bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epididymis-specific RNase A family genes regulate fertility and small RNA processing
Authors: Shaffer Joshua F. , Gupta Alka , Kharkwal Geetika , Linares Edgardo E. , Holmes Andrew D. , Katzman Sol , Sharma Upasna 
Published: August 2024

ABSTRACTSperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by cleavage of tRNAs, known as tRNA fragments (tRFs), are an abundant class of RNAs in mature sperm, and can be modulated by environmental conditions. The ribonuclease(s) responsible for the biogenesis of tRFs in the male reproductive tract remains unknown. Angiogenin, a member of the Ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namelyRnase9,Rnase10, Rnase11, andRnase12, are specifically expressed in the epididymis—a long, convoluted tubule where sperm mature and acquire fertility and motility. The biological functions of these genes remain largely unknown. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed “KO” for Knock Out), we report that these genes regulate fertility and RNA processing. KO mice showed complete male sterility. KO sperm fertilized oocytesin vitrobut failed to efficiently fertilize oocytesin vivo,likely due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of fragments of tRNAs (tRFs) and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, implying thatRnase9-12regulate the biogenesis and/or stability of tRFs and rsRNAs. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role ofRnase9-12in regulating sperm RNA composition. Together, our results reveal an unexpected role of four epididymis-specific non-canonical RNase A family genes in fertility and RNA processing.
Hydrogen peroxide damage to scavenging function and ultrastructure of liver sinusoidal endothelial cells is prevented by n-acetyl-cysteine but not GSH
Authors: Kruse Larissa D. , Holte Christopher , Zapotoczny Bartlomiej , Struck Eike C. , Schürstedt Jasmin , Hübner Wolfgang , Huser Thomas , Szafranska Karolina 
Published: August 2024

AbstractReactive oxygen species (ROS) are prevalent in the liver during intoxication, infection, inflammation, and ageing. Changes in liver sinusoidal endothelial cells (LSECs) are associated with various liver diseases. We investigated how oxidative stress induced by H2O2affects isolated rat LSECs at different concentrations (0.5-1000µM) and exposure times (10-120 min). Our findings show that H2O2exposure affects several LSEC functions in a dose- and time-dependent manner: (1) cell viability, reducing potential, and scavenging function decreased as H2O2concentration and exposure time increased; (2) intracellular ROS levels rose with higher H2O2concentrations; (3) fenestrations exhibited a dynamic response, initially closing but partially reopening at H2O2concentrations above 100µM after about 1 h; (4) scavenging function was affected after just 10 min of exposure, with the impact being irreversible and primarily affecting degradation rather than receptor-mediated uptake; (5) the tubulin network was disrupted in high H2O2concentration while the actin cytoskeleton appears to remain largely intact. Finally, we found that reducing agents and thiol donors such as N-Acetyl Cysteine (NAC) and Glutathione (GSH) could protect cells from ROS-induced damage but could not reverse existing damage. Pretreatment with NAC, but not GSH, reduced the negative effects of ROS exposure suggesting that LSEC does not store an excess amount of GSH but rather can readily produce it in the occurrence of oxidative stress conditions. The observed thresholds in dose and time-dependent changes as well as the treatments with NAC/GSH confirm the existence of ROS depleting system in LSEC.Abstract FigureHighlightsROS by H2O2irreversibly depletes LSEC endocytic/scavenging functionin vitroH2O2exposure causes dynamic, dose-dependent defenestration of LSEC within 0.5 hPartial refenestration can occur after about 1h of exposure to H2O2NAC/GSH mitigate H2O2-induced ROS effects in LSECLSEC do not store excess GSH but produce GSH when exposed to oxidative stress
Photoperiodicity in Glucose Metabolism in the Human Brain
Authors: Pak Kyoungjune , Shin Seunghyeon , Kim Keunyoung , Kim Jihyun , Nam Hyun-Yeol , Nummenmaa Lauri , Nuutila Pirjo , Liu Xingdang , Sun Lihua 
Published: August 2024

