bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mosaic display of stable hemagglutinin monomers induces broad immune responses
Authors: Kim Hyojin , Min Seong Cheol , Lee Dan Bi , Jeong Ju Hwan , Kim Eun Jeong , Maeng Jin Young , Seok Jong Hyeon , Lee Ji-Hye , Jang Yuyeon , Jang Ui Soon , Ysenbaert Tine , Catani João Paulo Portela , Lee JeongAh , Lee Yeongeun , Kim Youn Kyung , Lee Gyudo , Mun Ji Young , Jun Hyun Sik , Baek Yun Hee , Saelens Xavier , Lee Jiwon , Chung Mi Sook , Song Min-Suk , Kim Kyung Hyun 
Published: April 2024

AbstractThe nature of the interplay between immunity and viral variation is infinitely adaptive. Infection frequently induces immune responses against variation-prone epitopes, rather than against spatially hidden conserved epitopes. It thus remains a substantial challenge to elicit the immune responses to the conserved epitopes providing broad-spectrum immunity. We developed an approach of scaffold-mediated mosaic display to present monomeric influenza virus hemagglutinins (HAs), which exposes highly conserved stem and interface epitopes. Stable monomers were rationally engineered from H1 and H3 subtypes and B type HA trimers, with amino acid mutations at the monomer-monomer interface and for disulfide bond formation, and fused to a self-assembling scaffold, to generate a mosaic HA monomer-displaying nanoparticle, 3HA-np. Immunization with 3HA-np induced broadly neutralizing antibodies (bnAbs) in mice and ferrets and protected against challenges with H1N1 and H3N2 viruses. Competitive immunoassays revealed that 3HA-np induced high interface- and stem-binding Ab titers as compared to head Ab titers, indicating that the monomeric and mosaic nature of 3HA-np elicit cross-reactive Abs. Our results suggest that exposure of the hidden conserved epitope by monomer-displaying nanoparticles is a promising approach to generate a universal influenza vaccine.
Discrete photoentrainment of mammalian central clock is regulated by bi-stable dynamic network in the suprachiasmatic nucleus
Authors: Yeh Po-Ting , Jhan Kai-Chun , Chua Ern-Pei , Chen Wun-Ci , Chu Shi-Wei , Wu Shun-Chi , Chen Shih-Kuo 
Published: April 2024

AbstractThe circadian clock, an evolutionarily conserved mechanism regulating the majority of physiological functions in many organisms, is synchronized with the environmental light-dark cycle through circadian photoentrainment. This process is mediated by light exposure at specific times, leading to a discrete phase shift including phase delays during early subjective night, phase advances during late subjective night, and no shift at midday, known as the dead zone. In mammals, such as mice, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are crucial for conveying light information to the suprachiasmatic nucleus (SCN), the central clock consisting of approximately 20,000 neurons. While the intracellular signaling pathways that modulate clock gene expression post-light exposure are well-studied, the functional neuronal circuits responsible for the three discrete light responses are not well understood. Utilizingin vivotwo-photon microscopy with gradient-index (GRIN) endoscopes, we have identified seven distinct light responses from SCN neurons. Our findings indicate that light responses from individual SCN neurons are mostly stochastic from trial to trial. However, at the population level, light response composition remains similar across trials, with only minor variations between circadian times, suggesting a dynamic populational coding for light input. Additionally, only a small subset of SCN neurons shows consistent light responses. Furthermore, by utilizing the targeted recombination in active populations (TRAP) system to label neurons that respond to light during early subjective night, we demonstrate that their activation can induce phase delays at any circadian time, effectively breaking the gate that produce photoentrainment dead zone typically observed at midday. Our results suggest the existence of at least two separate time-dependent functional circuits within the SCN. We propose a dynamic bi-stable network model for circadian photoentrainment in the mammalian central clock, where a shifting clock is driven by a dynamic functional circuit utilizing population coding to integrate information flow similar to proposed cortical computational network, rather than a simplistic, consistent linear circuit.
Lysosomal Enzyme activity: Establishing Reference Intervals from Patient Data
Authors: Mordaunt Dylan , Stark Samantha , Fietz Michael , Fletcher Janice , Metz Michael 
Published: April 2024

