bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accounting for Cellular-Level Variation in Lysis: Implications for Virus-Host Dynamics
Authors: Dominguez-Mirazo Marian , Harris Jeremy D. , Demory David , Weitz Joshua S. 
Published: May 2024

AbstractViral impacts on microbial populations depend on interaction phenotypes - including viral traits spanning adsorption rate, latent period, and burst size. The latent period is a key viral trait in lytic infections. Defined as the time from viral adsorption to viral progeny release, the latent period of bacteriophage is conventionally inferred via one-step growth curves in which the accumulation of free virus is measured over time in a population of infected cells. Developed more than 80 years ago, one-step growth curves do not account for cellular-level variability in the timing of lysis, potentially biasing inference of viral traits. Here, we use nonlinear dynamical models to understand how individual-level variation of the latent period impacts virus-host dynamics. Our modeling approach shows that inference of latent period via one-step growth curves is systematically biased - generating estimates of shorter latent periods than the underlying population-level mean. The bias arises because variability in lysis timing at the cellular level leads to a fraction of early burst events which are interpreted, artefactually, as an earlier mean time of viral release. We develop a computational framework to estimate latent period variability from joint measurements of host and free virus populations. Our computational framework recovers both the mean and variance of the latent period within simulated infections including realistic measurement noise. This work suggests that reframing the latent period as a distribution to account for variability in the population will improve the study of viral traits and their role in shaping microbial populations.ImportanceQuantifying viral traits – including the adsorption rate, burst size, and latent period – is critical to characterize viral infection dynamics and to develop predictive models of viral impacts across scales from cells to ecosystems. Here, we revisit the gold standard of viral trait estimation – the one-step growth curve – to assess the extent to which assumptions at the core of viral infection dynamics lead to ongoing and systematic biases in inferences of viral traits. We show that latent period estimates obtained via one-step growth curves systematically under-estimate the mean latent period and, in turn, over-estimate the rate of viral killing at population scales. By explicitly incorporating trait variability into a dynamical inference framework that leverages both virus and host time series we provide a practical route to improve estimates of the mean and variance of viral traits across diverse virus-microbe systems.
Differential effects of PDE4A5 on cAMP-dependent forms of long-term potentiation
Authors: Tadinada Satya Murthy , Walsh Emily N. , Mukherjee Utsav , Abel Ted 
Published: May 2024

AbstractcAMP signaling is critical for memory consolidation and certain of forms long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messenger cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP selective PDEs, exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We find that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced 4-train stimulation (4X100Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental, and neurodegenerative disorders.Key PointsHippocampal overexpression of a PDE4A subfamily long isoform, PDE4A5, but not a short isoform PDE4A1, impairs spatial and contextual fear memory and the N-terminus of PDE4A5 is important for this effect.Hippocampal overexpression of PDE4A isoforms, PDE4A1 and PDE4A5 do not impair LTP induced by spaced tetanic stimulation at the CA3-CA1 synapses.Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus truncated PDE4A5 (PDE4A5Δ4) selectively impairs LTP induced by theta burst stimulation (TBS) at the CA3-CA1 synapses and expression of PDE4A5 in area CA1 is sufficient for the TBS-LTP deficit.These results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of TBS-LTP at the CA3-CA1 synapses.GRAPHICAL ABSTRACTSpaced tetanic stimulation and TBS induce cAMP synthesis and activation of PKA to promote signaling cascades that facilitate expression of long-lasting LTP at the CA3-CA1 synapses. PDE4A5 overexpression in the hippocampus selectively impairs cAMP and PKA dependent TBS-LTP at the CA3-CA1 synapses, while sparing LTP induced by spaced tetanization.
A Comprehensive Model to Differentiate Spontaneous, Drug-induced, and CSCs-related Drug Resistance
Authors: Zheng Kaixin 
Published: May 2024

