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The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.
Protein–protein interactions are at the core of all cellular functions and dynamic alterations in protein interactions regulate cellular signaling. In the last decade, mass spectrometry (MS)-based proteomics has delivered unprecedented insights into human protein interaction networks. Affinity purification-MS (AP-MS) has been extensively employed for focused and high-throughput studies of steady state protein–protein interactions. Future challenges remain in mapping transient protein interactions after cellular perturbations as well as in resolving the spatial organization of protein interaction networks. AP-MS can be combined with quantitative proteomics approaches to determine the relative abundance of purified proteins in different conditions, thereby enabling the identification of transient protein interactions. In addition to affinity purification, methods based on protein co-fractionation have been combined with quantitative MS to map transient protein interactions during cellular signaling. More recently, approaches based on proximity tagging that preserve the spatial dimension of protein interaction networks have been introduced. Here, we provide an overview of MS-based methods for analyzing protein–protein interactions with a focus on approaches that aim to dissect the temporal and spatial aspects of protein interaction networks.
Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5–10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that exogenous expression of the kinase fusions in HEK 293T cells leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1, and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug‐resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients.
On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM‐WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map.
The resulting CE‐ and/or SM‐enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces.
In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM‐WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.
We set up and solve a rich life-cycle model of household decisions involving consumption of both perishable goods and housing services, stochastic and unspanned labor income, stochastic house prices, home renting and owning, stock investments, and portfolio constraints. The model features habit formation for housing consumption, which leads to optimal decisions closer in line with empirical observations. Our model can explain (i) that stock investments are low or zero for many young agents and then gradually increasing over life, (ii) that the housing expenditure share is age- and wealth-dependent, (iii) that perishable consumption is more sensitive to wealth and income shocks than housing consumption, and (iv) that non-housing consumption is hump-shaped over life.
We show that the optimal consumption of an individual over the life cycle can have the hump shape (inverted U-shape) observed empirically if the preferences of the individual exhibit internal habit formation. In the absence of habit formation, an impatient individual would prefer a decreasing consumption path over life. However, because of habit formation, a high initial consumption would lead to high required consumption in the future. To cover the future required consumption, wealth is set aside, but the necessary amount decreases with age which allows consumption to increase in the early part of life. At some age, the impatience outweighs the habit concerns so that consumption starts to decrease. We derive the optimal consumption strategy in closed form, deduce sufficient conditions for the presence of a consumption hump, and characterize the age at which the hump occurs. Numerical examples illustrate our findings. We show that our model calibrates well to U.S. consumption data from the Consumer Expenditure Survey.
Background: Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.
Methods: Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.
Results: Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability.
Conclusions: Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.
Trial registration: ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
Background: Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients.
Methods: We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist.
Results: The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival.
Conclusions: This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.