Temporal and phylogenetic evolution of the sauropod dinosaur body plan

The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to date, there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here, we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton : body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass (CoM) in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad CoM shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic–Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and CoM position are not strongly correlated with inferred feeding habits. Instead the craniad CoM positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous

Improving packet delivery efficiency using multi-radio diversity in wireless LANs

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (p. 115-120).Data transmissions in Wireless Local Area Networks (WLANs) often suffer from bit errors that arise from the notoriously complex and time-varying signal propagation characteristics of the wireless medium. A number of physical factors such as attenuation and multi-path are prevalent indoors and can lead to high bit-error rates at the link layer. These in turn lead to packet losses, low throughput, and higher and more variable packet latencies observed at higher layers, degrading the performance of many delay-sensitive and traffic-intensive wireless applications such as games, file-sharing, voice-over-IP, and streaming video. We use the notion of path diversity to develop an approach that improves data delivery efficiency and throughput in presence of transmission errors. Path diversity relies on multiple access points (APs) covering a given area or multiple radios on the user's device (or both). The hypothesis underlying this system is as follows: because frame errors are often path-dependent (e.g., due to multi-path fading), location-dependent (e.g., due to noise), and statistically independent between different transmitting radios, transmissions are likely to succeed from at least one of the available transmitters (transmit diversity).(cont.) Likewise, multiple radios that all receive versions of the same transmission may together be able to correctly recover a frame, even when any given individual radio is not (receive diversity). Using these principles, we design and implement the Multi-Radio Diversity (MRD) system, which leverages the properties of path diversity at the transmitter and receiver to reduce frame loss rates in the link-layer, leading to increased throughput and packet delivery efficiency. We introduce several techniques that make path selection, retransmission, and rate adaptation work efficiently in a MRD system based on the 802.11 MAC. We used commodity PCs and wireless interfaces to build a MRD system and conducted a wide range of indoor experiments. Our experiments measured throughput gains up to three times over conventional schemes without consuming much extra wireless bandwidth.by Allen Ka Lun Miu.Ph.D

Anti-PD1 does not improve pyroptosis induced by γδ T cells but promotes tumor regression in a pleural mesothelioma mouse model

IntroductionMesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using γδ T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that Vδ2 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1.MethodsHuman Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis‐pivaloyloxymethyl 2‐(thiazole‐2‐ylamino) ethylidene‐1,1‐bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections.ResultsIndeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18.DiscussionVδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma

A dusty pinwheel nebula around the massive star WR 104

Wolf-Rayet (WR) stars are luminous massive blue stars thought to be immediate precursors to the supernova terminating their brief lives. The existence of dust shells around such stars has been enigmatic since their discovery some 30 years ago; the intense radiation field from the star should be inimical to dust survival. Although dust-creation models, including those involving interacting stellar winds from a companion star, have been put forward, high-resolution observations are required to understand this phenomena. Here we present resolved images of the dust outflow around Wolf-Rayet WR 104, obtained with novel imaging techniques, revealing detail on scales corresponding to about 40 AU at the star. Our maps show that the dust forms a spatially confined stream following precisely a linear (or Archimedian) spiral trajectory. Images taken at two separate epochs show a clear rotation with a period of 220 +/- 30 days. Taken together, these findings prove that a binary star is responsible for the creation of the circumstellar dust, while the spiral plume makes WR 104 the prototype of a new class of circumstellar nebulae unique to interacting wind systems.Comment: 7 pages, 2 figures, Appearing in Nature (1999 April 08

Is the pharmacy profession innovative enough?: meeting the needs of Australian residents with chronic conditions and their carers using the nominal group technique

Background Community pharmacies are ideally located as a source of support for people with chronic conditions. Yet, we have limited insight into what innovative pharmacy services would support this consumer group to manage their condition/s. The aim of this study was to identify what innovations people with chronic conditions and their carers want from their ideal community pharmacy, and compare with what pharmacists and pharmacy support staff think consumers want. Methods We elicited ideas using the nominal group technique. Participants included people with chronic conditions, unpaid carers, pharmacists and pharmacy support staff, in four regions of Australia. Themes were identified via thematic analysis using the constant comparison method. Results Fifteen consumer/carer, four pharmacist and two pharmacy support staff groups were conducted. Two overarching themes were identified: extended scope of practice for the pharmacist and new or improved pharmacy services. The most innovative role for Australian pharmacists was medication continuance, within a limited time-frame. Consumers and carers wanted improved access to pharmacists, but this did not necessarily align with a faster or automated dispensing service. Other ideas included streamlined access to prescriptions via medication reminders, electronic prescriptions and a chronic illness card. Conclusions This study provides further support for extending the pharmacist’s role in medication continuance, particularly as it represents the consumer’s voice. How this is done, or the methods used, needs to optimise patient safety. A range of innovative strategies were proposed and Australian community pharmacies should advocate for and implement innovative approaches to improve access and ensure continuity of care

