bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurophysiological and Autonomic Dynamics of Threat Processing During Sustained Social Fear Generalization
Authors: Pouliot Jourdan J. , Ward Richard T. , Traiser Caitlin M. , Chiasson Payton , Gilbert Faith E. , Keil Andreas
Published: April 2024

Survival in dynamic environments requires that organisms learn to predict danger from situational cues. One key facet of threat prediction is generalization from a predictive cue to similar cues, ensuring that a cue-outcome contingency is applied beyond the original learning environment. Generalization has been observed in laboratory studies of aversive conditioning: behavioral and physiological processes generalize responses from a stimulus paired with threat (the CS+) to unpaired stimuli, with response magnitudes varying with CS+ similarity. In contrast, work focusing on sensory responses in visual cortex has found a sharpening pattern, in which responses to stimuli closely resembling the CS+ are maximally suppressed, potentially reflecting lateral inhibitory interactions with the CS+ representation. Originally demonstrated with simple visual cues, changes in visuocortical tuning have also been observed in threat generalization learning across facial identities. It is unclear to what extent these visuocortical changes represent transient or sustained effects and if generalization learning requires prior conditioning to the CS+. The present study addressed these questions using EEG and pupillometry in an aversive generalization paradigm involving hundreds of trials using a gradient of facial identities. Visuocortical ssVEP sharpening occurred after dozens of trials of generalization learning without prior differential conditioning, but diminished as learning continued. By contrast, generalization of alpha power suppression, pupil dilation, and self-reported valence and arousal was seen throughout the experiment. Findings are consistent with threat processing models emphasizing the role of changing visucocortical and attentional dynamics when forming, curating, and shaping fear memories as observers continue learning about stimulus-outcome contingencies.
Depletion of Protein Phosphatase 1 Results in Persistent Activation of the Integrated Stress Response and Age-Associated Exacerbation of Pulmonary Veno-Occlusive Disease
Authors: Prabhakar Amit , Wadhwa Meetu , Ghatpande Prajakta , Kumar Rahul , Graham Brian B. , Lagna Giorgio , Hata Akiko
Published: April 2024

Pulmonary veno-occlusive disease (PVOD) is a form of pulmonary hypertension that affects individuals across the age spectrum. PVOD is characterized by the obstruction of small pulmonary vessels, causing increased pulmonary artery (PA) pressure and leading to right ventricular heart (RV) failure. Previous research showed that the administration of Mitomycin-C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase PKR and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function. In this study, we reveal that older rats experience more severe pulmonary vascular remodeling and RV hypertrophy than younger rats after MMC treatment due to lower levels of protein phosphatase 1, leading to prolonged eIF2 phosphorylation and ISR activation. We demonstrate that pharmacological blocking of the PKR-ISR pathway mitigates PVOD symptoms in both age groups, suggesting targeting the PKR-ISR axis as a potential PVOD therapeutic strategy.
OrganoLabeling: Quick and accurate annotation tool for organoid images
Authors: Kahveci Burak , Polatli Elifsu , Bastanlar Yalin , Guven Sinan
Published: April 2024

Organoids are self-assembled 3D cellular structures that resemble organs structurally and functionally, providing in vitro platforms for molecular and therapeutic studies. Generation of organoids from human cells often require long and costly procedures with arguably low efficiency. Prediction and selection of cellular aggregates that result in healthy and functional organoids can be achieved using artificial intelligence-based tools. Transforming images of 3D cellular constructs into digitally processible datasets for training deep learning models require labeling of morphological boundaries, which often is performed manually. Here we report an application named OrganoLabeling, which can create large image-based datasets in consistent, reliable, fast, and user-friendly manner. OrganoLabeling can create segmented versions of images with combinations of contrast adjusting, K-means clustering, CLAHE, binary and Otsu thresholding methods. We created embryoid body and brain organoid datasets, of which segmented images were manually created by human researchers and compared with OrganoLabeling. Validation is performed by training U-Net models, which are deep learning models specialized in image segmentation. U-Net models, that are trained with images segmented by OrganoLabeling, achieved similar or better segmentation accuracies than the ones trained with manually labeled reference images. OrganoLabeling can replace manual labeling, providing faster and more accurate results for organoid research free of charge.
Classification and Regression Trees to predict Transcription Factor Combinatorial Interaction in scRNA-seq data
Authors: Carluer Jean Baptiste , Steinmann Laura , Carré Clément , Mas André , Krouk Gabriel
Published: April 2024

