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The XENON1T experiment aims for the direct detection of dark matter in a detector filled with 3.3 tons of liquid xenon. In order to achieve the desired sensitivity, the background induced by radioactive decays inside the detector has to be sufficiently low. One major contributor is the β -emitter 85 Kr which is present in the xenon. For XENON1T a concentration of natural krypton in xenon nat Kr / Xe < 200 ppq   (parts per quadrillion,  1 ppq = 10 - 15 mol / mol ) is required. In this work, the design, construction and test of a novel cryogenic distillation column using the common McCabe–Thiele approach is described. The system demonstrated a krypton reduction factor of 6.4 · 10 5 with thermodynamic stability at process speeds above 3 kg/h. The resulting concentration of nat Kr / Xe < 26 ppq is the lowest ever achieved, almost one order of magnitude below the requirements for XENON1T and even sufficient for future dark matter experiments using liquid xenon, such as XENONnT and DARWIN.

We describe the design, construction, and characterization of a permanent magnet based, transverse-field Zeeman slower for lithium atoms. We use off-the-shelf compact permanent bar magnets in the Halbach configuration to create a uniform magnetic field in the transverse direction. We develop a general approach for a mechanical structure that supports the spatial distribution of magnets using 3D printing technology. The approach allows for flexible assembly and dismantling of the magnetic field on the target vacuum system. Finally, we verify that the Zeeman slower supports a high flux of slow atoms in the region of magneto-optical trap.

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation. Pik3cg -deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice. Causally linking a mutation to clinical phenotypes in rare hereditary diseases is both challenging and illuminating. Here the authors identify PI3Kɣ mutations in a patient with immune dysregulation, and recapitulate the phenotypes in PI3Kɣ-deficient mice by exposing them to natural microbiota from pet-shop mice.

In a recent manuscript (arXiv:1208.5046) Peter Sorensen claims that XENON100's upper limits on spin-independent WIMP-nucleon cross sections for WIMP masses below 10 GeV \"may be understated by one order of magnitude or more\". Having performed a similar, though more detailed analysis prior to the submission of our new result (arXiv:1207.5988), we do not confirm these findings. We point out the rationale for not considering the described effect in our final analysis and list several potential problems with his study.

ObjectiveTo examine the efficacy and safety of medical cannabis in benign essential blepharospasm (BEB).MethodsThis is a prospective, double-blind, placebo-controlled study. All consecutive adult BEB patients who had been treated with BTX-A injections without success between 3/2019 and 2/2020 were recruited. The study patients were randomly allocated into a treatment and a control (placebo) group in a 1:1 ratio. The treatment group used cannabis drops and the control group used cannabis oil drops during the first 6 weeks of the study, and both groups were treated with the medical cannabis drops during the second 6 weeks. The cannabis dose was gradually increased for each patient depending upon effect and tolerability.ResultsThree patients were included in each group (treatment and control groups). The mean duration of spasm attack during the first 6 weeks was 4.29 min in the treatment group and 73.9 min in the placebo group (P < 0.01). During the last 6 weeks, the treatment group used an average of 6.27 drops and the placebo group used an average of 5.36 drops (P = 0.478). There were 61 spasm events in the treatment group and 94 spasm events in the placebo group (P = 0.05). The mean duration of spasm attack was 1.77 and 8.96 min, respectively (P < 0.01). The side effects were mild, and they included general fatigue, dry mouth, and insomnia.ConclusionsMedical cannabis can be an effective and safe treatment for BEB as a second line after BTX-A injections when used for 3 months. No significant ocular or systemic side effects was associated with the treatment.

