bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractHigh 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

AbstractThe 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

AbstractThe 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

AbstractpiRNAs 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

AbstractOrganic 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

AbstractCommunication 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

AbstractThe 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

AbstractMetagenome-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

AbstractComputational 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

AbstractFecal 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

AbstractInterdiffusion-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

AbstractCyclophosphamide (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

AbstractRock 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

AbstractThe 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

AbstractClimate 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.