Understanding the regulatory mechanisms that govern gene expression is crucial for deciphering cellular functions. Transcription factors (TFs) play a key role in regulating gene expression. In particular TF combinatorial interactions (TFCI) are now thought to largely shape genomic transcriptional responses, but predicting TFCIper seis still a difficult task. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool providing a whole new readout of gene regulatory effects. In this study, we propose a machine learning approach utilizing Classification and Regression Trees (CART) for predicting TFCI in >110k scRNA-seq data points yielded fromArabidopsis thalianaroot. The proposed methodology provides a valuable tool for pointing to new TFCI mechanisms and could advance our understanding of Gene Regulatory Networks’ functioning.
Prolonged signaling of backbone-modified glucagon-like peptide-1 analogues with diverse receptor trafficking
Authors: Cary Brian P. , Hager Marlies V. , Morris Rylie K. , Belousoff Matthew J. , Sexton Patrick M. , Wootten Denise , Gellman Samuel H.
Published: April 2024

Signal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cAMP upon activation by the native hormone, GLP-1. cAMP production continues after the hormone-receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from (S,S)-trans-2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryo-electron microscopy (cryo-EM) structures of two GLP-1 analogues bound to the GLP- 1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profile. Our results advance understanding of the structural underpinnings of receptor activation and introduce new tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.
The drug disposition in the Spleen: A novel study of CYP and UGT-mediated drug metabolism
Authors: Inuwa Patience , Paine Stuart , Best Stuart , Mosinska-Kodzik Karolina , Rauch Cyril
Published: April 2024

Understanding the fate of a drug, its disposition and pharmacokinetics as it reaches the site of action is key to any pharmaceutical research and development. The emerging role of the spleen in its involvement in regulating the immune system has garnered interest in new immunotherapeutic strategies. Using novel precision immunotherapeutic drugs that will potentially engage with the host immune system to specifically target and eliminate diseased cells, makes this approach a better alternative to conventional therapies. The spleen poses as a potential immunotherapeutic target and confirmation of drugs reaching its site of action requires monitoring enzymes that engages with xenobiotics like drugs. The pig was selected as the model for human based on the close homology conveyed between pig and human using a phylogenetic construction of Cytochrome P450s (CYP450) and UDP-glucuronosyltransferases (UGT) in both species. Moreover, an RNAseq transcriptome analysis between the human spleen, pig liver and spleen tissues were obtained from a next generation sequencing (NGS) to identify genes associated with drug metabolism. Immunofluorescence and Western Blot analysis was carried out to determine the protein expression of metabolizing CYP450s and UGTs in pig spleen. Therefore, drug substrates and their metabolites known in human liver were investigated in pig spleen to determine the functional expression of CYP450s and UGTs. Promisingin-vitroresults has demonstrated the expression of these metabolic enzymes at a functional level from observations showing elimination of drug substrates and the apparent metabolites formed. Monitoring the enzyme activities would also indicate uptake of these substrates in splenocytes, confirm that the spleen can metabolize drugs, and provide further insight into therapeutic or toxic related implications from drug interactions.
Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer
Authors: Vlachavas Efstathios-Iason , Voutetakis Konstantinos , Kosmidou Vivian , Tsikalakis Spyridon , Roditis Spyridon , Pateas Konstantinos , Kim Ryangguk , Pagel Kymberleigh , Wolf Stephan , Warsow Gregor , Dimitrakopoulou-Strauss Antonia , Zografos Georgios N , Pintzas Alexander , Betge Johannes , Papadodima Olga , Wiemann Stefan
Published: April 2024

While colorectal cancer (CRC) patients with microsatellite instability (MSI) respond well to immunotherapy those with microsatellite stable (MSS) tumors rely on conventional chemotherapy, often with poor outcomes. Both types frequently carry mutations inKRASorBRAFproto-oncogenes, rendering them more resistant to treatment. New therapeutic biomarkers and treatments remain a clinical need, especially for MSS tumors. We performed whole exome and RNA-Sequencing from 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized colorectal cancer patients based on their MSI status, SNVs/CNAs, and pathway/transcription factor activities at the individual patient level. Variants were classified using a new computational score for integrative cancer variant annotation and prioritization. Complementing this molecular data with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be stronger activated in the MSS patients whereas JAK-STAT and MAPK molecular cascades were activated specifically in MSI. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified RUNX transcription factors as putative novel targets. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impactKRASmutations have on immunogenicity particularly in the MSS patient subgroup, with implications for diagnosis and treatment.
Diatom community shifts across oligotrophic-eutrophic seasonal gradients and bloom variability as a function of mixing depth in the subtropical Northern Red Sea
Authors: Avrahami Yoav , Koplovitz Gil , Frada Miguel
Published: April 2024

