Assessing thoraco‐pelvic covariation in Homo sapiens and Pan troglodytes: A 3D geometric morphometric approach

Objectives Understanding thoraco‐pelvic integration in Homo sapiens and their closest living relatives (genus Pan) is of great importance within the context of human body shape evolution. However, studies assessing thoraco‐pelvic covariation across Hominoidea species are scarce, although recent research would suggest shared covariation patterns in humans and chimpanzees but also species‐specific features, with sexual dimorphism and allometry influencing thoraco‐pelvic covariation in these taxa differently. Material and Methods N = 30 adult H. sapiens and N = 10 adult Pan troglodytes torso 3D models were analyzed using 3D geometric morphometrics and linear measurements. Effects of sexual dimorphism and allometry on thoraco‐pelvic covariation were assessed via regression analyses, and patterns of thoraco‐pelvic covariation in humans and chimpanzees were computed via Two‐Block Partial Least Squares analyses. Results Results confirm the existence of common aspects of thoraco‐pelvic covariation in humans and chimpanzees, and also species‐specific covariation in H. sapiens that is strongly influenced by sexual dimorphism and allometry. Species‐specific covariation patterns in chimpanzees could not be confirmed because of the small sample size, but metrics point to a correspondence between the most caudal ribs and iliac crest morphology that would be irrespective of sex. Conclusions This study suggests that humans and chimpanzees share common aspects of thoraco‐pelvic covariation but might differ in others. In humans, torso integration is strongly influenced by sexual dimorphism and allometry, whilst in chimpanzees it may not be. This study also highlights the importance not only of torso widths but also of torso depths when describing patterns of thoraco‐pelvic covariation in primates. Larger samples are necessary to support these interpretations

Aggressive behavior, emotional, and attention problems across childhood and academic attainment at the end of primary school

Purpose: To assess whether aggressive behavior and emotional problems from early childhood onwards are related to academic attainment at the end of primary education, and whether these associations are independent of attention problems. Methods: Data on 2546 children participating in a longitudinal birth cohort in Rotterdam were analyzed. Aggressive behavior, attention and emotional problems at ages 1½, 3, 5 and 10 years were assessed with the Child Behavior Checklist. Academic attainment at the end of primary school (12 years of age) was measured with the CITO test, a national Dutch academic test score. Results: Aggressive behavior from age 1½ to 10 years was negatively associated with academic attainment, but these associations attenuated to non-significance when accounting for comorbid attention problems. For emotional problems, first, only problems at 10 years were associated with poorer academic attainment. Yet, when accounting for attention problems, the association reversed: more emotional problems from 1½ to 10 years were associated with a better academic attainment. Attention problems at ages 1½ to 10 years were negatively associated with academic attainment, independent of comorbid emotional problems or aggressive behavior. Conclusions: Attention problems across childhood are related to a poorer academic attainment, while emotional problems predicted better academic attainment. Moreover, the relationship between aggressive behavior and academic attainment was explained by comorbid attention problems. Future research should determine the mechanisms through which attention problems and emotional problems affect academic attainment, to inform strategies for the promotion of better educational attainment

AmrZ is a major determinant of c-di-GMP levels in Pseudomonas fluorescens F113

The transcriptional regulator AmrZ is a global regulatory protein conserved within the pseudomonads. AmrZ can act both as a positive and a negative regulator of gene expression, controlling many genes implicated in environmental adaption. Regulated traits include motility, iron homeostasis, exopolysaccharides production and the ability to form biofilms. In Pseudomonas fluorescens F113, an amrZ mutant presents a pleiotropic phenotype, showing increased swimming motility, decreased biofilm formation and very limited ability for competitive colonization of rhizosphere, its natural habitat. It also shows different colony morphology and binding of the dye Congo Red. The amrZ mutant presents severely reduced levels of the messenger molecule cyclic-di-GMP (c-di-GMP), which is consistent with the motility and biofilm formation phenotypes. Most of the genes encoding proteins with diguanylate cyclase (DGCs) or phosphodiesterase (PDEs) domains, implicated in c-di-GMP turnover in this bacterium, appear to be regulated by AmrZ. Phenotypic analysis of eight mutants in genes shown to be directly regulated by AmrZ and encoding c-di-GMP related enzymes, showed that seven of them were altered in motility and/or biofilm formation. The results presented here show that in P. fluorescens, AmrZ determines c-di-GMP levels through the regulation of a complex network of genes encoding DGCs and PDEs

