Enhancing the possibilities of comprehensive two-dimensional liquid chromatography through hyphenation of purely aqueous temperature-responsive and reversed-phase liquid chromatography

Comprehensive two-dimensional liquid chromatography (LC X LC) allows for substantial gains in theoretical peak capacity in the field of liquid chromatography. However, in practice, theoretical performance is rarely achieved due to a combination of undersampling, orthogonality, and refocusing issues prevalent in many LC X LC applications. This is intricately linked to the column dimensions, flow rates, and mobile-phase compositions used, where, in many cases, incompatible or strong solvents are introduced in the second-dimension (D-2) column, leading to peak broadening and the need for more complex interfacing approaches. In this contribution, the combination of temperature-responsive (TR) and reversed-phase (RP) LC is demonstrated, which, due to the purely aqueous mobile phase used in TRLC, allows for complete and more generic refocusing of organic solutes prior to the second-dimension RP separation using a conventional 10-port valve interface. Thus far, this was only possible when combining other purely aqueous modes such as ion exchange or gel filtration chromatography with RPLC, techniques which are limited to the analysis of charged or high MW solutes, respectively. This novel TRLC x RPLC combination relaxes undersampling constraints and complete refocusing and therefore offers novel possibilities in the field of LC x LC including temperature modulation. The concept is illustrated through the TRLC x RPLC analysis of mixtures of neutral organic solutes

Unruptured brain arteriovenous malformations : primary ONYX embolization in ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-eligible patients

Background and Purpose: In light of evidence from ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations), neurovascular specialists had to reconsider deliberate treatment of unruptured brain arteriovenous malformations (uBAVMs). Our objective was to determine the outcomes of uBAVM treated with primary embolization using ethylene vinyl alcohol (ONYX). Methods: Patients with uBAVM who met the inclusion criteria of ARUBA and were treated with primary Onyx embolization were assigned to this retrospective study. The primary outcome was the modified Rankin Scale score. Secondary outcomes were stroke or death because of uBAVM or intervention and uBAVM obliteration. Results: Sixty-one patients (mean age, 38 years) were included. The median observation period was 60 months. Patients were treated by embolization alone (41.0%), embolization and radiosurgery (57.4%), or embolization and excision (1.6%). Occlusion was achieved in 44 of 57 patients with completed treatment (77.2%). Forty-seven patients (77.1%) had no clinical impairment at the end of observation (modified Rankin Scale score of <2). Twelve patients (19.7%) reached the outcome of stroke or death because of uBAVM or intervention. Treatment-related mortality was 6.6% (4 patients). Conclusions: In uBAVM, Onyx embolization alone or combined with stereotactic radiosurgery achieves a high occlusion rate. Morbidity remains a challenge, even if it seems lower than in the ARUBA trial

Stationarity analysis of V2I radio channel in a suburban environment

Due to rapid changes in the environment, vehicular communication channels no longer satisfy the assumption of wide-sense stationary uncorrelated scattering. The non-stationary fading process can be characterized by assuming local stationarity regionswith finite extent in time and frequency. The local scattering function (LSF) and channel correlation function (CCF) provide a framework to characterize the mean power and correlation of the non-stationary channel scatterers, respectively. In this paper, we estimate the LSF and CCF from measurements collected in a vehicle-to-infrastructure radio channel sounding campaign in a suburban environment in Lille, France. Based on the CCF, the stationarity region is evaluated in time as 567 ms and used to capture the non-stationary fading parameters. We obtain the time-varying delay and Doppler power profiles fromthe LSF, and we analyze the corresponding root-mean-square delay and Doppler spreads. We show that the distribution of these parameters follows a lognormal model. Finally, application relevance in terms of channel capacity and diversity techniques is discussed. Results show that the assumption of ergodic capacity and the performance of various diversity techniques depend on the stationarity and coherence parameters of the channel. The evaluation and statistical modeling of such parameters can provide away of tracking channel variation, hence, increasing the performance of adaptive schemes

Experimental characterization of non-stationary V2I radio channel in tunnels

The fading process in vehicular communications is inherently non-stationary. In this paper, vehicle-to-infrastructure (V2I) radio channel measurements are performed inside a tunnel for low and medium traffic conditions to estimate the stationarity time, in addition to the time-varying RMS delay and Doppler spreads. Furthermore, we show the good fit of the spreads to a lognormal distribution, as well as for the Rician K-factor of the fading amplitude. From our analysis we conclude that the traffic density has an impact on the large-scale parameters as it increases delay and Doppler spreads, while reducing the correlation between them as well as the average K-factor. Larger traffic densities may be required to impact the stationarity time

Nlrp3 inflammasome activation and Gasdermin D-driven pyroptosis are immunopathogenic upon gastrointestinal norovirus infection.