Diatom blooms dominate nutrient-rich ecosystems. Less is known about the ecology and bloom dynamics of diatom populations in oligotrophic ecosystems. Here, we investigated seasonal succession of planktonic diatoms in the Gulf of Aqaba (GoA) at the northern Red Sea. The GoA is a subtropical ecosystem alternating between stratified, oligotrophic profiles during summer, and deeply mixed, mesotrophic during winter. Diatom density and diversity were lower during the stratified season, dominated by pennate species, and increased at mid-winter as nitrate exceeded ~0.5 umol L-1. Diatom density lagged after total phytoplankton and entailed a transition to centric-diatom dominance, suggesting both higher nutrient requirements for diatom growth and ecophysiological differences between morphotypes. Ephemeral blooms were detected at the mixing-to-stratification transition. Under milder conditions, mixing was shallow and diatoms reached ~98 individuals. mL-1. Small-centric Thalassiosiraceae and several pennates dominated. However, during the following colder year, mixing depth reached ~700 m. Consequently, nutrient concentrations were higher and diatoms reached ~390 individuals. mL-1. This enabled emergence of chain-forming species (namely Chaetoceros and Leptocylindrus) along small-centric and pennates, and high spore abundance was detected. Restratification led to rapid bloom decline. These results illustrate diatom community succession and bloom development as a function of nutrient availability in subtropical ecosystems.
DOES EXPERIENCE MODULATE AUTOMATIC IMITATION? A NEW LOOK
Authors: Genovese Francesca , Fanghella Martina , Sinigaglia Corrado , Barchiesi Guido
Published: April 2024

Automatic imitation is a stimulus-response compatibility effect wherein observing an action automatically influences motor performance. However, the mechanism underlying this effect remains controversial. Associative Sequence Learning suggests that automatic imitation arises from contingent visual and motor activity associations. Prior studies have shown that exposure to counter-imitative training can alter these visuomotor associations, suggesting that automatic imitation can be modulated by experience. Here, we aim to bring new insight into how this modulation occurs by exploring the time course of automatic imitation before and after counter-imitative training. If automatic imitation is merely a result of contingent associations, as previously suggested, the effect should consistently be modulated following such training. However, if this is not the case, automatic imitation is not, or not only, a matter of contingent association, at least not as currently understood.
Circulating tumor cells shed large extracellular vesicles in capillary bifurcations that activate endothelial and immune cells
Authors: Vrynas Angelos , Bazban-Shotorbani Salime , Arfan Sara , Satia Karishma , Ashna Mymuna , Zhang Aoyu , Visan Diana , Chen Aisher , Carter Mathew , Blackhall Fiona , Simpson Kathryn L. , Dive Caroline , Huang Paul , Au Sam H.
Published: April 2024

Circulating tumor cells (CTCs) and their clusters are the drivers of metastasis, but we have an incomplete understanding of how they interact with capillary beds. Using microfluidic models mimicking human capillary bifurcations, we observed cell size- and bifurcation-dependent shedding of nuclei-free fragments by patient CTCs, CTC-derived explant cells and numerous cancer cell lines. Shedding reduced cell sizes up to 61%, facilitating their transit through bifurcations. We demonstrated that shed fragments were a novel subclass of large extracellular vesicles (LEVs), “shearosomes”, that require shear stress for their biogenesis and whose proteome was associated with immune-related pathways. Shearosomes exhibited functions characteristic of previously identified EVs including cell-directed internalization by endothelial and immune cells, and intercellular communication abilities such as disruption of endothelial barrier integrity, polarization of monocytes into M2 tumor-promoting macrophages and interactions between endothelial and immune cells. Cumulatively, these findings suggest that CTCs shed shearosomes in capillary beds that drive key processes involved in the formation of pre-metastatic niches.
Methods in cancer research: Assessing therapy response of spheroid cultures by life cell imaging using a Cost-Effective Live-Dead Staining Protocol
Authors: Phour Jaison , Vassella Erik
Published: April 2024