AbstractDrug resistance is a pivotal research area in oncology research, yet the integration of multiple sources of resistance into the evolution of drug resistance remains elusive. This study investigates dynamics of drug resistance in chemotherapy utilizing a mathematical model given a treatment protocol. The model categorizes drug resistance into spontaneous, drug-induced, and cancer stem cells (CSCs)-related types. Introducing a novel mathematical framework, this study incorporates explicit dosage-dependent terms to design tailored treatment strategies. A comparative analysis contrasts continuous constant therapy with periodic bolus injection. Virtual patients’ survival times are assessed under baseline dosages for both therapies, revealing the interplay between constant dosage in continuous therapy and maximum dosage in bolus injection on survival time. Our findings demonstrate that, at equivalent cumulative dosages, bolus injection markedly extends patient survival. Furthermore, a potentially bimodal relationship emerges between bolus injection efficacy and maximum dosage, suggesting that two optimal bolus injection strategies may hold.
Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice
Authors: El-Awaisi Juma , Perrella Gina , Mayor Nicolas , Tinkova Veronika , Cleary Simon J , Grygielska Beata , Watson Steve P , Dimitrov Jordan D , Brill Alexander , Nicolson Phillip LR , Kavanagh Dean , Kalia Neena , Rayes Julie 
Published: May 2024

AbstractSickle cell disease (SCD) leads to hemolytic anemia, vaso-occlusive crisis (VOC), hypoperfusion, and progressive organ damage. Hemin, released during hemolysis in SCD, induces platelet activation through CLEC-2, endothelial activation through TLR4, neutrophil adhesion and NETosis, all of which are regulated by spleen tyrosine kinase (Syk). In this study, we assessed neutrophil and platelet recruitment to the pulmonary, renal, splenic, and hepatic microvasculature in control and SCD mice following hemin injection and the effect of Syk inhibition on cell recruitment and organ perfusion. Compared to controls, SCD mice exhibited higher baseline neutrophil and platelet recruitment to the lungs without alterations in lung perfusion as measured by laser speckle contrast imaging. Injection of hemin increased cell recruitment to the pulmonary and renal vasculature with a concomitant reduction in organ perfusion. However, hemin injection did not change cell recruitment or organ perfusion in the spleen and liver, both of which were altered at baseline in SCD mice. Pretreatment of SCD mice with the Syk inhibitor BI-1002494 mitigated baseline and hemin-induced neutrophil and platelet adhesion in the pulmonary and renal microvasculature, with a corresponding normalization of perfusion. Syk regulates vascular integrity in the lung of SCD mice; whilst high concentrations of BI-1002494 increased bleeding, lowering drug concentrations preserved the inhibitory effect on platelet and neutrophil recruitment and lung perfusion and protected from bleeding complications. These data substantiate Syk as a mediator of vascular thrombo-inflammation and hypoperfusion in the lung and kidney of SCD and provide a rationale for pharmacological inhibition as a therapeutic strategy.
Velocity-selective arterial spin labelling bolus duration measurements: Implications for consensus recommendations
Authors: Driver Ian D , Chandler Hannah L , Patitucci Eleonora , Morgan Emma L , Murphy Kevin , Zappala Stefano , Wise Richard G , Germuska Michael 
Published: May 2024

AbstractVelocity-selective arterial spin labelling (VSASL) MRI is insensitive to arterial transit time. This is an advantage over other perfusion measurements, where long arterial transit times can lead to bias. Therefore, VSASL can be used to study perfusion in the presence of long arterial transit times, such as in the ageing brain, in vascular pathologies, and cancer, or where arterial transit time changes, such as during measurement of cerebrovascular reactivity (CVR). However, when calculating perfusion (cerebral blood flow, CBF, in the brain) from VSASL signal, it is assumed that images are acquired before the trailing edge of the labelled blood has arrived in the imaging slice. The arrival of the trailing edge of the labelled bolus of blood will cause an underestimation of perfusion. Here we measure bolus duration in young, healthy human brains, both at rest and during elevated CBF. Grey matter bolus duration was 1.61 ± 0.31 s, but there was a large spatial heterogeneity, with bolus duration being lower in anterior brain regions, with some areas having bolus duration < 1.2 s. We place these results in context of recommendations from a recent consensus paper, which recommends imaging 1.4 s after the label, potentially underestimating CBF in anterior regions. Further, we observed a 0.23 ± 0.12 s reduction in grey matter bolus duration with 5% CO2inhalation. These results can be used to inform the experimental design of future VSASL studies, to avoid underestimating perfusion by imaging after the arrival of the trailing edge of the labelled bolus.
COEXIST: Coordinated single-cell integration of serial multiplexed tissue images
Authors: Heussner Robert T. , Watson Cameron F. , Eddy Christopher Z. , Wang Kunlun , Cramer Eric M. , Creason Allison L. , Mills Gordon B. , Chang Young Hwan 
Published: May 2024

