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Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis 1,2 . However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3 ) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We present a long-range fiber-optic environmental deformation sensor based on active phase noise cancellation (PNC) in metrological frequency dissemination. PNC sensing exploits recordings of a compensation frequency that is commonly discarded. Without the need for dedicated measurement devices, it operates synchronously with metrological services, suggesting that existing phase-stabilized metrological networks can be co-used effortlessly as environmental sensors. The compatibility of PNC sensing with inline amplification enables the interrogation of cables with lengths beyond 1000 km, making it a potential contributor to earthquake detection and early warning in the oceans. Using spectral-element wavefield simulations that accurately account for complex cable geometry, we compare observed and computed recordings of the compensation frequency for a magnitude 3.9 earthquake in south-eastern France and a 123 km fiber link between Bern and Basel, Switzerland. The match in both phase and amplitude indicates that PNC sensing can be used quantitatively, for example, in earthquake detection and characterization., (© 2023. Springer Nature Limited.)

Introduction: Spinal cord injury (SCI) often results in chronic secondary health conditions related to autonomic and metabolic dysfunction. Epidural electrical stimulation (EES) combined with task-specific training has been shown to enable motor function in individuals with chronic paralysis. The reported effects of EES on secondary health conditions, such as bladder function and body composition, are limited. We report the impact of EES on SCI-related secondary health changes in bladder function and body composition. Methods: Two participants with motor and sensory complete SCI performed 6 months of rehabilitation without EES followed by 12 months of task-specific training with EES after implantation of a 16-electrode array on the surface of the lumbosacral spinal cord. Participants performed three days of training per week in the laboratory, and additionally performed task-specific activities with EES at home during this time frame. Changes in bladder and body composition were recorded via clinically-available testing of neurogenic bladder functionality and dual-energy X-ray absorptiometry, respectively. Results: In one participant, we observed an increase in episodes of urinary incontinence with worsening bladder compliance and pressures at the end of the study. Bone mineral density changes were insignificant in both participants; however, one participant showed a substantial increase in lean mass (+9.1 kg; 6 months of training) via redistribution of body fat through an android/gynoid ratio reduction (-0.15; 6 months of training). Conclusion: EES optimized for standing and stepping may negatively impact neurogenic bladder functionality. Close monitoring of bladder health is imperative to prevent undesirable bladder compliance, which can lead to upper urinary tract deteriorations. Conversely, EES may serve as an adjunct tool with regular exercise modalities to improve body composition through activation of musculature innervated by spinal segments that are below the SCI.

Frequency dissemination in phase-stabilized optical fiber networks for metrological frequency comparisons and precision measurements are promising candidates to overcome the limitations imposed by satellite techniques. However, in an architecture shared with telecommunication data traffic, network constraints restrict the availability of dedicated channels in the commonly-used C-band. Here, we demonstrate the dissemination of an SI-traceable ultrastable optical frequency in the L-band over a 456 km fiber network with ring topology, in which data traffic occupies the full C-band. We characterize the optical phase noise and evaluate a link instability of 4.7 × 10 -16 at 1 s and 3.8 × 10 -19 at 2000 s integration time, and a link accuracy of 2 × 10 -18 . We demonstrate the application of the disseminated frequency by establishing the SI-traceability of a laser in a remote laboratory. Finally, we show that our metrological frequency does not interfere with data traffic in the telecommunication channels. Our approach combines an unconventional spectral choice in the telecommunication L-band with established frequency-stabilization techniques, providing a novel, cost-effective solution for ultrastable frequency-comparison and dissemination, and may contribute to a foundation of a world-wide metrological network.

The tumor suppressor adenomatous polyposis coli (APC) is frequently mutated in colorectal cancers. APC and Axin are core components of a destruction complex that scaffolds GSK3β and CK1 to earmark β-catenin for proteosomal degradation. Disruption of APC results in pathologic stabilization of β-catenin and oncogenesis. However, the molecular mechanism by which APC promotes β-catenin degradation is unclear. Here, we find that the intrinsically disordered region (IDR) of APC, which contains multiple β-catenin and Axin interacting sites, undergoes liquid-liquid phase separation (LLPS) in vitro. Expression of the APC IDR in colorectal cells promotes Axin puncta formation and β-catenin degradation. Our results support the model that multivalent interactions between APC and Axin drives the β-catenin destruction complex to form biomolecular condensates in cells, which concentrate key components to achieve high efficient degradation of β-catenin.

