bluuebunny/crossref_metadata_2025_split huggingface dataset:
A miniaturized transit-time ultrasonic flowmeter based on ScAlN piezoelectric micromachined ultrasonic transducers for small-diameter applications
Authors: Gao Yunfei , Chen Minkan , Wu Zhipeng , Yao Lei , Tong Zhihao , Zhang Songsong , Gu Yuandong Alex , Lou Liang 
Published: April 2023

AbstractTransit-time ultrasonic flowmeters (TTUFs) are among the most widely used devices for flow measurements. However, traditional TTUFs are usually based on a bulk piezoelectric transducer, which limits their application in small-diameter channels. In this paper, we developed a miniaturized TTUF based on scandium-doped aluminum nitride (ScAlN) piezoelectric micromachined ultrasonic transducers (PMUTs). The proposed TTUF contains two PMUT-based transceivers and a π-type channel. The PMUTs contain 13 × 13 square cells with dimensions of 2.8 × 2.8 mm2. To compensate for the acoustic impedance mismatch with liquid, a layer of polyurethane is added to the surface of the PMUTs as a matching layer. The PMUT-based transceivers show good transmitting sensitivity (with 0.94 MPa/V surface pressure) and receiving sensitivity (1.79 mV/kPa) at a frequency of 1 MHz in water. Moreover, the dimensions of the π-type channel are optimized to achieve a measurement sensitivity of 82 ns/(m/s) and a signal-to-noise ratio (SNR) better than 15 dB. Finally, we integrate the fabricated PMUTs into the TDC-GP30 platform. The experimental results show that the developed TTUF provides a wide range of flow measurements from 2 to 300 L/h in a channel of 4 mm diameter, which is smaller than most reported channels. The accuracy and repeatability of the TTUF are within 0.2% and 1%, respectively. The proposed TTUF shows great application potential in industrial applications such as medical and chemical applications.
Neural complexity EEG biomarkers of rapid and post-rapid ketamine effects in late-life treatment-resistant depression: a randomized control trial
Authors: Murphy Nicholas , Tamman Amanda J. F. , Lijffijt Marijn , Amarneh Dania , Iqbal Sidra , Swann Alan , Averill Lynnette A. , O’Brien Brittany , Mathew Sanjay J. 
Published: April 2023

AbstractKetamine is an effective intervention for treatment-resistant depression (TRD), including late-in-life (LL-TRD). The proposed mechanism of antidepressant effects of ketamine is a glutamatergic surge, which can be measured by electroencephalogram (EEG) gamma oscillations. Yet, non-linear EEG biomarkers of ketamine effects such as neural complexity are needed to capture broader systemic effects, represent the level of organization of synaptic communication, and elucidate mechanisms of action for treatment responders. In a secondary analysis of a randomized control trial, we investigated two EEG neural complexity markers (Lempel-Ziv complexity [LZC] and multiscale entropy [MSE]) of rapid (baseline to 240 min) and post-rapid ketamine (24 h and 7 days) effects after one 40-min infusion of IV ketamine or midazolam (active control) in 33 military veterans with LL-TRD. We also studied the relationship between complexity and Montgomery-Åsberg Depression Rating Scale score change at 7 days post-infusion. We found that LZC and MSE both increased 30 min post-infusion, with effects not localized to a single timescale for MSE. Post-rapid effects of reduced complexity with ketamine were observed for MSE. No relationship was observed between complexity and reduction in depressive symptoms. Our findings support the hypothesis that a single sub-anesthetic ketamine infusion has time-varying effects on system-wide contributions to the evoked glutamatergic surge in LL-TRD. Further, changes to complexity were observable outside the time-window previously shown for effects on gamma oscillations. These preliminary results have clinical implications in providing a functional marker of ketamine that is non-linear, amplitude-independent, and represents larger dynamic properties, providing strong advantages over linear measures in highlighting ketamine’s effects.
The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer
Authors: Constantin Theodora A. , Varela-Carver Anabel , Greenland Kyle K. , de Almeida Gilberto Serrano , Olden Ellen , Penfold Lucy , Ang Simon , Ormrod Alice , Leach Damien A. , Lai Chun-Fui , Ainscow Edward K. , Bahl Ash K. , Carling David , Fuchter Matthew J. , Ali Simak , Bevan Charlotte L. 
Published: April 2023

Abstract
Background
Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.

Methods
The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.

Results
CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.

