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We report on a transportable and easy-to-operate optical clock utilizing the 2S1/2 - 2D3/2 transition of a single trapped 171Yb+ ion at 436 nm. Developed within a pilot project for quantum technology in Germany lead by industry, the clock is set up in two 19″ racks. In this way, transportation can easily be realized, and the large degree of automatization allows for operation outside highly specialized laboratories for applications beyond basic research. Comparisons to existing high-accuracy optical clock systems enable a verification of the clock's stability and uncertainty budget at the low 10−17 level. During these tests, operation with 99.8% availability over more than 14 days has been achieved.

Background: Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features., Methods: Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed a genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS., Results: We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts., Conclusions: In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts., (© 2024. The Author(s).)

We describe a high-performance optical frequency reference based on dual-frequency sub-Doppler spectroscopy (DFSDS) using a Cs vapor microfabricated cell and an external-cavity diode laser at 895 nm. Measured against a reference optical signal extracted from a cavity-stabilized laser, the microcell-stabilized laser demonstrates an instability of 3 × 10 -13 at 1 s, in agreement with a phase noise of +40 dBrad 2 /Hz at 1-Hz offset frequency, and below 5 × 10 -14 at 10 2 s. The laser short-term stability limit is in good agreement with the intermodulation effect from the laser frequency noise. These results suggest that DFSDS is a valuable approach for the development of ultra-stable microcell-based optical standards.

We report on the mid-term stability progress of a table-top coherent population trapping (CPT) microcell atomic clock, previously limited by light-shift effects and variations of the cell's inner atmosphere. The light-shift contribution is now mitigated through the use of a pulsed symmetric auto-balanced Ramsey (SABR) interrogation technique, combined with setup temperature, laser power, and microwave power stabilization. In addition, Ne buffer gas pressure variations in the cell are now greatly reduced through the use of a micro-fabricated cell built with low permeation alumino-silicate glass (ASG) windows. Combining these approaches, the clock Allan deviation is measured to be 1.4 × 10 -12 at 10 5 s. This stability level at one day is competitive with the best current microwave microcell-based atomic clocks.

Atomic devices such as atomic clocks and optically-pumped magnetometers rely on the interrogation of atoms contained in a cell whose inner content has to meet high standards of purity and accuracy. Glass-blowing techniques and craftsmanship have evolved over many decades to achieve such standards in macroscopic vapor cells. With the emergence of chip-scale atomic devices, the need for miniaturization and mass fabrication has led to the adoption of microfabrication techniques to make millimeter-scale vapor cells. However, many shortcomings remain and no process has been able to match the quality and versatility of glass-blown cells. Here, we introduce a novel approach to structure, fill and seal microfabricated vapor cells inspired from the century-old approach of glass-blowing, through opening and closing single-use zero-leak microfabricated valves. These valves are actuated exclusively by laser, and operate in the same way as the "make-seals" and "break-seals" found in the filling apparatus of traditional cells. Such structures are employed to fill cesium vapor cells at the wafer-level. The make-seal structure consists of a glass membrane that can be locally heated and deflected to seal a microchannel. The break-seal is obtained by breaching a silicon wall between cavities. This new approach allows adapting processes previously restricted to glass-blown cells. It can also be extended to vacuum microelectronics and vacuum-packaging of micro-electro-mechanical systems (MEMS) devices., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Given the clinical effect of progeria syndrome, understanding the cell mechanical behavior of this pathology could benefit the patient's treatment. Progeria patients show a point mutation in the lamin A/C gene (LMNA), which could change the cell's biomechanical properties. This paper reports a mechano-dynamic analysis of a progeria mutation (c.1824 C > T, p.Gly608Gly) in neonatal rat ventricular myocytes (NRVMs) using cell indentation by atomic force microscopy to measure alterations in beating force, frequency, and contractile amplitude of selected cells within cell clusters. Furthermore, we examined the beating rate variability using a time-domain method that produces a Poincaré plot because beat-to-beat changes can shed light on the causes of arrhythmias. Our data have been further related to our cell phenotype findings, using immunofluorescence and calcium transient analysis, showing that mutant NRVMs display changes in both beating force and frequency. These changes were associated with a decreased gap junction localization (Connexin 43) in the mutant NRVMs even in the presence of a stable cytoskeletal structure (microtubules and actin filaments) when compared with controls (wild type and non-treated cells). These data emphasize the kindred between nucleoskeleton (LMNA), cytoskeleton, and the sarcolemmal structures in NRVM with the progeria Gly608Gly mutation, prompting future mechanistic and therapeutic investigations.

