bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonspecific Membrane-Matrix Interactions Influence Diffusivity of Lipid Vesicles in Hydrogels
Authors: Tam Nicky W. , Schullian Otto , Cipitria Amaia , Dimova Rumiana 
Published: February 2023

AbstractThe diffusion of extracellular vesicles and liposomesin vivois affected by different tissue environmental conditions and is of great interest in the development of liposome-based therapeutics and drug-delivery systems. Here, we use a bottom-up biomi-metic approach to better isolate and study steric and electrostatic interactions and their influence on the diffusivity of synthetic large unilamellar vesicles in hydrogel environments. Single-particle tracking of these extracellular vesicle-like particles in agarose hydrogels as an extracellular matrix model shows that membrane deformability and surface charge affect the hydrogel pore spaces that vesicles have access to, which determines overall diffusivity. Moreover, we show that passivation of vesicles with PEGylated lipids, as often used in drug delivery systems enhances diffusivity, but that this effect cannot be fully explained with electrostatic interactions alone. Finally, we compare our experimental findings with existing computational and theoretical work in the field to help explain the non-specific interactions between diffusing particles and gel matrix environments.Statement of SignificanceThe diffusion of nanoparticles in human tissues is dependent on interactions with the surrounding environment. This has wide implications for the development of nanoparticle-based therapeutics and drug delivery systems. Studying these interactions in human tissues and even in model hydrogels composed of reconstituted tissue components can be hampered by the many different complex interactions that can occur. By using a bio-inert hydrogel material like agarose, we remove the influence of specific biochemical interactions, allowing the study of how particle diffusion can be tuned with simple material properties like charge and rigidity. Taking advantage of these non-specific interactions, nanoparticles could one day be engineered to target specific organs by optimizing diffusion in certain tissue environments or retention and immobilization in others.
Trends in mechanical circulatory support use and outcomes of patients with cardiogenic shock in Japan, 2010-2020: a nationwide inpatient database study
Authors: Nishimoto Yuji , Ohbe Hiroyuki , Matsui Hiroki , Nakata Jun , Takiguchi Toru , Nakajima Mikio , Sasabuchi Yusuke , Sato Yukihito , Watanabe Tetsuya , Yamada Takahisa , Fukunami Masatake , Yasunaga Hideo 
Published: February 2023

AbstractBackgroundLittle is known about the impact of the downgrade of guideline recommendations for intra-aortic balloon pump (IABP) use and the approval of the Impella in Japan, where IABPs have been enthusiastically used. This study aimed to describe the annual trends in the mechanical circulatory support (MCS) use and outcomes in patients with cardiogenic shock (CS) requiring MCS.MethodsUsing the Japanese Diagnosis Procedure Combination database from July 2010 to March 2021, we identified inpatients with CS requiring MCS. The patients were stratified into three groups: (i) IABP alone, (ii) Impella alone, and (iii) extracorporeal membrane oxygenation (ECMO) regardless of IABP or Impella use. The patient characteristics and outcomes were reported by the fiscal year.ResultsOf the 160,559 eligible patients, 117,599 (73.2%) used IABP alone, 1,465 (0.9%) Impella alone, and 41,495 (25.8%) ECMO. The prevalence of an IABP alone significantly decreased from 80.5% in 2010 to 65.3% in 2020 (P for trend <0.001), whereas the prevalence of an Impella alone significantly increased from 0.0% to 5.0% as well as ECMO from 19.5% to 29.6% (P for trend <0.001 for both). In-hospital mortality significantly increased from 29.3% in 2010 to 32.6% in 2020 in the overall patients with CS requiring MCS, but significantly decreased in those requiring ECMO from 73.7% to 64.1% (P for trend <0.001 for both).ConclusionsThere were significant annual changes in the patterns of MCS use and clinical outcomes in patients with CS requiring MCS.
Cell Population Growth Kinetics in the Presence of Stochastic Heterogeneity of Cell Phenotype
Authors: Wang Yue , Zhou Joseph X. , Pedrini Edoardo , Rubin Irit , Khalil May , Qian Hong , Huang Sui 
Published: February 2023

