Determination of the Concentration of Gases by Measurement of Pressure

For the determination of the concentration of gases by means of pressure measurement, a precise equation of state is given by which analysis can be carried out within an accuracy of 10 ppm. The parameters of the equation of state are explicitely reported for carbon dioxide, argon, and helium

Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies

Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the LMNA gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in LMNA and ZMPSTE24 , respectively. ZMPSTE24 in addition to ICMT encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with LMNA mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes LMNA, ZMPSTE24 and ICMT in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C>T (p.R644C) in LMNA in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In ZMPSTE24 and ICMT , no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy

Response of neovascular central serous chorioretinopathy to an extended upload of anti-VEGF agents

Purpose To determine the anatomical and functional outcomes of an extended 6-month intravitreal anti-vascular endothelial growth factor (anti-VEGF) upload in choroidal neovascularization (CNV) secondary to chronic central serous chorioretinopathy (CSCR). Methods A retrospective database analysis was performed applying the following inclusion criteria: (1) diagnosis of CSCR, (2) diagnosis of secondary CNV, and (3) treatment of at least six consecutive injections of anti-VEGF. Outcome measures included the change of central retinal subfield thickness, remodeling of the pigment epithelium detachments, and change in visual function. Results Twenty-one eyes of 21 patients were included. Mean patient age was 65 ± 8.3 years, and 35% of the patients (n = 8) were female. Mean disease duration before diagnosis of CNV was 48 ± 25.3 months. Mean central retinal thickness decreased from 346 ± 61 to 257 ± 57 μm (p < 0.01) after the sixth injection while mean visual acuity improved from 0.65 ± 0.35 to 0.49 ± 0.29 (logMAR; p < 0.01). Of note, an extended upload of six as opposed to three injections yielded an additional mean central retinal thickness reduction (280 ± 46 μm vs. 257 ± 57 μm, p = 0.038). Significant CNV remodeling was observed as a decrease in pigment epithelium detachment (PED) vertical (p = 0.021) and horizontal diameter (p = 0.024) as well as PED height (p < 0.01). Conclusion An extended anti-VEGF upload of six consecutive injections seems to be effective in inducing CNV remodeling and fluid resorption in CNV complicating chronic CSCR

Quasi-one-dimensional antiferromagnetism and multiferroicity in CuCrO4_4

The bulk magnetic properties of the new quasi-one-dimensional Heisenberg antiferromagnet, CuCrO$_4$, were characterized by magnetic susceptibility, heat capacity, optical spectroscopy, EPR and dielectric capacitance measurements and density functional evaluations of the intra- and interchain spin exchange interactions. We found type-II multiferroicity below the N\'{e}el temperature of 8.2(5) K, arising from competing antiferromagnetic nearest-neighbor ($J_{\rm nn}$) and next-nearest-neighbor ($J_{\rm nnn}$) intra-chain spin exchange interactions. Experimental and theoretical results indicate that the ratio $J_{\rm nn}/J_{\rm nnn}$ is close to 2, putting CuCrO$_4$ in the vicinity of the Majumdar-Ghosh point.Comment: 9 pages, 8 figures, submitted to PR

Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis

Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential

Supplementary Appendix. All-trans retinoic acid works synergistically with the γ- secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells

Supplement Figure 1: ATRA treatment does not affect the viability of myeloma cell lines. MM.1S, OPM-2 and NCI-H929 cells were treated with ATRA for up to 72 hours. Cell viability was measured by flow cytometry and 7AAD staining (n=6). Bar diagrams show mean values +SD.Supplement Figure 2: ATRA plus crenigacestat treatment enhance BCMA expression on myeloma cell lines. Bar diagram shows BCMA expression on OPM-2 cells (n=3) after treatment with 100 nM ATRA and/or 10 nM GSI crenigacestat for 72 hours. Bar diagram shows mean values +SD. P-values between indicated groups were calculated using unpaired t-test. *p<0.05, **p<0.01.Supplement Figure 3: ATRA treatment leads to increased BCMA transcripts in OPM-2 myeloma cells. BCMA RNA levels in OPM-2 were analyzed by quantitative reverse transcription PCR (qRT-PCR) assay after incubation with increasing doses of ATRA for 48 hours (n=3). Bar diagram shows mean values +SD. P-values between indicated groups were calculated using unpaired t-test. *p<0.05.Supplement Figure 4: ATRA treatment leads to enhanced BCMA expression on primary myeloma cells. Representative flow cytometric analysis of BCMA expression on primary myeloma cells that had been cultured in the absence or presence of ATRA at different concentrations for 72 hours. 7-AAD was used to exclude dead cells from analysis.Supplement Figure 5: ATRA treatment does not impair viability of primary myeloma cells. Viability of primary myeloma cells with or without 72 hours of ATRA treatment was analyzed by flow cytometry and 7-AAD staining (n=5 biological replicates). Bar diagram shows mean values +SD.Supplement Figure 6: sBCMA does not impair BCMA CAR T cell functionality. CD8+ BCMA-CAR T-cells were co-cultured with MM.1S target cells in absence or presence of 150 ng/ml of soluble BCMA. After 4 hours, cytotoxicity was evaluated by bioluminescence- based assay. Diagram shows mean values +/-SD.Supplement Figure 7: ATRA treatment does not increase shedding of sBCMA. sBCMA concentration in the supernatant of OPM-2 and NCI-H929 after incubation with increasing doses of ATRA was analyzed by ELISA. Cell lines were cultured at 1x106/well (n=3 technical replicates). Bar diagrams show mean values +SD, P-values between indicated groups were calculated using 2way ANOVA. n.s. = not significant, *p<0.05, **p<0.01.Supplement Figure 8: BCMA-CAR T-cells confer enhanced cytotoxicity against ATRA plus crenigacestat-treated OPM-2 cells in vitro. OPM-2 cells were incubated with 100 nM ATRA and/or 10 nM GSI for 72 hours or were left untreated. Cytolytic activity of CD8+ BCMA- CAR T-cells was determined in a bioluminescence-based assay after 4h of co-incubation with target cells. Assay was performed in triplicate wells with 5,000 target cells per well. Data are presented as mean values +SD (n=4 biological replicates). P-values between indicated groups were calculated using unpaired t-test. n.s. = not significant, *p<0.05.Supplement Figure 9: Patient-derived BCMA-CAR T-cells confer enhanced cytotoxicity against ATRA-treated MM.1S cells. MM.1S cells were incubated with 50 nM ATRA for 72 hours or were left untreated. Cytolytic activity of MM patient-derived CD8+ BCMA-CAR T-cells was determined in a bioluminescence-based assay after 4h of co-incubation with target cells. Data are presented as mean values +SD of triplicate wells. P-values between indicated groups were calculated using unpaired t-test. *p<0.05, **p<0.01.Peer reviewe

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant

Probing the Hofmeister Effect with Ultrafast Core Hole Spectroscopy

In the current work, X-ray emission spectra of aqueous solutions of different inorganic salts within the Hofmeister series are presented. The results reflect the direct interaction of the ions with the water molecules and therefore, reveal general properties of the salt-water interactions. Within the experimental precision a significant effect of the ions on the water structure has been observed but no ordering according to the structure maker/structure breaker concept could be mirrored in the results indicating that the Hofmeister effect-if existent-may be caused by more complex interactions