The massively parallel nature of biological information processing plays an important role due to its superiority in comparison to human-engineered computing devices. In particular, it may hold the key to overcoming the von Neumann bottleneck that limits contemporary computer architectures. Physical-model neuromorphic devices seek to replicate not only this inherent parallelism, but also aspects of its microscopic dynamics in analog circuits emulating neurons and synapses. However, these machines require network models that are not only adept at solving particular tasks, but that can also cope with the inherent imperfections of analog substrates. We present a spiking network model that performs Bayesian inference through sampling on the BrainScaleS neuromorphic platform, where we use it for generative and discriminative computations on visual data. By illustrating its functionality on this platform, we implicitly demonstrate its robustness to various substrate-specific distortive effects, as well as its accelerated capability for computation. These results showcase the advantages of brain-inspired physical computation and provide important building blocks for large-scale neuromorphic applications., (Copyright © 2019 Kungl, Schmitt, Klähn, Müller, Baumbach, Dold, Kugele, Müller, Koke, Kleider, Mauch, Breitwieser, Leng, Gürtler, Güttler, Husmann, Husmann, Hartel, Karasenko, Grübl, Schemmel, Meier and Petrovici.)

We implement a microscopic spin filter for cold fermionic atoms in a quantum point contact (QPC) and create fully spin-polarized currents while retaining conductance quantization. Key to our scheme is a near-resonant optical tweezer inducing a large effective Zeeman shift inside the QPC while its local character limits dissipation. We observe a renormalization of this shift due to interactions of only a few atoms in the QPC. Our work represents the analog of an actual spintronic device and paves the way to studying the interplay between spin splitting and interactions far from equilibrium.

The precise temporal and spatial coordination of histone lysine methylation dynamics across the epigenome regulates virtually all DNA-templated processes. A large number of histone lysine methyltransferase (KMT) enzymes catalyze the various lysine methylation events decorating the core histone proteins. Mutations, genetic translocations and altered gene expression involving these KMTs are frequently observed in cancer, developmental disorders and other pathologies. Therapeutic compounds targeting specific KMTs are currently being tested in the clinic, although overall drug discovery in the field is relatively underdeveloped. Here we review the biochemical and biological activities of histone KMTs and their connections to human diseases, focusing on cancer. We also discuss the scientific and clinical challenges and opportunities in studying KMTs.

Background: We report the first case of instillation of alteplase, a tissue plasminogen activator, to dissolve occlusive upper urinary tract blood clot. Case Presentation: A 67-year-old Caucasian man with a solitary kidney became dialysis dependent because of upper urinary tract clot obstruction after ureteral stent placement for obstructing ureterolithiasis. After failure of more conservative measures, 10 mg of alteplase was instilled through nephrostomy tube daily for 2 consecutive days 30 minutes before manual irrigation with physiologic saline. After alteplase instillation, the occlusive blood clot dissolved with rapid improvement in urinary output and creatinine. Conclusions: Alteplase instillation through nephrostomy tube is a viable option to dissolve obstructing upper urinary tract blood clots., Competing Interests: No competing financial interests exist., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

A non-invasive method for measurement of the bladder wall nonlinear elastic behavior is presented. The method is based on acoustoelasticity modeling of the elasticity changes in bladder tissue modulus at different volumetric strain levels. At each volume, tissue strain is obtained from the real-time ultrasound images. Using acoustic radiation force, a transient Lamb wave is excited on the bladder wall and instantaneous modulus of shear elasticity is obtained from the 2-D Fourier analysis of the spatial-temporal dispersion maps. Measured elasticity and strain data are then used in an acoustoelasticity formulation to obtain the third order elastic coefficient, referred to as nonlinearity parameter A, and initial resting elasticity μ 0 . The method was tested in ex vivo porcine bladder samples (N = 9) before and after treatment with formalin. The estimated nonlinearity parameter, A, was significantly higher in the treated samples compared to intact (p < 0.00062). The proposed method was also applied on 16 patients with neurogenic bladders (10 compliant and 6 non-compliant subjects). The estimated nonlinearity parameter A was significantly higher in the non-compliant cases compared to the compliant (p < 0.0293). These preliminary results promise a new method for non-invasive evaluation of the bladder tissue nonlinearity which may serve as a new diagnostic and prognostic biomarker for management of the patients with neurogenic bladders.