AbstractPhotoperiodicity in the human brain function, which is a critical factor for social well-being, has been widely debated. In this study, 432 healthy males underwent fasting-state brain [18F]fluorodeoxyglucose positron emission tomography (PET) scanning twice: first at the baseline and then at the 5-year follow-up. We analyzed the effect of day length on brain glucose uptake separately for the baseline and follow-up studies and examined changes in glucose consumption as a function of the day length deviation for each participant between the repeated PET scans. Glucose uptake in the cuneus was consistently predicted by the day length on the day of scanning and by within-participant day length deviations. This longitudinal large-scale PET study provides a landmark evidence for photoperiodicity in glucose metabolism in the human brain. The cuneus may be an essential part of the visual cortex, translating environmental photoperiodic changes into temporal cues that influence cognitive function and social behavior.Significance statementPhotoperiodicity in the human brain function has been widely debated. The current study provides a landmark evidence in this regard by demonstrating how the photoperiod shapes glucose metabolism in the brain of healthy males, highlighting the crucial role of the cuneus in processing visual information related to photoperiodic changes in the environment. Understanding photoperiodicity in the function of the human brain offers insights into how humans adapt to their environments for social well-being and underscores the potential health implications of changes in the exposure of natural light.
Biomechanical Evaluation of Temporomandibular Joint Implants Under Complete Mastication Cycle
Authors: Ghosh Rajdeep , Chandra Girish , Verma Vivek , Kaur Kamalpreet , Roychoudhury Ajoy , Mukherjee Sudipto , Chawla Anoop , Mukherjee Kaushik 
Published: August 2024

AbstractBackgroundTo ensure the long-term success of temporomandibular joint implants, it is imperative to understand their biomechanical performances under the mastication cycle.PurposeThis study aims to compare the biomechanical performance of two commercially available stock implants under a complete mastication cycle. This study has been further extended to understand the influence of bone-implant interface conditions on pre-clinical testing of implants.MethodsIn the present study, patient-specific QCT-based finite element models of a human mandible were developed. The left temporomandibular joint was virtually replaced by stock implants (narrow and standard). A complete mastication cycle involving six clenching tasks was simulated. A comparative biomechanical assessment between the intact and the implanted mandibles was performed based on maximum principal stress and strain distributions on the mandible.ResultsAs compared to contralateral occlusion, ipsilateral clenching resulted in higher strains in the mandible. However, contralateral occlusion produced a larger von Mises stress on the implant than ipsilateral occlusion. Furthermore, intercuspal biting was found to have produced the highest strain (1750-1880 µε) and stress (16.02-16.54 MPa) in the mandible. As compared to immediate post-operative non-osseointegrated conditions, an overall reduction of stress (narrow implant: 0.14 MPa; standard implant: 0.12 MPa) and strain (narrow implant: 30 µε; standard implant: 20 µε) was observed in post-operative osseointegrated phase.ConclusionsAlthough stresses and strains in mandible and implants are reduced in osseointegrated condition, standard temporomandibular joint implant produced higher stresses in cortical bone compared to narrow implant during non-osseointegrated conditions, which suggests the possible preference of narrow implant over standard ones.
Novel high throughput 3D ECM remodeling assay identifies MEK as key driver of fibrotic fibroblast activity
Authors: Liao Chen-Yi , Hundscheid Jasmijn HM , Crawford Justin , ten Dijke Peter , Coorneaert Beatrice , Danen Erik HJ 
Published: August 2024

ABSTRACTIn fibrotic tissues, activated fibroblasts remodel the collagen-rich extracellular matrix (ECM). Intervening with this process represents a candidate therapeutic strategy to attenuate disease progression. Models that generate quantitative data on 3D fibroblast-mediated ECM remodeling with the reproducibility and throughput needed for drug testing are lacking. Here, we develop a model that fits this purpose and produces combined quantitative information on drug efficacy and cytotoxicity. We use microinjection robotics to design patterns of fibrillar collagen-embedded fibroblast clusters and apply automated microscopy and image analysis to quantify ECM remodeling between-, and cell viability within clusters of TGFβ-activated primary human skin or lung fibroblasts. We apply this assay to compound screening and reveal actionable targets to suppress fibrotic ECM remodeling. Strikingly, we find that after an initial phase of fibroblast activation by TGFβ, canonical TGFβ signaling is dispensable and, instead, non-canonical activation of MEK-ERK signaling drives ECM remodeling. Moreover, we reveal that higher concentrations of two TGFβ receptor inhibitors while blocking canonical TGFβ signaling, in fact stimulate this MEK-mediated profibrotic ECM remodeling activity.
Foundation model for efficient biological discovery in single-molecule data
Authors: Li Jieming , Zhang Leyou , Johnson-Buck Alexander , Walter Nils G. 
Published: August 2024