AbstractObjectivesTo develop reference intervals for leukocyte lysosomal enzymology.DesignStandards-based establishment of reference intervals by analysis of 7851 for 17 assays of 15 lysosomal enzymes in leukocyte and plasma (January 1985 through September 2013).MethodsReference intervals were calculated using MedCalc for Windows version 12.5 (MedCalc Software, Ostend, Belgium), according to the Clinical and Laboratory Standards Institute C-28A protocol (CSLI-C28A).Results and ConclusionEvidence based reference intervals are presented in tabular form for seventeen assays of fifteen lysosomal enzymes.
SARS-CoV-2 Antigen Rapid Detection Tests: test performance during the COVID-19 pandemic and the impact of COVID-19 vaccination
Authors: Wagenhäuser Isabell , Knies Kerstin , Pscheidl Tamara , Eisenmann Michael , Flemming Sven , Petri Nils , McDonogh Miriam , Scherzad Agmal , Zeller Daniel , Gesierich Anja , Seitz Anna Katharina , Taurines Regina , Ernestus Ralf-Ingo , Forster Johannes , Weismann Dirk , Weißbrich Benedikt , Liese Johannes , Härtel Christoph , Kurzai Oliver , Dölken Lars , Gabel Alexander , Krone Manuel 
Published: April 2024

ABSTRACTIntroductionDuring the COVID-19 pandemic, SARS-CoV-2 antigen rapid detection tests (RDTs) emerged as point-of-care diagnostics in addition to the RT-qPCR as the gold standard for SARS-CoV-2 diagnostics. Facing the course of the COVID-19 pandemic to an endemic characterised by several SARS-CoV-2 virus variants of concern (VOC) and an increasing public COVID-19 vaccination rate the aim of the study was to investigate the long-term test performance of SARS-CoV-2 RDT in large-scale, clinical screening use during and its influencing factors, above all SARS-CoV-2 VOC and COVID-19 vaccination.MethodsIn a prospective performance assessment conducted at a single centre tertiary care hospital, RDTs from three manufacturers (NADAL®, Panbio™, MEDsan®) were compared to RT-qPCR among individuals aged ≥ 6 month. The evaluation involved the determination of standardised viral load from oropharyngeal swabs as well as the evaluation of their influencing factors, especially the COVID-19 vaccination, for detecting SARS-CoV-2 in a clinical point-of-care environment spanning from 12 November 2020 to 30 June 2023 among patients, staff, and visitors of the hospital.ResultsAmong the 78,798 RDT/RT-qPCR tandems analysed, 2,016 (2.6%) tandems tested positive for SARS-CoV-2, with an overall sensitivity of 34.5% (95% CI 32.4-36.6%). A logistic regression revealed that typical COVID-19 symptoms significantly declined over the course of the study and throughout the COVID-19 pandemic, and that among the vaccinated, significantly fewer presented with an infection exhibiting typical symptoms. The employed lasso regression model indicated that only higher viral load and typical COVID-19 symptoms significantly increase the likelihood of a positive RDT result in the case of a SARS-CoV-2 infection directly.ConclusionOur findings indicate that only viral load and COVID-19 symptoms directly influence RDT performance while the obtained effects of COVID-19 vaccination and Omicron VOC both reducing RDT performance were mediated by these two factors. RDTs remain an adequate diagnostic tool for detecting SARS-CoV-2 in individuals showing respiratory symptoms. RDTs show promise beyond SARS-CoV-2, proving adaptable for detecting other pathogens like Influenza and RSV, highlighting their ongoing importance in infection control and prevention efforts.
MOLGENIS VIP: an open-source and modular pipeline for high-throughput and integrated DNA variant analysis
Authors: Maassen W.T.K. , Johansson L.F. , Charbon B. , Hendriksen D. , van den Hoek S. , Slofstra M.K. , Mulder R. , Meems-Veldhuis M.T. , Sietsma R. , Lemmink H.H. , van Diemen C.C. , van Gijn M.E. , Swertz M.A. , van der Velde K.J. 
Published: April 2024

