bluuebunny/crossref_metadata_2025 huggingface dataset:
The First 100 Seconds of Sleep of rEEGs Can Be a Reliable Scoring Method for D/EE-SWAS
Authors: Kulkarni Neil , Klamer Brett , Drees Michael , Twanow Jaime D.
Published: June 2024

Purpose:

Developmental/epileptic encephalopathy with spike wave activation with sleep, formerly known as electrical status epilepticus in sleep, is an electrographic pattern in which the interictal epileptiform activity is augmented by transition to sleep. Recent studies demonstrate the utility of the first 100 seconds of sleep of long-term monitoring (LTM) as a scoring method for electrical status epilepticus in sleep. Our aim was to measure the reliability of the spike-wave index (SWI) of the first 100 seconds of sleep of routine EEG (rEEG) as a tool for diagnosis of developmental/epileptic encephalopathy with spike wave activation with sleep.

Methods:

Approximately three hundred forty LTMs were reviewed, and 25 studies from 25 unique patients had comparable rEEGs. Two neurophysiologists calculated the SWI of the first 100 seconds of spontaneous stage II non-random eye movement sleep, the first 5-minute bin of sleep, and three separate 5-minute bins throughout sleep in LTM. This was compared to the SWI of the first 100 seconds of sleep in rEEG. Agreement was analyzed using Lin's concordance correlation coefficient (CCC).

Results:

Using 50% as a diagnostic cut-off, we observed moderate agreement between the SWI of the first 100 seconds of sleep of rEEG and three bin LTM (CCC = 0.94, 95% CI: 0.88–0.97). Agreement was slightly higher for the comparison to first bin LTM SWI (CCC = 0.96, 95% CI: 0.92–0.98) and first 100 seconds LTM SWI (CCC = 0.96, 95% CI: 0.92–0.98).

Conclusions:

This study demonstrates the first 100 seconds of sleep of rEEG technique as a time efficient diagnostic tool for patients with concern for developmental/epileptic encephalopathy with spike wave activation with sleep.
The Effect of Remimazolam on Seizure Profile, Hemodynamics, and Recovery in Patients With Electroconvulsive Therapy Comparison With Propofol and Etomidate
Authors: Park Insun , Kim Hyeong Geun , Do Sang-Hwan , Hwang Jung Won , Yoon In-Young , Hong Jung Kyung , Ryu Jung-Hee
Published: June 2024

Objectives

To compare seizure-related, hemodynamic, and recovery outcomes when using remimazolam for ECT with those of other anesthetics, specifically propofol and etomidate.

Methods

A total of 49 patients who underwent 405 ECT treatment sessions under general anesthesia were retrospectively analyzed. Remimazolam, propofol, and etomidate were used for 93, 138, and 174 ECT sessions, respectively. The primary outcome was durations of motor and electroencephalogram (EEG) seizure activity, whereas secondary outcomes included hemodynamics (ie, mean arterial pressure [MAP] and heart rate [HR] at various time points from induction to postanesthesia care unit [PACU] discharge), antihypertensive drugs administration after electrical stimulus, and recovery profiles (ie, length of PACU stay and incidence of postictal confusion).

Results

Durations of motor and EEG seizures were shorter for remimazolam than etomidate (motor, P < 0.001; EEG, P = 0.003) but similar compared with propofol (motor, P = 0.191; EEG, P = 0.850). During seizure, remimazolam showed a comparable MAP and HR to etomidate (MAP: P = 0.806; HR: P = 0.116). The antihypertensive drug use was lowest for remimazolam (6.8%), followed by propofol (35.6%) and etomidate (65.6%), and the mean length of PACU stay was comparable for remimazolam (19.7 min), propofol (22.8 min), and etomidate (24.5 min). The occurrence of postictal confusion did not differ among the 3 agents (P > 0.050).

