chain variable fragment. This modification increased CD20-specific interleukin-2 release and reduced CD20-specific activation-induced cell death. We selected an optimized anti-CD19/CD20 bicistronic construct for clinical development.

Ileocecal intussusception as presentation for ascending colon carcinoma. Case report.

INTRODUCTION AND IMPORTANCE: Intussusception is described as invagination of a segment of the bowel into the lumen of an adjacent segment. Although it is the most frequent cause of intestine obstruction during childhood, it is unusual in adulthood, where intussusception represents 1% of all intestine obstructions and 5 % of all intussusceptions. CASE PRESENTATION: A 64-year-old female presented with a history of weight loss, intermittent diarrhea, and occasional transrectal bleeding. An abdominal computed tomography (CT scan) was performed showing a neoproliferative appearance and associated intussusception of the ascending colon. Colonoscopy revealed an ileocecal intussusception and a tumor on the ascending colon. Right hemicolectomy was performed. Histopathological findings were consistent with colon adenocarcinoma. CLINICAL DISCUSSION: Adults have an organic lesion within the intussusception in up to 70 % of cases. The clinical presentation of intussusception can vary significantly between children and adults, who will often exhibit chronic nonspecific symptoms including nausea, changes in bowel habits, and gastrointestinal bleeding. The imaging diagnosis of intussusception is a difficult subject, the basis for the diagnosis is a high index of clinical suspicion and noninvasive techniques. CONCLUSION: Intussusception is an extremely rare condition in adults, in this age group, the malignant entity is one of the main etiologies. Intussusception continues to be a rare entity and should be considered as a differential diagnosis of chronic abdominal pain and intestinal motility disorders; the treatment of choice continues to be surgical.

Variability in the energy reserves of swordfish (Xiphias gladius) of the southeastern Pacific Ocean: A temporal and intra-individual perspective.

The temporal dynamics of energy reserves are associated with the physiological processes (i.e., reproduction) in marine fishes, in which storage organs play a key role for efficient energy investment. We evaluated the temporal (i.e., seasons) and intra-individual (i.e., organs) dynamics of adult female swordfish (Xiphias gladius) during its feeding period off the Chilean coast in the southeastern Pacific Ocean (SEPO). The biochemical composition (i.e., lipids, proteins, and glucose), energy content and fatty acid profile of the muscle, liver and gonad were evaluated during the austral autumn, winter, and spring. Our results showed principally an intra-individual effect in both the muscle and liver in the autumn and spring. Herein, a trend of higher amounts of lipids and total energy were found in the muscle, while the liver showed greater protein and glucose contents. Consequently, the muscle showed a higher saturated, monounsaturated, and polyunsaturated fatty acid contents than the liver. Although the gonad showed no significant temporal effect in the lipids and proteins contents, an increasing trend of each biochemical constituent, fatty acid group and gonadosomatic index were found from autumn to winter. Consistently, the glucose and total energy content as well Fulton's condition factor were significantly higher in winter. These findings reflect the spatial-temporal physiological dynamic of swordfish based on the storage of energy reserves in different organs during its feeding period. In this way, the products obtained from swordfish could have an added value depending on the season and capture zone, which could benefit the exploitation and regulation measures of this resource under an ecological approach of conservation and sustainability in the SEPO.

Immune gene variation associated with chromosome-scale differences among individual zebrafish genomes.

Immune genes have evolved to maintain exceptional diversity, offering robust defense against pathogens. We performed genomic assembly to examine immune gene variation in zebrafish. Gene pathway analysis identified immune genes as significantly enriched among genes with evidence of positive selection. A large subset of genes was absent from analysis of coding sequences due to apparent lack of reads, prompting us to examine genes overlapping zero coverage regions (ZCRs), defined as 2 kb stretches without mapped reads. Immune genes were identified as highly enriched within ZCRs, including over 60% of major histocompatibility complex (MHC) genes and NOD-like receptor (NLR) genes, mediators of direct and indirect pathogen recognition. This variation was most highly concentrated throughout one arm of chromosome 4 carrying a large cluster of NLR genes, associated with large-scale structural variation covering more than half of the chromosome. Our genomic assemblies uncovered alternative haplotypes and distinct complements of immune genes among individual zebrafish, including the MHC Class II locus on chromosome 8 and the NLR gene cluster on chromosome 4. While previous studies have shown marked variation in NLR genes between vertebrate species, our study highlights extensive variation in NLR gene regions between individuals of the same species. Taken together, these findings provide evidence of immune gene variation on a scale previously unknown in other vertebrate species and raise questions about potential impact on immune function.