We report on coupled heat and particle transport measurements through a quantum point contact (QPC) connecting two reservoirs of resonantly interacting, finite temperature Fermi gases. After heating one of them, we observe a particle current flowing from cold to hot. We monitor the temperature evolution of the reservoirs and find that the system evolves after an initial response into a nonequilibrium steady state with finite temperature and chemical potential differences across the QPC. In this state any relaxation in the form of heat and particle currents vanishes. From our measurements we extract the transport coefficients of the QPC and deduce a Lorenz number violating the Wiedemann-Franz law by one order of magnitude, a characteristic persisting even for a wide contact. In contrast, the Seebeck coefficient takes a value close to that expected for a noninteracting Fermi gas and shows a smooth decrease as the atom density close to the QPC is increased beyond the superfluid transition. Our work represents a fermionic analog of the fountain effect observed with superfluid helium and poses challenges for microscopic modeling of the finite temperature dynamics of the unitary Fermi gas., Competing Interests: The authors declare no conflict of interest.

Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.

We present a scanning probe microscopy technique for spatially resolving transport in cold atomic gases, in close analogy with scanning gate microscopy in semiconductor physics. The conductance of a quantum point contact connected to two atomic reservoirs is measured in the presence of a tightly focused laser beam acting as a local perturbation that can be precisely positioned in space. By scanning its position and recording the subsequent variations of conductance, we retrieve a high-resolution map of transport through a quantum point contact. We demonstrate a spatial resolution comparable to the extent of the transverse wave function of the atoms inside the channel and a position sensitivity below 10 nm. Our measurements agree well with an analytical model and ab initio numerical simulations, allowing us to identify a regime in transport where tunneling dominates over thermal effects. Our technique opens new perspectives for the high-resolution observation and manipulation of cold atomic gases.

Purpose or Objective: The objective of this study is to assess correlation between bladder wall mechanical properties obtained by ultrasound bladder vibrometry (UBV) and urodynamic study (UDS) measurements in a group of patients undergoing clinical UDS procedure., Materials and Methods: Concurrent UBV and UDS were performed on 70 patients with neurogenic bladders (56 male and 14 female). Bladder wall mechanical properties measured by UBV at different filling volumes were correlated with recorded detrusor pressure (Pdet) values. Mean, median and standard deviation of correlation values were calculated and the significance of these observations was tested., Results: Bladder wall mechanical properties obtained by UBV as group velocity squared and elasticity showed high correlations with Pdet measured at different volumes (median correlation 0.73, CI: 0.64-0.80 and 0.72, CI: 0.56-0.82 respectively). The correlation of group velocity squared and elasticity with Pdet were both significantly higher than 0.5., Conclusions: The results of this study suggest that UBV can closely monitor changes in bladder wall mechanical properties at different volumes in a group of patients undergoing UDS. The high correlation between UBV parameters and detrusor pressure measurements suggests that UBV can be utilized as a reliable and cost-effective tool for assessment of the bladder wall mechanical changes in a noninvasive fashion.

We study particle and spin transport in a single-mode quantum point contact, using a charge neutral, quantum degenerate Fermi gas with tunable, attractive interactions. This yields the spin and particle conductance of the point contact as a function of chemical potential or confinement. The measurements cover a regime from weak attraction, where quantized conductance is observed, to the resonantly interacting superfluid. Spin conductance exhibits a broad maximum when varying the chemical potential at moderate interactions, which signals the emergence of Cooper pairing. In contrast, the particle conductance is unexpectedly enhanced even before the gas is expected to turn into a superfluid, continuously rising from the plateau at [Formula: see text] for weak interactions to plateau-like features at nonuniversal values as high as [Formula: see text] for intermediate interactions. For strong interactions, the particle conductance plateaus disappear and the spin conductance gets suppressed, confirming the spin-insulating character of a superfluid. Our observations document the breakdown of universal conductance quantization as many-body correlations appear. The observed anomalous quantization challenges a Fermi liquid description of the normal phase, shedding new light on the nature of the strongly attractive Fermi gas.