Conclusions

Remimazolam is a promising anesthetic option for ECT because of its comparable seizure profiles, stable hemodynamics, and comparable PACU stay when compared with propofol and etomidate without additional adverse events.
Activity-dependent diffusion trapping of AMPA receptors as a key step for expression of early LTP
Authors: Nowacka Agata , Getz Angela M. , Bessa-Neto Diogo , Choquet Daniel
Published: June 2024

This review focuses on the activity-dependent diffusion trapping of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as a crucial mechanism for the expression of early long-term potentiation (LTP), a process central to learning and memory. Despite decades of research, the precise mechanisms by which LTP induction leads to an increase in AMPAR responses at synapses have been elusive. We review the different hypotheses that have been put forward to explain the increased AMPAR responsiveness during LTP. We discuss the dynamic nature of AMPAR complexes, including their constant turnover and activity-dependent modifications that affect their synaptic accumulation. We highlight a hypothesis suggesting that AMPARs are diffusively trapped at synapses through activity-dependent interactions with protein-based binding slots in the post-synaptic density (PSD), offering a potential explanation for the increased synaptic strength during LTP. Furthermore, we outline the challenges still to be addressed before we fully understand the functional roles and molecular mechanisms of AMPAR dynamic nanoscale organization in LTP.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
The
N
-methyl-
d
-aspartate receptor hypothesis of ketamine’s antidepressant action: evidence and controversies
Authors: Jiang Yihao , Dong Yiyan , Hu Hailan
Published: June 2024

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an
N
-methyl-
d
-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine’s NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine’s molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Synaptic correlates of the corticocortical circuit in motor learning
Authors: Kim Yeonjun , Hong Ilgang , Kaang Bong-Kiun
Published: June 2024

Rodents actively learn new motor skills for survival in reaction to changing environments. Despite the classic view of the primary motor cortex (M1) as a simple muscle relay region, it is now known to play a significant role in motor skill acquisition. The secondary motor cortex (M2) is reported to be a crucial region for motor learning as well as for its role in motor execution and planning. Although these two regions are known for the part they play in motor learning, the role of direct connection and synaptic correlates between these two regions remains elusive. Here, we confirm M2 to M1 connectivity with a series of tracing experiments. We also show that the accelerating rotarod task successfully induces motor skill acquisition in mice. For mice that underwent rotarod training, learner mice showed increased synaptic density and spine head size for synapses between activated cell populations of M2 and M1. Non-learner mice did not show these synaptic changes. Collectively, these data suggest the potential importance of synaptic plasticity between activated cell populations as a potential mechanism of motor learning.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins
Authors: Ondrejcak Tomas , Klyubin Igor , Hu Neng-Wei , Yang Yin , Zhang Qiancheng , Rodriguez Brian J. , Rowan Michael J.
Published: June 2024

How the two pathognomonic proteins of Alzheimer’s disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick’s disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Src dependency of the regulation of LTP by alternative splicing of
GRIN1
exon 5
Authors: Li Hongbin , Rajani Vishaal , Sengar Ameet S. , Salter Michael W.
Published: June 2024

Alternative splicing of
Grin1
exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic
N
-methyl-
d
-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of
Grin1
.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Promiscuous involvement of metabotropic glutamate receptors in the storage of
N
-methyl-
d
-aspartate receptor-dependent short-term potentiation
Authors: Ingram Rachael , Volianskis Arturas
Published: June 2024

Short- and long-term forms of
N
-methyl-
d
-aspartate receptor (NMDAR)-dependent potentiation (most commonly termed short-term potentiation (STP) and long-term potentiation (LTP)) are co-induced in hippocampal slices by theta-burst stimulation, which mimics naturally occurring patterns of neuronal activity. While NMDAR-dependent LTP (NMDAR-LTP) is said to be the cellular correlate of long-term memory storage, NMDAR-dependent STP (NMDAR-STP) is thought to underlie the encoding of shorter-lasting memories. The mechanisms of NMDAR-LTP have been researched much more extensively than those of NMDAR-STP, which is characterized by its extreme stimulation dependence. Thus, in the absence of low-frequency test stimulation, which is used to test the magnitude of potentiation, NMDAR-STP does not decline until the stimulation is resumed. NMDAR-STP represents, therefore, an inverse variant of Hebbian synaptic plasticity, illustrating that inactive synapses can retain their strength unchanged until they become active again. The mechanisms, by which NMDAR-STP is stored in synapses without a decrement, are unknown and we report here that activation of metabotropic glutamate receptors may be critical in maintaining the potentiated state of synaptic transmission.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Abundant Parent-of-origin Effect eQTL in Humans: The Framingham Heart Study
Authors: Guan Yongtao , Levy Daniel
Published: June 2024

