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Owing to the low-gravity conditions in space, space-borne laboratories enable experiments with extended free-fall times. Because Bose–Einstein condensates have an extremely low expansion energy, space-borne atom interferometers based on Bose–Einstein condensation have the potential to have much greater sensitivity to inertial forces than do similar ground-based interferometers. On 23 January 2017, as part of the sounding-rocket mission MAIUS-1, we created Bose–Einstein condensates in space and conducted 110 experiments central to matter-wave interferometry, including laser cooling and trapping of atoms in the presence of the large accelerations experienced during launch. Here we report on experiments conducted during the six minutes of in-space flight in which we studied the phase transition from a thermal ensemble to a Bose–Einstein condensate and the collective dynamics of the resulting condensate. Our results provide insights into conducting cold-atom experiments in space, such as precision interferometry, and pave the way to miniaturizing cold-atom and photon-based quantum information concepts for satellite-based implementation. In addition, space-borne Bose–Einstein condensation opens up the possibility of quantum gas experiments in low-gravity conditions 1 , 2 . A Bose–Einstein condensate is created in space that has sufficient stability to enable its characteristic dynamics to be studied.

Background Calcium (Ca 2+ ) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via calcium release-activated calcium (CRAC) channels represents a major pathway for Ca 2+ influx from the extracellular space in multiple cell types. The impact of JAK2-V617F and CALR mutations which are disease initiating in myeloproliferative neoplasms (MPN) on SOCE, calcium flux from the endoplasmic reticulum (ER) to the cytosol, and related key signaling pathways in the presence or absence of erythropoietin (EPO) or thrombopoietin (TPO) is poorly understood. Thus, this study aimed to elucidate the effects of these mutations on the aforementioned calcium dynamics, in cellular models of MPN. Methods Intracellular Ca 2+ levels were measured over a time frame of 0–1080 s in Fura-2 AM labeled myeloid progenitor 32D cells expressing various mutations (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, and del52/MPL). Basal Ca 2+ concentrations were assessed from 0–108 s. Subsequently, cells were stimulated with EPO/TPO in Ca 2+ -free Ringer solution, measuring Ca 2+ levels from 109–594 s (store depletion). Then, 2 mM of Ca 2+ buffer resembling physiological concentrations was added to induce SOCE, and Ca 2+ levels were measured from 595–1080 s. Fura-2 AM emission ratios (F340/380) were used to quantify the integrated Ca 2+ signal. Statistical significance was assessed by unpaired Student's t-test or Mann–Whitney-U-test, one-way or two-way ANOVA followed by Tukey's multiple comparison test. Results Following EPO stimulation, the area under the curve (AUC) representing SOCE significantly increased in 32D-JAK2-V617F cells compared to JAK2-WT cells. In TPO-stimulated CALR cells, we observed elevated Ca 2+ levels during store depletion and SOCE in CALR-WT cells compared to CALR-ins5 and del52 cells. Notably, upon stimulation, key components of the Ca 2+ signaling pathways, including PLCγ-1 and IP3R, were differentially affected in these cell lines. Hyper-activated PLCγ-1 and IP3R were observed in JAK2-V617F but not in CALR mutated cells. Inhibition of calcium regulatory mechanisms suppressed cellular growth and induced apoptosis in JAK2-V617F cells. Conclusions This report highlights the impact of JAK2 and CALR mutations on Ca 2+ flux (store depletion and SOCE) in response to stimulation with EPO and TPO. The study shows that the JAK2-V617F mutation strongly alters the regulatory mechanism of EpoR/JAK2-dependent intracellular calcium balance, affecting baseline calcium levels, EPO-induced calcium entry, and PLCγ-1 signaling pathways. Our results reveal an important role of calcium flux in the homeostasis of JAK2-V617F positive cells.