AbstractModern data-intensive techniques offer ever deeper insights into biology, but render the process of discovery increasingly complex. For example, exploiting the unique ability of single-molecule fluorescence microscopy (SMFM)1–5. to uncover rare but critical intermediates often demands manual inspection of time traces and iterativead hocapproaches that are difficult to systematize. To facilitate systematic and efficient discovery from SMFM data, we introduce META-SiM, a transformer-based foundation model pre-trained on diverse SMFM analysis tasks. META-SiM achieves high performance—rivaling best-in-class algorithms—on a broad range of analysis tasks including trace selection, classification, segmentation, idealization, and stepwise photobleaching analysis. Additionally, the model produces high-dimensional embedding vectors that encapsulate detailed information about each trace, which the web-based META-SiM Projector (https://www.simol-projector.org) casts into lower-dimensional space for efficient whole-dataset visualization, labeling, comparison, and sharing. Combining this Projector with the objective metric of Local Shannon Entropy enables rapid identification of condition-specific behaviors, even if rare or subtle. As a result, by applying META-SiM to an existing single-molecule Förster resonance energy transfer (smFRET) dataset6, we discover a previously unobserved intermediate state in pre-mRNA splicing. META-SiM thus removes bottlenecks, improves objectivity, and both systematizes and accelerates biological discovery in complex single-molecule data.
A new tool in a toolbox: Addressing challenges in high-throughput microbiota surveys across diverse wild insects
Authors: Buczek Mateusz , Kolasa Michał R. , Prus-Frankowska Monika , Lipowska Małgorzata , Nowak Karol H. , Azarbad Hamed , Franco Diego Castilo , Marszałek Marzena , Roslin Tomas , Michalik Anna , Łukasik Piotr 
Published: August 2024

AbstractWith their significant effects on the biology of higher organisms, host-associated microbiota has attracted the research community’s attention. The rapid progress in sequencing techniques has greatly facilitated microbial community characterization. However, the most popular surveying technique, marker gene amplicon sequencing, has multiple caveats that are not often addressed satisfactorily, including the uncertainty about the identity of the surveyed wild-caught specimens, variable and sometimes very low abundance of microbes in some samples, or reagent- and cross-contamination. As a result, researchers often obtain incomplete, biased, and sometimes totally incorrect microbial community profiles.Here, we present a versatile, cost-effective, and high-throughput quantitative multi-target amplicon sequencing workflow for the characterization of host-associated microbial communities, combining laboratory and bioinformatic steps and addressing most of the known methodological issues. Optimized for the study of the microbiota of wild insects, it can be easily adapted for other sample types. Outputs include contamination-controlled data on the absolute abundance and identity of microbes present in insect samples, both at genotype- and OTU-level, as well as host barcodes alongside information on parasite infections. Using 1384 samples from Zackenberg Valley, NE Greenland, we demonstrate the potential of the workflow to study insect and symbiont diversity patterns across a large portion of a diverse natural community.
Center-surround inhibition by expectation: a neuro-computational account
Authors: Huang Ling , Shen Shiqi , Sun Yueling , Ou Shipei , Zhang Ruyuan , de Lange Floris P. , Zhang Xilin 
Published: August 2024