Parent-of-origin effect (POE) is a phenomenon whereby an allele’s effect on a phenotype depends both on its allelic identity and parent from whom the allele is inherited, as exemplified by the polar overdominance in the ovine callypyge locus and the human obesityDLK1locus. Systematic studies of POE of expression quantitative trait loci (eQTL) are lacking. In this study we use trios among participants in the Framingham Heart Study to examine to what extend POE exists for gene expression of whole blood using whole genome sequencing and RNA sequencing. For each gene and the SNPs in cis, we performed eQTL analysis using genotype, paternal, maternal, and joint models, where the genotype model enforces the identical effect sizes on paternal and maternal alleles, and the joint model allows them to have different effect sizes. We compared models using Bayes factors to identify paternal, maternal, and opposing eQTL, where paternal and maternal effects have opposite directions. The resultant variants are collectively called POE eQTL. The highlights of our study include: 1) There are more than 2, 000 genes harbor POE eQTL and majority POE eQTL are not in the vicinity of known imprinted genes; 2) Among 180 genes harboring opposing eQTL, 99 harbor exclusively opposing eQTL, and 58 of the 99 are phosphoprotein coding genes, reflecting significant enrichment; 3) Paternal eQTL are enriched with GWAS hits, and genes harboring paternal eQTL are enriched with drug targets. Our study demonstrates the abundance of POE in gene expression, illustrates the complexity of gene expression regulation, and provides a resource that is complementary to existing resources such as GTEx. We revisited two previous POE findings in light of our POE results. A SNP residing inKCNQ1that is maternally associated with diabetes is a maternal eQTL ofCDKN1C, notKCNQ1. A SNP residing inDLK1that showed paternal polar overdominance for human obesity is a maternal eQTL ofMEG3, offering an explanation for the baseline risk of homozygous samples through association betweenMEG3expression and obesity. Finally, we advised caution on conducting Mendelian randomization using gene expression as the exposure.
Bridging the Gap: biofilm-mediated establishment ofBacillus velezensisonTrichoderma guizhouensemycelia
Authors: Xie Jiyu , Sun Xinli , Xia Yanwei , Tao Lili , Tan Taimeng , Zhang Nan , Xun Weibing , Zhang Ruifu , Kovács Ákos T. , Xu Zhihui , Shen Qirong
Published: June 2024

Bacterial-fungal interactions (BFIs) are important in ecosystem dynamics, especially within the soil rhizosphere. The bacteriumBacillus velezensisSQR9 and the fungusTrichoderma guizhouenseNJAU 4742 have garnered considerable attention due to their roles in promoting plant growth and protecting their host against pathogens. In this study, we utilized these two model microorganisms to investigate BFI. We firstly demonstrate that while co-inoculation ofB. velezensisandT. guizhouensecould promote tomato growth, these two microorganisms display mutual antagonism on agar solidified medium. To resolve this contradiction, we developed an inoculation method, that allowsB. velezensiscolonization ofT. guizhouensehyphae and performed a transcriptome analysis. During colonization of the fungal hyphae,B. velezensisSQR9 upregulates expression of biofilm related genes (e.g.eps, tasA, andbslA)that is distinct from free-living cells. This result suggested an intricate association between extracellular matrix expression and hyphae colonization. In accordance, deletionepsD, tasA, orbothepsDandtasAgenes ofB. velezensisdiminished colonization of theT. guizhouensehyphae. The insights from our study demonstrate that soil BFIs are more complex than we understood, potentially involving both competition and cooperation. These intricate biofilm-mediated BFI dynamics might contribute to the remarkable diversity observed within soil microbiota, providing a fresh perspective for further exploration of BFIs in the plant rhizosphere.
Multi-strain carriage and intrahost diversity ofStaphylococcus aureusamong Indigenous adults in the US
Authors: Webb Julia , Cella Eleonora , Sutcliffe Catherine , Johnston Catherine , Hassouneh Sayf Al-Deen , Jubair Mohammad , Riley Dennie Parker , Tso Carol , Weatherholtz Robert C. , Hammitt Laura L. , Azarian Taj
Published: June 2024