T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells. The essential trace element zinc has reported immunomodulatory capacity and high zinc concentrations interfere with T cell function. However, how high doses of zinc affect T cell gene networks and metabolism remained so far elusive. Herein, we demonstrate by means of transcriptomic analysis that zinc aspartate (UNIZINK), a registered pharmaceutical infusion solution with high bioavailability, negatively regulates gene networks controlling DNA replication and the energy metabolism of murine CD3/CD28-activated CD4 + T cells. Specifically, in the presence of zinc, CD4 + T cells show impaired expression of cell cycle, glycolytic and tricarboxylic acid cycle genes, which functionally cumulates in reduced glycolysis, oxidative phosphorylation, metabolic fitness and viability. Moreover, high zinc concentrations impaired nuclear expression of the metabolic transcription factor MYC, prevented Th1 and Th2 differentiation in vitro and reduced Th1 autoimmune central nervous system (CNS) inflammation and Th2 asthmatic airway inflammation induced by house dust mites in vivo. Together, we find that higher zinc doses impair the metabolic fitness of CD4 + T cells and prevent Th1 CNS autoimmunity and Th2 allergy.

Early-onset Parkinson's Disease (EOPD) is a neurodegenerative disease with the clinical manifestation of movement symptoms before the age of 50. Patients with EOPD frequently have a positive family history of disease, with bi-allelic loss of function mutations in PRKN and PINK1 as the most common genetic cause. To date, the majority of genetic studies have been conducted on patients with European ancestry, limiting the understanding of the genetic heterogeneity of EOPD across populations. The aim of this study was to screen the PRKN and PINK1 genes in an Ecuadorian EOPD cohort, and improve the understanding of the genetic profile of patients in this population. Seventy unrelated patients with EOPD and with an average age at onset of 42.6 ± 5.6 years were recruited at the Hospital Eugenio Espejo in Quito, Ecuador, and screened for the presence of PRKN and PINK1 single nucleotide and copy number variations. Sanger sequencing identified six PRKN variants, and five resulted in nonsynonymous amino acid substitutions. Seven PINK1 variants were identified: four nonsynonymous, and three common (MAF > 1%), among the EOPD cohort. Multiplex ligation-dependent probe amplification (MLPA) identified three carriers with PRKN copy number variants. Overall, across the series, two patients carried pathogenic homozygous deletions of exons 3 and 4. Gaining insights into the genetics of EOPD in Latin America is important. In this study, we have identified two carriers of pathogenic PRKN copy number variants in a relatively large group of Ecuadorian patients with EOPD. Additional, familial, early-onset and sporadic PD studies are warranted to further expand the knowledge base regarding Latin American populations.

PurposeRadioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation.MethodsThis was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records.ResultsMost radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1–45.9) versus 30.9 months (19.6–46.8); p = 0.243); stage B: 18.4 months (11.2–19.4) versus 22.8 months (10.9–34.2); p = 0.815; and stage C: 8.8 months (7.1–10.8) versus 10.8 months (7.7–12.6); p = 0.976.ConclusionsRadioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.

Background: Patients with ulcerative colitis (UC) suffer from a chronic relapsing-remitting inflammatory bowel disease and show heterogeneous disease severity and therapy response. It was recently reported that rectal biopsies from patients with UC show a downregulation of various mitochondrial genes during active UC. Methods: We used dextran sulfate sodium (DSS)-induced colitis as a preclinical mouse model for UC to study metabolic characteristics of ex vivo colonic lamina propria CD4+ and CD8+ T cells, B cells, eosinophils, neutrophils and intestinal epithelial cells during experimental acute and chronic inflammatory bowel disease and remission state. Results: Our results indicate that CD4+ and CD8+ T cells in the colon produce significantly less mitochondrial reactive oxygen species and possess smaller mitochondria during chronic DSS-induced colitis, which is resolved during remission state. In addition, CD4+ and CD8+ T cells exhibit increased glucose uptake during acute but defective glucose consumption during chronic DSS colitis. Conclusions: Together, our data provide evidence for an atypical mitochondrial phenotype of colonic CD4+ and CD8+ T cells during chronic colitis that is resolved during the remission phase of the disease.

