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 effects of apparatus-induced dispersion on nonuniform, density-dependent flow in a cylindrical soil column were investigated using a finite-element model. To validate the model, the results with an analytical solution and laboratory column test data were analysed. The model simulations confirmed that flow nonuniformities induced by the apparatus are dissipated within the column when the distance to the apparatus outlet exceeds $3R/2$, where R represents the radius of the cylindrical column. Furthermore, the simulations revealed that convergent flow in the vicinity of the outlet introduces additional hydrodynamic dispersion in the soil column apparatus. However, this effect is minimal in the region where the column height exceeds $3R/2$. Additionally, it is found that an increase in the solution density gradient during the solute breakthrough period led to a decrease in flow velocity, which stabilized the flow and ultimately reduced dispersive mixing. Overall, this study provides insights into the behaviour of apparatus-induced dispersion in nonuniform, density-dependent flow within a cylindrical soil column, shedding light on the dynamics and mitigation of flow nonuniformities and dispersive mixing phenomena.

OBJECTIVES/GOALS: NSF often requires cross-disciplinary team composition to be competitive for funding. To what extent do research teams have multidisciplinary authorships after they win an award, given that awards are not contracts? We examined the quantity and quality of multidisciplinary collaboration of NSF-funded teams before and after receiving their award. METHODS/STUDY POPULATION: Our sample was 150 PIs and Co-PIs (67% male) from 58 NSF-funded EAGER (EArly-concept Grants for Exploratory Research) grants between 2013 and 2019. Using publicly available information, we collected the number of conference papers, publications, and grants PIs/co-PIs produced with each other (all PIs and co-PIs in a team or a partial subset). Based on Ph.D. fields, we also cataloged whether the combination of PIs/co-PI authors on outputs represented unidisciplinary or multidisciplinary collaboration after their NSF award. Multidisciplinary collaboration consisted of multidivisional (Ph.D. disciplines across NSF divisions, e.g., political science and cognitive psychology) or multidirectorate (Ph.D. disciplines across NSF directorates, e.g., psychology and engineering) authorship. RESULTS/ANTICIPATED RESULTS: Of the 74% of PI and co-PI teams who collaborated after their EAGER award, almost 9 out of 10 chose to work with a collaborator from a different discipline, and almost 8 out of 10 chose to work with a researcher from an extremely diverse discipline from their own (e.g., computer science and psychology). Research on interdisciplinary teams largely emphasizes the challenges and problems they face but the current research demonstrated that 90% of the sample chose to continue working together across disciplines after EAGER awards. Therefore, future research should dedicate more attention to the nontangible benefits members receive in interdisciplinary teams. Moreover, quality measures revealed higher H-indices for multidisciplinary than unidisciplinary journals and conferences. DISCUSSION/SIGNIFICANCE: Our archival results revealed that NSF EAGER grants are having their intended effect of being a catalyst for 1) continued multidisciplinary (and especially multidirectorate) collaboration) and 2) high-quality multidisciplinary publication and conference output. These results have contributed to NSF policy changes to reinstate the EAGER grant.

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.

Dry wind-tunnel (DWT) flutter test systems model the unsteady distributed aerodynamic force using various electromagnetic exciters. They can be used to test the aeroelastic and aeroservoelastic stability of smart aircraft or high-speed flight vehicles. A new parameterised modelling method at the full system level based on the generalised force equivalence for DWT flutter systems is proposed herein. The full system model includes the structural dynamic model, electromechanical coupling model and fast aerodynamic computation model. An optimisation search method is applied to determine the best locations for measurement and excitation by introducing Fisher’s information matrix. The feasibility and accuracy of the proposed system-level numerical DWT modelling method have been validated for a plate aeroelastic model with four exciters/transducers. The effects of key parameters including the number of exciters, the control time delay, the noise interference and the electrical parameters of the electromagnetic exciter model have also been investigated. The numerical and experimental results indicate that the proposed modelling method achieves good accuracy (with deviations of less than 1.5% from simulations and 4.5% from experimental test results for the flutter speed) and robust performance even in uncertain environments with a 10% noise level.