Parental Age in Relation to Offspring's Neurodevelopment

Objective: Advanced parenthood increases the risk of severe neurodevelopmental disorders like autism, Down syndrome and schizophrenia. Does advanced parenthood also negatively impact offspring’s general neurodevelopment? Method: We analyzed child-, father-, mother- and teacher-rated attention-problems (N = 38,024), and standardized measures of intelligence (N = 10,273) and educational achievement (N = 17,522) of children from four Dutch population-based cohorts. The mean age over cohorts varied from 9.73–13.03. Most participants were of Dutch origin, ranging from 58.7%-96.7% over cohorts. We analyzed 50% of the data to generate hypotheses and the other 50% to evaluate support for these hypotheses. We aggregated the results over cohorts with Bayesian research synthesis. Results: We mostly found negative linear relations between parental age and attention-problems, meaning that offspring of younger parents tended to have more attention problems. Maternal age was positively and linearly related to offspring’s IQ and educational achievement. Paternal age showed an attenuating positive relation with educational achievement and an inverted U-shape relation with IQ, with offspring of younger and older fathers at a disadvantage. Only the associations with maternal age remained after including SES. The inclusion of child gender in the model did not affect the relation between parental age and the study outcomes. Conclusions: Effects were small but significant, with better outcomes for children born to older parents. Older parents tended to be of higher SES. Indeed, the positive relation between parenta

Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48 and 43, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Ringer's lactate improves liver recovery in a murine model of acetaminophen toxicity

<p>Abstract</p> <p>Background</p> <p>Acetaminophen (APAP) overdose induces massive hepatocyte necrosis. Liver regeneration is a vital process for survival after a toxic insult. Since hepatocytes are mostly in a quiescent state (G₀), the regeneration process requires the priming of hepatocytes by cytokines such as TNF-α and IL-6. Ringer's lactate solution (RLS) has been shown to increase serum TNF-α and IL-6 in patients and experimental animals; in addition, RLS also provides lactate, which can be used as an alternative metabolic fuel to meet the higher energy demand by liver regeneration. Therefore, we tested whether RLS therapy improves liver recovery after APAP overdose.</p> <p>Methods</p> <p>C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (300 mg/kg dissolved in 1 mL sterile saline). Following 2 hrs of APAP challenge, the mice were given 1 mL RLS or Saline treatment every 12 hours for a total of 72 hours.</p> <p>Results</p> <p>72 hrs after APAP challenge, compared to saline-treated group, RLS treatment significantly lowered serum transaminases (ALT/AST) and improved liver recovery seen in histopathology. This beneficial effect was associated with increased hepatic tissue TNF-α concentration, enhanced hepatic NF-κB DNA binding and increased expression of cell cycle protein cyclin D1, three important factors in liver regeneration.</p> <p>Conclusion</p> <p>RLS improves liver recovery from APAP hepatotoxicity.</p

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

SOS Response Induces Persistence to Fluoroquinolones in Escherichia coli

Bacteria can survive antibiotic treatment without acquiring heritable antibiotic resistance. We investigated persistence to the fluoroquinolone ciprofloxacin in Escherichia coli. Our data show that a majority of persisters to ciprofloxacin were formed upon exposure to the antibiotic, in a manner dependent on the SOS gene network. These findings reveal an active and inducible mechanism of persister formation mediated by the SOS response, challenging the prevailing view that persisters are pre-existing and formed purely by stochastic means. SOS-induced persistence is a novel mechanism by which cells can counteract DNA damage and promote survival to fluoroquinolones. This unique survival mechanism may be an important factor influencing the outcome of antibiotic therapy in vivo

Identification of the CRE-1 Cellulolytic Regulon in Neurospora crassa

Background: In filamentous ascomycete fungi, the utilization of alternate carbon sources is influenced by the zinc finger transcription factor CreA/CRE-1, which encodes a carbon catabolite repressor protein homologous to Mig1 from Saccharomyces cerevisiae. In Neurospora crassa, deletion of cre-1 results in increased secretion of amylase and b-galactosidase. Methodology/Principal Findings: Here we show that a strain carrying a deletion of cre-1 has increased cellulolytic activity and increased expression of cellulolytic genes during growth on crystalline cellulose (Avicel). Constitutive expression of cre-1 complements the phenotype of a N. crassa Dcre-1 strain grown on Avicel, and also results in stronger repression of cellulolytic protein secretion and enzyme activity. We determined the CRE-1 regulon by investigating the secretome and transcriptome of a Dcre-1 strain as compared to wild type when grown on Avicel versus minimal medium. Chromatin immunoprecipitation-PCR of putative target genes showed that CRE-1 binds to only some adjacent 59-SYGGRG-39 motifs, consistent with previous findings in other fungi, and suggests that unidentified additional regulatory factors affect CRE-1 binding to promoter regions. Characterization of 30 mutants containing deletions in genes whose expression level increased in a Dcre-1 strain under cellulolytic conditions identified novel genes that affect cellulase activity and protein secretion