Spheroid cultures of cancer cell lines or primary cells represent a more clinically relevant model for predicting therapy response compared to two-dimensional cell culture. However, current live-dead staining protocols used for treatment response in spheroid cultures are often expensive, toxic to the cells, or limited in their ability to monitor therapy response over an extended period due to reduced stability. In our study, we have developed a cost-effective method utilizing calcein-AM and Helix NP™ Blue for live-dead staining, enabling the monitoring of therapy response of spheroid cultures for up to 10 days. Using the example of glioblastoma cell lines and primary glioblastoma cells we show that spheroid cultures typically exhibit a green outer layer of viable cells, a turquoise mantle of hypoxic quiescent cells, and a blue core of necrotic cells when visualized using confocal microscopy. Upon treatment of spheroids with the alkylating agent temozolomide, we observed a reduction in the viability of glioblastoma cells after an incubation period of six to seven days. This method can also be adapted for monitoring therapy response in different cancer systems, offering a versatile and cost-effective approach for assessing therapy efficacy in three-dimensional culture models.
Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development
Authors: Nekooie Marnany Nioosha , Dady Alwyn , Relaix Frédéric , Motterlini Roberto , Foresti Roberta , Dufour Sylvie , Duband Jean-Loup
Published: April 2024

Metabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important stem cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a novel role for glutamine and its catabolizing enzyme glutaminase in delamination. Specifically, glutamine is required for nuclear translocation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.
First endangered black-footed ferrets,Mustela nigripes, cloned for genetic rescue
Authors: Novak Ben J. , Gober Pete , Bortner Robyn , Garelle Della , Wright Mary , Chuven Justin , Houck Marlys L. , Ryder Oliver A. , Milutinovich Dennis , Benavidez Jill , Ryan Kerry , Walker Shawn , Arenivas Sanaz Sadeghieh , Aston Lauren , Russell Blake , Marinari Paul , Crosier Adrienne , Helmick Kelly , Gibson Mary R. , Carlsen Daniel P. , Swanson Bradley J. , Wisely Samantha M. , White Zoe S. , Lynch Colleen , Phelan Ryan
Published: April 2024

An endangered black-footed ferret female that died in 1988 with no living descendants in the current population was successfully cloned from cryopreserved cells using cross-species somatic cell nuclear transfer, producing three healthy kits. Incorporating progeny from these clones would provide an 8th founder to the breeding program and increase genetic variation to the species’ limited gene-pool. This marks the first time a native U.S. endangered species has been cloned.
Whatandwherein electromagnetic brain imaging
Authors: de Cheveigné Alain
Published: April 2024

To understand the brain, we need to observe the nature and dynamics of the activity (the “what”), and the location or distribution of its sources (the “where”). This paper proposes a new approach in which these two elements are derived in parallel from separate columns of a data-driven analysis matrix. A subset of columns enhances the activity of interest, and its complement defines spatial filters that suppress that activity (null filters). Each null filter is combined with an anatomy-dependent source model to estimate a set of locations within the sources space in which the source might reside (the “zero set” of that filter) and the final estimate is derived from the intersection of zero sets. There is no theoretical limit to the accuracy with which the location of a source can be estimated in this way, but practical limits may arise from noise in the data, imperfect calibration, or an incomplete or inaccurate source model. The method is illustrated with simulated and real data from EEG, MEG and SEEG.
Nutribloods: novel synthetic lepidopteran haemolymphs for understanding insect-microbe interactionsin vitro
Authors: Holdbrook Robert , Randall Joanna L. , Reavey Catherine E. , Andongma Awawing A. , Rice Annabel , Smith Judith A. , Simpson Stephen J. , Cotter Sheena C. , Wilson Kenneth
Published: April 2024

Understanding the role of nutrients in microbial population dynamics relies on a sound appreciation of their nutritional environment and how this may vary in different habitats. For microbial pathogens and commensals, this can be especially challenging because the microbe may share nutritional resources with its host. Here we design a series of 20 synthetic haemolymphs (nutribloods) that mimic haemolymph nutrient profiles of caterpillars fed on one of 20 chemically-defined diets, that vary in their protein:carbohydrate (P:C) ratio and caloric density. Using these, we are able to simulate the range of nutritional conditions that insect blood pathogens might face, providing a model system for understanding the role of nutrition in microbial growth. We tested this using the entomopathogen,Xenorhabdus nematophila, a gram-positive extracellular bacterium of insect hosts. This revealed that whilst bacterial fitness peaked innutribloodnutrient space that was high in carbohydrates and low in proteins, levels of amino acids in the nutribloods also appear to be an important driving force for bacterial growth. Using synthetic haemolymphs that had average levels of all nutrients other than carbohydrate, protein or amino acids, we also established that bacterial growth is generally enhanced by carbohydrate and amino acids but reduced by proteins. Here, we have established a tractable model system for examining the role that nutrition plays in the growth of an entomopathogenic bacterium. In future work, this model host-pathogen system can be used to test a range of nutritionally-driven processes, including competition during co-infection and interactions with the host microbiome, as well as comparative studies of other entomopathogens.
Comparative study on the accuracy of speech recognition using a contact microphone attached to the surface of the head and neck
Authors: Asakura Takumi , Konuma Yuki
Published: April 2024