AbstractIn silicovariant interpretation pipelines have become an integral part of genetics research and genome diagnostics. However, challenges remain for automated variant interpretation and candidate shortlisting. Their reliability is affected by variability in input data caused due the use of differing sequencing platforms, erroneous nomenclature and changing experimental conditions. Similarly, differences in predictive algorithms can result in discordant results. Finally, scalability is essential to accommodate large amounts of input data, such as in whole genome sequencing (WGS). To accelerate causal variant detection and innovation in genome diagnostics and research, we developed the MOLGENIS Variant Interpretation Pipeline (VIP). VIP is a flexible open-source computational pipeline that generates interactive reports of variants in whole exome sequencing (WES) and WGS data for expert interpretation. VIP can process short- and long-read data from different platforms and offers tools for increased sensitivity: a configurable decision-tree, filters based on human phenotype ontology (HPO) and gene inheritance that can be used to pinpoint disease-causing variants or finetune a query for specific variants. Here, alongside presenting VIP, we provide a step-by-step protocol for how to use VIP to annotate, classify and filter genetic variants of patients with a rare disease that has a suspected genetic cause. Finally, we demonstrate how VIP performs using 25,664 previously classified variants from the data sharing initiative of the Vereniging van Klinisch Genetische Laboratoriumdiagnostiek (VKGL), a cohort of 18 diagnosed patients from routine diagnostics and a cohort of 41 patients with a rare disease (RD) who were not diagnosed in routine diagnostics but were diagnosed using novel omics approaches within the EU-wide project to solve rare diseases (EU-Solve-RD). VIP requires bioinformatic knowledge to configure, but once configured, any diagnostic professional can perform an analysis within 5 hours.
Structural and Dynamic Insights into the Biased Signaling Mechanism of the Human Kappa Opioid Receptor
Authors: Suno-Ikeda Chiyo , Nishikawa Ryo , Suzuki Riko , Iwata Seiya , Takai Tomoyo , Ogura Takaya , Hirose Mika , Inoue Akitoshi , Asai Eri , Kise Ryoji , Sugita Yukihiko , Kato Takayuki , Nagase Hiroshi , Saitoh Tsuyoshi , Katayama Kota , Inoue Asuka , Kandori Hideki , Kobayashi Takuya , Suno Ryoji 
Published: April 2024

ABSTRACTThe κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, responsible for modulating cellular responses through transducers such as G proteins and arrestins. G protein-biased KOR agonists hold promise due to their potential to mitigate side effects such as drug aversion and sedation while preserving analgesic and antipruritic effects. Here, we shed light on the structural dynamics of the human KOR-Gisignaling complex bound with either nalfurafine (a G-protein-biased agonist) or U-50,488H (a balanced agonist) using cryo-electron microscopy (cryo-EM). Cryo-EM structures of the KOR-Gisignaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy analysis reveals changes in the ligand-binding pocket upon binding to these ligands. Cell-based mutant experiments pinpoint four amino acids (K2275.40, C2866.47, H2916.52, and Y3127.34; Ballesteros–Weinstein numbering is shown in superscript) that play crucial roles in arrestin recruitment. Among these four amino acids, H2916.52and Y3127.34are also implicated in G-protein coupling. Our findings pave the way for targeting specific residues in the KOR ligand-binding pocket to enhance KOR-mediated therapeutic effects while mitigating unwanted side effects.
Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence
Authors: Lin Hongyu , Olaniran Adedayo , Luo Xiang , Strauch Jessica , Burke Megan AM , Matheson Chloe L. , Li Xuan 
Published: April 2024

AbstractRelapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, and we previously demonstrated a causal role of the orbitofrontal cortex (OFC) in this incubation of oxycodone craving after forced abstinence. Here, we explored critical downstream targets of OFC by focusing on dorsal striatum (DS). We first examined dorsal striatal Fos (a neuronal activity marker) expression associated with oxycodone seeking after abstinence. Using a dopamine D1 receptor (D1R) antagonist, we also tested the causal role of DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a series of pharmacological procedures to examine the causal role of the interaction between glutamatergic projections from OFC and D1R signaling in DS in incubation of oxycodone craving. We found that dorsal striatal Fos expression in DS exhibited a time-dependent increase in parallel with incubation of oxycodone craving, and DS inactivation decreased incubated oxycodone seeking. Moreover, OFC→DS projections were activated during incubated oxycodone seeking, and anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving.
Overcoming the preferred orientation problem in cryoEM with self-supervised deep-learning
Authors: Liu Yun-Tao , Fan Hongcheng , Hu Jason J. , Zhou Z. Hong 
Published: April 2024

