Reducing the linewidth of a diode laser below 30 Hz by stabilization to a reference cavity with finesse above 10^5

An extended cavity diode laser operating in the Littrow configuration emitting near 657 nm is stabilized via its injection current to a reference cavity with a finesse of more than 10^5 and a corresponding resonance linewidth of 14 kHz. The laser linewidth is reduced from a few MHz to a value below 30 Hz. The compact and robust setup appears ideal for a portable optical frequency standard using the Calcium intercombination line.Comment: 8 pages, 4 figures on 3 additional pages, corrected version, submitted to Optics Letter

Effects of serum and serum heat-inactivation on human bone derived osteoblast progenitor cells

Generally, heat inactivated foetal calf serum (FCS) containing media are used for the cultivation of animal and human cells. The role of serum source and serum treatment on the behaviour of cells has long been neglected. The present study was performed to investigate the effects of serum heat inactivation and serum source on trabecular bone derived progenitor cells (HBC). Furthermore, it was investigated in how far these reactions differed from those seen in bone marrow derived mesenchymal progenitor cells (HBMC) cultures. We found that HBC cultures performed differently in the presence of FCS and HS with or without heat inactivation. The reactions similar to some degree those observed in HBMC cultures. The implications of the results on cell-implant surface interaction studies are discusse

Long-term monitoring of fatty acid oxidation defects: results from a MetabERN survey

BACKGROUND: Implementation of long-chain fatty acid oxidation defects (LCFAOD) in newborn screening (NBS) programs allows for pre-symptomatic diagnosis and treatment. The long-term natural history of NBS LCFAOD patients is largely unknown and may differ from clinically diagnosed pre-NBS patients. This complicates long-term monitoring of LCFAOD and may cause high monitoring variability. To gain insight in current clinical practice, we performed a web-based questionnaire among all metabolic members of the European Reference Network for Hereditary Metabolic Disorders (MetabERN). RESULTS: Thirty-seven colleagues representing at least 35 European metabolic centres shared their experience and results were discussed at the European Metabolic Group (EMG) meeting 2022. The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening. Main discrepancies comprised hepatic imaging, glucose monitoring and electrophysiological investigations. CONCLUSIONS: Discrepancies may reflect differences in local availability of monitoring tools, the inclusion of LCFAOD in NBS programs as well as differences in local genotypes and phenotypes. Because monitoring strategies are largely based on the natural disease course of clinically identified patients, there might be over-monitoring of some NBS patients. Nevertheless, we advocate long-term monitoring because resulting information is essential to further characterize the natural disease course, develop evidence-based guidelines and provide a basis for evaluation of future therapies

Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum.

BACKGROUND: Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. METHODS: We describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months. RESULTS: MRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased. CONCLUSIONS: Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms

A Search for Variations of Fundamental Constants using Atomic Fountain Clocks

Over five years we have compared the hyperfine frequencies of 133Cs and 87Rb atoms in their electronic ground state using several laser cooled 133Cs and 87Rb atomic fountains with an accuracy of ~10^{-15}. These measurements set a stringent upper bound to a possible fractional time variation of the ratio between the two frequencies : (d/dt)ln(nu_Rb/nu_Cs)=(0.2 +/- 7.0)*10^{-16} yr^{-1} (1 sigma uncertainty). The same limit applies to a possible variation of the quantity (mu_Rb/mu_Cs)*alpha^{-0.44}, which involves the ratio of nuclear magnetic moments and the fine structure constant.Comment: 4 pages, 3 figures, 1 table submitted to Phys. Rev. Let

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible?

AbstractMedium‐chain acyl‐CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial β‐oxidation. Confirmation diagnostics after newborn screening (NBS) can be performed either by enzyme testing and/or by sequencing of the ACADM gene. Here, we report the results from enzyme testing in lymphocytes with gene variants from molecular analysis of the ACADM gene and with the initial acylcarnitine concentrations in the NBS sample. From April 2013 to August 2019, in 388 individuals with characteristic acylcarnitine profiles suggestive of MCADD the octanoyl‐CoA‐oxidation was measured in lymphocytes. In those individuals with residual activities 35% excluding MCADD. In the remaining 21 individuals, MCAD residual activity ranged from 30% to 35%. The latter group comprised both heterozygous carriers and individuals carrying two gene variants on different alleles. Twenty new variants could be identified and functionally classified based on their effect on enzyme function. C6 and C8 acylcarnitine species in NBS correlated with MCAD activity and disease severity. MCADD was only confirmed in half of the cases referred suggesting a higher false positive rate than expected. Measurement of the enzyme function in lymphocytes allowed fast confirmation diagnostics and clear determination of the pathogenicity of new gene variants. There is a clear correlation between genotype and enzyme function underlining the reproducibility of the functional measurement in vitro

Cold atom Clocks and Applications

This paper describes advances in microwave frequency standards using laser-cooled atoms at BNM-SYRTE. First, recent improvements of the $^{133}$Cs and $^{87}$Rb atomic fountains are described. Thanks to the routine use of a cryogenic sapphire oscillator as an ultra-stable local frequency reference, a fountain frequency instability of $1.6\times 10^{-14}\tau^{-1/2}$ where $\tau$ is the measurement time in seconds is measured. The second advance is a powerful method to control the frequency shift due to cold collisions. These two advances lead to a frequency stability of $2\times 10^{-16}$ at $50,000s for the first time for primary standards. In addition, these clocks realize the SI second with an accuracy of$7\times 10^{-16}$, one order of magnitude below that of uncooled devices. In a second part, we describe tests of possible variations of fundamental constants using$^{87}$Rb and$^{133}$Cs fountains. Finally we give an update on the cold atom space clock PHARAO developed in collaboration with CNES. This clock is one of the main instruments of the ACES/ESA mission which is scheduled to fly on board the International Space Station in 2008, enabling a new generation of relativity tests.Comment: 30 pages, 11 figure