Background: Late-onset Pompe disease (LOPD) is caused by a deficiency of acid α-glucosidase (GAA), leading to progressive muscle and respiratory decline. Cipaglucosidase alfa (cipa), a recombinant human GAA naturally enriched with bis-mannose-6-phosphate, exhibits improved muscle uptake but is limited by inactivation at near-neutral blood pH. Miglustat (mig), an enzyme stabiliser, binds competitively and reversibly to cipa, enhancing its stability and activity. Methods: In dose-finding studies, Gaa-/- mice were treated with cipa (20 mg/kg) +/- mig (10 mg/kg; equivalent human dose ~260 mg). Clinical study methodologies have been published (Schoser et al. Lancet Neurol 2021:20;1027–37; Schoser et al. J Neurol 2024:271;2810–23). Results: In Gaa-/- mice, cipa+mig improved muscle glycogen reduction more than cipa alone and grip strength to levels approaching wild-type mice. LOPD patients (n=11) treated with cipa alone showed dose-dependent decreases in hexose tetrasaccharide (Hex4) levels by ~15% from baseline, decreasing another ~10% with added mig (260 mg). In a head-to-head study, cipa+mig had a similar safety profile to alglucosidase alfa. Among 151 patients (three trials), mig-related adverse events occurred in 21 (13.9%), none serious. Conclusions: Mig stabilised cipa in circulation, improving cipa exposure, further reducing Hex4 levels and was well tolerated in clinical studies in patients with LOPD. Sponsored by Amicus Therapeutics, Inc.

The chemistry of Al transformation has been well documented, though little is known about the mechanisms of structural perturbation of Al precipitates by carbonates at a molecular level. The purpose of the present study was to investigate the structural perturbation of Al precipitates formed under the influence of carbonates. Initial carbonate/Al molar ratios (MRs) used were 0, 0.1, and 0.5 after aging for 32 days, then the samples were analyzed by X-ray absorption near edge structure spectroscopy (XANES), X-ray diffraction (XRD), Fourier-transform infrared absorption spectroscopy (FTIR), and chemical analysis. The XRD data were in accord with the FTIR results, which revealed that as the carbonate/Al MR was increased from 0 to 0.1, carbonate preferentially retarded the formation of gibbsite and had relatively little effect on the formation of bayerite. As the carbonate/Al MR was increased to 0.5, however, the crystallization of both gibbsite and bayerite was completely inhibited. The impact of carbonate on the nature of Al precipitates was also evident in the increase of adsorbed water and inorganic C contents with increasing carbonate/Al MR. The Al K- and L- edge XANES data provide the first evidence illustrating the change in the coordination number of Al from 6-fold to mixed 6- and 4-fold coordination in the structural network of short-range ordered (SRO) Al precipitates formed under the increasing perturbation of carbonate. The fluorescence yield spectra of the O K-edge show that the intensity of the peak at 534.5 eV assigned to σ* transitions of Al-O and O-H bonding decreased with increasing carbonate/Al MR. The XANES data, along with the evidence from XRD, FTIR, and chemical analysis showed clearly that carbonate caused the alteration of the coordination nature of the Al-O bonding through perturbation of the atomic bonding and structural configuration of Al hydroxides by complexation with Al in the SRO network of Al precipitates. The surface reactivity of an Al-O bond is related to its covalency and coordination geometry. The present findings were, therefore, of fundamental significance in understanding the low-temperature geochemistry of Al and its impacts on the transformation, transport, and fate of nutrients and pollutants in the ecosystem.

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.

We describe a new low-frequency wideband radio survey of the southern sky. Observations covering 72–231 MHz and Declinations south of $+30^\circ$ have been performed with the Murchison Widefield Array “extended” Phase II configuration over 2018–2020 and will be processed to form data products including continuum and polarisation images and mosaics, multi-frequency catalogues, transient search data, and ionospheric measurements. From a pilot field described in this work, we publish an initial data release covering 1,447$\mathrm{deg}^2$ over $4\,\mathrm{h}\leq \mathrm{RA}\leq 13\,\mathrm{h}$, $-32.7^\circ \leq \mathrm{Dec} \leq -20.7^\circ$. We process twenty frequency bands sampling 72–231 MHz, with a resolution of 2′–45′′, and produce a wideband source-finding image across 170–231 MHz with a root mean square noise of $1.27\pm0.15\,\mathrm{mJy\,beam}^{-1}$. Source-finding yields 78,967 components, of which 71,320 are fitted spectrally. The catalogue has a completeness of 98% at ${{\sim}}50\,\mathrm{mJy}$, and a reliability of 98.2% at $5\sigma$ rising to 99.7% at $7\sigma$. A catalogue is available from Vizier; images are made available via the PASA datastore, AAO Data Central, and SkyView. This is the first in a series of data releases from the GLEAM-X survey.