Background: Abnormalities in Ca 2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca 2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive., Methods: We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as , a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca 2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart., Results: We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca 2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca 2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA., Conclusions: These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. COPD represents one of many areas of research where identifying complex pathways and networks of interacting biomarkers is an important avenue toward studying disease progression and potentially discovering cures. Recently, sparse multiple canonical correlation network analysis (SmCCNet) was developed to identify complex relationships between omics associated with a disease phenotype, such as lung function. SmCCNet uses two sets of omics datasets and an associated output phenotypes to generate a multi-omics graph, which can then be used to explore relationships between omics in the context of a disease. Detecting significant subgraphs within this multi-omics network, i.e., subgraphs which exhibit high correlation to a disease phenotype and high inter-connectivity, can help clinicians identify complex biological relationships involved in disease progression. The current approach to identifying significant subgraphs relies on hierarchical clustering, which can be used to inform clinicians about important pathways involved in the disease or phenotype of interest. The reliance on a hierarchical clustering approach can hinder subgraph quality by biasing toward finding more compact subgraphs and removing larger significant subgraphs. This study aims to introduce new significant subgraph detection techniques. In particular, we introduce two subgraph detection methods, dubbed Correlated PageRank and Correlated Louvain, by extending the Personalized PageRank Clustering and Louvain algorithms, as well as a hybrid approach combining the two proposed methods, and compare them to the hierarchical method currently in use. The proposed methods show significant improvement in the quality of the subgraphs produced when compared to the current state of the art., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abdel-Hafiz, Najafi, Helmi, Pratte, Zhuang, Liu, Kechris, Bowler, Lange and Banaei-Kashani.)

End stage heart failure is a major cause of death in the US. At present, organ transplant and left-ventricular assist devices remain the only viable treatments for these patients. Cardiac tissue engineering presents the possibility of a new option. Nanomaterials such as gold nanorods (AuNRs) and carbon nanotubes (CNTs) present unique properties that are beneficial for cardiac tissue engineering approaches. In particular, these nanomaterials can modulate electrical conductivity, hardness, and roughness of bulk materials to improve tissue functionality. Moreover, they can deliver bioactive cargo to affect cell phenotypes. This review covers recent advances in the use of nanomaterials for cardiac tissue engineering.

The demonstration of miniature atomic clocks (MACs) based on coherent population trapping (CPT) with improved mid- and long-term frequency stability benefits from the implementation of additional stabilization loops to reduce temperature-induced light-shift effects. In this article, we report and highlight the individual and combined benefits of such servo loops on the frequency stability of a CPT-based MAC. The first loop stabilizes the actual temperature of the vertical-cavity surface-emitting laser (VCSEL) chip using a compensation method in which the reading of external temperature variations is derived from the atomic vapor output signal. The second loop maintains the total microwave power absorbed by the laser to a value that maximizes the optical absorption and significantly reduces the laser power dependence of the clock frequency. Experimental tests are performed onto a miniaturized CPT-clock physics package using a chip-VCSEL tuned on the Cs D 1 line ( λ = 895 nm). The VCSEL temperature compensation technique improves, by a factor of 4, the Allan deviation of the clock at 10 4 s. The simultaneous operation of both servo loops improves, by a factor of 7, the clock fractional frequency stability at 10 4 s. The clock demonstrates a fractional frequency stability of 7.5×10 -11 at 1 s and better than 2×10 -11 at 1 day.

