The magnetospheric imaging instrument (MIMI) is a neutral and charged particle detection system on the Cassini orbiter spacecraft designed to perform both global imaging and in-situ measurements to ...study the overall configuration and dynamics of Saturn's magnetosphere and its interactions with the solar wind, Saturn's atmosphere, Titan, and the icy satellites. Further, the Jovian magnetosphere and lo torus will be imaged during Jupiter flyby. The Titan exosphere and its cometary interaction with magnetospheric plasmas will be imaged in detail on each flyby. CHEMS (charge-energy-mass-spectrometer) uses electrostatic deflection, TOF, and energy measurement to determine ion energy, charge state, mass, and 3-D anisotropy in the range 3 to 220 keV/e with good (approximately 0.05 sq cm sr) sensitivity. Similarily, measurements in cis-Jovian space include the first detailed charge state determination of logenic ions and several ENA images of that planet's magnetosphere.
Pemphigus is a group of bullous diseases characterized by acantholysis and skin blisters. As for other autoimmune diseases, the strongest genetic associations found so far for pemphigus foliaceus ...(PF) and vulgaris (PV) are with alleles of HLA genes. However, apart from protein-coding genes, the MHC region includes a set of poorly explored long non-coding RNA (lncRNA) genes, the HLA complex group (HCG).
To investigate if HCG lncRNA alleles are associated with pemphigus susceptibility.
We analyzed SNPs in 13 HCG lncRNA genes, both in PV (Germany: 241 patients; 1,188 controls) and endemic PF (Brazil: 227 patients; 194 controls), applying multivariate logistic regression. We found 55 associations with PV (pcorr < 0.01) and nine with endemic PF (pcorr < 0.05), the majority located in TSBP1-AS1 (which includes HCG23) and HCG27 lncRNA genes, independently of HLA alleles previously associated with pemphigus. The association of TSBP1-AS1 rs3129949*A allele was further replicated in sporadic PF (p = 0.027, OR = 0.054; 75 patients and 150 controls, all from Germany). Next, we evaluated the expression levels of TSBP1-AS1, TSBP1, HCG23, and HCG27 in blood mononuclear cells of Brazilian patients and controls. HCG27 was upregulated in endemic PF (p = 0.035, log2 FC = 1.3), while TSBP1-AS1 was downregulated in PV (p = 0.029, log2 FC = −1.29). The same expression patterns were also seen in cultured keratinocytes stimulated with IgG antibodies from patients and controls from Germany. TSBP1 mRNA levels were also decreased in endemic PF blood cells (p = 0.042, log2 FC = −2.14). TSBP1-AS1 and HCG27 were also observed downregulated in CD19+ cells of endemic PF (p < 0.01, log2 FC = −0.226 and −0.46 respectively).
HCG lncRNAs are associated with susceptibility to pemphigus, being TSBP1-AS1 and HCG27 also differentially expressed in distinct cell populations. These results suggest a role for HCG lncRNAs in pemphigus autoimmunity.
•This is the first association study investigating the whole set of HLA-Complex Group (HCG) long non-coding RNAs (lncRNAs).•TSBP1-AS1 (which includes HCG23) and HCG27 are the most strongly associated genes with pemphigus.•TSBP1-AS1 rs3129949*A allele is also associated with sporadic PF.•The HCG associations are independent of HLA alleles.•TSBP1-AS1 and HCG27 are differentially expressed in pemphigus vulgaris and pemphigus foliaceus (respectively).