Norovirus infection is the leading cause of food-borne gastroenteritis worldwide, being responsible for over 200,000 deaths annually. Studies with murine norovirus (MNV) showed that protective STAT1 signaling controls viral replication and pathogenesis, but the immune mechanisms that noroviruses exploit to induce pathology are elusive. Here, we show that gastrointestinal MNV infection leads to widespread IL-1β maturation in MNV-susceptible STAT1-deficient mice. MNV activates the canonical Nlrp3 inflammasome in macrophages, leading to maturation of IL-1β and to Gasdermin D (GSDMD)-dependent pyroptosis. STAT1-deficient macrophages displayed increased MAVS-mediated expression of pro-IL-1β, facilitating elevated Nlrp3-dependent release of mature IL-1β upon MNV infection. Accordingly, MNV-infected Stat1-/- mice showed Nlrp3-dependent maturation of IL-1β as well as Nlrp3-dependent pyroptosis as assessed by in vivo cleavage of GSDMD to its active N-terminal fragment. While MNV-induced diarrheic responses were not affected, Stat1-/- mice additionally lacking either Nlrp3 or GSDMD displayed lower levels of the fecal inflammatory marker Lipocalin-2 as well as delayed lethality after gastrointestinal MNV infection. Together, these results uncover new insights into the mechanisms of norovirus-induced inflammation and cell death, thereby revealing Nlrp3 inflammasome activation and ensuing GSDMD-driven pyroptosis as contributors to MNV-induced immunopathology in susceptible STAT1-deficient mice.Wellcome Trust BBSR

Experimental study on the impact of antenna characteristics on non-stationary V2I channel parameters in tunnels

This paper analyses the experimentally-assessed dual-polarized (DP) mobile channel in a tunnel environment at 1.35 GHz under traffic conditions. We investigate the impact of antenna polarization and radiation pattern on the non-stationary vehicle-to-infrastructure (V2I) channel. Basic channel evaluation metrics are examined including path gain, co-polarization ratio (CPR), and cross-polarization discrimination (XPD). In addition, the stationarity region is estimated using the channel correlation function approach, and used to calculate the time-varying delay and Doppler power profiles. Statistical models are presented for parameters like CPR, XPD, RMS delay and Doppler spreads, where the lognormal distribution provides the best fit. The polarization and the opening angle of the antennas into the propagation channel are found to strongly influence the observed non-stationarity of the channel. They impact the degree of multipath richness that is captured, thus providing different path gain, delay and Doppler spreads. Based on our analysis, the directional antenna with vertical polarization provides the longest stationarity time of 400 ms at 90 km/h, as well as the highest path gain and lowest dispersion. Furthermore, the DP channel capacity is calculated and its dependence on different normalization approaches is investigated. We propose a more accurate normalization for the DP channels that takes the conservation of energy into account. Moreover, the subchannels correlation coefficients are determined. While the condition number is found to be low on average, the correlation results show high correlation among the DP subchannels. As conclusion, we show how the CPR and XPD play the main role in providing multiplexing gain for DP tunnel channels

Increasing Use of Allogeneic Hematopoietic Cell Transplantation in Patients Aged 70 Years and Older in the United States

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥ 70 years with hematologic malignancies across the United States. Adults ≥ 70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥ 70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P \u3c .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥ 3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥ 70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant

Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42⋅guanosine triphosphate and SNX9 activate N-WASP–WIP- and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX–BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease–associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome.J.L. Gallop is supported by a Wellcome Trust Research Career Development Fellowship (grant WT095829AIA). F.  Daste, A.  Walrant, J.R. Gadsby, and J. Mason are supported by an H2020 European Research Council Starting Grant (281971) awarded to J.L. Gallop. Gurdon Institute funding is provided by the Wellcome Trust (grant 092096) and Cancer Research UK (grant C6946/A14492). The Swedish Medical Research Council and the Swedish Foundation for Strategic Research supported the work of M.R. Holst and R. Lundmark. S.F. Lee is funded by a Royal Society University Research Fellowship (grant UF120277). M. Mettlen is funded by grant MH73125 to Sandra L. Schmid (University of Texas Southwestern Medical Center)

The Fetal Hypothalamus Has the Potential to Generate Cells with a Gonadotropin Releasing Hormone (GnRH) Phenotype

Neurospheres (NS) are colonies of neural stem and precursor cells capable of differentiating into the central nervous system (CNS) cell lineages upon appropriate culture conditions: neurons, and glial cells. NS were originally derived from the embryonic and adult mouse striatum subventricular zone. More recently, experimental evidence substantiated the isolation of NS from almost any region of the CNS, including the hypothalamus. Here we report a protocol that enables to generate large quantities of NS from both fetal and adult rat hypothalami. We found that either FGF-2 or EGF were capable of inducing NS formation from fetal hypothalamic cultures, but that only FGF-2 is effective in the adult cultures. The hypothalamic-derived NS are capable of differentiating into neurons and glial cells and most notably, as demonstrated by immunocytochemical detection with a specific anti-GnRH antibody, the fetal cultures contain cells that exhibit a GnRH phenotype upon differentiation. This in vitro model should be useful to study the molecular mechanisms involved in GnRH neuronal differentiation