The early evolution of theropod dinosaurs is poorly understood. Whereas sauropodomorphs are well-known from the oldest dinosaur bearing outcrops, the record of theropods is fragmentary and ambiguous. ...The Triassic deposits from Brazil yielded some of the oldest dinosaurs worldwide. These dinosaurs came from two distinct Assemblage Zones (AZ): the Hyperodapedon AZ (Carnian) and the Riograndia AZ (early Norian). Here, a specimen previously assigned to cf. Dinosauromorpha is reassessed. CAPPA/UFSM 0157 comes from an enigmatic assemblage with predominance of the traversodotind cynodont Siriusgnathus. This assemblage has been tentatively assigned to the Riograndia AZ. However, the absence of index fossils still hampers a reliable assignation. The specimen, which comprises a proximal portion of a left femur, belongs to a new theropod taxon erected here as Erythrovenator jacuiensis gen. et sp. nov. The new dinosaur differs from all other known Triassic dinosaurs based on the absence of a raised dorsolateral trochanter of the femur. Erythrovenator jacuiensis gen. et sp. nov. is regarded as a theropod on the basis of the pyramidal shape of the anterior trochanter in anterior view. The results of a phylogenetic analysis corroborate this assignation. Therefore, the new dinosaur represents one of the oldest theropod dinosaurs worldwide, shedding lights on some of the earliest theropod features. Finally, the new specimen also represents the first carnivorous dinosaur from the assemblage dominated by the traversodontid cynodont Siriusgnathus, increasing our knowledge of the faunal content of this enigmatic assemblage.
•A new theropod dinosaur from the Late Triassic of Brazil is described.•It is one of the oldest known theropods worldwide.•This sheds light on some of the earliest theropod features.•The new theropod comes from a peculiar fauna dominated by traversodontid cynodonts.•The new theropod represents the first carnivorous dinosaur from this assemblage.
Diarrhea is the second leading cause of death of children up to five years old in the developing countries. Among the etiological diarrheal agents are atypical enteropathogenic Escherichia coli ...(aEPEC), one of the diarrheagenic E. coli pathotypes that affects children and adults, even in developed countries. Currently, genotypic and biochemical approaches have helped to demonstrate that some strains classified as aEPEC are actually E. albertii, a recently recognized human enteropathogen. Studies on particular strains are necessary to explore their virulence potential in order to further understand the underlying mechanisms of E. albertii infections. Here we demonstrated for the first time that infection of fragments of rat intestinal mucosa is a useful tool to study the initial steps of E. albertii colonization. We also observed that an E. albertii strain can translocate from the intestinal lumen to Mesenteric Lymph Nodes and liver in a rat model. Based on our finding of bacterial translocation, we investigated how E. albertii might cross the intestinal epithelium by performing infections of M-like cells in vitro to identify the potential in vivo translocation route. Altogether, our approaches allowed us to draft a general E. albertii infection route from the colonization till the bacterial spreading in vivo.
Most competitions in combat sports are divided into weight classes, theoretically allowing for fairer and more evenly contested disputes between athletes of similar body size, strength and agility. ...It has been well documented that most athletes, regardless of the combat sports discipline, reduce significant amounts of body weight in the days prior to competition to qualify for lighter weight classes. Rapid weight loss is characterised by the reduction of a significant amount of body weight (typically 2-10 %, although larger reductions are often seen) in a few days prior to weigh-in (mostly in the last 2-3 days) achieved by a combination of methods that include starvation, severe restriction of fluid intake and intentional sweating. In doing so, athletes try to gain a competitive advantage against lighter, smaller and weaker opponents. Such a drastic and rapid weight reduction is only achievable via a combination of aggressive strategies that lead to hypohydration and starvation. The negative impact of these procedures on health is well described in the literature. Although the impact of rapid weight loss on performance is debated, there remains robust evidence showing that rapid weight loss may not impair performance, and translates into an actual competitive advantage. In addition to the health and performance implications, rapid weight loss clearly breaches fair play and stands against the spirit of the sport because an athlete unwilling to compete having rapidly reduced weight would face unfair contests against opponents who are 'artificially' bigger and stronger. The World Anti-Doping Agency Code states that a prohibited method must meet at least two of the following criteria: (1) enhances performance; (2) endangers an athlete's health; and (3) violates the spirit of the sport. We herein argue that rapid weight loss clearly meets all three criteria and, therefore, should be banned from the sport. To quote the World Anti-Doping Agency Code, this would "protect the athletes' fundamental right to participate in a doping-free sport and thus promote health, fairness and equality".
Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic ...microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.
•Deregulated complement activation underpins the pathophysiology of severe COVID-19•Complement inhibition abrogates COVID-19 hyper-inflammation leading to resolution of SARS-CoV-2-associated ARDS•Divergent profiles of C3 vs C5 inhibition point to a broader impact of C3 inhibition on NET-driven thromboinflammation
The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal ...hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.
Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ...ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the benefits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results.
The combination of ivosidenib - an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) - and azacitidine showed encouraging clinical activity in a phase 1b trial involving patients with newly ...diagnosed
-mutated acute myeloid leukemia.