AbstractRecent studies at individual cell resolution have revealed phenotypic heterogeneity in nominally clonal tumor cell populations. The heterogeneity affects cell growth behaviors, which can result in departure from the idealized exponential growth. Here we measured the stochastic time courses of growth of an ensemble of populations of HL60 leukemia cells in cultures, starting with distinct initial cell numbers to capture the departure from the exponential growth model in the initial growth phase. Despite being derived from the same cell clone, we observed significant variations in the early growth patterns of individual cultures with statistically significant differences in growth kinetics and the presence of subpopulations with different growth rates that endured for many generations. Based on the hypothesis of existence of multiple inter-converting subpopulations, we developed a branching process model that captures the experimental observations.
Coronary Artery Disease risk variant dampens the expression of CALCRL by reducing HSF binding to shear stress responsive enhancer in endothelial cells
Authors: Selvarajan Ilakya , Li Jin , Pölönen Petri , Örd Tiit , Õunap Kadri , Ravindran Aarthi , Mäklin Kiira , Toropainen Anu , Stolze Lindsey K. , White Stephen , Romanoski Casey E. , Heinäniemi Merja , Fang Yun , Kaikkonen-Määttä Minna 
Published: February 2023

ABSTRACTCoronary artery disease (CAD) is one of the major causes of mortality worldwide. Recent genome-wide association studies have started to unravel the genetic architecture of the disease. Such efforts have identified Calcitonin receptor-like (CALCRL), an important mediator of the endothelial fluid shear stress response, associated with CAD risk variants. In this study we functionally characterized the non-coding regulatory elements carrying CAD risks SNPs and studied their role in the regulation ofCALCRLexpression in endothelial cells. We demonstrate that rs880890-harboring regulatory element exhibits high enhancer activity and significant allelic bias with A allele showing 40% more activity than G allele. We also observed that the A allele of rs880890 is favored over the G allele under shear stress. CRISPR deletion of rs880890-enhancer resulted in downregulation ofCALCRLexpression. EMSA further showed that heat shock factors are binding to the enhancer with a preference for A allele over the G allele. In line with this, HSF1 knockdown resulted in a significant decrease inCALCRLexpression.CALCRLknockdown as well as variant perturbation experiments confirmed the role of CALCRL in the regulation of eNOS, apelin, angiopoietin, prostaglandins and endothelin-1 signaling pathways while demonstrating a significant decrease in cell proliferation and tube formation. Overall, our results demonstrate the existence of an endothelial-specific heat shock factor regulated transcriptional enhancer carrying a CAD risk SNP rs880890 that regulatesCALCRLexpression. Better understanding ofCALCRLgene regulation and the role of SNPs in modulation ofCALCRLexpression could provide important steps towards understanding genetic regulation of shear stress signaling responses.
Effect of exportin 1/XPO1 nuclear export pathway inhibition on coronavirus replication
Authors: Rahman Masmudur M. , Estifanos Bereket , Glenn Honor L. , Gutierrez-Jensen Ami D. , Kibler Karen , Li Yize , Jacobs Bertram , McFadden Grant , Hogue Brenda G. 
Published: February 2023

AbstractNucleocytoplasmic transport of proteins using XPO1 (exportin 1) plays a vital role in cell proliferation and survival. Many viruses also exploit this pathway to promote infection and replication. Thus, inhibiting the XPO1-mediated nuclear export pathway with selective inhibitors has a diverse effect on virus replication by regulating antiviral, proviral, and anti-inflammatory pathways. The XPO1 inhibitor, Selinexor, is an FDA-approved anticancer drug predicted to have antiviral or proviral functions against viruses. Here, we observed that pretreatment of cultured cell lines from human or mouse origin with nuclear export inhibitor Selinexor significantly enhanced protein expression and replication of Mouse Hepatitis Virus (MHV), a mouse coronavirus. Knockdown of cellular XPO1 protein expression also significantly enhanced the replication of MHV in human cells. However, for SARS-CoV-2, selinexor treatment had diverse effects on virus replication in different cell lines. These results indicate that XPO1-mediated nuclear export pathway inhibition might affect coronavirus replication depending on cell types and virus origin.
A resurrection ecology test for the effects of ionizing radiation and other environmental correlates onDaphniaevolution
Authors: Neely-Streit Twyla , O’Toole Megan C. , Ciolak Emily M. , Islam Musharrat , Heathcote Adam J. , Masterson Andrew L. , Walsh Matthew R. , Stuart Yoel E. 
Published: February 2023