Staphylococcus aureus(SA) is an opportunistic pathogen and human commensal that is frequently present in the upper respiratory tract, gastrointestinal tract, and on the skin. While SA can cause disease ranging from minor skin infections to life-threatening bacteremia, it can also be carried asymptomatically. Indigenous individuals in the Southwest United States experience high rates of invasive SA disease. As carriage is the most significant risk factor for disease, understanding the dynamics of SA carriage, and in particular co-carriage of multiple strains, is important to develop strategies to prevent transmission in vulnerable communities. Here we investigated SA co-carriage and intrahost evolution by performing high density sampling from multiple anatomical sites and whole-genome sequencing (WGS) on 310 SA isolates collected from 60 Indigenous adults participating in a cross-sectional carriage study. We assessed the richness and diversity of SA isolates via differences in multi-locus sequence type (MLST), core-genome single-nucleotide-polymorphisms (SNPs), and genome content. Using WGS data, we identified 95 distinct SA populations among 60 participants; co-carriage was detected in 42% (25/60). Notably, two participants each carried four distinct SA strains. Variation in antibiotic resistance determinants among carried strains was identified among 42% (25/60) of participants. Lastly, we found unequal distribution of clonal complex by body site, suggesting that certain lineages may be adapted to specific anatomical sites. Together, these findings suggest that co-carriage may occur more frequently than previously appreciated and further our understanding of SA intrahost diversity during carriage, which has implications for surveillance activities and epidemiological investigations.
Evaluating the Diagnostic Accuracy of Anti- Zinc Transporter 8 Antibodies in Type 1 Diabetes: A Systematic Review and Meta-Analysis
Authors: de Oliveira Andrade Luís Jesuíno , de Oliveira Gabriela Correia Matos , Rocha Roseanne Montargil , Vinhaes Bittencourt Alcina Maria , David Túlio Matos , Matos de Oliveira Luís
Published: June 2024

Background

The association between autoantibodies and the risk of type 1 diabetes mellitus (T1DM) is well established. However, there is still a lack of quantitative insight into the role of anti-zinc transporter 8 (anti-ZnT8) antibodies and their efficacy in T1DM diagnosis.

Objective

To conduct a systematic review and meta-analysis on the association between anti-ZnT8 autoantibodies and the risk of T1DM.

Methods

Relevant studies were retrieved from the PubMed database and analyzed using a fixed or random-effects model.

Results

Out of 211 screened articles, 23 studies were selected and a total of 14,172 patients were included in the analysis. Our pooled analysis revealed that anti-ZnT8 autoantibody expression was significantly associated with an increased risk of T1DM development in both children and adults [OR 1.14 (95% CI: 1.12-1.16); P = 0.07].

Conclusion

Our systematic review and meta-analysis provides robust evidence supporting a significant association between anti-ZnT8 autoantibody positivity and an increased risk of T1DM development.
nipalsMCIA: Flexible Multi-Block Dimensionality Reduction in R via Non-linear Iterative Partial Least Squares
Authors: Mattessich Max , Reyna Joaquin , Aron Edel , Ay Ferhat , Kilmer Misha , Kleinstein Steven H. , Konstorum Anna
Published: June 2024

Motivation

With the increased reliance on multi-omics data for bulk and single cell analyses, the availability of robust approaches to perform unsupervised analysis for clustering, visualization, and feature selection is imperative. Joint dimensionality reduction methods can be applied to multi-omics datasets to derive a global sample embedding analogous to single-omic techniques such as Principal Components Analysis (PCA). Multiple co-inertia analysis (MCIA) is a method for joint dimensionality reduction that maximizes the covariance between block- and global-level embeddings. Current implementations for MCIA are not optimized for large datasets such such as those arising from single cell studies, and lack capabilities with respect to embedding new data.