Epidemiologic and Clinical Characteristics of Human Bocavirus Infection in Children with or without Acute Gastroenteritis in Acre, Northern Brazil.

Human bocavirus (HBoV) is an emerging virus detected around the world that may be associated with cases of acute gastroenteritis (AGE). However, its contribution to AGE has not been elucidated. This study aimed to describe the frequency, clinical features, and HBoV species circulation in children up to 5 years with or without AGE symptoms in Acre, Northern Brazil. A total of 480 stool samples were collected between January and December 2012. Fecal samples were used for extraction, nested PCR amplification, and sequencing for genotyping. Statistical analysis was applied to verify the association between epidemiological and clinical characteristics. Overall, HBoV-positivity was 10% (48/480), with HBoV-positive rates of 8.4% (19/226) and 11.4% (29/254) recorded in diarrheic and non-diarrheic children, respectively. The most affected children were in the age group ranging between 7 and 24 months (50%). HBoV infection was more frequent in children who live in urban areas (85.4%), use water from public networks (56.2%), and live with adequate sewage facilities (50%). Co-detection with other enteric viruses was 16.7% (8/48) and the most prevalent coinfection was RVA+ HBoV (50%, 4/8). HBoV-1 was the most frequent species detected in diarrheic and non-diarrheic children, responsible for 43.8% (21/48) of cases, followed by HBoV-3 (29.2%, 14/48) and HBoV-2 (25%, 12/48). In this study, HBoV infection was not always associated with AGE, as most HBoV cases belonged to the non-diarrheal group. Future studies are warranted in order to determine the role of HBoV in causing acute diarrhea disease.

Factors Associated with Tuberculosis Outcome in a Hyperendemic City in the North of Brazil.

Ananindeua city, State of Pará, North of Brazil, is a hyperendemic area for tuberculosis (TB), with a cure rate below the recommendation by the Brazilian Ministry of Health. We aimed to describe: (I) the TB incidence coefficient of Ananindeua municipality comparatively against Brazilian data; (II) TB treatment outcomes; (III) to compare the socioeconomic and epidemiological characteristics of abandonment versus cure outcome; and (IV) to evaluate the risk factors associated with TB treatment abandonment in Ananindeua city, from 2017 to 2021. This is a retrospective, descriptive, and cross-sectional epidemiological study which used secondary TB entries. Data were analyzed by linear regression, descriptive statistics, and associations were made using the Chi-square test and G-test, followed by univariate and multivariate logistic regression analyses. Cure rates ranged from 28.7% to 70.1%, abandonment between 7.3% and 11.8%, deaths from the disease ranged from 0% to 1.6%, and drug-resistant tuberculosis (TB-DR) rates had frequencies from 0% to 0.9%. Patient transfer rates to other municipalities were between 4.9% and 12.5%. The multivariate analysis showed that alcohol is almost 2 times more likely to lead an individual to abandon treatment and use of illicit drugs was almost 3 times more likely. Individuals between 20 and 59 years of age were also more likely to abandon treatment almost twice as often. Finally, data obtained in the present report is of great relevance to strengthen epidemiological surveillance and minimize possible discrepancies between the information systems and the reality of public health in high endemicity areas.

AIDS-related mortality in Pará Province, Brazilian Amazon region: Spatial and temporal analysis.

Despite considerable therapeutic advances in the care of people living with human immunodeficiency virus (HIV) and with the acquired immunodeficiency syndrome (AIDS) and an overall reduction of 47% in the AIDS mortality rate in the last decade, the AIDS-mortality rates remains high. The social determinants of health (SDH) have a direct influence on the dynamics of this phenomenon. However, changes in SDH caused by the implemented policies against HIV have been poorly investigated. Moreover, the Brazilian rainforest has had the highest and continuously increasing AIDS mortality rate in Brazil since the 1980s. In this study, AIDS mortality in a province of the Brazilian rainforest was examined by using temporal and spatial analyses. METHODS: In this ecological study, data from 2007 to 2018 were extracted from the Mortality Information System provided by the State Department of Public Health of Pará. For the temporal analysis, the integrated autoregressive model of moving average (ARIMA) and locally weighted polynomial regression (STLF) were used to forecast AIDS mortality from 2019 to 2022. For the spatial analysis, spatial autocorrelation and geographically weighted regression (GWR) analyses were employed. RESULTS: The samples consisted of 6,498 notifications for AIDS-related deaths. From 2007 to 2013, the AIDS mortality rates showed an upward trend, followed by a stabilization until 2018 and an upward forecasted trend from 2019 to 2022. High mortality rates and high-high clusters were found in economic pole municipalities. Furthermore, AIDS mortality risk was directly associated with per capita income and demographic density, except in the southwestern region of Pará, which exhibited an inverse association with population density. CONCLUSION: Although the policies against HIV may have contributed to the stabilization of AIDS mortality rates from 2013 in Pará, the upward forecasted trend until 2022 raises an alert and concern to health authorities to provide reinforcement of the policies. The geographic variability of AIDS mortality promoted by SDH provides subsidies to health authorities to implement SDH-focused strategies for AIDS mortality reduction.