AbstractAcute exposure to ionizing radiation has well-documented, immediate negative consequences for individuals. However, the evolutionary consequences for populations exposed to ionizing radiation is unclear. For example, a meta-analysis of taxa exposed to Chernobyl fallout found some evidence for elevated mutation rates in animal and plant taxa; however, in people,de novomutation rates in offspring of parents exposed to radiation during and after the Chernobyl accident were no higher than controls. Furthermore, whether irradiation and increased mutation rates drive adaptation to radiation also has mixed support. Ambiguity in both cases likely arises from the difficulty of studying mutation rates and adaptation after rare nuclear events whose ionizing radiation is distributed heterogeneously in time and space. Here, we report an attempt to better address this difficulty with a “resurrection ecology” study ofDaphnia spp. in Utah lakes that experienced nuclear fallout from US Department of Energy weapons testing in the 1950s and 1960s. The idea was to recover dormantDaphniaeggs from sediment cores that spanned the nuclear testing era in the American West. We predicted that survival and fecundity of eggs hatched in the lab would show fitness declines correlated with ionizing radiation fallout and a potential recovery once nuclear testing stopped. We successfully obtained multiple cores from three lakes that dated back to the 1800s. We isolated >4700 dormant eggs from those cores, spanning the nuclear era, but were only able to hatch a single egg in the lab. Thus, we could not conduct life history experiments to test our prediction. The purpose of this manuscript, therefore, is to describe the study and make our radioisotope core dating and sedimentation data available to other paleolimnological researchers. We also report a side study of stable isotope change through time measured from dormant eggs and the sediment.
Odor cueing of declarative memories during sleep enhances coordinated spindles and slow oscillations
Authors: Sánchez-Corzo Andrea , Baum David M , Irani Martín , Hinrichs Svenja , Reisenegger Renate , Whitaker Grace A , Born Jan , Klinzing Jens G , Sitaram Ranganatha 
Published: February 2023

AbstractLong-term memories are formed by repeated reactivation of newly encoded information during sleep. This process can be enhanced by using memory-associated reminder cues like sounds and odors. While auditory cueing has been researched extensively, few electrophysiological studies have exploited the various benefits of olfactory cueing. We used high-density electroencephalography in an odor-cueing paradigm that was designed to isolate the neural responses specific to the cueing of declarative memories. We show widespread cueing-induced increases in the duration and rate of sleep spindles. Higher spindle rates were most prominent over centro-parietal areas and largely overlapping with a concurrent increase in the amplitude of slow oscillations (SOs). Interestingly, greater SO amplitudes were linked to a higher likelihood of coupling a spindle and coupled spindles expressed during cueing were more numerous in particular around SO up states. We thus identify temporally and spatially coordinated enhancements to sleep spindles and slow oscillations as a candidate mechanism behind the benefits of odor cueing. Our results further demonstrate the feasibility of studying neural activity patterns related to memory processing using olfactory cueing during sleep.Statement of SignificanceMemory cueing during sleep allows insights into memory consolidation. This study is the first to investigate olfactory cueing-induced declarative memory processing using high-density EEG, while robustly controlling for critical confounding factors. The use of odors as cues, instead of more common auditory stimuli, further minimizes possible distortions due to sensory-evoked potentials. We demonstrate intricate changes in brain activity in response to cueing, such as the patterns of sleep spindles, slow oscillations, and their spatiotemporal coupling. We provide evidence that the enhancement of slow oscillation amplitudes, together with associated increases in sleep spindle rates, could be the key mechanism behind cueing-related memory benefits. We moreover show that prior findings obtained using auditory cueing are not the mere result of tone-evoked responses but might be genuine signatures of memory processing.
The Effects of Speech Masking on Neural Tracking of Acoustic and Semantic Features of Natural Speech
Authors: Yasmin Sonia , Irsik Vanessa C. , Johnsrude Ingrid S. , Herrmann Björn 
Published: February 2023