TGF-beta 1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Background: Fibroblastic foci are characteristic features in lung parenchyma of patients with idiopathic pulmonary fibrosis (IPF). They comprise aggregates of mesenchymal cells which underlie sites of unresolved epithelial injury and are associated with progression of fibrosis. However, the cellular origins of these mesenchymal phenotypes remain unclear. We examined whether the potent fibrogenic cytokine TGF-β1 could induce epithelial mesenchymal transition (EMT) in the human alveolar epithelial cell line, A549, and investigated the signaling pathway of TGF-β1-mediated EMT. Methods: A549 cells were examined for evidence of EMT after treatment with TGF-β1. EMT was assessed by: morphology under phase-contrast microscopy; Western analysis of cell lysates for expression of mesenchymal phenotypic markers including fibronectin EDA (Fn-EDA), and expression of epithelial phenotypic markers including E-cadherin (E-cad). Markers of fibrogenesis, including collagens and connective tissue growth factor (CTGF) were also evaluated by measuring mRNA level using RT-PCR, and protein by immunofluorescence or Western blotting. Signaling pathways for EMT were characterized by Western analysis of cell lysates using monoclonal antibodies to detect phosphorylated Erk1/2 and Smad2 after TGF-β1 treatment in the presence or absence of MEK inhibitors. The role of Smad2 in TGF-β1-mediated EMT was investigated using siRNA. Results: The data showed that TGF-β1, but not TNF-α or IL-1β, induced A549 cells with an alveolar epithelial type II cell phenotype to undergo EMT in a time-and concentration-dependent manner. The process of EMT was accompanied by morphological alteration and expression of the fibroblast phenotypic markers Fn-EDA and vimentin, concomitant with a downregulation of the epithelial phenotype marker E-cad. Furthermore, cells that had undergone EMT showed enhanced expression of markers of fibrogenesis including collagens type I and III and CTGF. MMP-2 expression was also evidenced. TGF-β1-induced EMT occurred through phosphorylation of Smad2 and was inhibited by Smad2 gene silencing; MEK inhibitors failed to attenuate either EMT-associated Smad2 phosphorylation or the observed phenotypic changes. Conclusion: Our study shows that TGF-β1 induces A549 alveolar epithelial cells to undergo EMT via Smad2 activation. Our data support the concept of EMT in lung epithelial cells, and suggest the need for further studies to investigate the phenomenon

Large-scale assessment of 7-11-year-olds’ cognitive and sensorimotor function within the Born in Bradford longitudinal birth cohort study [version 1; peer review: 1 approved, 1 approved with reservations]

Background: Cognitive ability and sensorimotor function are crucial aspects of children’s development, and are associated with physical and mental health outcomes and educational attainment. The current project forms part of the Born in Bradford (BiB) longitudinal birth-cohort study, and involved measuring sensorimotor and cognitive function in over 15,000 children aged 7-10 years. This paper describes the large-scale data collection process and presents initial analyses of the data, including the relationship between cognition/sensorimotor ability and age and task difficulty, and associations between tasks. Method: Data collection was completed in 86 schools between May 2016 and July 2019. Children were tested at school, individually, using a tablet computer with a digital stylus or finger touch for input. Assessments comprised a battery of three sensorimotor tasks (Tracking, Aiming, & Steering) and five cognitive tasks (three Working Memory tasks, Inhibition, and Processing Speed), which took approximately 40 minutes. Results: Performance improved with increasing age and decreasing task difficulty, for each task. Performance on all three sensorimotor tasks was correlated, as was performance on the three working memory tasks. In addition, performance on a composite working memory score correlated with performance on both inhibition and processing speed. Interestingly, within age-group variation was much larger than between age-group variation. Conclusions: The current project collected computerised measures of a range of cognitive and sensorimotor functions at 7-10 years of age in over 15,000 children. Performance varied as expected by age and task difficulty, and showed the predicted correlations between related tasks. Large within-age group variation highlights the need to consider the profile of individual children in studying cognitive and sensorimotor development. These data can be linked to the wider BiB dataset including measures of physical and mental health, biomarkers and genome-wide data, socio-demographic information, and routine data from local health and education services

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD

Toll-Like Receptor 4 Signaling is Involved in IgA-Stimulated Mesangial Cell Activation

PURPOSE: Deposition of polymeric IgA1 in the kidney mesangium is the hallmark of IgA nephropathy, but the molecular mechanisms of IgA-mediated mesangial responses and inflammatory injuries remain poorly understood. We hypothesize that Toll-like receptor 4 (TLR4) is involved in IgA-induced mesangial cell activation. MATERIALS AND METHODS: Mouse mesangial cells were stimulated with lipopolysaccharide (LPS) (1 μg/mL), IgA (20 μg/mL), or both, and TLR4 expression was measured by real time RT-PCR and Western blot. Intracellular responses to LPS or IgA were assessed by Western blot for ERK1/2, JNK, p38 MAP kinases (MAPKs), Iκ-Bα degradation and fibronectin secretion. MCP-1 secretion was assessed by ELISA. Small interfering RNA (siRNA) of TLR4 was used to confirm that the effects were caused by TLR4 activity. RESULTS: LPS- or IgA-treatment upregulated the levels of TLR4 mRNA and protein in cultured MMC at 24 h. LPS and IgA induced rapid phosphorylation of MAPKs, but degradation of Iκ-Bα was observed only in LPS-treated MMC. LPS, but not IgA, induced increased secretion of MCP-1 and fibronectin at 24 h or 48 h. Combined LPS and IgA treatment did not cause additional increases in TLR4 mRNA and protein levels or Iκ-Bα degradation, and MCP-1 and fibronectin secretions were less than with LPS alone. LPS- or IgA-induced TLR4 protein levels and MAPK activation were inhibited by transfection with TLR4 siRNA. CONCLUSION: These results indicate that the activation of MAPKs and MCP-1 secretion are mediated by TLR4, at least in part, in IgA-treated mesangial cells. TLR4 is involved in mesangial cell injury by induction of pro-inflammatory cytokines in IgA nephropathy.ope