Conclusions
This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.
Active learning-assisted neutron spectroscopy with log-Gaussian processes
Authors: Teixeira Parente Mario , Brandl Georg , Franz Christian , Stuhr Uwe , Ganeva Marina , Schneidewind Astrid 
Published: April 2023

AbstractNeutron scattering experiments at three-axes spectrometers (TAS) investigate magnetic and lattice excitations by measuring intensity distributions to understand the origins of materials properties. The high demand and limited availability of beam time for TAS experiments however raise the natural question whether we can improve their efficiency and make better use of the experimenter’s time. In fact, there are a number of scientific problems that require searching for signals, which may be time consuming and inefficient if done manually due to measurements in uninformative regions. Here, we describe a probabilistic active learning approach that not only runs autonomously, i.e., without human interference, but can also directly provide locations for informative measurements in a mathematically sound and methodologically robust way by exploiting log-Gaussian processes. Ultimately, the resulting benefits can be demonstrated on a real TAS experiment and a benchmark including numerous different excitations.
DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features
Authors: Luppino Federica , Adzhubei Ivan A. , Cassa Christopher A. , Toth-Petroczy Agnes 
Published: April 2023

AbstractDespite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.0, ACMG SF v2.0). DeMAG improves performance over existing VEPs by reaching balanced specificity (82%) and sensitivity (94%) on clinical data, and includes a novel epistatic feature, the ‘partners score’, which leverages evolutionary and structural partnerships of residues. The ‘partners score’ provides a general framework for modeling epistatic interactions, integrating both clinical and functional information. We provide our tool and predictions for all missense variants in 316 clinically actionable disease genes (demag.org) to facilitate the interpretation of variants and improve clinical decision-making.
Multi-omic underpinnings of epigenetic aging and human longevity
Authors: Mavromatis Lucas A. , Rosoff Daniel B. , Bell Andrew S. , Jung Jeesun , Wagner Josephin , Lohoff Falk W. 
Published: April 2023

AbstractBiological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.
Atlantic water intrusion triggers rapid retreat and regime change at previously stable Greenland glacier
Authors: Chudley T. R. , Howat I. M. , King M. D. , Negrete A. 
Published: April 2023

AbstractIce discharge from Greenland’s marine-terminating glaciers contributes to half of all mass loss from the ice sheet, with numerous mechanisms proposed to explain their retreat. Here, we examine K.I.V Steenstrups Nordre Bræ (‘Steenstrup’) in Southeast Greenland, which, between 2018 and 2021, retreated ~7 km, thinned ~20%, doubled in discharge, and accelerated ~300%. This rate of change is unprecedented amongst Greenland’s glaciers and now places Steenstrup in the top 10% of glaciers by contribution to ice-sheet-wide discharge. In contrast to expected behaviour from a shallow, grounded tidewater glacier, Steenstrup was insensitive to high surface temperatures that destabilised many regional glaciers in 2016, appearing instead to respond to a >2 °C anomaly in deeper Atlantic water (AW) in 2018. By 2021, a rigid proglacial mélange had developed alongside notable seasonal variability. Steenstrup’s behaviour highlights that even long-term stable glaciers with high sills are vulnerable to sudden and rapid retreat from warm AW intrusion.
Calibration of cognitive tests to address the reliability paradox for decision-conflict tasks
Authors: Kucina Talira , Wells Lindsay , Lewis Ian , de Salas Kristy , Kohl Amelia , Palmer Matthew A. , Sauer James D. , Matzke Dora , Aidman Eugene , Heathcote Andrew 
Published: April 2023

AbstractStandard, well-established cognitive tasks that produce reliable effects in group comparisons also lead to unreliable measurement when assessing individual differences. This reliability paradox has been demonstrated in decision-conflict tasks such as the Simon, Flanker, and Stroop tasks, which measure various aspects of cognitive control. We aim to address this paradox by implementing carefully calibrated versions of the standard tests with an additional manipulation to encourage processing of conflicting information, as well as combinations of standard tasks. Over five experiments, we show that a Flanker task and a combined Simon and Stroop task with the additional manipulation produced reliable estimates of individual differences in under 100 trials per task, which improves on the reliability seen in benchmark Flanker, Simon, and Stroop data. We make these tasks freely available and discuss both theoretical and applied implications regarding how the cognitive testing of individual differences is carried out.
Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion
Authors: Triglia Tony , Scally Stephen W. , Seager Benjamin A. , Pasternak Michał , Dagley Laura F. , Cowman Alan F. 
Published: April 2023

