bluuebunny/crossref_metadata_2025 huggingface dataset:
On the robustness of social norm elicitation
Authors: König-Kersting Christian
Published: August 2024

We study the robustness of Krupka and Weber's method (2013) for eliciting social norms. In two online experiments with more than 1200 participants on Amazon Mechanical Turk, we find that participants’ response patterns are invariant to differences in the salience of the monetarily incentivized coordination aspect. We further demonstrate that asking participants for their personal first- and second-order beliefs without monetary incentives results in qualitatively identical responses in the case that beliefs and social norms are well aligned. Overall, Krupka and Weber's method produces remarkably robust response patterns.
The relationship between childhood education and adult learner characteristics
Authors: Dunagin Miller Christine , Greenberg Daphne , Hendrick Robert , Tighe Elizabeth L.
Published: August 2024

Childhood education affects how individuals adapt to the challenges of adulthood. Although various generalizations are made relating childhood educational experiences to characteristics of adults, there is scant evidence to support those assertions for adult literacy learners in the United States. This study investigates the relationship of childhood educational attainment to other characteristics of adult learners. In this study, 201 native English-speaking adult learners in the United States who read at the 3.0–7.9 grade equivalency levels were administered surveys and tests to better understand the relationships between childhood educational attainment and the following characteristics: childhood school disability status and grade repetition; as well as adult characteristics including current reading-related skills, reading avoidance behaviors, reading practices for informational and digital texts, employment status, and Readiness-to-Learn. Results indicated that only school disability status was correlated with educational attainment (Cramer’s V test, V = 0.279, p = 0.004). The results contribute to the body of knowledge about adult learners who want to develop literacy skills and the nuances of childhood schooling experiences in this population. Based on these results, caution should be exercised when treating educational attainment as a signal of other characteristics, including reading skills, among adult literacy students. These findings align with other international research findings.
Beyond benchmarks: Exploring views of success among adult basic education learners
Authors: Frey Shannon
Published: August 2024

Educational policy is built on “benchmarks and measurable ways of being literate” that learners must meet to be considered successful (Compton-Lilly et al. 2012, p. 54). This qualitative study conducted in the northeastern United States is situated in literature on success in ABE (Belzer 2004; Sandlin 2006; St. Clair 2004) and explores six adult basic education (ABE) learners’ perceptions of success and their perceptions of success connected to their adult education classes. The study identified ‘fulfillment’ as a key component of success, going beyond measurable objectives to include satisfaction, accomplishment, emotions, and personal growth, among others.

The study findings emphasized the relationship between learners’ perception of fulfillment and the involvement in ABE programs. Although participants viewed ABE program involvement as part of a path to success, their ideas of achievement extended beyond conventional metrics, focusing on emotional well-being and meaningful connections with others. Additionally, participants viewed success as a collective accomplishment and opportunity to positively influence their family and others in their lives.

Participants’ narratives highlight the complexity of success, wherein emotions, personal growth, and positive effects on others shape their views of achievement. The findings offer insights for educational and career development initiatives, promoting a more holistic understanding of success that cultivates emotional well-being and meaningful connections. By recognizing the importance of ‘fulfillment,’ literacy programs can better support adult learners in their educational journey, fostering personal accomplishments and contributions to their communities.
Computational modelling of thermal plasmas for industry
Authors: Murphy Anthony B.
Published: August 2024

Thermal plasma processes are widely used in industrial applications, including arc welding, plasma cutting, plasma spraying, waste treatment and particle spheroidisation. Computational modelling of such processes is widely used by academic researchers and is increasingly used in industry. This paper considers different ways in which academic researchers can assist industry with their modelling requirements. Three case studies based on the author’s work are presented. The first concerns the arc plasma formed in high-voltage circuit breakers. In this case, the thermophysical properties of the plasmas formed from several gas mixtures were calculated and provided to a company for use in their own model. The results obtained played an important role in designing a high-voltage circuit breaker using a gas mixture containing (CF3)2CFCN to replace the standard SF6 gas. In the second case, a model of a plasma waste treatment process was developed and run, and the results of the model were provided to industrial collaborators. The model solved a critical problem in the destruction of ozone-depleting substances by predicting that adding steam to the ozone-depleting substance prevented the formation of other ozone-depleting substances in the process. In the final case, an in-house computational model of arc welding was extended to industrially relevant welding geometries, packaged as Windows software, and then transferred to industrial users. The requirements of each case are considered, and the benefits to the academic researcher and industry are discussed.
Filgotinib bei Colitis ulcerosa: ein Review
Authors: Blesl Andreas , Novacek Gottfried , Reinisch Walter , Kienbauer Melanie , Platzer Reingard , Wolzt Michael , Koch Robert , Högenauer Christoph , Ribarics Reiner , Moschen Alexander
Published: August 2024

Colitis ulcerosa ist eine chronisch entzündliche Darmerkrankung mit Befall des Kolons. Die häufigsten Symptome sind blutige und schleimige Durchfälle, Stuhldrang sowie abdominelle Schmerzen. Diese Symptome stellen für die Betroffenen oft eine wesentliche gesundheitliche Beeinträchtigung dar.