AbstractWhile advances in single-particle cryoEM have enabled the structural determination of macromolecular complexes at atomic resolution, particle orientation bias (the so-called “preferred” orientation problem) remains a complication for most specimens. Existing solutions have relied on biochemical and physical strategies applied to the specimen and are often complex and challenging. Here, we develop spIsoNet, an end-to-end self-supervised deep-learning-based software to address the preferred orientation problem. Using preferred-orientation views to recover molecular information in under-sampled views, spIsoNet improves both angular isotropy and particle alignment accuracy during 3D reconstruction. We demonstrate spIsoNet’s capability of generating near-isotropic reconstructions from representative biological systems with limited views, including ribosomes, β-galactosidases, and a previously intractable hemagglutinin trimer dataset. spIsoNet can also be generalized to improve map isotropy and particle alignment of preferentially oriented molecules in subtomogram averaging. Therefore, without additional specimen-preparation procedures, spIsoNet provides a general computational solution to the preferred orientation problem.
Modeling cardiac microcirculation for the simulation of coronary flow and 3D myocardial perfusion
Authors: Montino Pelagi Giovanni , Regazzoni Francesco , Huyghe Jacques M. , Baggiano Andrea , Alì Marco , Bertoluzza Silvia , Valbusa Giovanni , Pontone Gianluca , Vergara Christian 
Published: April 2024

AbstractPurposeaccurate modeling of blood dynamics in the coronary microcirculation is a crucial step towards the clinical application ofin silicomethods for the diagnosis of coronary artery disease (CAD). In this work, we present a new mathematical model of microcirculatory hemodynamics accounting for microvasculature compliance and cardiac contraction; we also present its application to a full simulation of hyperemic coronary blood flow and 3D myocardial perfusion in real clinical cases.Methodsmicrovasculature hemodynamics is modeled with acompliantmulti-compartment Darcy formulation, with the new compliance terms depending on the local intramyocardial pressure generated by cardiac contraction. Nonlinear analytical relationships for vessels distensibility are included based on experimental data, and all the parameters of the model are reformulated based on histologically relevant quantities, allowing a deeper model personalization.ResultsPhasic flow patterns of high arterial inflow in diastole and venous outflow in systole are obtained, with flow waveforms morphology and pressure distribution along the microcirculation reproduced in accordance with experimental andin vivomeasures. Phasic diameter change for arterioles and capillaries is also obtained with relevant differences depending on the depth location. Coronary blood dynamics exhibits a disturbed flow at the systolic onset, while the obtained 3D perfusion maps reproduce the systolic impediment effect and show relevant regional and transmural heterogeneities in myocardial blood flow (MBF).Conclusionthe proposed model successfully reproduces microvasculature hemodynamics over the whole heartbeat and along the entire intramural vessels. Quantification of phasic flow patterns, diameter changes, regional and transmural heterogeneities in MBF represent key steps ahead in the direction of the predictive simulation of cardiac perfusion.
“Poly (A) Binding Protein 2 is critical for stem-progenitor differentiation during regeneration in the planarianSchmidtea mediterranea.”
Authors: Mukundan Namita , Hariharan Nivedita , Sasidharan Vidyanand , Lakshmanan Vairavan , Palakodeti Dasaradhi , Jamora Colin 
Published: April 2024

AbstractPost-transcriptional regulation has emerged as a key mechanism to regulate stem cell renewal and differentiation, which is essential for understanding tissue regeneration and homeostasis. Poly(A)-binding proteins are a family of RNA-binding proteins that play a vital role in post-transcriptional regulation by controlling mRNA stability and protein synthesis. The involvement of poly(A) binding proteins in a wide range of cellular functions is increasingly being investigated. In this study, we used the regenerative model organism planarianSchmidtea mediterranea, to demonstrate the critical role of poly(A)-binding protein 2 (PABP2) in regulating neoblast maintenance and differentiation. A deficit in PABP2 blocks the transition of neoblasts towards immediate early progenitors, leading to an enhanced pool of non-committed neoblasts and a decreased progenitor population. This is reflected in variations in the transcriptome profile, providing evidence of downregulation in multiple lineages. Thus, insufficiency of PABP2 resulted in defective formation and organization of tissue leading to abnormal regeneration. Our study reveals the essential role of PABP2 in regulating genes that mediate stem cell commitment to early progenitors during tissue regeneration.
The neonicotinoid acetamiprid is highly toxic to wild non-target insects
Authors: Sedlmeier Jan Erik , Grass Ingo , Bendalam Prasanth , Höglinger Birgit , Walker Frank , Gerhard Daniel , Piepho Hans-Peter , Brühl Carsten A. , Petschenka Georg 
Published: April 2024