AbstractPlasmodium falciparum causes the most severe form of malaria in humans. The protozoan parasite develops within erythrocytes to mature schizonts, that contain more than 16 merozoites, which egress and invade fresh erythrocytes. The aspartic protease plasmepsin X (PMX), processes proteins and proteases essential for merozoite egress from the schizont and invasion of the host erythrocyte, including the leading vaccine candidate PfRh5. PfRh5 is anchored to the merozoite surface through a 5-membered complex (PCRCR), consisting of Plasmodium thrombospondin-related apical merozoite protein, cysteine-rich small secreted protein, Rh5-interacting protein and cysteine-rich protective antigen. Here, we show that PCRCR is processed by PMX in micronemes to remove the N-terminal prodomain of PhRh5 and this activates the function of the complex unmasking a form that can bind basigin on the erythrocyte membrane and mediate merozoite invasion. The ability to activate PCRCR at a specific time in merozoite invasion most likely masks potential deleterious effects of its function until they are required. These results provide an important understanding of the essential role of PMX and the fine regulation of PCRCR function in P. falciparum biology.
Causal structure of interacting Weyl fermions in condensed matter systems
Authors: Chiu Wei-Chi , Chang Guoqing , Macam Gennevieve , Belopolski Ilya , Huang Shin-Ming , Markiewicz Robert , Yin Jia-Xin , Cheng Zi-Jia , Lee Chi-Cheng , Chang Tay-Rong , Chuang Feng-Chuan , Xu Su-Yang , Lin Hsin , Hasan M. Zahid , Bansil Arun 
Published: April 2023

AbstractThe spacetime light cone is central to the definition of causality in the theory of relativity. Recently, links between relativistic and condensed matter physics have been uncovered, where relativistic particles can emerge as quasiparticles in the energy-momentum space of matter. Here, we unveil an energy-momentum analogue of the spacetime light cone by mapping time to energy, space to momentum, and the light cone to the Weyl cone. We show that two Weyl quasiparticles can only interact to open a global energy gap if they lie in each other’s energy-momentum dispersion cones–analogous to two events that can only have a causal connection if they lie in each other’s light cones. Moreover, we demonstrate that the causality of surface chiral modes in quantum matter is entangled with the causality of bulk Weyl fermions. Furthermore, we identify a unique quantum horizon region and an associated ‘thick horizon’ in the emergent causal structure.
Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase
Authors: Maschietto Federica , Morzan Uriel N. , Tofoleanu Florentina , Gheeraert Aria , Chaudhuri Apala , Kyro Gregory W. , Nekrasov Peter , Brooks Bernard , Loria J. Patrick , Rivalta Ivan , Batista Victor S. 
Published: April 2023

AbstractAllosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations and nuclear magnetic resonance spectroscopy are used to investigate how increases in temperature affect allostery in imidazole glycerol phosphate synthase. Results demonstrate that temperature increase triggers a cascade of local amino acid-to-amino acid dynamics that remarkably resembles the allosteric activation that takes place upon effector binding. The differences in the allosteric response elicited by temperature increase as opposed to effector binding are conditional to the alterations of collective motions induced by either mode of activation. This work provides an atomistic picture of temperature-dependent allostery, which could be harnessed to more precisely control enzyme function.
Complex computation from developmental priors
Authors: Barabási Dániel L. , Beynon Taliesin , Katona Ádám , Perez-Nieves Nicolas 
Published: April 2023

AbstractMachine learning (ML) models have long overlooked innateness: how strong pressures for survival lead to the encoding of complex behaviors in the nascent wiring of a brain. Here, we derive a neurodevelopmental encoding of artificial neural networks that considers the weight matrix of a neural network to be emergent from well-studied rules of neuronal compatibility. Rather than updating the network’s weights directly, we improve task fitness by updating the neurons’ wiring rules, thereby mirroring evolutionary selection on brain development. We find that our model (1) provides sufficient representational power for high accuracy on ML benchmarks while also compressing parameter count, and (2) can act as a regularizer, selecting simple circuits that provide stable and adaptive performance on metalearning tasks. In summary, by introducing neurodevelopmental considerations into ML frameworks, we not only model the emergence of innate behaviors, but also define a discovery process for structures that promote complex computations.
The structural basis of tRNA recognition by arginyl-tRNA-protein transferase
Authors: Abeywansha Thilini , Huang Wei , Ye Xuan , Nawrocki Allison , Lan Xin , Jankowsky Eckhard , Taylor Derek J. , Zhang Yi 
Published: April 2023