Results

We introducenipalsMCIA, an MCIA implementation that solves the objective function using an extension to Non-linear Iterative Partial Least Squares (NIPALS), and shows significant speed-up over earlier implementations that rely on eigendecompositions for single cell multi-omics data. It also removes the dependence on an eigendecomposition for calculating the variance explained, and allows users to perform out-of-sample embedding for new data.nipalsMCIAprovides users with a variety of pre-processing and parameter options, as well as ease of functionality for down-stream analysis of single-omic and global-embedding factors.

Availability

nipalsMCIAis available as a BioConductor package athttps://bioconductor.org/packages/release/bioc/html/nipalsMCIA.html, and includes detailed documentation and application vignettes. Supplementary Materials are available online.
Spatial self-organization of cancer stem cell niches revealed by live single-cell imaging
Authors: Brulé Mathilde , Horochowska Anaïs , Fontaine Emeline , Torero-Ibad Raoul , Woesteland Flavie , Denoulte Marie , Pesez Jean , Adriaenssens Eric , Toillon Robert-Alain , Le Bourhis Xuefen , Pfeuty Benjamin , Lagadec Chann , Anquez François
Published: June 2024

Phenotypic plasticity is a major factor of tumor heterogeneity and treatment resistance. In particular, cancer stem cells (CSCs) represent a small subpopulation within tumors with self-renewal and tumor-forming capabilities. Understanding reprogramming, maintenance, and lineage properties of CSCs requires dedicated tools to disentangle the respective influences of phenotypic inheritance and cell-cell interactions. Here we set up ultra-wide field microscopy of breast cancer cell lines expressing a stemness fluorescent reporter for several days. The fluorescent reporter distinguishes three phenotypes: cancer stem cells (CSCs), cancer differentiated cells (CDCs) and intermediate/transiting cancer cells (iCCs). Spatial statistics indicate significant zonation, aka phenotypic niches, with CSC clustering near each other but away from CDCs. Surprisingly, single cell time series reveal spontaneous reprogramming events from CDC to CSC even in unperturbed populations. We identify that such transitions are prone to arise during the cell cycle. Moreover, lineage analysis shows that the phenotype is partially inherited from ancestor cells. However, such heredity is not sufficient to explain the spatial properties of the cell population, which also depend on cell-cell interactions. Indeed, we identified that phenotypic transitions of cancer cells are influenced by the phenotypic state of neighboring cells. Reprogramming into CSCs is respectively promoted and inhibited by the presence of CSCs and CDCs in the neighborhood. Altogether, our results disentangle how phenotypic inheritance and intercellular interactions orchestrate the spatio-temporal self-organization of cancer cell heterogeneity, maintaining a subpopulation of CSCs within niches.
Development of self-healing hydrogels to support choroidal endothelial cell transplantation for the treatment of early age related macular degeneration
Authors: Pandala Narendra , Han Ian , Tobin Kevin , Brogden Nicole , Mulfaul Kelly , Mullins Robert , Tucker Budd
Published: June 2024

In retinal diseases such as age-related macular degeneration (AMD) and choroideremia, a key pathophysiologic step is loss of endothelial cells of the choriocapillaris, the dense vascular bed required for maintaining health and function of the retina. As such, repopulation of choroidal vasculature early in the disease process may halt disease progression. Prior studies have shown that injection of donor cells in suspension results in significant cellular efflux and poor cell survival. As such, the goal of this study was to develop a hydrogel system designed to support CEC transplantation. A library of hydrogels was synthesized using laminin (i.e., LN111, LN121, and LN421), carboxy methyl chitosan, and oxidized dextran via reversible Schiff base chemistry. Each of the developed hydrogels was readily injectable into the suprachoroidal space, with excellent gelation, mechanical, and degradation properties. Laminin-based hydrogels were compatible with immortalized CEC survival in vitro, and suprachoroidal injection of LN111 and LN121 containing gels were well-tolerated in an in vivo rat model, whereas LN421 containing gels caused significant chorioretinal inflammation. Hydrogels were detected in the suprachoroidal space of immunosuppressed rats at 1-week post-injection and were completely resorbed by 1-month post-injection. There were significantly more CECs retained in immunosuppressed rats that received cell laden hydrogels than those that received unsupported cell suspensions (i.e., CECs only). These findings pave the way for future CEC replacement studies in animal models of choroidal cell loss toward the development of future therapies.