Luminal breast cancers express estrogen (ER) and progesterone (PR) receptors, and respond to endocrine therapies. However, some ER+PR+ tumors display intrinsic or acquired resistance, possibly related to PR. Two PR isoforms, PR-A and PR-B, regulate distinct gene subsets that may differentially influence tumor fate. A high PR-A:PR-B ratio is associated with poor prognosis and tamoxifen resistance. We speculate that excessive PR-A marks tumors that will relapse early. Here we address mechanisms by which PR-A regulate transcription, focusing on SUMOylation. We use receptor mutants and synthetic promoter/reporters to show that SUMOylation deficiency or the deSUMOylase SENP1 enhance transcription by PR-A, independent of the receptors' dimerization interface or DNA binding domain. De-SUMOylation exposes the agonist properties of the antiprogestin RU486. Thus, on synthetic promoters, SUMOylation functions as an independent brake on transcription by PR-A. What about PR-A SUMOylation of endogenous human breast cancer genes? To study these, we used gene expression profiling. Surprisingly, PR-A SUMOylation influences progestin target genes differentially, with some upregulated, others down-regulated, and others unaffected. Hormone-independent gene regulation is also PR-A SUMOylation dependent. Several SUMOylated genes were analyzed in clinical breast cancer database. In sum, we show that SUMOylation does not simply repress PR-A. Rather it regulates PR-A activity in a target selective manner including genes associated with poor prognosis, shortened survival, and metastasis., Competing Interests: The authors declare no conflict of interest.

This paper reports on an original architecture of microfabricated alkali vapor cell designed for miniature atomic clocks. The cell combines diffraction gratings with anisotropically etched single-crystalline silicon sidewalls to route a normally-incident beam in a cavity oriented along the substrate plane. Gratings have been specifically designed to diffract circularly polarized light in the first order, the latter having an angle of diffraction matching the (111) sidewalls orientation. Then, the length of the cavity where light interacts with alkali atoms can be extended. We demonstrate that a longer cell allows to reduce the beam diameter, while preserving the clock performances. As the cavity depth and the beam diameter are reduced, collimation can be performed in a tighter space. This solution relaxes the constraints on the device packaging and is suitable for wafer-level assembly. Several cells have been fabricated and characterized in a clock setup using coherent population trapping spectroscopy. The measured signals exhibit null power linewidths down to 2.23 kHz and high transmission contrasts up to 17%. A high contrast-to-linewidth ratio is found at a linewidth of 4.17 kHz and a contrast of 5.2% in a 7-mm-long cell despite a beam diameter reduced to 600 μm.

We report on the development and characterization of novel 4.596 GHz and 6.834 GHz microwave frequency synthesizers devoted to be used as local oscillators in high-performance Cs and Rb vapor-cell atomic clocks. The key element of the synthesizers is a custom module that integrates a high spectral purity 100 MHz oven controlled quartz crystal oscillator frequency-multiplied to 1.6 GHz with minor excess noise. Frequency multiplication, division, and mixing stages are then implemented to generate the exact output atomic resonance frequencies. Absolute phase noise performances of the output 4.596 GHz signal are measured to be -109 and -141 dB rad(2)/Hz at 100 Hz and 10 kHz Fourier frequencies, respectively. The phase noise of the 6.834 GHz signal is -105 and -138 dB rad(2)/Hz at 100 Hz and 10 kHz offset frequencies, respectively. The performances of the synthesis chains contribute to the atomic clock short term fractional frequency stability at a level of 3.1 × 10(-14) for the Cs cell clock and 2 × 10(-14) for the Rb clock at 1 s averaging time. This value is comparable with the clock shot noise limit. We describe the residual phase noise measurements of key components and stages to identify the main limitations of the synthesis chains. The residual frequency stability of synthesis chains is measured to be at the 10(-15) level for 1 s integration time. Relevant advantages of the synthesis design, using only commercially available components, are to combine excellent phase noise performances, simple-architecture, low-cost, and to be easily customized for signal output generation at 4.596 GHz or 6.834 GHz for applications to Cs or Rb vapor-cell frequency standards.