The accuracy of speech recognition through an air-conducted microphone can be less accurate under a highly noisy environment or when the volume of the user’s voice is relatively low. One solution to this problem is the use of contact microphones. However, neither the microphone locations that provide optimal speech recognition accuracy for each user nor the mechanisms underlying these contact forces have been clarified. In this study, we experimentally investigated the effects of placement, contact force, user gender, and speech recognition platform on the accuracy of speech recognition with contact microphones placed on the surface of the head and neck. The experimental results indicated that the mechanism underlying the influence of each factor on speech recognition accuracy differs for speech acquired at the neck and head locations. In particular, the effect of the user’s gender was significant for the neck-acquired sound, but not the head-acquired sound. The results also revealed that the microphone contact force did not affect the recognition accuracy or user discomfort for the head-acquired sound. Moreover, the results of speech recognition experiments in a simulated noisy environment showed that bone-conducted sounds acquired on the head and neck surfaces were more robust than air-conducted sounds.
5’-S-(3-aminophenyl)-5’-thioadenosine, a novel chemoprotective agent for reducing toxic side effects of fluorouracil in treatment of MTAP-deficient cancers
Authors: Zhang Si , Xue Hui , Wong Nelson K.Y. , Doerksen Thomas , Ban Fuqiang , Aderson Shawn , Volik Stanislav , Lin Yen-Yi , Dai Zhongye , Bratanovic Ivica , Cheng Hongwei , Collins Colin C. , Cherkasov Artem , Wulff Jeremy , Wang Yuzhuo
Published: April 2024

Background

Nucleobase analogue (NBA) drugs are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests the use ofS-methyl-5’-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We intended to find an MTA analogue that can exert MTA function while minimize the undesired side effects of MTA. Thus, such an analogue can be used in combination with NBAs in selectively targeting MTAP-deficient cancers.

Methods

We screened a library of MTA analogues for the following criteria: 1) being substrates of MTAP; 2) selectively protection on MTAP-expressing cells from NBA toxicity usingMTAP-isogenic cell lines; 3) ability to protect the host from NBA toxicity without hypothermic effect; and 4) lack of interference on the tumor-suppressive effect of NBA in mice bearing MTAP-deficient tumors.

Results

We identified 5’-S-(3-aminophenyl)-5’-thioadenosine (m-APTA) that did not induce hypothermia at the effective doses. We demonstrated that m-APTA could be converted to adenine by MTAP. Consequently, m-APTA selectively protected mouse hosts from 5-FU-induced toxicity (i.e. anemia); yet it did not interfere with the drug efficacy on MTAP-deficient bladder cancers.In silicodocking studies revealed that, unlike MTA, m-APTA interact inefficiently with adenosine A1receptor, providing a plausible explanation of the superior safety profile of m-APTA.

Conclusion

m-APTA can significantly improve the translational potential of the NBA toxicity reduction strategy in selectively targeting MTAP-deficient cancers.
Dirichlet distribution parameter estimation with applications in microbiome analyses
Authors: Fuller Daniel T. , Mondal Sumona , Sur Shantanu , Pal Nabendu
Published: April 2024

Microbiomes are of vital importance for understanding human and environmental health. However, quantifying microbial composition remains challenging and relies on statistical modeling of either the raw taxonomic counts or the relative abundances. Relative abundance measures are commonly preferred over the absolute counts to analyze and interpret microbiome (as the sampling fraction are unknown in sequence data) but currently there is no ideal distribution for carrying out this modeling . In this work, the Dirichlet distribution is proposed to model the relative abundances of taxa directly without the use of any further transformation. In a comprehensive simulation study, we compared biases and standard errors of two Methods of Moments Estimators (MMEs) and Maximum Likelihood Estimator (MLE) of the Dirichlet distribution. Comparison of each estimator is done over three different cases of differing sample size and dimension: (i) small dimension and small sample size; (ii) small dimension and large sample size; (iii) large dimension with both large and small sample size. We demonstrate the Dirichlet modeling methodology with four real world microbiome datasets and show how the results of the Dirichlet model differ from those obtained by a commonly used method, namely Bayesian Dirichlet-Multinomial estimation (BDME). We find that the results of parameter estimation can be dependent upon the sequencing depth and sequencing technique used to produce a given microbiome dataset. However, for all datasets, the Dirichlet MLE (DMLE) results are comparable to the BDME results while requiring less computational time in each case.
Impact of Pathogenic Variants of the Ras-MAPK Pathway on Major White Matter Tracts in the Human Brain
Authors: Siqueiros-Sanchez Monica , Dai Erpeng , McGhee Chloe A. , McNab Jennifer A. , Raman Mira M. , Green Tamar
Published: April 2024