The LOng-Range Reconnaissance Imager (LORRI) is the high-resolution imaging instrument for the New Horizons mission to Pluto, its giant satellite Charon, its small moons Nix and Hydra, and the Kuiper ...Belt, which is the vast region of icy bodies extending roughly from Neptune’s orbit out to 50 astronomical units (AU). New Horizons launched on January 19, 2006, as the inaugural mission in NASA’s New Frontiers program. LORRI is a narrow-angle (field of view=0.29°), high-resolution (4.95 μrad pixels), Ritchey-Chrétien telescope with a 20.8-cm diameter primary mirror, a focal length of 263 cm, and a three-lens, field-flattening assembly. A 1,024×1,024 pixel (optically active region), thinned, backside-illuminated charge-coupled device (CCD) detector is used in the focal plane unit and is operated in frame-transfer mode. LORRI provides panchromatic imaging over a bandpass that extends approximately from 350 nm to 850 nm. LORRI operates in an extreme thermal environment, situated inside the warm spacecraft with a large, open aperture viewing cold space. LORRI has a silicon carbide optical system, designed to maintain focus over the operating temperature range without a focus adjustment mechanism. Moreover, the spacecraft is thruster-stabilized without reaction wheels, placing stringent limits on the available exposure time and the optical throughput needed to satisfy the measurement requirements.
To report visual acuity during the first three years after iodine 125 (I
125) brachytherapy for medium-sized choroidal melanoma and to identify important baseline and treatment factors associated ...with posttreatment visual acuity in a group of patients who were treated and observed prospectively as part of a large, randomized clinical trial.
Observational case series within a randomized, multicenter study.
Patients enrolled in the Collaborative Ocular Melanoma Study randomized trial of I
125 brachytherapy versus enucleation had choroidal melanoma of at least 2.5 mm but no more than 10.0 mm in apical height, and no more than 16.0 mm in largest basal dimension. One thousand three hundred seventeen patients enrolled from February 1987 through July 1998; 657 patients were assigned to I
125 brachytherapy. Visual acuity data for 623 patients who received I
125 brachytherapy as randomly assigned and who have been observed for at least 1 year were analyzed for this report.
Under study protocol, an ophthalmic evaluation, including best-corrected visual acuity measurement of each eye, was performed at baseline, every 6 months thereafter for 5 years, and once yearly thereafter. Two poor vision outcomes, visual acuity of 20/200 or worse that was confirmed at the next follow-up examination and loss of six lines or more of visual acuity from baseline that was confirmed at the next follow-up examination, were analyzed to identify baseline and treatment characteristics that were associated with posttreatment visual acuity.
At baseline, median visual acuity in the eye with choroidal melanoma was 20/32, with 70% of eyes having 20/40 or better and 10% of eyes having 20/200 or worse visual acuity. Three years after I
125 brachytherapy, median visual acuity was 20/125, with 34% having 20/40 or better and 45% having 20/200 or worse visual acuity, including eyes that were enucleated within 3 years of treatment. Life-table estimates of percentages of patients who lost six or more lines of visual acuity from baseline, a quadrupling of the minimum angle of resolution, with this finding confirmed at the next 6-month follow-up examination, were 18% by 1 year, 34% by 2 years, and 49% by 3 years after treatment. Life-table estimates of percentages of patients with baseline visual acuity better than 20/200 whose visual acuity decreased to 20/200 or worse, confirmed at the next follow-up examination, were 17% by 1 year, 33% by 2 years, and 43% by 3 years after treatment. As soon as a poor vision outcome was observed, improvement of visual acuity to a level that no longer met the definition for a poor vision outcome was rare. Greater baseline tumor apical height and shorter distance between the tumor and the foveal avascular zone (FAZ) were the factors most strongly associated with loss of six or more lines of visual acuity after treatment. These two factors and baseline visual acuity also were strongly associated with visual acuity 20/200 or worse after treatment. Patient history of diabetes, presence of tumor-associated retinal detachment, and tumors that were not dome shaped also were associated with greater risk for both of the poor vision outcomes.
Forty-three percent to 49% of treated eyes had substantial impairment in visual acuity by 3 years after I
125 brachytherapy, defined as a loss of six or more lines of visual acuity from the pretreatment level (49% of eyes) or visual acuity of 20/200 or worse (43% of eyes) that was confirmed at the next 6-month examination. Patients with a history of diabetes and patients whose eyes had thicker tumors, tumors close to or beneath the FAZ, tumor-associated retinal detachment, or tumors that were not dome shaped were those most likely to have a poor visual acuity outcome within 3 years after I
125 brachytherapy.