A highly diverse set of novel immunoglobulin-like transcript (NILT) genes in zebrafish indicates a wide range of functions with complex relationships to mammalian receptors.

Multiple novel immunoglobulin-like transcripts (NILTs) have been identified from salmon, trout, and carp. NILTs typically encode activating or inhibitory transmembrane receptors with extracellular immunoglobulin (Ig) domains. Although predicted to provide immune recognition in ray-finned fish, we currently lack a definitive framework of NILT diversity, thereby limiting our predictions for their evolutionary origin and function. In order to better understand the diversity of NILTs and their possible roles in immune function, we identified five NILT loci in the Atlantic salmon (Salmo salar) genome, defined 86 NILT Ig domains within a 3-Mbp region of zebrafish (Danio rerio) chromosome 1, and described 41 NILT Ig domains as part of an alternative haplotype for this same genomic region. We then identified transcripts encoded by 43 different NILT genes which reflect an unprecedented diversity of Ig domain sequences and combinations for a family of non-recombining receptors within a single species. Zebrafish NILTs include a sole putative activating receptor but extensive inhibitory and secreted forms as well as membrane-bound forms with no known signaling motifs. These results reveal a higher level of genetic complexity, interindividual variation, and sequence diversity for NILTs than previously described, suggesting that this gene family likely plays multiple roles in host immunity.

Multifaceted Interplay among Social Dominance, Body Condition, Appetitive and Consummatory Sexual Behaviors, and Semen Quality in Dorper Rams during Out-Of-Season and Transition Periods.

Dorper rams (n = 24) were evaluated during the sexual resting season to determine their social rank (SR), either high (HSR) or low (LSR), under intensive management conditions in northern Mexico (25° N). Aggressive behaviors were quantified during male-to-male interactions, and appetitive and consummatory sexual behaviors during male-to-female interactions. Morphometric, live weight (LW), and body condition score (BCS) were recorded. During the early reproductive season, male-to-female behaviors were newly itemized simultaneously by seminal quality and quantity sampling. Finally, the dependent variables of the hemogram components were also quantified. Neither LW (61.25 ± 2.4 kg) nor morphometric variables differed between SR groups. However, BCS (2.25 vs. 2.66 u), sexual behaviors (i.e., approaches: 59.6 vs. 21.73 n, mating with ejaculation: 77.7 vs. 42.86 %, latency to ejaculation: 16.6 vs. 143.07 s), ejaculate volume (0.57 vs. 0.23 mL), and hemogram components favored the HSR rams (p < 0.05). Moreover, in their first male-to-female interaction, >50% of the LSR rams failed to display any sexual activity. HSR rams displayed a greater number of threatening behaviors, managing to displace LSR rams when exposed to estrus ewes during the male sexual resting season; more sexual behaviors; and an increased seminal volume in a non-live weight-dependent fashion.

Goats as Valuable Animal Model to Test the Targeted Glutamate Supplementation upon Antral Follicle Number, Ovulation Rate, and LH-Pulsatility.

The potential effect of intravenous administration of glutamate on the ovarian activity and the LH secretion pattern, considering the anestrous yearling goat as an animal model, were assessed. In late April, yearling goats (n = 20) were randomly assigned to either (1) Glutamate supplemented (GLUT; n = 10, Live Weight (LW) = 29.6 ± 1.02 kg, Body Condition (BCS) = 3.4 ± 0.2 units; i.v. supplemented with 7 mg GLUT kg−1 LW) or (2) Non-supplemented (CONT; n = 10; LW = 29.2 ± 1.07 kg, BCS = 3.5 ± 0.2 units; i.v. saline). The oats were estrus-synchronized; blood sampling (6 h × 15 min) was carried out for LH quantification. Response variables included pulsatility (PULSE), time to first pulse (TTFP), amplitude (AMPL), nadir (NAD), and area under the curve (AUC) of LH. Ovaries were ultra-sonographically scanned to assess ovulation rate (OR), number of antral follicles (AF), and total ovarian activity (TOA = OR + AF). LH-PULSE was quantified with the Munro algorithm; significant treatment x time interactions were evaluated across time. The variables LW and BCS did not differ (p > 0.05) between the experimental groups. Nevertheless, OR (1.77 vs. 0.87 ± 0.20 units), TOA (4.11 vs. 1.87 ± 0.47 units) and LH-PULSE (5.0 vs. 2.2 pulses 6 h-1) favored (p < 0.05) to the GLUT group. Our results reveal that targeted glutamate supplementation, the main central nervous system neurotransmitter, arose as an interesting strategy to enhance the hypothalamic−hypophyseal−ovarian response considering the anestrous-yearling goat as an animal model, with thought-provoking while promising translational applications.