Noonan syndrome (NS) and Neurofibromatosis type-1 (NF1) are genetic conditions linked to pathogenic variants in genes of the Ras-MAPK signaling pathway. Both conditions hyperactivate signaling of the Ras pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of NS and NF1 and human imaging studies show white-matter abnormalities in both conditions. While these findings suggest Ras pathway hyper-activation effects on white-matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of NS and NF1 on human white-matter microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with NS (n=24), NF1 (n=28), and age and sex-matched controls (n=31). We contrasted the clinical groups (NS or NF1) and controls using voxel-wise, tract-based, and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD). NS and NF1 showed similar patterns of reduced FA and increased AD, RD, and MD on white-matter relative to controls and different spatial patterns. NS presented a more extensive spatial effect than NF1 on white-matter integrity as measured by FA. Tract-based analysis also demonstrated differences in effect magnitude with overall lower FA in NS compared to NF1 (d=0.4). At the tract-level, NS specific-effects on FA were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; p’s <0.012) and NF1 specific-effects were detected in the corpus callosum (p’s<0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-MAPK pathway are associated with white-matter abnormalities as measured by diffusion in the developing brain. Overall NS and NF1 show common effects on FA and diffusion scalars, as well as specific unique effects, namely on temporoparietal-frontal tracts (intra-hemispheric) in NS and on the corpus callosum (inter-hemispheric) in NF1. The observed specific effects not only confirm prior observations from independent cohorts of NS and NF1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras pathway.
Circular DNA vcDNA-S7 derived from segmented-dsRNA virus BmCPV attenuated viral infection through RNase H1
Authors: Pan Jun , Tong Xinyu , Ding Yuming , Lei Chao , Wei Shulin , Xu An , Han Yaxuan , Qiu Qunnan , Pang Huilin , Hu Xiaolong , Gong Chengliang , Zhu Min
Published: April 2024

Viral circDNA derived from insect positive-sense single-stranded RNA viruses plays a crucial role in regulating viral infections depending on the RNAi pathway. Our previous research has revealed thatBombyx moricypovirus (BmCPV), a segmented-dsRNA virus, can generate viral circDNA vcDNA-S7, which can be transcribed to form RNA and further processed into small RNAs to defend against the virus through RNAi. However, whether vcDNA-S7 employs other mechanisms to resist the viruses. Presently, vcDNA-S7 has been found to resist BmCPV infection via a novel mechanism that depends on ribonuclease RNase H1 activity. It was found that the expression level of RNase H1 increased upon BmCPV infection (RNA virus) but not uponB. morinucleopolyhedrovirus (BmNPV) (DNA virus) infection. RNase H1 has been shown to negatively regulate BmCPV infections. In addition, vcDNA-S7 was found to form a heteroduplex with the viral RNA and subsequently recruit RNase H1 to degrade the viral RNA within the heteroduplex, ultimately leading to the suppression of viral replication. Furthermore, the resistance of vcDNA-S7 to viruses was significantly reduced when cellular RNase H1 gene was silenced. These findings not only reveal a new antiviral mechanism involving circular DNA formed by reovirus but also offer intriguing insights into the antiviral function of RNase H1 in cells.
A qualitative exploration of barriers to efficient and effective Structured Medication Reviews in Primary Care: Findings from the DynAIRx study
Authors: Abuzour Aseel S , Wilson Samantha A , Woodall Alan A , Mair Frances S , Clegg Andrew , Shantsila Eduard , Gabbay Mark , Abaho Michael , Aslam Asra , Bollegala Danushka , Cant Harriet , Griffiths Alan , Hama Layik , Leeming Gary , Lo Emma , Maskell Simon , O’Connell Maurice , Popoola Olusegun , Relton Sam , Ruddle Roy A , Schofield Pieta , Sperrin Matthew , Van Staa Tjeerd , Buchan Iain , Walker Lauren E
Published: April 2024

Introduction

Structured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them.

Methods

Qualitative focus groups and semi-structured interviews took place between 2022-2023. Nine focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n=21), and three patient focus groups with patients at high-risk of rapidly worsening health from multimorbidity (n=13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using a thematic approach.

Results

Two key themes limiting the effectiveness of SMRs in clinical practice were identified: ‘Medication Reviews in Practice’ and ‘Medication-related Challenges’. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication.