Statement of significance

Age related macular degeneration (AMD) is a leading cause of untreatable blindness in the industrial world. A key pathologic step in AMD is loss of the choriocapillaris endothelial cells, which provide vascular support to the overlying retina, including the light-sensing photoreceptors. We believe that choroidal cell replacement early in disease may prevent retinal cell death and subsequent vision loss. In this study, we present a strategy for repopulating the choriocapillaris using choroidal endothelial cell laden hydrogels. Specifically, we demonstrate the synthesis and characterization of 3 different laminin-based hydrogel systems. LN111 and LN121 hydrogels were found to increase retention of choroidal endothelial cells following suprachoroidal transplantation. These findings pave the way for future cell replacement studies in animal models of choroidal cell dropout.
Playbook Workflow Builder: Interactive Construction of Bioinformatics Workflows from a Network of Microservices
Authors: Clarke Daniel J.B. , Evangelista John Erol , Xie Zhuorui , Marino Giacomo B. , Maurya Mano R. , Srinivasan Sumana , Yu Keyang , Petrosyan Varduhi , Roth Matthew E. , Milinkov Miroslav , King Charles Hadley , Vora Jeet Kiran , Keeney Jonathon , Nemarich Christopher , Khan William , Lachmann Alexander , Ahmed Nasheath , Jenkins Sherry L. , Agris Alexandra , Pan Juncheng , Ramachandran Srinivasan , Fahy Eoin , Esquivel Emmanuel , Mihajlovic Aleksandar , Jevtic Bosko , Milinovic Vuk , Kim Sean , McNeely Patrick , Wang Tianyi , Wenger Eric , Brown Miguel A. , Sickler Alexander , Zhu Yuankun , Blood Philip D. , Taylor Deanne M. , Resnick Adam C. , Mazumder Raja , Milosavljevic Aleksandar , Subramaniam Shankar , Ma’ayan Avi
Published: June 2024

Many biomedical research projects produce large-scale datasets that may serve as resources for the research community for hypothesis generation, facilitating diverse use cases. Towards the goal of developing infrastructure to support the findability, accessibility, interoperability, and reusability (FAIR) of biomedical digital objects and maximally extracting knowledge from data, complex queries that span across data and tools from multiple resources are currently not easily possible. By utilizing existing FAIR application programming interfaces (APIs) that serve knowledge from many repositories and bioinformatics tools, different types of complex queries and workflows can be created by using these APIs together. The Playbook Workflow Builder (PWB) is a web-based platform that facilitates interactive construction of workflows by enabling users to utilize an ever-growing network of input datasets, semantically annotated API endpoints, and data visualization tools contributed by an ecosystem. Via a user-friendly web-based user interface (UI), workflows can be constructed from contributed building-blocks without technical expertise. The output of each step of the workflows are provided in reports containing textual descriptions, as well as interactive and downloadable figures and tables. To demonstrate the ability of the PWB to generate meaningful hypotheses that draw knowledge from across multiple resources, we present several use cases. For example, one of these use cases sieves novel targets for individual cancer patients using data from the GTEx, LINCS, Metabolomics, GlyGen, and the ExRNA Communication Consortium (ERCC) Common Fund (CF) Data Coordination Centers (DCCs). The workflows created with the PWB can be published and repurposed to tackle similar use cases using different inputs. The PWB platform is available from:https://playbook-workflow-builder.cloud/.
Neuroimage Denoiser - a Deep Learning Framework for Removing Noise from Transient Fluorescent Signals in Functional Imaging
Authors: Weißbach Stephan , Borghi Michela , Milkovits Jonas , Amaral Carolina , El Khallouqi Abderazzaq , Gerber Susanne , Heine Martin
Published: June 2024