Filgotinib ist ein Medikament, das in oraler Form zur Behandlung der moderat bis schwer aktiven Colitis ulcerosa angewendet wird. Es zählt zur Klasse der Januskinase-Inhibitoren und blockiert bevorzugt das Enzym Januskinase 1, das zytokinvermittelte Inflammationsprozesse bei Colitis ulcerosa aufrechterhält. Die Wirksamkeit und Sicherheit von Filgotinib im Vergleich zu Placebo zur Behandlung der moderat bis schwer aktiven Colitis ulcerosa wurden in der SELECTION-Studie über 58 Wochen untersucht. Filgotinib 200 mg führte im Vergleich zu Placebo bei signifikant mehr Patienten zu einer schnellen Verbesserung klinischer Symptome innerhalb der ersten 3–4 Tage der Anwendung. Es führte weiters zu einer höheren Rate an klinischer, endoskopischer und histologischer Remission sowohl nach 10 als auch nach 58 Wochen. Das Sicherheitsprofil der Substanz wurde in einer Langzeitstudie evaluiert. Dabei wurden am häufigsten Übelkeit, Infektionen der oberen Atemwege und der Harnwege, Schwindelgefühl und Lymphopenie berichtet. Die Häufigkeiten von schwerwiegenden Infektionen, Thrombosen und schweren kardialen Nebenwirkungen waren gering und vergleichbar zwischen Filgotinib und Placebo.

Besondere Merkmale von Filgotinib sind die einmal tägliche orale Anwendung, die gute Steuerbarkeit aufgrund der kurzen Halbwertzeit sowie die nicht vorhandene Immunogenität im Gegensatz zu den Biologika.
Comparison of explicit criteria for potentially inappropriate drug prescribing among the elderly: a narrative review
Authors: Vukoja M. , Mimica S.
Published: August 2024

The appropriateness and quality of prescribing in the elderly can be assessed through various methods and protocols. Each of them has certain advantages and disadvantages which should be taken into account when they are utilized in everyday practice and care for the geriatric population (people ≥ 65 years). The study aimed to perform a comprehensive literature review and comparison of the existing tools for the assessment of potentially inappropriate drug prescribing in the elderly. The literature search on explicit tools for potentially inappropriate prescribing drugs was performed through the PubMed databases for the period from 1991 until December 2022. The results are structurally presented with the year of publication of the criteria, organization of criteria, and their advantages and disadvantages. Twenty-five different explicit criteria were found in 92 published articles, based on different settings and written in different countries. Many protocols for the detection of potentially inappropriate drugs have been published in recent years, with overlaps between them and different implications for everyday practice. Further research is needed to determine the optimal characteristics of a tool for PIM detection and its role in the optimization of drug prescribing.
Surveying the Impact of Generative Artificial Intelligence on Political Science Education
Authors: Wu Nicole , Wu Patrick Y.
Published: August 2024

Recent applications of new innovations in artificial intelligence have brought up questions about how this new technology will change the landscape and practices in a wide range of industries and sectors. This article focuses on the impact of generative large language models on teaching, learning, and academic assessment in political science education by analyzing two novel surveys administered by the discipline’s major professional body, the American Political Science Association. We present the results of these surveys and conclude with recommendations.
Citations to the Publications of Male and Female Political Scientists Revisited
Authors: Hill Kim Quaile
Published: August 2024

Prior research finds that women earn fewer citations than men for their publications, and it offers various reasons why this is the case. This study provides new evidence on these citation differences from two datasets on career citations earned by male and female political scientists. Our findings extend and elaborate on those in earlier research. Most notably, we find that older cohorts of women demonstrate substantial progress toward citation equity with their male peers.
Causal Inference in the Outer Radiation Belt: Evidence for Local Acceleration
Authors: Manshour P. , Papadimitriou C. , Balasis G. , Paluš M.
Published: August 2024

Currently, there is no clear understanding of the comprehensive set of variables that controls fluxes of relativistic electrons within the outer radiation belt. Herein, the methodology based on causal inference is applied for identification of factors that control fluxes of relativistic electrons in the outer belt. The patterns of interactions between the solar wind, geomagnetic activity and belt electrons have been investigated. We found a significant information transfer from solar wind, geomagnetic activity and fluxes of very low energy electrons (54 keV), into fluxes of relativistic (470 keV) and ultra‐relativistic (2.23 MeV) electrons. We present evidence of a direct causal relationship from relativistic into ultra‐relativistic electrons, which points to a local acceleration mechanism for electrons energization. It is demonstrated that the observed information transfer from low energy electrons at 54 keV into energetic electrons at 470 keV is due to the presence of common external drivers such as substorm activity.
Fundamental Properties of Adjoint Model and Adjoint Sensitivity Under Fully Nonlinear Hydrostatic Internal Gravity Waves
Authors: Shimizu Kenji
Published: August 2024