Conclusion

SMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems.
A Meta-analysis of the efficacy of topical antibiotics in spinal surgery for the prevention of surgical site infection
Authors: Wang Yanfei , Song Ke , Cai Songlin , Wu Weifei
Published: April 2024

Background

Despite significant advancements in clinical aseptic techniques and wound infection control, surgical site infections (SSIs) continue to pose a significant risk and complication following spinal surgery. The use of intrawound antibiotics for the prevention of SSIs after spine surgery is a controversial method.

Objective

To conduct a review of the current literature on the use of antibiotics in wound care and evaluate their effectiveness in preventing postoperative SSIs.

Methods

Keywords such as “spinal surgery” or “spine”, “antibiotics”, “local” or “topical”, “prevention of infection”, and “infection” were used based on PubMed, Web of Science, Cochrane and Embase database. The literature was screened based on the title, abstract, full text reading, and extraction of relevant research data. Comparisons of the data were performed using RevMan 5.3 software.

Results

A total of 18922 patients from 24 studies were included in the final analysis, 8878 patients received antibiotics (experimental group) to prevent SSIs, and 10044 patients did not receive any additional antibiotics (control group). In the experimental group, 178 patients developed SSIs, compared to 356 patients in the control group. The results of the meta-analysis indicated that the incidence of SSIs in the experimental group was significant lower than that in the control group (95% confidence interval, 0.36-0.75, p=0.0004).

Conclusion

The topical application of antibiotics within the wound site is a crucial and efficient method to prevent SSIs after spinal surgery.
Clinical Outcomes Following Optical Coherence Tomographic versus Intravascular Ultrasound-Guided Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials
Authors: Dodoo Sheriff N. , Ibrahim Sammudeen , Osman Abdul-Fatawu , Salih Rayan , Kilaru Vikas , Ampadu Dennis Kwaku , Dodoo Afia S. , Egolum Ugochukwu , Ghasemzadeh Nima , Ramadan Ronnie , Giugliano Gregory , Henry Glen , Ibebuogu Uzoma , Samady Habib
Published: April 2024

Background

Optical coherence tomography (OCT) and intravascular ultrasound (IVUS) are adjunctive intracoronary imaging modalities used for optimizing the implantation of coronary stents. However, the impact of the choice of OCT versus IVUS on clinical outcomes and periprocedural complications is unclear.

Objective

To perform a meta-analysis of all vetted randomized controlled trials comparing OCT-guided versus IVUS-guided percutaneous coronary intervention.

Methods

We queried MEDLINE, Cochrane Library, Scopus, andclinicalTrials.govdatabases from their commencement to February 2024 for all randomized controlled trials that compared OCT-guided versus IVUS-guided percutaneous coronary interventions. The primary endpoint was major adverse periprocedural events (MAPE), a composite of stent thrombosis (ST), distal embolization (DE), and distal edge dissection (DED). The secondary endpoints included stent thrombosis, distal embolization, distal edge dissection, Major-adverse-cardiac events (MACE)-[a composite of cardiac death, Target vessel myocardial infarction (TVMI), and target vessel revascularization (TVR)], all-cause mortality, cardiac death, TVMI, TVR, and nonfatal stroke. The odds ratio (OR) with a 95% confidence interval (CI) was analyzed using a random-effect model.

Results

Seven randomized controlled trials were included in the analysis, and 4446 patients were enrolled. OCT was associated with lower MAPE (OR: 0.65, CI:0.47-0.91, p= 0.01) compared to IVUS. ST, DE, and DED were similar between OCT and IVUS. There were no significant differences in MACE (OR: 0.86, CI:0.64-1.16, p= 0.32), all-cause mortality (OR: 0.83, CI:0.42-1.66, p= 0.60), Cardiac death (OR: 0.62, CI:0.20-1.89, p= 0.40), TVMI (OR: 0.69, CI:0.33-1.46, p= 0.33), TVR, (OR: 1.09, CI:0.70-1.71, p= 0.70), and non-fatal stroke (OR: 1.82, CI:0.67-4.95, p= 0.24) one year following the index procedure.