We developed Neuroimage Denoiser, a novel U-Net-based model that effectively removes noise from microscopic recordings of transient local fluorescent signals. The model makes the denoising process independent of the recording frequency and the kinetics of the sensor used. The framework is easy to use for denoising and training and has minimal hardware requirements, thus, making it accessible for an average laboratory to create a custom version specific to their experimental setup. Neuroimage Denoiser significantly enhances the quality of functional microscopy recordings by effectively removing noise, thereby facilitating a more accurate and reliable analysis of neural activity.

Highlights

-

Neuroimage Denoiser is a deep learning framework to remove noise from functional microscopic recordings, particularly trained and tested for glutamate imaging

-

Neuroimage Denoiser balances the removal of noise while preserving the amplitude of responses

-

Neuroimage Denoiser operates without re-training for different sensors (when the localization is similar) and recording frequencies

Motivation

Accurate measurements of neuronal activity through functional imaging are critical in understanding mechanisms of synaptic plasticity and learning concerning changes in the molecular composition of single synapses. Traditional denoising methods, such as Gaussian or Median filters, indiscriminately smooth entire recordings, reducing temporal and spatial resolutions considerably. Existing frameworks are not suited to remove noise from glutamate recordings due to the fast dynamics of the sensor. Therefore, a specialized tool for the challenges imposed by glutamate recordings, i.e. faster dynamics, and synaptic localization, is needed.
SpaDE: Semantic Locality Preserving Biclustering for Neuroimaging Data
Authors: Rahaman Md Abdur , Fu Zening , Iraji Armin , Calhoun Vince
Published: June 2024

The most discriminative and revealing patterns in the neuroimaging population are often confined to smaller subdivisions of the samples and features. Especially in neuropsychiatric conditions, symptoms are expressed within micro subgroups of individuals and may only underly a subset of neurological mechanisms. As such, running a whole-population analysis yields suboptimal outcomes leading to reduced specificity and interpretability. Biclustering is a potential solution since subject heterogeneity makes one-dimensional clustering less effective in this realm. Yet, high dimensional sparse input space and semantically incoherent grouping of attributes make post hoc analysis challenging. Therefore, we propose a deep neural network called semantic locality preserving auto decoder (SpaDE), for unsupervised feature learning and biclustering. SpaDE produces coherent subgroups of subjects and neural features preserving semantic locality and enhancing neurobiological interpretability. Also, it regularizes for sparsity to improve representation learning. We employ SpaDE on human brain connectome collected from schizophrenia (SZ) and healthy control (HC) subjects. The model outperforms several state-of-the-art biclustering methods. Our method extracts modular neural communities showing significant (HC/SZ) group differences in distinct brain networks including visual, sensorimotor, and subcortical. Moreover, these biclustered connectivity substructures exhibit substantial relations with various cognitive measures such as attention, working memory, and visual learning.
Easy-to-set-up image analysis characterizes phenotypic diversity in the growth of mushroom-forming fungusSchizophyllum commune
Authors: Matsumae Hiromi , Sudo Megumi , Imanishi Tadashi , Hosoya Tsuyoshi
Published: June 2024