AbstractExpectation is beneficial for adaptive behavior through quickly deducing plausible interpretations of information. The profile and underlying neural computations of this process, however, remain unclear. When participants expected a grating with a specific orientation, we found a center-surround inhibition profile in orientation space, which was independent from attentional modulations by task-relevance. Using computational modeling, we showed that this center-surround inhibition could be reproduced by either a sharpening of tuning curves of expected orientation or a shift of tuning curves of unexpected orientations. Intriguingly, these two computations were further supported by orientation-adjustment and orientation-discrimination experiments. Finally, the ablation studies in convolutional neural networks revealed that predictive coding feedback played a critical role in the center-surround inhibition in expectation. Altogether, our study reveals for the first time that expectation results in both enhancement and suppression, optimizing plausible interpretations during perception by enhancing expected and attenuating similar but irrelevant and potentially interfering representations.
Immunophenotypic changes in peripheral blood of colorectal cancer patients: a potential diagnostic marker for CD4+ monocytes
Authors: Thin Khin Aye , Cross Andrew , Angsuwatcharakon Phonthep , Mutirangura Apiwat , Puttipanyalears Charoenchai , Pike Thomas , Jones Robert , Skaife Paul , Edwards Steven W 
Published: August 2024

AbstractColorectal cancer (CRC) can induce stresses on the immune system that can affect both the numbers and function of these cells and the ability of the tumours to evade immune-surveillance. Changes in immune functions can also occur during ageing and these may affect both the ability to fight infections and to protect against cancers. As the incidence of CRC is age-related, the aim of this work was to identify changes in immune cell subtypes that are specific to CRC and not merely due to age-related changes. The immunophenotypes of peripheral blood lymphocytes and monocytes of CRC patients and age-matched healthy controls (HC) were analysed using flow cytometry and surface marker staining. Compared to HC, a lower L:M ratio was observed starting from the early stages of CRC, while numbers of B lymphocytes were lower and CD4+ monocytes were higher in CRC patients. In most patients with CRC, the numbers of helper T cells were lower, while cytotoxic T cells and NK T cells together with CD4+ NKT and CD8+ NKT cells were higher: classical monocytes were lower while intermediate monocytes were higher throughout the stages of CRC, and HLA-DRlowmonocytes were also higher. NKbrightcells were higher while NKdimcells were lower in patients with large tumours. Most of the increased numbers of T cells and monocytes in CRC relate to immunosuppressive phenotypes that may aid tumour evasion. The increase in CD4+ monocytes is likely related to increased numbers of intermediate monocytes, and a threshold of 11.6% CD4+ monocytes can be used as diagnostic marker for CRC with a 60% sensitivity and 88% specificity.
The KU70-SAP domain has an overlapping function with DNA-PKcs in limiting the lateral movement of KU along DNA
Authors: Zhu Yimeng , Lee Brian J. , Fujii Shingo , Jonchhe Sagun , Zhang Hanwen , Li Angelina , Wang Kyle J. , Rothenberg Eli , Modesti Mauro , Zha Shan 
Published: August 2024

AbstractThe non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting additional factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that caps the ends and pushes KU inward. The C-terminus of Ku70 in higher eukaryotes includes a flexible linker and a SAP domain, whose physiological role remains poorly understood. To investigate this, we generated a mouse model with knock-in deletion of the SAP domain (Ku70ΔSAP/ΔSAP).Ku70ΔSAPsupports KU stability and its recruitment to DNA damage sitesin vivo. In contrast to the growth retardation and immunodeficiency seen inKu70−/−mice,Ku70ΔSAP/ΔSAPmice show no defects in lymphocyte development and maturation. Structural modeling of KU on long dsDNA, but not dsRNA suggests that the SAP domain can bind to an adjacent major groove, where it can limit KU’s rotation and lateral movement along the dsDNA. Accordingly, in the absence of DNA-PKcs that caps the ends, Ku70ΔSAPfails to support stable DNA damage-induced KU foci. InDNA-PKcs−/−mice,Ku70ΔSAPabrogates the leaky T cell development and reduces both the qualitative and quantitative aspects of residual V(D)J recombination. In the absence of DNA-PKcs, purified Ku70ΔSAPhas reduced affinity for DNA ends and dissociates more readily at lower concentration and accumulated as multimers at high concentration. These findings revealed a physiological role of the SAP domain in NHEJ by restricting KU rotation and lateral movement on DNA that is largely masked by DNA-PKcs.HighlightKu70 is a conserved non-homologous end-joining (NHEJ) factor. Using genetically engineered mouse models and biochemical analyses, our study uncovered a previously unappreciated role of the C-terminal SAP domain of Ku70 in limiting the lateral movement of KU on DNA ends and ensuring end protection. The presence of DNA-PKcs partially masks this role of the SAP domain.
Automated non-invasive laser speckle imaging of the chick heart rate and extraembryonic blood vessels and their response to nifedipine and amlodipine drugs
Authors: Readhead Carol , Mahler Simon , Dong Zhenyu , Sato Yuki , Yang Changhuei , Bronner Marianne E. 
Published: August 2024