AbstractListening environments contain background sounds that mask speech and lead to communication challenges. Sensitivity to slow acoustic fluctuations in speech can help segregate speech from background noise. Semantic context can also facilitate speech perception in noise, for example, by enabling prediction of upcoming words. However, not much is known about how different degrees of background masking affect the neural processing of acoustic and semantic features during naturalistic speech listening. In the current electroencephalography (EEG) study, participants listened to engaging, spoken stories masked at different levels of multi-talker babble to investigate how neural activity in response to acoustic and semantic features changes with acoustic challenges, and how such effects relate to speech intelligibility. The pattern of neural response amplitudes associated with both acoustic and semantic speech features across masking levels was U-shaped, such that amplitudes were largest for moderate masking levels. This U-shape may be due to increased attentional focus when speech comprehension is challenging, but manageable. The latency of the neural responses increased linearly with increasing background masking, and neural latency change associated with acoustic processing most closely mirrored the changes in speech intelligibility. Finally, tracking responses related to semantic dissimilarity remained robust until severe speech masking (−3 dB SNR). The current study reveals that neural responses to acoustic features are highly sensitive to background masking and decreasing speech intelligibility, whereas neural responses to semantic features are relatively robust, suggesting that individuals track the meaning of the story well even in moderate background sound.
The disordered N-terminal tail of SARS CoV-2 Nucleocapsid protein forms a dynamic complex with RNA
Authors: Cubuk Jasmine , Alston Jhullian J. , Incicco J. Jeremías , Holehouse Alex S. , Hall Kathleen B , Stuchell-Brereton Melissa D. , Soranno Andrea 
Published: February 2023

ABSTRACTThe SARS-CoV-2 Nucleocapsid (N) protein is responsible for condensation of the viral genome. Characterizing the mechanisms controlling nucleic acid binding is a key step in understanding how condensation is realized. Here, we focus on the role of the RNA Binding Domain (RBD) and its flanking disordered N-Terminal Domain (NTD) tail, using single-molecule Förster Resonance Energy Transfer and coarse-grained simulations. We quantified contact site size and binding affinity for nucleic acids and concomitant conformational changes occurring in the disordered region. We found that the disordered NTD increases the affinity of the RBD for RNA by about 50-fold. Binding of both nonspecific and specific RNA results in a modulation of the tail configurations, which respond in an RNA length-dependent manner. Not only does the disordered NTD increase affinity for RNA, but mutations that occur in the Omicron variant modulate the interactions, indicating a functional role of the disordered tail. Finally, we found that the NTD-RBD preferentially interacts with single-stranded RNA and that the resulting protein:RNA complexes are flexible and dynamic. We speculate that this mechanism of interaction enables the Nucleocapsid protein to search the viral genome for and bind to high-affinity motifs.
Deep spatial-omics to aid personalization of precision medicine in metastatic recurrent Head & Neck Cancers
Authors: Causer Andrew , Tan Xiao , Lu Xuehan , Moseley Philip , Teoh Min , McGrath Margaret , Kim Taehyun , Simpson Peter , Perry Christopher , Frazer Ian , Panizza Benedict , Ladwa Rahul , Nguyen Quan , Gonzalez-Cruz Jazmina L 
Published: February 2023