Adjoint sensitivity modeling plays an important role in inverse problems, including four‐dimensional variational data assimilation or state estimation, by providing the sensitivity of the objective (or cost) function to the model input data. Although data assimilation has become common in regional ocean modeling, and the model resolution has become high enough to resolve internal tides, it remains unclear whether physically sensible and stable adjoint sensitivity modeling is feasible in the presence of internal waves. As a first step to tackle this problem, this study investigates fundamental properties of the adjoint of a time‐dependent circulation model, and the resulting sensitivity under internal waves. The theoretical and numerical results, based on simple‐internal‐wave theory and MITgcm modeling, show that stable adjoint sensitivity modeling is feasible under fully nonlinear (but stable) hydrostatic internal waves. However, it requires a careful choice of the objective function to obtain sensitivity which has the same propagation properties as (real‐world) internal waves, because the definition primarily controls the directionality and vertical‐mode content of internal‐wave signals in the adjoint model. Also, it should be noted that the internal‐wave signals lack indirect sensitivity through the dependence of the wave‐propagation speed on the model's prognostic variables. An important implication of the results is that the standard form of the objective function, which has been used in data assimilation studies for quasi‐geostrophic flows and barotropic tides, could be problematic for internal tides.
GOLD Observations of the Merging of the Southern Crest of the Equatorial Ionization Anomaly and Aurora During the 10 and 11 May 2024 Mother's Day Super Geomagnetic Storm
Authors: Karan Deepak Kumar , Martinis Carlos R. , Daniell Robert E. , Eastes Richard W. , Wang Wenbin , McClintock William E. , Michell Robert G. , England Scott
Published: August 2024

Using NASA's Global‐scale Observations of the Limb and Disk (GOLD) imager, we report nightside ionospheric changes during the G5 super geomagnetic storm of 10 and 11 May 2024. Specifically, the nightside southern crest of the Equatorial Ionization Anomaly (EIA) was observed to merge with the aurora near the southern tip of South America. During the storm, the EIA southern crest was seen moving poleward as fast as 450 m/s. Furthermore, the aurora extended to mid‐latitudes reaching the southern tips of Africa and South America. The poleward shift of the equatorial ionospheric structure and equatorward motion of the aurora means there was no mid‐latitude ionosphere in this region. These observations offer unique insights into the ionospheric response to extreme geomagnetic disturbances, highlighting the complex interplay between solar activity and Earth's upper atmosphere.
Internal Tide Variability Off Central California: Multiple Sources, Seasonality, and Eddying Background
Authors: Cai Tongxin , Zhao Zhongxiang , D'Asaro Eric , Wang Jinbo , Fu Lee‐Lueng
Published: August 2024

Two moorings deployed for 75 days in 2019 and long‐term satellite altimetry data reveal a spatially complex and temporally variable internal tidal field at the Surface Water and Ocean Topography (SWOT) Cal/Val site off central California due to the interference of multiple seasonally‐variable sources. These two data sets offer complementary insights into the variability of internal tides in various time scales. The in situ measurements capture variations occurring from days to months, revealing ∼45% coherent tides. The north mooring displays stronger mode‐1 M2 with an amplitude of ∼5.1 mm and exhibits distinct time‐varying energy and modal partitioning compared to the south mooring, which is only 30‐km away. The 27‐year altimetry data unveils the mean and seasonal variations of internal tides. The results indicate that the complex internal tidal field is attributed to multiple sources and seasonality. Mode‐1 tides primarily originate from the Mendocino Ridge and the 36.5–37.5°N California continental slope, while mode‐2 tides are generated by local seamounts and Monterey Bay. Seasonality is evident for mode‐1 waves from three directions. The highest variability of energy flux is found in the westward waves (±22%), while the lowest is in the southward waves (±13%). The large variability observed from the moorings cannot be solely explained by seasonality; additional factors like mesoscale eddies also play a role. This study emphasizes the importance of incorporating the seasonality and spatial variability of internal tides for the SWOT internal tidal correction, particularly in regions characterized by multiple tidal sources.
Toward Large‐Scale Riverine Phosphorus Estimation Using Remote Sensing and Machine Learning
Authors: Ramtel Pradeep , Feng Dongmei , Gardner John
Published: August 2024