Background: Commercial infant formulas attempt to imitate human milk’s unique composition. However, lactose-free and milk protein-free formulas are often chosen due to medical reasons or personal preferences. The aim of this study was to determine the glycemic and insulinemic indices of a variety of infant formulas. Methods: We conducted a three-arm, randomized, double-blind, crossover study. Participants were 25–40-year-old healthy adults. Three commercial infant formulas (cow’s milk protein-based [“standard”], soy protein-based, and lactose-free) were randomly given to each participant. Glycemic and insulinemic responses were determined and compared between the three formulas. Results: Twenty subjects were enrolled (11 females/9 males, mean age 32.8 ± 2.9 years). No significant difference was found in the glycemic index between the three formulas (21.5, 29.1, and 21.5 for the standard, soy protein-based, and lactose-free formulas, respectively, p = 0.21). However, maximal glucose levels were significantly higher for the soy protein-based formula compared to both the standard and lactose-free formulas (111.5 compared to 101.8 and 105.8 mg/dL, respectively, p = 0.001). Conclusion: Cow’s milk protein-based, soy protein-based, and lactose-free formulas have a similar glycemic index. However, soy protein-based formula produced a significantly higher increase in postprandial glucose levels. The implication and biological significance of these results have yet to be determined.

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Severe disseminated Coccidioides is rare while localized, contained disease is common. We report a family with disseminated coccidioidomycosis due to a novel homozygous C186Y mutation in interleukin (IL)-12 receptor β1. This family confirms the centrality of the IL-12/IFN-γ axis to human immunity to Coccidioides spp.

Background Accumulating evidences suggest that tumors are driven by a small population of cells, termed “cancer stem cells” (CSCs), which may be resistant to current therapeutic approaches. In breast carcinoma, the CSCs have been identified as a CD44 + /CD24 − cell population. These rare cells are able to grow as non-adherent sphere-like structures, termed “mammospheres”, which enables their isolation and expansion in culture. To design efficient strategies for the complete eradication of CSCs, it is important to identify enzymes and proteins that are known as anti-cancer targets, and differ in their properties from those present in the none CSCs. Here we investigated the activity and expression of type I and type II DNA topoisomerases (topo I and topo II) in CSCs and their response to anti-topoisomerase inhibitors. Methods MCF7 breast cancer cells, PC3 prostate cancer cells and 4 T1-Luc-Oct3/4pG mouse mammary carcinoma cells were grown on low-attachment dishes in specific medium and allowed to form spheres. Enrichment of CSC population was verified by immunostaining, flow cytometry or fluorescent microscopy imaging. Nuclear protein extracts were prepared and topoisomerases activity and protein levels were determined. Cell viability was examined by the MTT and Neutral Red assays. Results Unlike the adherent MCF7 cell line, topo I activity is decreased and topo II activity is increased in the CSCs. However, the relative levels of the enzyme proteins were similar in both mammospheres and adherent cells. Topo I activity in mammospheres is regulated, at least in part, by PARP-1, as observed by the recovery of topo I activity after treatment with PARP-1 inhibitor 3-Aminobenzamide. Mammosphere-derived cells show reduced sensitivity to topo I inhibitor, camptothecin, and increased sensitivity to topo II inhibitor etoposide. Intact mammospheres show increased resistance to both drugs. A combined treatment of intact mammospheres with either CPT and gefitinib, or etoposide and erlotinib, increased the anti-cancer effect of both drugs. Conclusions The data of this study suggest that the understanding of biological behavior of essential enzymes such as topoisomerases, in CSCs’ progression and early stages of tumor development, is important for developing new strategies for cancer treatment as well as new therapies for advanced disease.

In this paper, we describe the XENON100 data analyses used to assess the target-intrinsic background sources radon ([InlineMediaObject not available: see fulltext.]), thoron ([InlineMediaObject not available: see fulltext.]) and krypton ([InlineMediaObject not available: see fulltext.]). We detail the event selections of high-energy alpha particles and decay-specific delayed coincidences. We derive distributions of the individual radionuclides inside the detector and quantify their abundances during the main three science runs of the experiment over a period of ∼4years, from January 2010 to January 2014. We compare our results to external measurements of radon emanation and krypton concentrations where we find good agreement. We report an observed reduction in concentrations of radon daughters that we attribute to the plating-out of charged ions on the negatively biased cathode.