Many of the academic analyses calling Medellín's development an \"urban miracle\" fall short with regard to discussion of the political economic implications of institutional shifts. An emerging transnational capitalist class promoted 'good governance' reforms and the embedding of neoliberalism in the urban context. Medellín's neoliberal development agenda is not only a market-led strategy but also a particular form of hierarchic rule and distribution of power. Increased economic activities in the tertiary sector, the promotion of flexible labor markets, and the incorporation of the city into the global economy at the lower end of the value chain have not served as sustainable growth escalators for Medellín's economy. The city continues to have high rates of un- and underemployment and is still the country's most unequal city. These developments can by no means be described as miraculous. Muchos de los análisis académicos que describen el desarrollo de Medellín como un \"milagro urbano\" se quedan cortos en cuanto a la discusión de las implicaciones político-económicas de los cambios institucionales. Una nueva clase capitalista transnacional promovió las reformas de buena gobernanza y la incorporación del neoliberalismo en el contexto urbano. El plan de desarrollo neoliberal de Medellín no es sólo una estrategia orientada al mercado sino que también es una forma jerárquica de gobierno y distribución del poder. El aumento de las actividades económicas en el sector sectario, la promoción de un mercado laboral flexible y la incorporación de la ciudad en la economía global en el nivel más bajo de la cadena de valor no han servido como palancas para el crecimiento económico sustentable de Medellín. La ciudad sigue teniendo las tasas de desempleo y subempleo más altas de Colombia y todavía es la ciudad más desigual del país. Estos desarrollos no pueden ser descritos en modo alguno como milagrosos.

BackgroundIn total knee arthroplasty the femoral posterior condylar offset (PCO) may serve as a potential branch for correct femoral component positioning. The technique of adjusting the sagittal magnetic resonance imaging (MRI)-scan on which it is measured has not been investigated in previous literature, but may be subject to variances due to knee joint positioning or axial localizer scan angulation. The purpose of this study was to investigate the effect of simulated femur rotation on the accuracy of PCO measurement.Materials and methodsTen asymptomatic knee joints underwent MRI investigations. A sagittal plane perpendicular to the transepicondylar axis was defined as the true-sagittal plane (tsP). Sagittal images were reformatted in the tsP and angulated by 5° and − 5° in medial and lateral direction. In total each knee received three scans in 0°, 5° and − 5° axial localizer scan angulation. Medial and lateral PCO measurement was performed in each MRI-scan angulation.ResultsSimulated external rotation decreased medial PCO size by 1.7 mm (95% CI 0.5994–3.127) (p = 0.012), and simulated internal rotation increased medial PCO size by 2.1 mm (95% CI 1.142–2.994) (p = 0.001). Lateral PCO size increased by 1.9 mm (95% CI 0.5660–3.412) and decreased by 2.1 mm (95% CI 1.142–2.994) with simulated external and internal rotation, respectively (p = 0.011; p = 0.0007).ConclusionThis study shows the high sensitivity of medial and lateral PCO measurements to small changes of MRI axial localizer scan angulations simulating minor degrees of internal or external femur rotation. Thus, absolute PCO values should be interpreted with caution if the sagittal image acquisition is not standardized.

The virulence of intracellular pathogens relies largely on the ability to survive and replicate within phagocytes but also on release and transfer into new host cells. Such cell-to-cell transfer could represent a target for counteracting microbial pathogenesis. However, our understanding of the underlying cellular and molecular processes remains woefully insufficient. Using intravital 2-photon microscopy of caspase-3 activation in the Leishmania major-infected (L. major-infected) live skin, we showed increased apoptosis in cells infected by the parasite. Also, transfer of the parasite to new host cells occurred directly without a detectable extracellular state and was associated with concomitant uptake of cellular material from the original host cell. These in vivo findings were fully recapitulated in infections of isolated human phagocytes. Furthermore, we observed that high pathogen proliferation increased cell death in infected cells, and long-term residency within an infected host cell was only possible for slowly proliferating parasites. Our results therefore suggest that L. major drives its own dissemination to new phagocytes by inducing host cell death in a proliferation-dependent manner.