Phosphorus pollution is a major water quality issue impacting the environment and human health. Traditional methods limit the frequency and extent of total phosphorus (TP) measurements across many rivers. However, remote sensing can accurately estimate riverine TP; nevertheless, no large‐scale assessment of riverine TP using remote sensing exists. Large‐scale models using remote sensing can provide a fast and consistent method for TP measurement, important for data generalization and accessing extensive spatial‐temporal change in TP. Our study uses remote sensing and machine learning to estimate the TP in rivers in the contiguous United States (CONUS). Initially, we developed a national scale matchup data set for Landsat detectable rivers (river width >30 m) using in situ TP and surface reflectance. We used in situ data from the Water Quality Portal (WQP), alongside water surface reflectance data from Landsat 5, 7, and 8 spanning from 1984 to 2021. Then, we used this data set to develop a machine learning (ML) model using different preprocessing methods and algorithms. We found that using high‐level vegetation in the clustering approach and over‐sampling or under‐sampling our training data in the sampling approach improved our model estimation accuracy. We compared XGBLinear, XGBTree, Regularized Random Forest (RRF), and K‐Nearest neighbors ML algorithms and selected XGBLinear as the best model with an R2 of 0.604, RMSE of 0.103 mg/L, mean average error of 0.83, and NSE of 0.602. Finally, we identified human footprint, elevation, river area, and soil erosion as the main attributes influencing the accuracy of estimated TP from the ML model.
LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling
Authors: Schelker Roland C. , Fioravanti Jessica , Mastrogiovanni Fabio , Baldwin Jeremy G. , Rana Nisha , Li Peng , Chen Ping , Vadász Timea , Spolski Rosanne , Heuser-Loy Christoph , Slavkovic-Lukic Dragana , Noronha Pedro , Damiano Giuseppe , Raccosta Laura , Maggioni Daniela , Pullugula Sree , Lin Jian-Xin , Oh Jangsuk , Grandinetti Patrick , Lecce Mario , Hesse Leo , Kocks Emilia , Martín-Santos Azucena , Gebhard Claudia , Telford William G. , Ji Yun , Restifo Nicholas P. , Russo Vincenzo , Rehli Michael , Herr Wolfgang , Leonard Warren J. , Gattinoni Luca
Published: August 2024

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.
How do teeth erupt?
Authors: Stonehouse-Smith Daniel , Ota Laura , Seehra Jadbinder , Kwok Jerry , Liu Catherine , Seppala Maisa , Cobourne Martyn T.
Published: August 2024

The development of normal occlusion requires eruptive migration of teeth from their developmental position in the jaw into a functional position within the oral cavity. This process involves significant and coordinated movement in an axial direction and appropriate eruption through the gingival tissues. The mechanisms regulating these developmental events are poorly understood, and teeth retain eruptive potential throughout their lifespan. In recent years, the use of mouse models has helped to elucidate some of the underlying molecular and biological mechanisms of mammalian tooth eruption. Here, we outline our current understanding of tooth eruption mechanisms and discuss their relevance in terms of known human disorders of tooth eruption.
Direct serotonin release in humans shapes aversive learning and inhibition
Authors: Colwell Michael J. , Tagomori Hosana , Shang Fei , Cheng Hoi Iao , Wigg Chloe E. , Browning Michael , Cowen Philip J. , Murphy Susannah E. , Harmer Catherine J.
Published: August 2024

The role of serotonin in human behaviour is informed by approaches which allow in vivo modification of synaptic serotonin. However, characterising the effects of increased serotonin signalling in human models of behaviour is challenging given the limitations of available experimental probes, notably selective serotonin reuptake inhibitors. Here we use a now-accessible approach to directly increase synaptic serotonin in humans (a selective serotonin releasing agent) and examine its influence on domains of behaviour historically considered core functions of serotonin. Computational techniques, including reinforcement learning and drift diffusion modelling, explain participant behaviour at baseline and after week-long intervention. Reinforcement learning models reveal that increasing synaptic serotonin reduces sensitivity for outcomes in aversive contexts. Furthermore, increasing synaptic serotonin enhances behavioural inhibition, and shifts bias towards impulse control during exposure to aversive emotional probes. These effects are seen in the context of overall improvements in memory for neutral verbal information. Our findings highlight the direct effects of increasing synaptic serotonin on human behaviour, underlining its role in guiding decision-making within aversive and more neutral contexts, and offering implications for longstanding theories of central serotonin function.
Inherited defects of piRNA biogenesis cause transposon de-repression, impaired spermatogenesis, and human male infertility
Authors: Stallmeyer Birgit , Bühlmann Clara , Stakaitis Rytis , Dicke Ann-Kristin , Ghieh Farah , Meier Luisa , Zoch Ansgar , MacKenzie MacLeod David , Steingröver Johanna , Okutman Özlem , Fietz Daniela , Pilatz Adrian , Riera-Escamilla Antoni , Xavier Miguel J. , Ruckert Christian , Di Persio Sara , Neuhaus Nina , Gurbuz Ali Sami , Şalvarci Ahmet , Le May Nicolas , McEleny Kevin , Friedrich Corinna , van der Heijden Godfried , Wyrwoll Margot J. , Kliesch Sabine , Veltman Joris A. , Krausz Csilla , Viville Stéphane , Conrad Donald F. , O’Carroll Dónal , Tüttelmann Frank
Published: August 2024

piRNAs are crucial for transposon silencing, germ cell maturation, and fertility in male mice. Here, we report on the genetic landscape of piRNA dysfunction in humans and present 39 infertile men carrying biallelic variants in 14 different piRNA pathway genes, including PIWIL1, GTSF1, GPAT2, MAEL, TDRD1, and DDX4. In some affected men, the testicular phenotypes differ from those of the respective knockout mice and range from complete germ cell loss to the production of a few morphologically abnormal sperm. A reduced number of pachytene piRNAs was detected in the testicular tissue of variant carriers, demonstrating impaired piRNA biogenesis. Furthermore, LINE1 expression in spermatogonia links impaired piRNA biogenesis to transposon de-silencing and serves to classify variants as functionally relevant. These results establish the disrupted piRNA pathway as a major cause of human spermatogenic failure and provide insights into transposon silencing in human male germ cells.
Bistable organic electrochemical transistors: enthalpy vs. entropy
Authors: Bongartz Lukas M. , Kantelberg Richard , Meier Tommy , Hoffmann Raik , Matthus Christian , Weissbach Anton , Cucchi Matteo , Kleemann Hans , Leo Karl
Published: August 2024