ABSTRACTMultiplexed tissue imaging (MTI) and other spatial profiling technologies commonly utilize serial tissue sectioning to comprehensively profile samples by imaging each section with unique biomarker panels or assays. The dependence on serial sections is attributed to technological limitations of MTI panel size or incompatible multi-assay protocols. Although image registration can align serially sectioned MTIs, integration at the single-cell level poses a challenge due to inherent biological heterogeneity. Existing computational methods overlook both cell population heterogeneity across modalities and spatial information, which are critical for effectively completing this task. To address this problem, we first use Monte-Carlo simulations to estimate the overlap between serial 5μm-thick sections. We then introduce COEXIST, a novel algorithm that synergistically combines shared molecular profiles with spatial information to seamlessly integrate serial sections at the single-cell level. We demonstrate COEXIST necessity and performance across several applications. These include combining MTI panels for improved spatial single-cell profiling, rectification of miscalled cell phenotypes using a single MTI panel, and the comparison of MTI platforms at single-cell resolution. COEXIST not only elevates MTI platform validation but also overcomes the constraints of MTI’s panel size and the limitation of full nuclei on a single slide, capturing more intact nuclei in consecutive sections and thus enabling deeper profiling of cell lineages and functional states.
The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation
Authors: Abidi Syeda Nayab Fatima , Chan Sara , Seidel Kerstin , Lafkas Daniel , Vermeulen Louis , Peale Frank , Siebel Christian W. 
Published: May 2024

AbstractThe sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.
Analysis of time-to-positivity data in tuberculosis treatment studies: Identifying a new limit of quantification
Authors: Dufault Suzanne M. , Davies Geraint R. , Svensson Elin M. , Sloan Derek J. , McCallum Andrew D. , Patel Anu , Van Brantegem Pieter , Denti Paulo , Phillips Patrick P. J. 
Published: May 2024

AbstractThe BACTEC Mycobacteria Growth Indicator Tube (MGIT) machine is the standard globally for detecting viable mycobacteria in patients’ sputum. Samples are observed for no longer than 42 days, at which point the sample is declared “negative” for tuberculosis (TB). This time to detection of bacterial growth, referred to as time-to-positivity (TTP), is increasingly of interest not solely as a diagnostic tool, but as a continuous biomarker wherein change in TTP over time can be used for comparing the bactericidal activity of different TB treatments. However, as a continuous measure, there are oddities in the distribution of TTP values observed, particularly at higher values. We explored whether there is evidence to suggest setting an upper limit of quantification (ULOQM) lower than the diagnostic limit of detection (LOD) using data from several TB-PACTS randomized clinical trials and PanACEA MAMS-TB. Across all trials, less than 7.1% of all weekly samples returned TTP measurements between 25 and 42 days. Further, the relative absolute prediction error (%) was highest in this range. When modeling with ULOQMs of 25 and 30 days, the precision in estimation improved for 23 of 25 regimen-level slopes as compared to models using the diagnostic LOD while also improving the discrimination between regimens based on Bayesian posteriors. While TTP measurements between 25 days and the diagnostic LOD may be important for diagnostic purposes, TTP values in this range may not contribute meaningfully to its use as a quantitative measure, particularly when assessing treatment response, and may lead to under-powered clinical trials.HighlightsThe BACTEC Mycobacteria Growth Indicator Tube (MGIT) machine is the STAND, PaMZard globally for the detection and diagnosis of tuberculosis.As MGIT machine use becomes more ubiquitous, its time-to-positivity (TTP) measures are increasingly of interest as a continuous biomarker for evaluating bactericidal activity of TB treatment regimens.Using data from seven previously published trials, this work highlights the evidence for setting a limit of quantification for quantitative analyses that is below the diagnostic limit of detection. TTP values near the upper limit of detection appear to be noisier and sparser, with precision improving for estimation of 23 of 25 regimen-specific rates of change in TTP when analyzed with a lower limit of quantification.While TTP measurements between 25 days and the diagnostic LOD may be important for diagnostic purposes, TTP values in this range may not contribute meaningfully to its use as a quantitative measure, particularly when assessing early treatment response.
Inotropes and mortality in patients with cardiogenic shock: An instrumental variable analysis from the SWEDEHEART registry
Authors: Petursson Petur , Gudmundsson Thorsteinn , Råmunddal Truls , Angerås Oskar , Rawshani Araz , Mohammad Moman A. , Persson Jonas , Alfredsson Joakim , Hofmann Robin , Jernberg Tomas , Fröbert Ole , Erlinge David , Redfors Björn , Omerovic Elmir 
Published: May 2024

