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A novel implantable total artificial heart, hereinafter referred to as the ShuttlePump, is currently under development in a research collaboration between the Medical University of Vienna, the Power Electronic Systems Laboratory of ETH Zurich and Charite Berlin. Its novel, low-complexity, pulsatile pumping principle requires a specially shaped piston performing a controlled, synchronized linear-rotary motion while providing the necessary hydraulic force and torque. The machine design of the Permanent Magnet Synchronous Machine (PMSM)-based linear-rotary actuator was conducted in previous work of the authors, leading to the construction of a hardware prototype satisfying the application requirements in terms of electromechanical force, torque, power losses, and volume. This article provides the details of the closed-loop linear-rotary position control system required to operate the ShuttlePump. The design of the position control system targets tight reference tracking ($\pm$8 mm linear stroke and continuous rotation) up to an operational frequency of 5 Hz, under the heavy disturbance introduced by the axial hydraulic load force, as high as 45 N. The experimental measurements show successful linear-rotary position tracking under the specified axial load, with a maximum error of 1 mm and 5$^{\circ }$.

In the context of a collaboration between the Medical University of Vienna, the Power Electronic Systems Laboratory of ETH Zurich, and Charité Berlin, the novel implantable total artificial heart ShuttlePump is currently being developed. Its novel low-complexity pumping concept requires a compact linear–rotary actuator (LiRA). The linear actuator (LA) part was designed, realized, and experimentally verified in previous work, and it can provide a peak axial force of about 45 N with about 8 W of continuous power dissipation. This article presents the details of the rotary actuator (RA) part. This has considerably lower output power requirements (about 100 mW) due to the low operating torque and angular speed (3.1 mN$\cdot$m and up to 300 r/min, respectively). However, the RA is highly constrained spatially, as it needs to be integrated very close to the previously realized LA. This forces a permanent magnet synchronous machine (PMSM) design with a rotor only partially equipped with permanent magnets and stators covering only half of the total circumference, which introduces a considerable cogging component to the total torque. The proposed PMSM is, hence, optimized using finite-element method simulations to select a final design with low power losses and low cogging-induced angular speed ripple. The machine is realized as a hardware prototype, and the experimental measurements confirm that the proposed RA can meet the continuous torque requirement with 324 mW of power losses. The successful implementation of the RA (and LA) finally verifies the practical feasibility of the integrated LiRA and provides the basis for a comprehensive test of the complete ShuttlePump in a hydraulic test rig in the course of further research.

This paper investigates the design of an Eddy Current Sensor (ECS) for position measurement of a moving conductive target located behind a fixed conductive shielding surface. Such a sensor can e.g. be used in completely sealed actuators with magnetically levitated rotor or mover for high purity applications. Starting from the analysis of the sensor’s operating principle, the design of the excitation coil, the achievable sensitivity and bandwidth as well as the temperature stability of the sensor are investigated. Subsequently, a suitable sensor interface, consisting of the driving and signal conditioning electronics, is selected. With this it is possible to distinguish between position and temperature variations, for which the optimal operational frequencies are identified. The results are finally verified with measurements on a hardware sensor prototype, showing that the ECS can achieve a sensitivity of 1 mV/µm, a position resolution of 1 µm, with a measurement bandwidth of 30 kHz and can hence be used to capture the mover’s position in an active magnetic bearing feedback control structure.

Abstract Neurexins are key adhesion proteins that coordinate extracellular and intracellular synaptic components. Nonetheless, the low abundance of these multidomain proteins has complicated any localization and structure-function studies. Here we combine an ALFA tag (AT)/nanobody (NbALFA) tool with classic genetics, cell biology and electrophysiology to examine the distribution and function of the Drosophila Nrx-1 in vivo. We generate full-length and ΔPDZ ALFA-tagged Nrx-1 variants and find that the PDZ binding motif is key to Nrx-1 surface expression. A PDZ binding motif provided in trans, via genetically encoded cytosolic NbALFA-PDZ chimera, fully restores the synaptic localization and function of NrxΔPDZ-AT. Using cytosolic NbALFA-mScarlet intrabody, we achieve compartment-specific detection of endogenous Nrx-1, track live Nrx-1 transport along the motor neuron axons, and demonstrate that Nrx-1 co-migrates with Rab2-positive vesicles. Our findings illustrate the versatility of the ALFA system and pave the way towards dissecting functional domains of complex proteins in vivo.