The great demographic pressure brings tremendous volume of beef demand. The key to solve this problem is the growth and development of Chinese cattle. In order to find molecular markers conducive to the growth and development of Chinese cattle, sequencing was used to determine the position of copy number variations (CNVs), bioinformatics analysis was used to predict the function of ZNF146 gene, real-time fluorescent quantitative polymerase chain reaction (qPCR) was used for CNV genotyping and one-way analysis of variance was used for association analysis. The results showed that there exists CNV in Chr 18: 47225201-47229600 (5.0.1 version) of ZNF146 gene through the early sequencing results in the laboratory and predicted ZNF146 gene was expressed in liver, skeletal muscle and breast cells, and was amplified or overexpressed in pancreatic cancer, which promoted the development of tumour through bioinformatics. Therefore, it is predicted that ZNF146 gene affects the proliferation of muscle cells, and then affects the growth and development of cattle. Furthermore, CNV genotyping of ZNF146 gene was three types (deletion type, normal type and duplication type) by Real-time fluorescent quantitative PCR (qPCR). The association analysis results showed that ZNF146-CNV was significantly correlated with rump length of Qinchuan cattle, hucklebone width of Jiaxian red cattle and heart girth of Yunling cattle. From the above results, ZNF146-CNV had a significant effect on growth traits, which provided an important candidate molecular marker for growth and development of Chinese cattle.

Frequent freezing injury greatly influences winter wheat production; thus, effective prevention and a command of agricultural production are vital. The freezing injury monitoring method integrated with ‘3S’ (geographic information systems (GIS), global positioning system (GPS) and remote sensing (RS)) technology has an unparalleled advantage. Using HuanJing (HJ)-1A/1B satellite images of a winter wheat field in Shanxi Province, China plus a field survey, crop types and winter wheat planting area were identified through repeated visual interpretations of image information and spatial analyses conducted in GIS. Six vegetation indices were extracted from processed HJ-1A/1B satellite images to determine whether the winter wheat suffered from freezing injury and its degree of severity and recovery, using change vector analysis (CVA), the freeze injury representative vegetation index and the combination of the two methods, respectively. Accuracy of the freezing damage classification results was verified by determining the impact of freezing damage on yield and quantitative analysis. The CVA and the change of normalized difference vegetation index (ΔNDVI) monitoring results were different so a comprehensive analysis of the combination of CVA and ΔNDVI was performed. The area with serious freezing injury covered 0.9% of the total study area, followed by the area of no freezing injury (3.5%), moderate freezing injury (10.2%) and light freezing injury (85.4%). Of the moderate and serious freezing injury areas, 0.2% did not recover; 1.2% of the no freezing injury and light freezing injury areas showed optimal recovery, 15.6% of the light freezing injury and moderate freezing injury areas showed poor recovery, and the remaining areas exhibited general recovery.

To investigate the influences of dietary riboflavin (RF) addition on nutrient digestion and rumen fermentation, eight rumen cannulated Holstein bulls were randomly allocated into four treatments in a repeated 4 × 4 Latin square design. Daily addition level of RF for each bull in control, low RF, medium RF and high RF was 0, 300, 600 and 900 mg, respectively. Increasing the addition level of RF, DM intake was not affected, average daily gain tended to be increased linearly and feed conversion ratio decreased linearly. Total tract digestibilities of DM, organic matter, crude protein (CP) and neutral-detergent fibre (NDF) increased linearly. Rumen pH decreased quadratically, and total volatile fatty acids (VFA) increased quadratically. Acetate molar percentage and acetate:propionate ratio increased linearly, but propionate molar percentage and ammonia-N content decreased linearly. Rumen effective degradability of DM increased linearly, NDF increased quadratically but CP was unaltered. Activity of cellulase and populations of total bacteria, protozoa, fungi, dominant cellulolytic bacteria, Prevotella ruminicola and Ruminobacter amylophilus increased linearly. Linear increase was observed for urinary total purine derivatives excretion. The data suggested that dietary RF addition was essential for rumen microbial growth, and no further increase in performance and rumen total VFA concentration was observed when increasing RF level from 600 to 900 mg/d in dairy bulls.

Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.

To evaluate the impacts of guanidinoacetic acid (GAA) and coated folic acid (CFA) on growth performance, nutrient digestion and hepatic gene expression, fifty-two Angus bulls were assigned to four groups in a 2 × 2 factor experimental design. The CFA of 0 or 6 mg/kg dietary DM folic acid was supplemented in diets with GAA of 0 (GAA−) or 0·6 g/kg DM (GAA+), respectively. Average daily gain (ADG), feed efficiency and hepatic creatine concentration increased with GAA or CFA addition, and the increased magnitude of these parameters was greater for addition of CFA in GAA− diets than in GAA+ diets. Blood creatine concentration increased with GAA or CFA addition, and greater increase was observed when CFA was supplemented in GAA+ diets than in GAA− diets. DM intake was unchanged, but rumen total SCFA concentration and digestibilities of DM, crude protein, neutral-detergent fibre and acid-detergent fibre increased with the addition of GAA or CFA. Acetate:propionate ratio was unaffected by GAA, but increased for CFA addition. Increase in blood concentrations of albumin, total protein and insulin-like growth factor-1 (IGF-1) was observed for GAA or CFA addition. Blood folate concentration was decreased by GAA, but increased with CFA addition. Hepatic expressions of IGF-1, phosphoinositide 3-kinase, protein kinase B, mammalian target of rapamycin and ribosomal protein S6 kinase increased with GAA or CFA addition. Results indicated that the combined supplementation of GAA and CFA could not cause ADG increase more when compared with GAA or CFA addition alone.