AbstractAlthough pesticides are seen as one of the main drivers of insect decline, there are still only few studies that assess their effects on non-target species under field conditions. Here we investigated the effects of the neonicotinoid insecticide Mospilan®SG (active ingredient acetamiprid) on plant bugs (Heteroptera: Miridae), a dominant group of European grassland insect communities. Abundance of three focal mirid species was reduced by up to 78% two days after field exposure at concentrations expected at field margins, with mortality varying considerably among species. Follow-up feeding assays with insecticide-treated host plants in the greenhouse and controlled dose-response assays in the laboratory confirmed the strong negative effects on non-target species. Strikingly, the neonicotinoid was nearly 10,000 times more toxic to plant bugs than to honeybees. In addition, male bugs were 20 times more sensitive than females in two of the three tested species. Thus, continuous exposure to neonicotinoids in the field may reduce the plant bug populations and promote a shift towards more insecticide-tolerant species, altering community composition. We suggest that sex-specific sensitivity should be considered in risk assessment and conclude that the real risk to non-target insects is currently greatly underestimated.
TheC. elegansuv1 neuroendocrine cells provide direct mechanosensory feedback of vulval opening
Authors: Yan Lijie , Claman Alexander , Bode Addys , Collins Kevin M. 
Published: April 2024

AbstractNeuroendocrine cells react to physical, chemical, and synaptic signals originating from tissues and the nervous system, releasing hormones that regulate various body functions beyond the synapse. Neuroendocrine cells are often embedded in complex tissues making direct tests of their activation mechanisms and signaling effects difficult to study. In the nematode wormC. elegans, four uterine-vulval (uv1) neuroendocrine cells sit above the vulval canal next to the egg-laying circuit, releasing tyramine and neuropeptides that feedback to inhibit egg laying. We have previously shown uv1 cells are mechanically deformed during egg laying, driving uv1 Ca2+transients. However, whether egg-laying circuit activity, vulval opening, and/or egg release triggered uv1 Ca2+activity was unclear. Here we show uv1 responds directly to mechanical activation. Optogenetic vulval muscle stimulation triggers uv1 Ca2+activity following muscle contraction even in sterile animals. Direct mechanical prodding with a glass probe placed against the worm cuticle triggers robust uv1 Ca2+activity similar to that seen during egg laying. Direct mechanical activation of uv1 cells does not require other cells in the egg-laying circuit, synaptic or peptidergic neurotransmission, or TRPV and Piezo channels. EGL-19 L-type Ca2+channels, but not P/Q/N-type or Ryanodine Receptor Ca2+channels, promote uv1 Ca2+activity following mechanical activation. L-type channels also facilitate the coordinated activation of uv1 cells across the vulva, suggesting mechanical stimulation of one uv1 cells cross-activates the other. Our findings show how neuroendocrine cells like uv1 report on the mechanics of tissue deformation and muscle contraction, facilitating feedback to local circuits to coordinate behavior.Significance StatementNeuroendocrine cells respond to diverse physical and chemical signals from the body, releasing hormones that control reproduction, gut motility, and fight or flight responses. Neuroendocrine cells are often found embedded in complex tissues, complicating studies of how they are activated. Using the genetic and experimental accessibility ofC. elegans, we find the uv1 neuroendocrine cells of the egg-laying motor behavior circuit respond directly to mechanical stimulation and vulval opening. We show that L-type voltage-gated Ca2+channels facilitate uv1 mechanical activation and also coordinate cell activation across the vulval opening. In contrast to other mechanically activated cells, uv1 activation does not require Piezo or TRPV channels. This work shows how neuroendocrine cells relay critical mechanosensory feedback to circuits that control reproduction.