314 research outputs found
An āorientation sphereā visualization for examining animal head movements
Animal behavior is elicited, in part, in response to external conditions, but understanding how animals perceive the environment and make the decisions that bring about these behavioral responses is challenging.Animal heads often move during specific behaviors and, additionally, typically have sensory systems (notably vision, smell, and hearing) sampling in defined arcs (normally to the front of their heads). As such, headāmounted electronic sensors consisting of accelerometers and magnetometers, which can be used to determine the movement and directionality of animal heads (where head āmovementā is defined here as changes in heading [azimuth] and/or pitch [elevation angle]), can potentially provide information both on behaviors in general and also clarify which parts of the environment the animals might be prioritizing (āenvironmental framingā).We propose a new approach to visualize the data of such headāmounted tags that combines the instantaneous outputs of head heading and pitch in a single intuitive spherical plot. This sphere has magnetic heading denoted by ālongitudeā position and head pitch by ālatitudeā on this āorientation sphereā (Oāsphere).We construct the Oāsphere for the head rotations of a number of vertebrates with contrasting body shape and ecology (oryx, sheep, tortoises, and turtles), illustrating various behaviors, including foraging, walking, and environmental scanning. We also propose correcting head orientations for body orientations to highlight specific headingāindependent head rotation, and propose the derivation of Oāsphereāmetrics, such as angular speed across the sphere. This should help identify the functions of various head behaviors.Visualizations of the Oāsphere provide an intuitive representation of animal behavior manifest via head orientation and rotation. This has ramifications for quantifying and understanding behaviors ranging from navigation through vigilance to feeding and, when used in tandem with body movement, should provide an important link between perception of the environment and response to it in freeāranging animals
The Imaging Magnetograph eXperiment (IMaX) for the Sunrise balloon-borne solar observatory
The Imaging Magnetograph eXperiment (IMaX) is a spectropolarimeter built by
four institutions in Spain that flew on board the Sunrise balloon-borne
telesocope in June 2009 for almost six days over the Arctic Circle. As a
polarimeter IMaX uses fast polarization modulation (based on the use of two
liquid crystal retarders), real-time image accumulation, and dual beam
polarimetry to reach polarization sensitivities of 0.1%. As a spectrograph, the
instrument uses a LiNbO3 etalon in double pass and a narrow band pre-filter to
achieve a spectral resolution of 85 mAA. IMaX uses the high Zeeman sensitive
line of Fe I at 5250.2 AA and observes all four Stokes parameters at various
points inside the spectral line. This allows vector magnetograms, Dopplergrams,
and intensity frames to be produced that, after reconstruction, reach spatial
resolutions in the 0.15-0.18 arcsec range over a 50x50 arcsec FOV. Time
cadences vary between ten and 33 seconds, although the shortest one only
includes longitudinal polarimetry. The spectral line is sampled in various ways
depending on the applied observing mode, from just two points inside the line
to 11 of them. All observing modes include one extra wavelength point in the
nearby continuum. Gauss equivalent sensitivities are four Gauss for
longitudinal fields and 80 Gauss for transverse fields per wavelength sample.
The LOS velocities are estimated with statistical errors of the order of 5-40
m/s. The design, calibration and integration phases of the instrument, together
with the implemented data reduction scheme are described in some detail.Comment: 17 figure
Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease
The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)āinduced gamma-activating factorāmediated immunity and interferon alpha (IFNA)āinduced interferon-stimulated genes factor 3āmediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factorāmediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3āmediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding
Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort.
Background
Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies.
Methods
Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed.
Results
Forty patients, median age 19 (range 3ā62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics.
Discussion
The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan
Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase Ī“.
Phosphoinositide 3-kinase Ī“ (PI3KĪ“), a lipid kinase consisting of a catalytic (p110Ī“, encoded by PIK3CD) and a regulatory subunit (p85, encoded by PIK3R1), generates the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in the plasma membrane of leukocytes downstream of antigen and cytokine receptors.1 Signaling via PDK1, AKT, mTOR and downstream targets such as FOXO1, contributes to the metabolic and transcriptional changes required for the expansion, differentiation and effector function of lymphocytes. Activating germline mutations in PIK3CD cause the immune dysregulatory disease activated PI3KĪ“ syndrome (APDS), usually presenting
with recurrent sinopulmonary infections in childhood, herpesvirus infections and CD4+ lymphopenia, underscoring the important role of balanced p110Ī“ activity in human adaptive immunity.