Organic electrochemical transistors (OECTs) underpin a range of emerging technologies, from bioelectronics to neuromorphic computing, owing to their unique coupling of electronic and ionic charge carriers. In this context, various OECT systems exhibit significant hysteresis in their transfer curve, which is frequently leveraged to achieve non-volatility. Meanwhile, a general understanding of its physical origin is missing. Here, we introduce a thermodynamic framework that readily explains the emergence of bistable OECT operation via the interplay of enthalpy and entropy. We validate this model through temperature-resolved characterizations, material manipulation, and thermal imaging. Further, we reveal deviations from Boltzmann statistics for the subthreshold swing and reinterpret existing literature. Capitalizing on these findings, we finally demonstrate a single-OECT Schmitt trigger, thus compacting a multi-component circuit into a single device. These insights provide a fundamental advance for OECT physics and its application in non-conventional computing, where symmetry-breaking phenomena are pivotal to unlock new paradigms of information processing.
High-performance deep spiking neural networks with 0.3 spikes per neuron
Authors: Stanojevic Ana , Woźniak Stanisław , Bellec Guillaume , Cherubini Giovanni , Pantazi Angeliki , Gerstner Wulfram
Published: August 2024

Communication by rare, binary spikes is a key factor for the energy efficiency of biological brains. However, it is harder to train biologically-inspired spiking neural networks than artificial neural networks. This is puzzling given that theoretical results provide exact mapping algorithms from artificial to spiking neural networks with time-to-first-spike coding. In this paper we analyze in theory and simulation the learning dynamics of time-to-first-spike-networks and identify a specific instance of the vanishing-or-exploding gradient problem. While two choices of spiking neural network mappings solve this problem at initialization, only the one with a constant slope of the neuron membrane potential at threshold guarantees the equivalence of the training trajectory between spiking and artificial neural networks with rectified linear units. For specific image classification architectures comprising feed-forward dense or convolutional layers, we demonstrate that deep spiking neural network models can be effectively trained from scratch on MNIST and Fashion-MNIST datasets, or fine-tuned on large-scale datasets, such as CIFAR10, CIFAR100 and PLACES365, to achieve the exact same performance as that of artificial neural networks, surpassing previous spiking neural networks. Our approach accomplishes high-performance classification with less than 0.3 spikes per neuron, lending itself for an energy-efficient implementation. We also show that fine-tuning spiking neural networks with our robust gradient descent algorithm enables their optimization for hardware implementations with low latency and resilience to noise and quantization.
Cryo-EM structure of the CDK2-cyclin A-CDC25A complex
Authors: Rowland Rhianna J. , Korolchuk Svitlana , Salamina Marco , Tatum Natalie J. , Ault James R. , Hart Sam , Turkenburg Johan P. , Blaza James N. , Noble Martin E. M. , Endicott Jane A.
Published: August 2024

The cell division cycle 25 phosphatases CDC25A, B and C regulate cell cycle transitions by dephosphorylating residues in the conserved glycine-rich loop of CDKs to activate their activity. Here, we present the cryo-EM structure of CDK2-cyclin A in complex with CDC25A at 2.7 Å resolution, providing a detailed structural analysis of the overall complex architecture and key protein-protein interactions that underpin this 86 kDa complex. We further identify a CDC25A C-terminal helix that is critical for complex formation. Sequence conservation analysis suggests CDK1/2-cyclin A, CDK1-cyclin B and CDK2/3-cyclin E are suitable binding partners for CDC25A, whilst CDK4/6-cyclin D complexes appear unlikely substrates. A comparative structural analysis of CDK-containing complexes also confirms the functional importance of the conserved CDK1/2 GDSEID motif. This structure improves our understanding of the roles of CDC25 phosphatases in CDK regulation and may inform the development of CDC25-targeting anticancer strategies.
Non-redundant metagenome-assembled genomes of activated sludge reactors at different disturbances and scales
Authors: Neshat Soheil A. , Santillan Ezequiel , Seshan Hari , Wuertz Stefan
Published: August 2024