Conclusion

Optical coherence tomographic-guided PCI was associated with lower major adverse peri-procedural events (MAPE), including stent thrombosis, distal embolization, and distal edge dissection, compared to intravascular ultrasound-guided PCI. However, there was no difference in overall major adverse cardiac events, target vessel myocardial infarction, target vessel revascularization, and nonfatal stroke.
Transcriptional Variabilities in Human hiPSC-derived Cardiomyocytes: All Genes Are Not Equal and Their Robustness May Foretell Donor’s Disease Susceptibility
Authors: Charles Gu C. , Matter Andrea , Turner Amy , Aggarwal Praful , Yang Wei , Sun Xiao , Hunt Steven C. , Lewis Cora E. , Arnett Donna K , Anson Blake , Kattman Steve , Broeckel Ulrich
Published: April 2024

Human induced pluripotent stem cells (hiPSCs) are frequently used to study disease-associated variations. We characterized transcriptional variability from a hiPSC-derived cardiomyocyte (hiPSC-CM) study of left ventricular hypertrophy (LVH) using donor samples from the HyperGEN study. Multiple hiPSC-CM differentiations over reprogramming events (iPSC generation) across 7 donors were used to assess variabilities from reprogramming, differentiation, and donor LVH status. Variability arising from pathological alterations was assessed using a cardiac stimulant applied to the hiPSC-CMs to trigger hypertrophic responses. We found that for most genes (73.3%∼85.5%), technical variability was smaller than biological variability. Further, we identified and characterized lists of“noise” genesshowing greater technical variability and“signal” genesshowing greater biological variability. Together, they support a “genetic robustness” hypothesis of disease-modeling whereby cellular response torelevantstimuli in hiPSC-derived somatic cells fromdiseased donorstends to showmoretranscriptional variability. Our findings suggest that hiPSC-CMs can provide a valid model for cardiac hypertrophy and distinguish between technical and disease-relevant transcriptional changes.
AMHY and sex determination in egg-laying mammals
Authors: Shearwin-Whyatt Linda , Fenelon Jane , Yu Hongshi , Major Andrew , Qu Zhipeng , Zhou Yang , Shearwin Keith , Galbraith James , Stuart Alexander , Adelson David , Zhang Guojie , Pyne Michael , Johnston Stephen , Smith Craig , Renfree Marilyn B , Grützner Frank
Published: April 2024

The sex chromosomes of egg-laying mammals (monotremes), which lack the sex determining gene SRY, evolved independently to those of all therian mammals. Here we characterise the candidate monotreme sex determining gene, the Y-localised anti-Müllerian hormone gene (AMHY) and trace its expression during the period of sexual differentiation. Monotreme AMHX and AMHY gametologues have significant sequence divergence at the promoter, gene and protein level, likely following an original allele inversion in the common monotreme ancestor but retain conserved features of TGF-β molecules. Expression of sexual differentiation genes in the echidna fetal gonad were significantly different from that of therian mammals. AMHY expression was seen exclusively in the male gonad during sexual differentiation, whereas AMHX was expressed in both sexes. Experimental ectopic expression of platypus AMHX or AMHY in the chicken embryo did not masculinise the female urogenital system, a possible result of mammalian specific changes to AMH proteins preventing function in the chicken. Our results provide fundamental insight into the first steps of monotreme sex chromosome evolution and sex determination with developmental expression data strongly supporting AMHY as the primary male sex determination gene.
Exploring the Influence of Pore Shape on Conductance and Permeation
Authors: Seiferth David , Biggin Philip C.
Published: April 2024

There are increasing numbers of ion channel structures featuring heteromeric subunit assembly, exemplified by synaptic α1βBGlycine and α4β2 Nicotinic receptors. These structures exhibit inherent pore asymmetry, but the relevance of this to function is unknown. Furthermore, molecular dynamics simulations performed on symmetrical homomeric channels often leads to thermal distortion whereby conformations of the resulting ensemble are also asymmetrical. When functionally annotating ion channels, researchers often rely on minimal constrictions determined via radius-profile calculations performed with computer programs, such as HOLE or CHAP, coupled with an assessment of pore hydrophobicity. However, such tools typically employ spherical probe particles, limiting their ability to accurately capture pore asymmetry. Here, we introduce an algorithm that employs ellipsoidal probe particles, enabling a more comprehensive representation of the pore geometry. Our analysis reveals that the use of non-spherical ellipsoids for pore characterization, provides a more accurate and easily interpretable depiction of conductance. To quantify the implications of pore asymmetry on conductance, we systematically investigated carbon nanotubes (CNTs) with varying degrees of pore asymmetry as model systems. The conductance through these channels shows surprising effects that would otherwise not be predicted with spherical probes. The results have broad implications not only for the functional annotation of biological ion channels, but also for the design of synthetic channel systems for use in areas such as water filtration. Furthermore, we make use of the more accurate characterization of channel pores to refine a physical conductance model to obtain a heuristic estimate for single channel conductance. The code is freely available, obtainable as pip-installable python package and provided as a webservice.