ABSTRACTBackgroundThe use of inotropic agents in treating cardiogenic shock (CS) remains controversial. We aimed to investigate the effect of treatment with inotropes on 30-day mortality in patients with CS from the SWEDEHEART registry (The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies).MethodsWe used data from the national SWEDEHEART registry on all patients diagnosed with CS in Sweden between 2000 and 2022. The primary endpoint was 30-day all-cause mortality. We used multilevel Cox proportional-hazards regression with instrumental variable and inverse probability weighting propensity score to adjust for known and unknown confounders. The treatment-preference instrument was the quintile of preference for using inotropes at the treating hospital.ResultsIn total, 16,214 patients (60.5% men and 39.5% women) were included; 23.5% had diabetes, 10.2% had a previous myocardial infarction (MI), and 13.8% had previous heart failure (HF). The median age was 70 years (interquartile range; 19), and 66.4% were >70. Acute coronary syndrome (ACS) was the cause of CS in 82.9% of patients. Inotropic agents were used in 43.8% of patients, while 56.2% did not receive inotropic agents. There were 7,875 (48.1%) deaths. On average, patients treated with inotropes were two years younger and more likely to have ACS. Patients not treated with inotropes were more likely to have previous MI and previous PCI but less likely to undergo PCI. The number of patients with CS decreased by 12% per year (Ptrend<0.001). There was a considerable variation between hospitals in the preference for using inotropes ranging from 25 to 78% (P<0.001). Inotropes increased by 5% per year (Ptrend<0.001). The unadjusted mortality in CS increased by 2% per calendar year (Ptrend<0.001). The risk of death was higher in patients treated with inotropes [adjusted hazard ratio (HRadj) 1.72; 95% confidence interval (CI) 1.26-2.35; P=0.001]. There was a quantitative interaction between inotrope treatment and age and diagnosis (Pinteraction< 0.001 and Pinteraction= 0.018, respectively).ConclusionsIn this observational study, using inotropes was associated with a higher mortality risk in patients with CS. The increased risk of death was more pronounced in patients younger than 70. The number of patients with CS is decreased, while the use of inotropes and mortality increased in Sweden.
Insulin regulates lymphatic endothelial function via palmitoylation
Authors: Gonzalez-Nieves Silvia , Wei Xiaochao , McQuillan Jay , Zhang Qiang , Zhang Jinsong , McGuffee Reagan M. , Ford David A. , Love-Gregory Latisha , Abumrad Nada A. , Gelman Andrew E , Semenkovich Clay F. , Cifarelli Vincenza 
Published: May 2024

ABSTRACTLipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. However, the role of lipid metabolism in LEC function is not well understood.Insulin is a key regulator of lipid metabolism and protein palmitoylation, the reversible post-translational protein modification by palmitate that affects protein stability, trafficking, protein-protein, and protein-membrane interactions. Human LECs are highly sensitive to insulin and can develop insulin resistancein vitro, but whether insulin regulates LEC protein palmitoylation and function is unknown.To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin regulated targets and profiled differences in palmitoylation between lymphatic and blood endothelial cells. Palmitoylation occurred primarily in proteins involved in LEC vesicular or membrane trafficking, translation initiation, and in those found in membrane rafts. Insulin enriched palmitoylation of LEC proteins involved in GTPase signaling, ubiquitination, and junctional anchoring. We also determined that the long-chain fatty acid receptor CD36 mediates optimal lymphatic palmitoylation. CD36 silencing in LECs doubled palmitoylation targets involving proteins related to inflammation and neutrophil degranulation contributing to anactivatedinflamed endothelium. These results suggest that the coordination of the process of palmitoylation is critical for normal lymphatic endothelial function.