Reduced Satb1 expression predisposes CD4+ T conventional cells to Treg suppression and promotes transplant survival.

Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs' susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes.

Selecting Representative Samples From Complex Biological Datasets Using K-Medoids Clustering.

Rapid growth of single-cell sequencing techniques enables researchers to investigate almost millions of cells with diverse properties in a single experiment. Meanwhile, it also presents great challenges for selecting representative samples from massive single-cell populations for further experimental characterization, which requires a robust and compact sampling with balancing diverse properties of different priority levels. The conventional sampling methods fail to generate representative and generalizable subsets from a massive single-cell population or more complicated ensembles. Here, we present a toolkit called Cookie which can efficiently select out the most representative samples from a massive single-cell population with diverse properties. This method quantifies the relationships/similarities among samples using their Manhattan distances by vectorizing all given properties and then determines an appropriate sample size by evaluating the coverage of key properties from multiple candidate sizes, following by a k-medoids clustering to group samples into several clusters and selects centers from each cluster as the most representatives. Comparison of Cookie with conventional sampling methods using a single-cell atlas dataset, epidemiology surveillance data, and a simulated dataset shows the high efficacy, efficiency, and flexibly of Cookie. The Cookie toolkit is implemented in R and is freely available at https://wilsonimmunologylab.github.io/Cookie/.

Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.

Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells' proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimer's disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.

A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth.

Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.

MAOA-LPR polymorphism and math anxiety: A marker of genetic susceptibility to social influences in girls?

Math anxiety (MA) seems to result from an interaction of genetic vulnerability with negative experiences learning mathematics. Although mathematics achievement does not substantially differ between the sexes, MA levels are usually higher in girls. Molecular genetic markers of MA vulnerability have been seldom explored. This article examines the contribution of the monoamine oxidase A gene (MAOA) to MA and to sex differences in MA. Five hundred and sixty-eight third to fifth graders were genotyped for the MAOA-LPR polymorphism (a repetitive element in MAOA promoter that has been associated with MAOA enzymatic activity), and assessed on general cognitive ability, mathematics achievement, and the cognitive and affective dimensions of MA. MAOA-LPR genotypes were classified as high (MAOA-H) or low (MAOA-L) according to their predicted enzymatic activity. Mixed models controlling for effects of school, sex, general cognitive ability, and mathematics achievement were evaluated. The best fitting model included school, math achievement, sex, MAOA-LPR, and the MAOA-LPR by sex interaction. This indicated that under the MAOA-H dominant model, anxiety toward mathematics interacted with the MAOA genotype: girls with an MAOA-L genotype exhibited higher levels of MA, with a small but significant effect. The association between MAOA-L genotype and MA in girls may represent an example of developmental plasticity.

Identification and evaluation of boronic compounds ameliorating cognitive deficit in orchiectomized rats.

BACKGROUND: Boron is a trace element with increasing importance in drug design. In this sense, boronic acids are emerging as therapeutic agents for several diseases. METHODS: Herein, 3- and 4- acetamidophenylboronic acids and 4-acetamidophenylboronic acid pinacol ester were identified as potential inhibitors of acetylcholinesterase through docking assays on eel, rat, and human acetylcholinesterases indicating binding on the gorge region of the target enzymes. Then, these compounds were evaluated in vitro and in vivo. RESULTS: It was found these compounds showed ability to inhibit acetylcholinesterase as competitive and non-competitive inhibitors. But also, these compounds were non-toxic to PC12 cells at micromolar concentration, and they have the ability to protect those cells against damage by amyloid-beta. CONCLUSIONS: Noticeably, intraperitoneal administration of these boronic compounds to rats with the cognitive deficit induced by orchiectomy provided ameliorative effects on disrupted behavior and neuronal damage induced by hormonal deprivation. Additional approaches are required to evaluate the possibility of multiple mechanisms of action for the observed effects in the central nervous system.