Purpose: We propose a novel method to monitor bladder wall mechanical properties as a function of filling volume, with the potential application to bladder compliance assessment. The proposed ultrasound bladder vibrometry (UBV) method uses ultrasound to excite and track Lamb waves on the bladder wall from which its mechanical properties are derived by fitting measurements to an analytical model. Of particular interest is the shear modulus of bladder wall at different volumes, which we hypothesize, is similar to measuring the compliance characteristics of the bladder., Materials and Methods: Three experimental models were used: 1) an ex vivo porcine model where normal and aberrant (stiffened by formalin) bladders underwent evaluation by UBV; 2) an in vivo study to evaluate the performance of UBV on patients with clinically documented compliant and noncompliant bladders undergoing UDS; and 3) a noninvasive UBV protocol to assess bladder compliance using oral hydration and fractionated voiding on three healthy volunteers., Results: The ex vivo studies showed a high correlation between the UBV parameters and direct pressure measurement (R2 = 0.84-0.99). A similar correlation was observed for 2 patients with compliant and noncompliant bladders (R2 = 0.89-0.99) undergoing UDS detrusor pressure-volume measurements. The results of UBV on healthy volunteers, performed without catheterization, were comparable to a compliant bladder patient., Conclusion: The utility of UBV as a method to monitor changes in bladder wall mechanical properties is validated by the high correlation with pressure measurements in ex vivo and in vivo patient studies. High correlation UBV and UDS in vivo studies demonstrated the potential of UBV as a bladder compliance assessment tool. Results of studies on healthy volunteers with normal bladders demonstrated that UBV could be performed noninvasively. Further studies on a larger cohort are needed to fully validate the use of UBV as a clinical tool for bladder compliance assessment.

The MORC family of GHKL ATPases are an enigmatic class of proteins with diverse chromatin related functions. In Arabidopsis, AtMORC1, AtMORC2, and AtMORC6 act together in heterodimeric complexes to mediate transcriptional silencing of methylated DNA elements. Here, we studied Arabidopsis AtMORC4 and AtMORC7. We found that, in contrast to AtMORC1,2,6, they act to suppress a wide set of non-methylated protein-coding genes that are enriched for those involved in pathogen response. Furthermore, atmorc4 atmorc7 double mutants show a pathogen response phenotype. We found that AtMORC4 and AtMORC7 form homomeric complexes in vivo and are concentrated in discrete nuclear bodies adjacent to chromocenters. Analysis of an atmorc1,2,4,5,6,7 hextuple mutant demonstrates that transcriptional de-repression is largely uncoupled from changes in DNA methylation in plants devoid of MORC function. However, we also uncover a requirement for MORC in both DNA methylation and silencing at a small but distinct subset of RNA-directed DNA methylation target loci. These regions are characterized by poised transcriptional potential and a low density of sites for symmetric cytosine methylation. These results provide insight into the biological function of MORC proteins in higher eukaryotes.

Point contacts provide simple connections between macroscopic particle reservoirs. In electric circuits, strong links between metals, semiconductors, or superconductors have applications for fundamental condensed-matter physics as well as quantum information processing. However, for complex, strongly correlated materials, links have been largely restricted to weak tunnel junctions. We studied resonantly interacting Fermi gases connected by a tunable, ballistic quantum point contact, finding a nonlinear current-bias relation. At low temperature, our observations agree quantitatively with a theoretical model in which the current originates from multiple Andreev reflections. In a wide contact geometry, the competition between superfluidity and thermally activated transport leads to a conductance minimum. Our system offers a controllable platform for the study of mesoscopic devices based on strongly interacting matter., (Copyright © 2015, American Association for the Advancement of Science.)

In transport experiments, the quantum nature of matter becomes directly evident when changes in conductance occur only in discrete steps, with a size determined solely by Planck's constant h. Observations of quantized steps in electrical conductance have provided important insights into the physics of mesoscopic systems and have allowed the development of quantum electronic devices. Even though quantized conductance should not rely on the presence of electric charges, it has never been observed for neutral, massive particles. In its most fundamental form, it requires a quantum-degenerate Fermi gas, a ballistic and adiabatic transport channel, and a constriction with dimensions comparable to the Fermi wavelength. Here we report the observation of quantized conductance in the transport of neutral atoms driven by a chemical potential bias. The atoms are in an ultraballistic regime, where their mean free path exceeds not only the size of the transport channel, but also the size of the entire system, including the atom reservoirs. We use high-resolution lithography to shape light potentials that realize either a quantum point contact or a quantum wire for atoms. These constrictions are imprinted on a quasi-two-dimensional ballistic channel connecting the reservoirs. By varying either a gate potential or the transverse confinement of the constrictions, we observe distinct plateaux in the atom conductance. The conductance in the first plateau is found to be equal to the universal conductance quantum, 1/h. We use Landauer's formula to model our results and find good agreement for low gate potentials, with all parameters determined a priori. Our experiment lets us investigate quantum conductors with wide control not only over the channel geometry, but also over the reservoir properties, such as interaction strength, size and thermalization rate.