In this phase 3 trial, we randomly assigned patients with newly diagnosed
-mutated acute myeloid leukemia who were ineligible for intensive induction chemotherapy to receive oral ivosidenib (500 mg once daily) and subcutaneous or intravenous azacitidine (75 mg per square meter of body-surface area for 7 days in 28-day cycles) or to receive matched placebo and azacitidine. The primary end point was event-free survival, defined as the time from randomization until treatment failure (i.e., the patient did not have complete remission by week 24), relapse from remission, or death from any cause, whichever occurred first.
The intention-to-treat population included 146 patients: 72 in the ivosidenib-and-azacitidine group and 74 in the placebo-and-azacitidine group. At a median follow-up of 12.4 months, event-free survival was significantly longer in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group (hazard ratio for treatment failure, relapse from remission, or death, 0.33; 95% confidence interval CI, 0.16 to 0.69; P = 0.002). The estimated probability that a patient would remain event-free at 12 months was 37% in the ivosidenib-and-azacitidine group and 12% in the placebo-and-azacitidine group. The median overall survival was 24.0 months with ivosidenib and azacitidine and 7.9 months with placebo and azacitidine (hazard ratio for death, 0.44; 95% CI, 0.27 to 0.73; P = 0.001). Common adverse events of grade 3 or higher included febrile neutropenia (28% with ivosidenib and azacitidine and 34% with placebo and azacitidine) and neutropenia (27% and 16%, respectively); the incidence of bleeding events of any grade was 41% and 29%, respectively. The incidence of infection of any grade was 28% with ivosidenib and azacitidine and 49% with placebo and azacitidine. Differentiation syndrome of any grade occurred in 14% of the patients receiving ivosidenib and azacitidine and 8% of those receiving placebo and azacitidine.
Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population. Febrile neutropenia and infections were less frequent in the ivosidenib-and-azacitidine group than in the placebo-and-azacitidine group, whereas neutropenia and bleeding were more frequent in the ivosidenib-and-azacitidine group. (Funded by Agios Pharmaceuticals and Servier Pharmaceuticals; AGILE ClinicalTrials.gov number, NCT03173248.).
We study the incidence (rate of occurrence), persistence (rate of reoccurrence immediately after occurrence), and impact (effect on behavior) of students’ cognitive–affective states during their use ...of three different computer-based learning environments. Students’ cognitive–affective states are studied using different populations (Philippines, USA), different methods (quantitative field observation, self-report), and different types of learning environments (dialogue tutor, problem-solving game, and problem-solving-based Intelligent Tutoring System). By varying the studies along these multiple factors, we can have greater confidence that findings which generalize across studies are robust. The incidence, persistence, and impact of boredom, frustration, confusion, engaged concentration, delight, and surprise were compared. We found that boredom was very persistent across learning environments and was associated with poorer learning and problem behaviors, such as gaming the system. Despite prior hypothesis to the contrary, frustration was less persistent, less associated with poorer learning, and did not appear to be an antecedent to gaming the system. Confusion and engaged concentration were the most common states within all three learning environments. Experiences of delight and surprise were rare. These findings suggest that significant effort should be put into detecting and responding to boredom and confusion, with a particular emphasis on developing pedagogical interventions to disrupt the “vicious cycles” which occur when a student becomes bored and remains bored for long periods of time.
Abstract
Saturation is an intriguing phenomenon that has captured the attention of scientists since the time of Froude when he reported it for ship motion in the mid of the nineteenth century. This ...work presents the demonstration and a comprehensive study of the nonlinear saturation phenomenon on a compound micromachined structure of U-shape (micro portal frame). The frame is designed and fabricated as a multi-input and multi-output device for actuating the 1st (sway) and 2nd (symmetric) in-plane vibration modes. Geometric nonlinearities along with the softening effect of the electrostatic force present the necessary conditions for the activation of a 2:1 internal (auto-parametric) resonance between the 1st and 2nd modes. Experimental data complemented with analytical simulations are obtained showing the internal resonance and the saturation phenomenon. These results are promising for further exploration of such compound structures and for further in-depth studies of the saturation phenomenon on a variety of other systems and applications.
Eosinophils are the prominent cells in asthma, allergic bronchopulmonary mycosis (ABPMs), and fungal‐sensitization‐associated asthma, but their roles in the immunopathology of these disorders are not ...well understood. Moreover, the immunological mechanisms underlying the molecular direct effector interactions between fungi and eosinophils are rare and not fully known. Here, we provide an overview of eosinophil contributions to allergic asthma and ABPMs. We also revise the major general mechanisms of fungal recognition by eosinophils and consider past and recent advances in our understanding of the molecular mechanisms associated with eosinophil innate effector responses to different fungal species relevant to ABPMs (Alternaria alternata, Candida albicans, and Aspergillus fumigatus). We further examine and speculate about the therapeutic relevance of these findings in fungus‐associated allergic pulmonary diseases.
Eosinophil roles in fungal‐associated allergic pulmonary disorders: contributions, mechanisms of fungal recognition and potential therapeutic relevance.
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