AbstractImmune checkpoint inhibitor (ICI) modality has had a limited success (<20%) in treating metastatic recurrent Head & Neck Oropharyngeal Squamous cell carcinomas (OPSCCs). To improve response rates to ICIs, tailored approaches capable to capture the tumor complexity and dynamics of each patient’s disease are needed. Here, we performed advanced analyses of spatial proteogenomic technologies to demonstrate that: (i) compared to standard histopathology, spatial transcriptomics better-identified tumor cells and could specifically classify them into two different metabolic states with therapeutic implications; (ii) our new method (Spatial Proteomics-informed cell deconvolution method orSPiD) improved profiling of local immune cell types relevant to disease progression, (iii) identified clinically relevant alternative treatments and a rational explanation for checkpoint inhibitor therapy failure through comparative analysis of pre- and post-failure tumor data and, (iv) discovered ligand-receptor interactions as potential lead targets for personalized drug treatments. Our work establishes a clear path for incorporating spatial-omics in clinical settings to facilitate treatment personalization.
In vivoLocus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals
Authors: Koshmanova Ekaterina , Berger Alexandre , Beckers Elise , Campbell Islay , Mortazavi Nasrin , Sharifpour Roya , Paparella Ilenia , Balda Fermin , Berthomier Christian , Degueldre Christian , Salmon Eric , Lamalle Laurent , Bastin Christine , Egroo Maxime Van , Phillips Christophe , Maquet Pierre , Collette Fabienne , Muto Vincenzo , Chylinski Daphne , Jacobs Heidi IL , Talwar Puneet , Sherif Siya , Vandewalle Gilles 
Published: February 2023

AbstractThe locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.
Pharmaceutical patent landscaping: A novel approach to understand patents from the drug discovery perspective
Authors: Gadiya Yojana , Gribbon Philip , Hofmann-Apitius Martin , Zaliani Andrea 
Published: February 2023

AbstractPatents play a crucial role in the drug discovery process by providing legal protection for discoveries and incentivising investments in research and development. By identifying patterns within patent data resources, researchers can gain insight into the market trends and priorities of the pharmaceutical and biotechnology industries, as well as provide additional perspectives on more fundamental aspects such as the emergence of potential new drug targets. In this paper, we used the patent enrichment tool, PEMT, to extract, integrate, and analyse patent literature for rare diseases (RD) and Alzheimer’s disease (AD). This is followed by a systematic review of the underlying patent landscape to decipher trends and applications in patents for these diseases. To do so, we discuss prominent organisations involved in drug discovery research in AD and RD. This allows us to gain an understanding of the importance of AD and RD from specific organisational (pharmaceutical or university) perspectives. Next, we analyse the historical focus of patents in relation to individual therapeutic targets and correlate them with market scenarios allowing the identification of prominent targets for a disease. Lastly, we identified drug repurposing activities within the two diseases with the help of patents. This resulted in identifying existing repurposed drugs and novel potential therapeutic approaches applicable to the indication areas. The study demonstrates the expanded applicability of patent documents from legal to drug discovery, design, and research, thus, providing a valuable resource for future drug discovery efforts. Moreover, this study is an attempt towards understanding the importance of data underlying patent documents and raising the need for preparing the data for machine learning-based applications.
Fitting Force Field parameters to NMR Relaxation Data
Authors: Kümmerer Felix , Orioli Simone , Lindorff-Larsen Kresten 
Published: February 2023

AbstractWe present an approach to optimise force field parameters using time-dependent data from NMR relaxation experiments. To do so, we scan parameters in the dihedral angle potential energy terms describing the rotation of the methyl groups in proteins, and compare NMR relaxation rates calculated from molecular dynamics simulations with the modified force fields to deuterium relaxation measurements of T4 lysozyme. We find that a small modification of Cγmethyl groups improves the agreement with experiments both for the protein used to optimize the force field, and when validating using simulations of CI2 and ubiquitin. We also show that these improvements enable a more effectivea posteriorireweighting of the MD trajectories. The resulting force field thus enables more direct comparison between simulations and side-chain NMR relaxation data, and makes it possible to construct ensembles that better represent the dynamics of proteins in solution.