AbstractArginyl-tRNA-protein transferase 1 (ATE1) is a master regulator of protein homeostasis, stress response, cytoskeleton maintenance, and cell migration. The diverse functions of ATE1 arise from its unique enzymatic activity to covalently attach an arginine onto its protein substrates in a tRNA-dependent manner. However, how ATE1 (and other aminoacyl-tRNA transferases) hijacks tRNA from the highly efficient ribosomal protein synthesis pathways and catalyzes the arginylation reaction remains a mystery. Here, we describe the three-dimensional structures of Saccharomyces cerevisiae ATE1 with and without its tRNA cofactor. Importantly, the putative substrate binding domain of ATE1 adopts a previously uncharacterized fold that contains an atypical zinc-binding site critical for ATE1 stability and function. The unique recognition of tRNAArg by ATE1 is coordinated through interactions with the major groove of the acceptor arm of tRNA. Binding of tRNA induces conformational changes in ATE1 that helps explain the mechanism of substrate arginylation.
CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion
Authors: Davidson Iain F. , Barth Roman , Zaczek Maciej , van der Torre Jaco , Tang Wen , Nagasaka Kota , Janissen Richard , Kerssemakers Jacob , Wutz Gordana , Dekker Cees , Peters Jan-Michael 
Published: April 2023

AbstractIn eukaryotes, genomic DNA is extruded into loops by cohesin1. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)2,3 that have important roles in gene regulation and recombination during development and disease1,4–7. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear8. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin’s loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.
Mirusviruses link herpesviruses to giant viruses
Authors: Gaïa Morgan , Meng Lingjie , Pelletier Eric , Forterre Patrick , Vanni Chiara , Fernandez-Guerra Antonio , Jaillon Olivier , Wincker Patrick , Ogata Hiroyuki , Krupovic Mart , Delmont Tom O. 
Published: April 2023

AbstractDNA viruses have a major influence on the ecology and evolution of cellular organisms1–4, but their overall diversity and evolutionary trajectories remain elusive5. Here we carried out a phylogeny-guided genome-resolved metagenomic survey of the sunlit oceans and discovered plankton-infecting relatives of herpesviruses that form a putative new phylum dubbed Mirusviricota. The virion morphogenesis module of this large monophyletic clade is typical of viruses from the realm Duplodnaviria6, with multiple components strongly indicating a common ancestry with animal-infecting Herpesvirales. Yet, a substantial fraction of mirusvirus genes, including hallmark transcription machinery genes missing in herpesviruses, are closely related homologues of giant eukaryotic DNA viruses from another viral realm, Varidnaviria. These remarkable chimaeric attributes connecting Mirusviricota to herpesviruses and giant eukaryotic viruses are supported by more than 100 environmental mirusvirus genomes, including a near-complete contiguous genome of 432 kilobases. Moreover, mirusviruses are among the most abundant and active eukaryotic viruses characterized in the sunlit oceans, encoding a diverse array of functions used during the infection of microbial eukaryotes from pole to pole. The prevalence, functional activity, diversification and atypical chimaeric attributes of mirusviruses point to a lasting role of Mirusviricota in the ecology of marine ecosystems and in the evolution of eukaryotic DNA viruses.
The Smc5/6 complex is a DNA loop-extruding motor
Authors: Pradhan Biswajit , Kanno Takaharu , Umeda Igarashi Miki , Loke Mun Siong , Baaske Martin Dieter , Wong Jan Siu Kei , Jeppsson Kristian , Björkegren Camilla , Kim Eugene 
Published: April 2023

AbstractStructural maintenance of chromosomes (SMC) protein complexes are essential for the spatial organization of chromosomes1. Whereas cohesin and condensin organize chromosomes by extrusion of DNA loops, the molecular functions of the third eukaryotic SMC complex, Smc5/6, remain largely unknown2. Using single-molecule imaging, we show that Smc5/6 forms DNA loops by extrusion. Upon ATP hydrolysis, Smc5/6 reels DNA symmetrically into loops at a force-dependent rate of one kilobase pair per second. Smc5/6 extrudes loops in the form of dimers, whereas monomeric Smc5/6 unidirectionally translocates along DNA. We also find that the subunits Nse5 and Nse6 (Nse5/6) act as negative regulators of loop extrusion. Nse5/6 inhibits loop-extrusion initiation by hindering Smc5/6 dimerization but has no influence on ongoing loop extrusion. Our findings reveal functions of Smc5/6 at the molecular level and establish DNA loop extrusion as a conserved mechanism among eukaryotic SMC complexes.