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.

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.

Lameness is a very important disorder of periparturient dairy cows with implications on milk production and composition as well as with consequences on reproductive performance. The aetiology of lameness is not clear although there have been various hypotheses suggested over the years. The objective of this study was to metabotype the urine of dairy cows prior to, during and after the onset of lameness by evaluating at weeks −8, −4 pre-calving, the week of lameness diagnosis, and +4 and +8 weeks post-calving. We used a metabolomics approach to analyse urine samples collected from dairy cows around calving (6 cows with lameness v. 20 healthy control cows). A total of 153 metabolites were identified and quantified using an in-house MS library and classified into 6 groups including: 11 amino acids (AAs), 39 acylcarnitines (ACs), 3 biogenic amines (BAs), 84 glycerophospholipids, 15 sphingolipids and hexose. A total of 23, 36, 40, 23 and 49 metabolites were observed to be significantly different between the lame and healthy cows at −8 and −4 weeks pre-calving, week of lameness diagnosis as well as at +4 and +8 weeks post-calving, respectively. It should be noted that most of the identified metabolites were elevated; however, a few of them were also lower in lame cows. Overall, ACs and glycerophospholipids, specifically phosphatidylcholines (PCs), were the metabolite groups displaying the strongest differences in the urine of pre-lame and lame cows. Lysophosphatidylcholines (LysoPCs), although to a lesser extent than PCs, were altered at all time points. Alterations in urinary AA concentrations were also observed during the current study for four time points. During the pre-calving period, there was an observed elevation of arginine (−8 week), tyrosine (−8 week) and aspartate (−4 week), as well as a depression of urinary glutamate (−4 weeks). In the current study, it was additionally observed that concentrations of several sphingomyelins and one BA were altered in pre-lame and lame cows. Symmetric dimethylarginine was elevated at both −8 weeks pre-calving and the week of lameness diagnosis. Data showed that urinary fingerprinting might be a reliable methodology to be used in the future to differentiate lame cows from healthy ones.

The Square Kilometre Array (SKA) is a planned large radio interferometer designed to operate over a wide range of frequencies, and with an order of magnitude greater sensitivity and survey speed than any current radio telescope. The SKA will address many important topics in astronomy, ranging from planet formation to distant galaxies. However, in this work, we consider the perspective of the SKA as a facility for studying physics. We review four areas in which the SKA is expected to make major contributions to our understanding of fundamental physics: cosmic dawn and reionisation; gravity and gravitational radiation; cosmology and dark energy; and dark matter and astroparticle physics. These discussions demonstrate that the SKA will be a spectacular physics machine, which will provide many new breakthroughs and novel insights on matter, energy, and spacetime.

The first fundamental theorem of invariant theory for the orthosymplectic supergroup scheme $\text{OSp}(m|2n)$ states that there is a full functor from the Brauer category with parameter $m-2n$ to the category of tensor representations of $\text{OSp}(m|2n)$. This has recently been proved using algebraic supergeometry to relate the problem to the invariant theory of the general linear supergroup. In this work, we use the same circle of ideas to prove the second fundamental theorem for the orthosymplectic supergroup. Specifically, we give a linear description of the kernel of the surjective homomorphism from the Brauer algebra to endomorphisms of tensor space, which commute with the orthosymplectic supergroup. The main result has a clear and succinct formulation in terms of Brauer diagrams. Our proof includes, as special cases, new proofs of the corresponding second fundamental theorems for the classical orthogonal and symplectic groups, as well as their quantum analogues, which are independent of the Capelli identities. The results of this paper have led to the result that the map from the Brauer algebra ${\mathcal{B}}_{r}(m-2n)$ to endomorphisms of $V^{\otimes r}$ is an isomorphism if and only if $r<(m+1)(n+1)$.