Particle acceleration mechanisms in supermassive black hole jets, such as shock acceleration, magnetic reconnection, and turbulence, are expected to have observable signatures in the multiwavelength ...polarization properties of blazars. The recent launch of the Imaging X-Ray Polarimetry Explorer (IXPE) enables us, for the first time, to use polarization in the X-ray band (2–8 keV) to probe the properties of the jet synchrotron emission in high-synchrotron-peaked BL Lac objects (HSPs). We report the discovery of X-ray linear polarization (degree Πx = 15% ± 2% and electric vector position angle ψx = 35° ± 4°) from the jet of the HSP Mrk 421 in an average X-ray flux state. At the same time, the degree of polarization at optical, infrared, and millimeter wavelengths was found to be lower by at least a factor of 3. During the IXPE pointing, the X-ray flux of the source increased by a factor of 2.2, while the polarization behavior was consistent with no variability. The higher level of Πx compared to longer wavelengths, and the absence of significant polarization variability, suggest a shock is the most likely X-ray emission site in the jet of Mrk 421 during the observation. The multiwavelength polarization properties are consistent with an energy-stratified electron population, where the particles emitting at longer wavelengths are located farther from the acceleration site, where they experience a more disordered magnetic field.
We report on a ∼5σ detection of polarized 3–6 keV X-ray emission from the supernova remnant Cassiopeia A (Cas A) with the Imaging X-ray Polarimetry Explorer (IXPE). The overall polarization degree of ...1.8% ± 0.3% is detected by summing over a large region, assuming circular symmetry for the polarization vectors. The measurements imply an average polarization degree for the synchrotron component of ∼2.5%, and close to 5% for the X-ray synchrotron-dominated forward shock region. These numbers are based on an assessment of the thermal and nonthermal radiation contributions, for which we used a detailed spatial-spectral model based on Chandra X-ray data. A pixel-by-pixel search for polarization provides a few tentative detections from discrete regions at the ∼ 3σ confidence level. Given the number of pixels, the significance is insufficient to claim a detection for individual pixels, but implies considerable turbulence on scales smaller than the angular resolution. Cas A's X-ray continuum emission is dominated by synchrotron radiation from regions within ≲1017 cm of the forward and reverse shocks. We find that (i) the measured polarization angle corresponds to a radially oriented magnetic field, similar to what has been inferred from radio observations; (ii) the X-ray polarization degree is lower than in the radio band (∼5%). Since shock compression should impose a tangential magnetic-field structure, the IXPE results imply that magnetic fields are reoriented within ∼1017 cm of the shock. If the magnetic-field alignment is due to locally enhanced acceleration near quasi-parallel shocks, the preferred X-ray polarization angle suggests a size of 3 × 1016 cm for cells with radial magnetic fields.
Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the ...causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A p.Leu552∗ and c.280G>A p.Asp94Asn) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552∗ alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3β phosphorylation that is observed after wild-type APPL1 transfection. These findings—linking APPL1 mutations to familial forms of diabetes—reaffirm the critical role of APPL1 in glucose homeostasis.
Abstract
The launch of the Imaging X-ray Polarimetry Explorer (IXPE) on 2021 December 9 has opened a new window in X-ray astronomy. We report here the results of the first IXPE observation of a ...weakly magnetized neutron star, GS 1826−238, performed on 2022 March 29–31 when the source was in a high soft state. An upper limit (99.73% confidence level) of 1.3% for the linear polarization degree is obtained over the IXPE 2–8 keV energy range. Coordinated INTEGRAL and NICER observations were carried out simultaneously with IXPE. The spectral parameters obtained from the fits to the broadband spectrum were used as inputs for Monte Carlo simulations considering different possible geometries of the X-ray emitting region. Comparing the IXPE upper limit with these simulations, we can put constraints on the geometry and inclination angle of GS 1826–238.
Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells ...with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma-derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors.
The chemistry of light dipnictenes has been widely investigated in the last century with remarkable achievements especially for azobenzene derivatives. In contrast, distibenes and dibismuthenes are ...relatively rare and show very limited reactivity. Herein, we have designed a protocol using visible light to enhance the reactivity of heavy dipnictenes. Exploiting the distinctive π–π* transition, we have been able to isolate unique examples of dipnictene‐cobalt complexes. The reactivity of the distibene complex was further exploited using red light in the presence of a diazoolefin to access an unusual four‐membered bicyclo1.1.0butane analog, containing only a single carbon atom. These findings set the bases to a conceptually new strategy in heavy element double bonds chemistry where visible light is at the front seat of bond activation.