Metagenome-assembled genomes (MAGs) are microbial genomes reconstructed from metagenomic data and can be assigned to known taxa or lead to uncovering novel ones. MAGs can provide insights into how microbes interact with the environment. Here, we performed genome-resolved metagenomics on sequencing data from four studies using sequencing batch reactors at microcosm (~25 mL) and mesocosm (~4 L) scales inoculated with sludge from full-scale wastewater treatment plants. These studies investigated how microbial communities in such plants respond to two environmental disturbances: the presence of toxic 3-chloroaniline and changes in organic loading rate. We report 839 non-redundant MAGs with at least 50% completeness and 10% contamination (MIMAG medium-quality criteria). From these, 399 are of putative high-quality, while sixty-seven meet the MIMAG high-quality criteria. MAGs in this catalogue represent the microbial communities in sixty-eight laboratory-scale reactors used for the disturbance experiments, and in the full-scale wastewater treatment plant which provided the source sludge. This dataset can aid meta-studies aimed at understanding the responses of microbial communities to disturbances, particularly as ecosystems confront rapid environmental changes.
CREMP: Conformer-rotamer ensembles of macrocyclic peptides for machine learning
Authors: Grambow Colin A. , Weir Hayley , Cunningham Christian N. , Biancalani Tommaso , Chuang Kangway V.
Published: August 2024

Computational and machine learning approaches to model the conformational landscape of macrocyclic peptides have the potential to enable rational design and optimization. However, accurate, fast, and scalable methods for modeling macrocycle geometries remain elusive. Recent deep learning approaches have significantly accelerated protein structure prediction and the generation of small-molecule conformational ensembles, yet similar progress has not been made for macrocyclic peptides due to their unique properties. Here, we introduce CREMP, a resource generated for the rapid development and evaluation of machine learning models for macrocyclic peptides. CREMP contains 36,198 unique macrocyclic peptides and their high-quality structural ensembles generated using the Conformer-Rotamer Ensemble Sampling Tool (CREST). Altogether, this new dataset contains nearly 31.3 million unique macrocycle geometries, each annotated with energies derived from semi-empirical extended tight-binding (xTB) DFT calculations. Additionally, we include 3,258 macrocycles with reported passive permeability data to couple conformational ensembles to experiment. We anticipate that this dataset will enable the development of machine learning models that can improve peptide design and optimization for novel therapeutics.
Sustained mucosal colonization and fecal metabolic dysfunction by Bacteroides associates with fecal microbial transplant failure in ulcerative colitis patients
Authors: Zhang Bing , Magnaye Kevin M. , Stryker Emily , Moltzau-Anderson Jacqueline , Porsche Cara E. , Hertz Sandra , McCauley Kathryn E. , Smith Byron J. , Zydek Martin , Pollard Katherine S. , Ma Averil , El-Nachef Najwa , Lynch Susan V.
Published: August 2024

Fecal microbial transplantation (FMT) offers promise for treating ulcerative colitis (UC), though the mechanisms underlying treatment failure are unknown. This study harnessed longitudinally collected colonic biopsies (n = 38) and fecal samples (n = 179) from 19 adults with mild-to-moderate UC undergoing serial FMT in which antimicrobial pre-treatment and delivery mode (capsules versus enema) were assessed for clinical response (≥ 3 points decrease from the pre-treatment Mayo score). Colonic biopsies underwent dual RNA-Seq; fecal samples underwent parallel 16S rRNA and shotgun metagenomic sequencing as well as untargeted metabolomic analyses. Pre-FMT, the colonic mucosa of non-responsive (NR) patients harbored an increased burden of bacteria, including Bacteroides, that expressed more antimicrobial resistance genes compared to responsive (R) patients. NR patients also exhibited muted mucosal expression of innate immune antimicrobial response genes. Post-FMT, NR and R fecal microbiomes and metabolomes exhibited significant divergence. NR metabolomes had elevated concentrations of immunostimulatory compounds including sphingomyelins, lysophospholipids and taurine. NR fecal microbiomes were enriched for Bacteroides fragilis and Bacteroides salyersiae strains that encoded genes capable of taurine production. These findings suggest that both effective mucosal microbial clearance and reintroduction of bacteria that reshape luminal metabolism associate with FMT success and that persistent mucosal and fecal colonization by antimicrobial-resistant Bacteroides species may contribute to FMT failure.
Dilatational-plasticity opens a new mechanistic pathway for macromolecular transport across glassy interfaces
Authors: Vallabh Ajay , Padhye Nikhil
Published: August 2024

Interdiffusion-based macromolecular transport across glassy interfaces is reportedly achieved at high temperatures in accordance with the classical model of reptation. Here, for the first time, we report a new mechanistic pathway for achieving solid-state glassy joining by triggering rapid macromolecular acceleration through mechanical deformation. Large-scale molecular simulations reveal that active plastic deformation in glassy polymers, at temperatures well below the bulk (and surface) glass transition temperatures $$\text {T}_g^b$$