AbstractUsing our recently developed laser speckle contrast imaging (LSCI) to visualize blood vessels and monitor blood flow, here we test the utility of the chick embryo for drug screening. To this end, we examined the effects of antihypertensive agents Nifedipine and Amlodipine, belonging to the L-type calcium channel antagonist family, on blood flow visualized noninvasively through the intact shell. Guided by the live view mode, the drugs were injected through the shell and ventral to HH16-19 chick embryos. Our results show a significant reduction in the chick heart rate, blood flow, and vascular size within 5-20 minutes after Nifedipine or Amlodipine injection. For moderate Nifedipine concentrations, these parameters returned to initial values within 2-3 hours. In contrast, Amlodipine showed a rapid reduction in heart rate and blood flow dynamics at a more than ten times higher concentration than Nifedipine. These findings show that our LSCI system can monitor and distinguish the chick heart’s response to injected drugs from the same family. This serves as proof-of-concept, paving the way for a rapid, cost effective, and quantitative test system for screening drugs that affect the cardiovascular system of live chick embryos. Live noninvasive imaging may also provide insights into the development and functioning of the vertebrate heart.Graphical AbstractHighlightsNon-invasive Laser Speckle Contrast Imaging (LSCI) of the chick chorioallantoic membrane (CAM) in whole incubated eggsSimultaneous recording images of the CAM, dynamics of blood flow, and heart rateLive view mode to identify size, heart position, and location of the embryo in the eggAutomated system for data acquisition and analysisLongitudinal quantification of the impact of a calcium channel antagonists, nifedipidine and amlodipine on the embryonic heart rate, CAM’s blood flow, size and number of vessels
Would you agree if N is three? On statistical inference for small N
Authors: Psarou Eleni , Katsanevaki Christini , Maris Eric , Fries Pascal 
Published: August 2024

AbstractNon-human primate studies traditionally use two or three animals. We previously used standard statistics to argue for using either one animal, for an inference about that sample, or five or more animals, for a useful inference about the population. A recently proposed framework argued for testing three animals and accepting the outcome found in the majority as the outcome that is most representative for the population. The proposal tests this framework under various assumptions about the true probability of the representative outcome in the population, i.e. its typicality. On this basis, it argues that the framework is valid across a wide range of typicalities. Here, we show (1) that the error rate of the framework depends strongly on the typicality of the representative outcome, (2) that an acceptable error rate requires this typicality to be very high (87% for a single type of outlier), which actually renders empirical testing beyond a single animal obsolete, (3) that moving from one to three animals decreases error rates mainly for typicality values of 70-90%, and much less for both lower and higher values. Furthermore, we use conjunction analysis to demonstrate that two out of three animals with a given outcome only allow to infer a lower bound to typicality of 9%, which is of limited value. Thus, the use of two or three animals does not allow a useful inference about the population, and if this option is nevertheless chosen, the inferred lower bound of typicality should be reported.
Accounting for digital promises: restoring and transforming promissory narratives
Authors: Carlsson-Wall Martin , Laurell Christofer , Lindqvist Parbratt Oliver , Ots Mart 
Published: August 2024

PurposeThe paper investigates the relationship between accounting and promises in the context of digital change.Design/methodology/approachRelying on emergent literature on accounting and promises, a qualitative field study has been conducted covering 57 interviews with municipal directors, digitalization strategists, administration managers and CFOs in a Swedish region consisting of 13 municipalities.FindingsThe paper provides insights into how municipalities draw on accounting in attempts to reconstruct promissory narratives of the digital. By highlighting two contrasting cases, we show how this can involve practices of either restoration or transformation. Likewise, we find that attempts to restore promises can sometimes have unanticipated effects, in our case a transformation of the promise instead.Originality/valueWe introduce a “promise” lens to the literature on accounting and digital change and empirically describe how accounting is implicated in shaping promises in the context of public sector digital change.