The manuscript describes the first example of visible‐light‐promoted addition of pnictogen‐pnictogen double bonds to a late transition metal. The use of light has been essential to unlock the reactivity of this otherwise unreactive class of compounds.
Although programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced ...NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized.
In this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT.
Among 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38).
In advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.
In this study we evaluated whether investing in more spatially detailed environmental covariates improves the accuracy of digital soil maps. We used a case study from Southern Brazil to map clay ...content (CLAY), organic carbon content (SOC), and effective cation exchange capacity (ECEC) of the topsoil for a~2000ha area located on the edge of the plateau of the Paraná Sedimentary Basin. Five covariates, each with two levels of spatial detail were used: area-class soil maps, digital elevation models (DEM), geologic maps, land use maps, and satellite images. Thirty-two multiple linear regression models were calibrated for each soil property using all spatial detail combinations of the covariates. For each combination, stepwise regression was used to select predictor variables incorporated in the model. Model evaluation was done using the adjusted R-square of the regression. The baseline model, calibrated with the less detailed version of each covariate, and the best performing model were used to calibrate two linear mixed models for each soil property. Model parameters were estimated using restricted maximum likelihood. Spatial prediction was performed using the empirical best linear unbiased predictor. Validation of baseline and best performing linear multiple regression and linear mixed models was done using cross-validation. Results show that for CLAY the prediction accuracy did not considerably improve by using more detailed covariates. The amount of variance explained increased only ~2 percentage points (pp), less than that obtained by including the kriging step, which explained 4pp. On the other hand, prediction of SOC and ECEC improved by ~13pp when the baseline model was replaced by the best performing model. Overall, the increase in prediction performance was modest and may not outweigh the extra costs of using more detailed covariates. It may be more efficient to spend extra resources on collecting more soil observations, or increasing the detail of only those covariates that have the strongest improvement effect. In our case study, the latter would only work for SOC and ECEC, by investing in a more detailed land use map and possibly also a more detailed geologic map and DEM.
•We assess whether more detailed covariates deliver more accurate digital soil maps.•We evaluate five covariates simultaneously.•Increase in model performance is modest and may not outweigh the extra costs.•Including a kriging step can be as efficient as purchasing more detailed covariates.
Administrative databases are widely available and have been extensively used to provide estimates of chronic disease prevalence for the purpose of surveillance of both geographical and temporal ...trends. There are, however, other sources of data available, such as medical records from primary care and national surveys. In this paper we compare disease prevalence estimates obtained from these three different data sources.
Data from general practitioners (GP) and administrative transactions for health services were collected from five Italian regions (Veneto, Emilia Romagna, Tuscany, Marche and Sicily) belonging to all the three macroareas of the country (North, Center, South). Crude prevalence estimates were calculated by data source and region for diabetes, ischaemic heart disease, heart failure and chronic obstructive pulmonary disease (COPD). For diabetes and COPD, prevalence estimates were also obtained from a national health survey. When necessary, estimates were adjusted for completeness of data ascertainment.
Crude prevalence estimates of diabetes in administrative databases (range: from 4.8% to 7.1%) were lower than corresponding GP (6.2%-8.5%) and survey-based estimates (5.1%-7.5%). Geographical trends were similar in the three sources and estimates based on treatment were the same, while estimates adjusted for completeness of ascertainment (6.1%-8.8%) were slightly higher. For ischaemic heart disease administrative and GP data sources were fairly consistent, with prevalence ranging from 3.7% to 4.7% and from 3.3% to 4.9%, respectively. In the case of heart failure administrative estimates were consistently higher than GPs' estimates in all five regions, the highest difference being 1.4% vs 1.1%. For COPD the estimates from administrative data, ranging from 3.1% to 5.2%, fell into the confidence interval of the Survey estimates in four regions, but failed to detect the higher prevalence in the most Southern region (4.0% in administrative data vs 6.8% in survey data). The prevalence estimates for COPD from GP data were consistently higher than the corresponding estimates from the other two sources.
This study supports the use of data from Italian administrative databases to estimate geographic differences in population prevalence of ischaemic heart disease, treated diabetes, diabetes mellitus and heart failure. The algorithm for COPD used in this study requires further refinement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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