Abstract Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is ...poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS G13D ) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS G13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
We examined the effects of medially wedged foot orthoses on knee and hip joint mechanics during running in females with and without patellofemoral pain syndrome (PFPS). We also tested if these ...effects depend on standing calcaneal eversion angle. Twenty female runners with and without PFPS participated. Knee and hip joint transverse and frontal plane peak angle, excursion, and peak internal knee and hip abduction moment were calculated while running with and without a 6° full-length medially wedged foot orthoses. Separate 3-factor mixed ANOVAs (group PFPS, control x condition medial wedge, no medial wedge x standing calcaneal angle everted, neutral, inverted) were used to test the effect of medially wedged orthoses on each dependent variable. Knee abduction moment increased 3% (P = .03) and hip adduction excursion decreased 0.6° (P < .01) using medially wedged foot orthoses. No significant group x condition or calcaneal angle x condition effects were observed. The addition of medially wedged foot orthoses to standardized running shoes had minimal effect on knee and hip joint mechanics during running thought to be associated with the etiology or exacerbation of PFPS symptoms. These effects did not appear to depend on injury status or standing calcaneal posture.
Background. Mannan-binding lectin (MBL), a soluble protein of innate immunity, is known to play a role in pathogen recognition and clearance. For more than a decade, it has been proposed that MBL ...deficiency may be protective against intracellular pathogens, such as Mycobacterium leprae. Methods. The polymorphisms at the promoter and exon 1 regions of the MBL2 gene were assessed by polymerase chain reaction and sequencing performed on 264 patients with leprosy and 214 matched healthy control subjects from southern Brazil. Results. The distribution of MBL2-gene polymorphisms in patients was significantly different from that in controls, with a decreased frequency of haplotypes/genotypes associated with low expression of circulating MBL in lepromatous patients when compared with tuberculoid patients (odds ratio OR for haplotypes, 0.56 95% confidence interval {CI}, 0.33–0.93 P=.020; OR for genotypes, 0.31 95% CI, 0.13–0.71 P=.004). The LYPA haplotype was associated with susceptibility to leprosy per se (OR, 2.25 95% CI, 1.31–3.88 P=.003) and to progression to the lepromatous (OR, 2.2 95% CI, 1.21–4.05 P=.008) and borderline (OR, 2.98 95% CI, 1.29–6.87 P=.008) forms of the disease. Conclusions. These results suggest that MBL2-gene polymorphisms play a role in susceptibility to leprosy per se and in the clinical progression of the disease.
Although the frequency of noninferiority trials is increasing, the consistency of the reporting of these trials can vary. The aim of this systematic review was to assess the reporting quality of ...radiation therapy noninferiority trials.
The PubMed, Embase, and Cochrane databases were queried for randomized controlled radiation therapy trials with noninferiority hypotheses published in English between January 2000 and July 2022, and this was performed by an information scientist. Descriptive statistics were used to summarize data.
Of 423 records screened, 59 (14%) were included after full-text review. All were published after 2003 and open label. The most common primary cancer type was breast (n = 15, 25%). Altered radiation fractionation (n = 26, 45%) and radiation de-escalation (n = 11, 19%) were the most common types of interventions. The most common primary endpoints were locoregional control (n = 17, 29%) and progression-free survival (n = 14, 24%). Fifty-three (90%) reported the noninferiority margin, and only 9 (17%) provided statistical justification for the margin. The median absolute noninferiority margin was 9% (interquartile range, 5%-10%), and the median relative margin was 1.51 (interquartile range, 1.33-2.04). Sample size calculations and confidence intervals were reported in 54 studies (92%). Both intention-to-treat and per-protocol analyses were reported in 27 studies (46%). In 31 trials (53%), noninferiority of the primary endpoint was reached.
There was variability in the reporting of key components of noninferiority trials. We encourage consideration of additional statistical reasoning such as guidelines or previous trials in the selection of the noninferiority margin, reporting both absolute and relative margins, and the avoidance of statistically vague or misleading language in the reporting of future noninferiority trials.
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