T
g
b

(and $$\text {T}_g^s$$

T
g
s

), causes segmental translations of macromolecules leading to interfacial interpenetrations, and the formation of new entanglements. The mechanistic basis for this new type of bonding is identified as molecular-scale dilatations and densifications during deformation-induced mobility. The reported insights open promising avenues for achieving quick, strong, and energetically less-intensive joining of polymeric glasses across various sectors.
The protection afforded by kefir against cyclophosphamide induced testicular toxicity in rats by oxidant antioxidant and histopathological evaluations
Authors: Cetik Yildiz Songul , Demir Cemil , Cengiz Mustafa , Irmak Halit , Peker Cengiz Betul , Ayhanci Adnan
Published: August 2024

Cyclophosphamide (CTX) is the most commonly used effective alkylating drug in cancer treatment, but its use is restricted because its toxic side effect causes testicular toxicity. CTX disrupts the tissue redox and antioxidant balance and the resulting tissue damage causes oxidative stress. In our study based on this problem, kefir against CTX-induced oxidative stress and testicular toxicity were investigated. Rats were divided into 6 groups: control, 150 mg/kg CTX, 5 and 10 mg/kg kefir, 5 and 10 mg/kg kefir + 150 CTX. While the fermented kefirs were mixed and given to the rats for 12 days, CTX was given as a single dose on the 12th day of the experiment. Testis was scored according to spermatid density, giant cell formation, cells shed into tubules, maturation disorder, and atrophy. According to our biochemical findings, the high levels of total oxidant status (TOS), and the low levels of total antioxidant status (TAS) in the CTX group, which are oxidative stress markers, indicate the toxic effect of CTX, while the decrease in TOS levels and the increase in TAS levels in the kefir groups indicate the protective effect of kefir. In the CTX-administered group, tubules with impaired maturation and no spermatids were observed in the transverse section of the testicle, while in the kefir groups, the presence of near-normal tubule structures and tubule lumens despite CTX showed the protective effect of kefir. In our study, it was observed that kefir had a protective and curative effect on CTX-induced toxicity and oxidative stress and could be a strong protector.
Rock slope stability analysis of a limestone quarry in a case study of a National Cement Factory in Eastern Ethiopia
Authors: Bezie Getaneh , Chala Endalu Tadele , Jilo Nagessa Zerihun , Birhanu Sisay , Berta Kalkidan Kefale , Assefa Siraj Mulugeta , Gissila Biruk
Published: August 2024

Rock slope failures pose significant challenges in geotechnical engineering due to the intricate nature of rock masses, discontinuities, and various destabilizing factors during and after excavation. In mining industries, such as national cement factories, multi-benched excavation systems are commonly used for quarrying. However, cut slopes are often designed with steep angles to maximize economic benefits, inadvertently neglecting critical slope stability issues. This oversight can lead to slope instability, endangering human lives and property. This study focuses on analyzing the stability of existing quarry cut slopes, estimating their final depth, and conducting a parametric study of geometric profiles including bench height, width, face angle, and rump width. Kinematic analysis helps identify potential failure modes. The results reveal that the existing quarry cut slope is prone to toppling, wedge failure, and planar failure with probabilities of 42.68%, 19.53%, and 14.23%, respectively. Numerical modeling using the finite element method (Phase2 8.0 software) was performed under both static and dynamic loading conditions. The shear reduction factor (SRF) of the existing quarry cut slope was 1.01 under static loading and 0.86 under dynamic loading. Similarly, for the estimated depth, the SRF was 0.82 under static loading and 0.7 under dynamic loading. These values indicate that the slope stability falls significantly below the minimum acceptable SRF, rendering it unstable. The parametric study highlights the face angle of the bench as the most influential parameter in slope stability. By adjusting the bench face angle from 90° to 75°, 70°, and 65°, the SRF increased by 31.6%, 35.4%, and 37.9%, respectively. Among these, a 70° bench face angle is recommended for optimal stability with a SRF of 1.27 under static loading and 1.18 under dynamic loading.
Recent two decades witness an uptick in monsoon depressions over the northern Arabian Sea
Authors: Chilukoti Nagaraju , Nimmakanti Mahendra , Chowdary Jasti S.
Published: August 2024

The analysis reveals that the occurrence of summer Monsoon Depressions (MDs) over the North Arabian Sea is doubling during 2001–2022 compared to the 1981–2000 period. This increase stems from changes in the region’s dynamic and thermodynamic conditions. The heightened genesis potential parameter with sea surface temperature and moisture flux transport and its convergence over the North Arabian Sea inducing MDs formation, contrasting to the Bay of Bengal. The dynamic processes involved in its formation, a combination of barotropic and dynamical instability, are leading to increased rainfall over northwestern India. Strong East Asian jet variability, with an anomalous anticyclone in the north and weak cyclonic anomalies in the south, induces prevailing easterly wind anomalies along the monsoon trough. This leads to a poleward shift (~1.13°) in the low-level jet, significantly altering dynamic and thermodynamic parameters in the northern Arabian Sea region leading to a notable increase in MDs.
Combined effects of fine and coarse marine aerosol on vertical raindrop size distribution
Authors: Liu Fan , Rosenfeld Daniel , Pan Zengxin , Zang Lin , Mao Feiyue
Published: August 2024