PURPOSETo better understand immigration disparities among a Spanish Early-Onset Colorectal Cancer (SECOC) subset, according to the country of origin.PATIENTS AND METHODSWe selected 250 consecutive participants from the SECOC consortium. Data on baseline patient and tumor characteristics, family history of colorectal cancer (CRC), and follow-up were collected. The presence of mismatch repair deficiency was also assessed. Special data regarding country of origin, time of stay in Spain in case of other different country, and a 10-year cutoff that specifies the obtaining of Spanish nationality defined the variables of interest for comparison.RESULTSSeventy-five percent of patients with early-onset CRC (EOCRC) (188) were born in Spain, whereas the other 25% were born outside of Spain. The mean time of living in Spain until the EOCRC diagnosis was 16.5 years. Comparatively, most of the analyzed features showed equivalent proportions between cohorts. Only Spanish patients appeared to have more familial cancer component in first degree in general (32.3%; P = .01), compared with non-Spaniards, which showed a predominant sporadic component (56.4%; P < .001). Among immigrants, those patients living in Spain before CRC diagnosis ≤10 years were younger at diagnosis (39.1 v 42.5), more frequently male (77.8 v 47.7), were in more advanced stages (88.8% diagnosed at stage III and IV [P = .01]), and had a worse prognosis regarding recurrence rates (29.4% v 6.3%).CONCLUSIONAlthough there were few differences between Spanish and non-Spanish EOCRC, the most remarkable difference was that linked with the situation of those immigrants who have recently arrived in Spain, in relation to their lower health coverage, which could be associated with the delay in the diagnosis and their subsequent worse prognosis.

Case series summary Medical records of two kittens diagnosed with type I phimosis were reviewed. Clinical signs on presentation, investigations, description of the surgical technique, and short- and long-term follow-up were reported. Type I phimosis was diagnosed in both kittens based on the clinical, radiographic and surgical exploration findings. Modified circumferential preputioplasty using 4 and 6 mm Keyes biopsy punches was performed by the same surgeon in each case. The biopsy punch was centred over the existing narrowed preputial orifice and rotated clockwise and anticlockwise to obtain a sharp circumferential cut through the skin and submucosa of predictable diameter. The underlying mucosa was resected with micro curved scissors and mucocutaneous apposition was achieved with simple interrupted sutures placed circumferentially. Minor protrusion of the tip of the penis was recorded in the short-term follow-up (2 weeks) but resolved on the long-term follow-up (10 and 72 months). No evidence of urinary tract infection, strictures or clinical signs associated with phimosis were recorded at long-term follow-up. Relevance and novel information This short case series describes the surgical correction of type I phimosis by circumferential preputioplasty implemented using a Keyes biopsy punch in two kittens. The technique described in this case series can be considered alongside other reported surgical techniques, and appears to provide a reliable, rapid and accurate removal of preputial skin in the two reported cases.

KneeBones3Dify is a Python software tool that supports detailed analysis of knee pathologies and preoperative planning for knee replacement surgery based on patient-specific 3D models. It produces printable 3D bones in a stereolithography file format by automatically segmenting the femur, patella, and tibia from high-resolution Magnetic Resonance (MR) images with nearly isotropic voxel dimensions. Our software avoids time-consuming and subjective manual segmentation by specialists, offering an accurate and efficient alternative employing GPU acceleration. We validated the results by computing objective metrics against the ground truth voxel-wise segmentation produced for a 3D MR image by specialists, who also confirmed the reconstruction accuracy qualitatively. KneeBones3Dify and annotated data are publicly available, enabling broader research and clinical practice use.

Abstract Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.

This work discusses the challenges of space exploration, focusing on microgravity-induced physiological changes, particularly those affecting the vestibular system, which significantly alters human performance in space, necessitating effective countermeasures. In microgravity, astronauts experience disorientation and space motion sickness due to changes in vestibular input, leading to symptoms like vertigo and headache. Postflight, astronauts show various neurological changes, similar to symptoms in individuals with vestibular disorders experiencing significant cognitive and perceptual difficulties. Studies have also shown that microgravity affects cortical and sensory responses, altering perception, motor function, and brain connectivity. Galvanic Vestibular Stimulation (GVS) is explored as a countermeasure, using modulated electrical currents to evoke neuronal activity in vestibular end-organs, potentially stabilizing posture and gaze in microgravity. The work proposes that GVS could serve as a non-invasive intervention to help adapt to space environments by enhancing vestibular function and possibly aiding cognitive functions and underscores the need for continued research into the vestibular system’s role in human health and performance during space missions. It highlights the potential of GVS as a promising countermeasure for the challenges posed by microgravity.

Abstract Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.