Ablation of p110Ī“ in mice leads to aberrant T cell responses and intestinal inflammation. In humans, immune dysregulation including severe colitis is present in many cancer patients who are treated with the p110Ī“-specific inhibitor Idelalisib. Recently, one patient with autosomal recessive deficiency of p85Ī± and two patients with loss-of function mutations in p110Ī“ have been described who developed humoral immunodeficiency and colitis
The effect of luminal content and rate of occlusion on the interpretation of colonic manometry
This is the accepted version of the following article: [Arkwright, J. W., Dickson, A., Maunder, S. A., Blenman, N. G., Lim, J., OāGrady, G., Archer, R., Costa, M., Spencer, N. J., Brookes, S., Pullan, A. and Dinning, P. G. (2013), The effect of luminal content and rate of occlusion on the interpretation of colonic manometry. Neurogastroenterology & Motility, 25: e52āe59.], which has been published in final form at [http://dx.doi.org/10.1111/nmo.12051]. In addition, authors may also transmit, print and share copies with colleagues, provided that there is no systematic distribution of the submitted version, e.g. posting on a listserve, network or automated delivery.Background Manometry is commonly used for diagnosis of esophageal and anorectal motility disorders. In the colon, manometry is a useful tool, but clinical application remains uncertain. This uncertainty is partly based on the belief that manometry cannot reliably detect non-occluding colonic contractions and, therefore, cannot identify reliable markers of dysmotility. This study tests the ability of manometry to record pressure signals in response to non-lumen-occluding changes in diameter, at different rates of wall movement and with content of different viscosities. Methods A numerical model was built to investigate pressure changes caused by localized, non-lumen-occluding reductions in diameter, similar to those caused by contraction of the gut wall. A mechanical model, consisting of a sealed pressure vessel which could produce localized reductions in luminal diameter, was used to validate the model using luminal segments formed from; (i) natural latex; and (ii) sections of rabbit proximal colon. Fluids with viscosities ranging from 1 to 6800 mPa s-1 and luminal contraction rates over the range 5-20 mmHg s-1 were studied. Key Results Manometry recorded non-occluding reductions in diameter, provided that they occurred with sufficiently viscous content. The measured signal was linearly dependent on the rate of reduction in luminal diameter and also increased with increasing viscosity of content (R2 = 0.62 and 0.96 for 880 and 1760 mPa s-1, respectively). Conclusions & Inferences Manometry reliably registers non-occluding contractions in the presence of viscous content, and is therefore a viable tool for measuring colonic motility. Interpretation of colonic manometric data, and definitions based on manometric results, must consider the viscosity of luminal content.Australian National Health & Medical Research Counci
Laboratory safety of dupilumab in patients aged 6ā11 years with severe atopic dermatitis : results from a phase III clinical trial
Background
Previous studies of dupilumab in adolescents and adults with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful adverse changes in laboratory parameters.
Objective
The aim of this study was to assess laboratory outcomes in children aged 6ā11 years with severe AD in a randomized, placebo-controlled, phase III trial of dupilumab.
Methods
Children aged 6ā11 years with severe AD were randomized 1:1:1 to 16 weeks of dupilumab 300 mg every 4 weeks, 100 or 200 mg every 2 weeks, or matching placebo, all with concomitant topical corticosteroids (TCS). Blood samples were collected at baseline and Weeks 4, 8, and 16; urine samples were collected at baseline and Weeks 4 and 16.
Results
Of 367 patients enrolled in the study, 362 were included in the safety analysis, 351 completed study treatment, and 4 withdrew due to treatment-emergent adverse events not related to laboratory abnormalities. Both dupilumab + TCS groups showed overall trends toward increases in mean blood levels of eosinophils and alkaline phosphatase, and decreases in mean blood levels of platelets, neutrophils, and lactate dehydrogenase levels, without corresponding mean changes in the placebo + TCS group. None of these changes were associated with symptoms or clinically meaningful adverse outcomes, and none led to treatment modification. No clinically significant changes or trends were observed for other measured laboratory parameters.
Conclusion
There were no clinically meaningful adverse changes in routine laboratory parameters attributable to treatment with dupilumab + TCS. Changes in platelet counts and lactate dehydrogenase levels likely reflect reduced inflammation. These results confirm similar findings in adults and adolescents, and suggest that there is no need for routine laboratory monitoring of children aged 6ā11 years treated with dupilumab + TCS for severe AD.
Trial Registration
ClinicalTrials.gov Identifier: NCT03345914
STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis
We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency
DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice
In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7? phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells
Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cellādependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10ā and IL-21āmediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21āinduced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human
B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic
difference in the mechanism underlying differentiation of naive versus memory B cells.This work was funded by project and program grants from the National Health
and Medical Research Council (NHMRC) of Australia (to E.K. Deenick, C.S. Ma, D.A.
Fulcher, M.C. Cook, and S.G. Tangye) and the Rockefeller University Center for 541
Clinical and Translational science (5UL1RR024143 to J.L. Casanova). C.S. Ma is a
recipient of a Career Development Fellowship, L.J. Berglund is a recipient of a
Medical Postgraduate Scholarship, and S.G. Tangye is a recipient of a Principal
Research Fellowship from the NHMRC of Australia. L. Moens is the recipient of a
Postdoctoral Fellowship from the Research Foundation-Flanders (FWO), Belgium
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