Climate models commonly overestimate warm rain frequency and underestimate its intensity over the ocean, primarily due to insufficient representation of the aerosol effects. This pertains to both fine aerosols (FA) and coarse sea spray aerosols (CSA), where the latter is mostly absent in the models. Here, our observations show that adding CSA enhances vertical warm rain structure, in contrast to the effect of FA. The magnitude of the effect of CSA is larger than the opposite effect of the FA. For rain with top heights of 2–3 km, the raindrop size, concentration, and rain rate can be increased by factors of 1.03, 1.47, and 1.60, respectively. These CSA-induced changes are larger for thicker clouds, reaching a maximum by factors of 1.12, 1.85, and 2.21, respectively. Therefore, the combined FA and CSA effects should be incorporated into climate models for accurately simulated precipitation microphysical processes.
Effects of volume management on free flap perfusion and metabolism in a large animal model study
Authors: Thiem Daniel G. E. , Stephan Daniel , Ziebart Alexander , Ruemmler Robert , Riedel Julian , Vinayahalingam Shankeeth , Al-Nawas Bilal , Blatt Sebastian , Kämmerer Peer W.
Published: August 2024

Free flap failure represents a substantial clinical burden. The role of intraoperative volume management remains controversial, with valid studies lacking. Here, using a large animal model, we investigated the influence of volume management on free flap perfusion and metabolism. Autotransfer of a musculocutaneous gracilis flap was performed on 31 German domestic pigs, with arterial anastomosis and catheterization of the pedicle vein for sequential blood sampling. Flap reperfusion was followed by induction of a hemorrhagic shock with maintenance for 30 min and subsequent circulation stabilization with crystalloid solution, crystalloid solution and catecholamine, autotransfusion or colloidal solution. Flap perfusion and oxygenation were periodically assessed using hyperspectral imaging. Flap metabolism was assessed via periodic blood gas analyses. Hyperspectral imaging revealed no difference in either superficial or deep tissue oxygen saturation, tissue hemoglobin or tissue water content between the test groups at any time point. Blood gas analyses showed that lactate levels were significantly increased in the group that received crystalloid solution and catecholamine, after circulatory stabilization and up to 2 h after. We conclude that, in hemorrhagic shock, volume management impacts acid–base balance in free flaps. Crystalloid solutions with norepinephrine increase lactate levels, yet short-term effects on flap perfusion seem minimal, suggesting that vasopressors are not detrimental.
Responsible development of clinical speech AI: Bridging the gap between clinical research and technology
Authors: Berisha Visar , Liss Julie M.
Published: August 2024

This perspective article explores the challenges and potential of using speech as a biomarker in clinical settings, particularly when constrained by the small clinical datasets typically available in such contexts. We contend that by integrating insights from speech science and clinical research, we can reduce sample complexity in clinical speech AI models with the potential to decrease timelines to translation. Most existing models are based on high-dimensional feature representations trained with limited sample sizes and often do not leverage insights from speech science and clinical research. This approach can lead to overfitting, where the models perform exceptionally well on training data but fail to generalize to new, unseen data. Additionally, without incorporating theoretical knowledge, these models may lack interpretability and robustness, making them challenging to troubleshoot or improve post-deployment. We propose a framework for organizing health conditions based on their impact on speech and promote the use of speech analytics in diverse clinical contexts beyond cross-sectional classification. For high-stakes clinical use cases, we advocate for a focus on explainable and individually-validated measures and stress the importance of rigorous validation frameworks and ethical considerations for responsible deployment. Bridging the gap between AI research and clinical speech research presents new opportunities for more efficient translation of speech-based AI tools and advancement of scientific discoveries in this interdisciplinary space, particularly if limited to small or retrospective datasets.
Solvent induced amyloid polymorphism and the uncovering of the elusive class 3 amyloid topology
Authors: Dürvanger Zsolt , Bencs Fruzsina , Menyhárd Dóra K. , Horváth Dániel , Perczel András
Published: August 2024

Aggregation-prone-motifs (APRs) of proteins are short segments, which – as isolated peptides - form diverse amyloid-like crystals. We introduce two APRs - designed variants of the incretin mimetic Exendin-4 - that both display crystal-phase polymorphism. Crystallographic and spectroscopic analysis revealed that a single amino-acid substitution can greatly reduce topological variability: while LYIQWL can form both parallel and anti-parallel β-sheets, LYIQNL selects only the former. We also found that the parallel/anti-parallel switch of LYIQWL can be induced by simply changing the crystallization temperature. One crystal form of LYIQNL was found to belong to the class 3 topology, an arrangement previously not encountered among proteinogenic systems. We also show that subtle environmental changes lead to crystalline assemblies with different topologies, but similar interfaces. Spectroscopic measurements showed that polymorphism is already apparent in the solution state. Our results suggest that the temperature-, sequence- and environmental sensitivity of physiological amyloids is reflected in assemblies of the APR segments, which, complete with the new class 3 crystal form, effectively sample all the originally proposed basic topologies of amyloid-like aggregates.