The low-frequency linearly polarised radio source population is largely unexplored. However, a renaissance in low-frequency polarimetry has been enabled by pathfinder and precursor instruments for the Square Kilometre Array. In this second paper from the POlarised GaLactic and Extragalactic All-Sky MWA Survey-the POlarised GLEAM Survey, or POGS-we present the results from our all-sky MWA Phase I Faraday Rotation Measure survey. Our survey covers nearly the entire Southern sky in the Declination range $-82^\circ$ to $+30^\circ$ at a resolution between around three and seven arcminutes (depending on Declination) using data in the frequency range 169−231 MHz. We have performed two targeted searches: the first covering 25 489 square degrees of sky, searching for extragalactic polarised sources; the second covering the entire sky South of Declination $+30^\circ$, searching for known pulsars. We detect a total of 517 sources with 200 MHz linearly polarised flux densities between 9.9 mJy and 1.7 Jy, of which 33 are known radio pulsars. All sources in our catalogues have Faraday rotation measures in the range $-328.07$ to $+279.62$ rad m−2. The Faraday rotation measures are broadly consistent with results from higher-frequency surveys, but with typically more than an order of magnitude improvement in the precision, highlighting the power of low-frequency polarisation surveys to accurately study Galactic and extragalactic magnetic fields. We discuss the properties of our extragalactic and known-pulsar source population, how the sky distribution relates to Galactic features, and identify a handful of new pulsar candidates among our nominally extragalactic source population.

In this paper, the generation of relativistic electron mirrors (REM) and the reflection of an ultra-short laser off the mirrors are discussed, applying two-dimension particle-in-cell simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapid expansion. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads to the resonance between laser and REM. The reflected radiation near this interval and corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, a certain part of the reflected field could be selectively amplified or depressed, leading to the selective adjustment of the corresponding spectra.

Human-computer hybrid teams can meet challenges in designing complex engineered systems. However, the understanding of interaction in the hybrid teams is lacking. We review the literature and identify four key attributes to construct design research platforms that support multi-phase design, hybrid teams, multiple design scenarios, and data logging. Then, we introduce a platform for unmanned aerial vehicle (UAV) design embodying these attributes. With the platform, experiments can be conducted to study how designers and intelligent computational agents interact, support, and impact each other.

Ovarian follicle selection is a natural biological process in the pre-ovulatory hierarchy in birds that drives growing follicles to be selected within the ovulatory cycle. Follicle selection in birds is strictly regulated, involving signaling pathways mediated by dietary nutrients, gonadotrophic hormones and paracrine factors. This study aimed to test the hypothesis that dietary Ca may participate in regulating follicle selection in laying ducks through activating the signaling pathway of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/extracellular signal-regulated kinase (ERK), possibly mediated by gonadotrophic hormones. Female ducks at 22 weeks of age were initially fed one of two Ca-deficient diets (containing 1.8% or 0.38% Ca) or a Ca-adequate control diet (containing 3.6% Ca) for 67 days (depletion period), then all birds were fed the Ca-adequate diet for an additional 67 days (repletion period). Compared with the Ca-adequate control, ducks fed 0.38% Ca during the depletion period had significantly decreased (P < 0.05) numbers of hierarchical follicles and total ovarian weight, which were accompanied by reduced egg production. Plasma concentration of FSH was decreased by the diet containing 1.8% Ca but not by that containing 0.38%. The ovarian content of cAMP was increased with the two Ca-deficient diets, and phosphorylation of PKA and ERK1/2 was increased with 0.38% dietary Ca. Transcripts of ovarian estradiol receptor 2 and luteinizing hormone receptor (LHR) were reduced in the ducks fed the two Ca-deficient diets (P < 0.05), while those of the ovarian follicle stimulating hormone receptor (FSHR) were decreased in the ducks fed 0.38% Ca. The transcript abundance of ovary gap junction proteins, A1 and A4, was reduced with the Ca-deficient diets (P < 0.05). The down-regulation of gene expression of gap junction proteins and hormone receptors, the increased cAMP content and the suppressed hierarchical follicle numbers were reversed by repletion of dietary Ca. These results indicate that dietary Ca deficiency negatively affects follicle selection of laying ducks, independent of FSH, but probably by activating cAMP/PKA/ERK1/2 signaling pathway.

This report is on the synthesis by electrospinning of multiferroic core-shell nanofibers of strontium hexaferrite and lead zirconate titanate or barium titanate and studies on magneto-electric (ME) coupling. Fibers with well-defined core–shell structures showed the order parameters in agreement with values for nanostructures. The strength of ME coupling measured by the magnetic field-induced polarization showed the fractional change in the remnant polarization as high as 21%. The ME voltage coefficient in H-assembled films showed the strong ME response for the zero magnetic bias field. Follow-up studies and potential avenues for enhancing the strength of ME coupling in the core–shell nanofibers are discussed.