Schizophyllum commune, a common wood-decay mushroom known for its extremely high genetic diversity and as a rare cause of human respiratory diseases, could be a promising model fungus contributing to both biology and medicine. To better understand its phenotypic diversity, we developed an image analysis system that quantifies whole morphological traits of mycelia in Petri dishes. This study evaluated growth of six wild and one clinical isolates of JapaneseS. commune, subjected to different temperatures and glucose concentrations, including a condition mimicking the human respiratory environment. Our analysis revealed that combinations of two growth indices, area and whiteness, highlighted strain-specific responses, with profiling growth patterns using clustering algorithms. Notably, the clinical isolate exhibited the strongest whiteness under the respiratory-like condition. We also found that the growth rate was strongly determined by glucose concentration, while the effects of temperature on growth varied among the strains, suggesting that while glucose preference is common in this species, responses to temperature differ between strains. Our results suggest that the system possesses sufficient sensitivity to detect growth traits of mycelia. This study provides a key to unravelling unknown traits behind the high polymorphisms inS. commune, including the ability to colonize the human respiratory tract.
Multicenter Analysis on Morbidity, Mortality, and Medical Care in Neonates at the Hospital Gineco Obstétrico Isidro Ayora, Hospital General Docente de Calderón, and Hospital Gineco Obstétrico Pediátrico de Nueva Aurora Luz Elena Arismendi, January 2008 - June 2024, Quito-Ecuador (clinical research design protocol)
Authors: Vasco-Morales Santiago , Yánez Valencia Mercedes Elina , Toapanta-Pinta Paola
Published: June 2024

Introduction

In 1983, the Latin American Center for Perinatology/Women’s Health and Reproductive Health published the Perinatal Information System, which records perinatal information of the mother and newborn. At the Isidro Ayora Gynecological Obstetric Hospital, there has been an electronic record of this database since 2008. In 2016, the Ministry of Public Health adapted and added registration variables to this medical history. Similarly, at the General Teaching Hospital of Calderón and the Pediatric Gynecological Obstetric Hospital of Nueva Aurora Luz Elena Arismendi, there are records of neonatal care such as neonatal anthropometry, perinatal risk factors, admission diagnoses, and length of hospital stay. These variables can be integrated with the database of the Isidro Ayora Gynecological Obstetric Hospital.

Objectives

Analyze the variables of the perinatal clinical history to identify factors associated with changes in fetal-neonatal morbidity and mortality.

Methods

Descriptive, analytical, observational study using secondary sources. Frequentist and Bayesian statistical analyses will be applied. To determine the association between qualitative variables, the Chi-square test and logistic regression models will be used. The t-test and linear regression will be used to analyze numerical variables. Statistical significance will be set at p<0.05, and Odds Ratios with a 95% confidence interval will be calculated. Neonatal growth curves stratified by sex and gestational age will be developed. The statistical program R will be used.

Expected Results

The characteristics of the population served in the hospitals in the north, central, and south of Quito, as well as the demographic and obstetric data of the mothers and their neonates, will be known. Perinatal characteristics associated with an increase or decrease in neonatal morbidity and mortality will be identified. Trends in maternal and child health will be detected and compared with national and international standards.
Needle-Plug/Piston-Based Modular Mesoscopic Design Paradigm Coupled with Microfluidic Device for Large-scale Point-of-Care Pooled Testing
Authors: Lin Baobao , Li Bao , Zeng Wu , Zhao Yulan , Li Huiping , Gu Yin , Liu Peng
Published: June 2024

Emerging diagnostic scenarios, such as population surveillance by pooled testing and on-site rapid diagnosis, highlight the importance of advanced microfluidic systems for in vitro diagnostics. However, the widespread adoption of microfluidic technology faces challenges due to the lack of standardized design paradigms, posing difficulties in managing macro-micro fluidic interfaces, reagent storage, and complex macrofluidic operations. This paper introduces a novel modular-based mesoscopic design paradigm, featuring a core “needle-plug/piston” structure with versatile variants for complex fluidic operations. These structures can be easily coupled with various microfluidic platforms to achieve truly self-contained microsystems. Incorporated into a “3D extensible” design architecture, the mesoscopic design meets the demands of function integration, macrofluid manipulations, and flexible throughputs for point-of-care nucleic acid testing. Using this approach, we developed an ultra-sensitive nucleic acid detection system with a limit of detection of 10 copies of SARS-CoV-2 per mL. This system efficiently conducts large-scale pooled testing from 50 pharyngeal swabs in a tube with an uncompromised sensitivity, enabling a truly “sample-in-answer-out” microsystem with exceptional performance.
Service availability, readiness and health-seeking behavior of gender based violence survivor services in primary healthcare facilities in Dodoma, Tanzania. An Explanatory-sequential study design
Authors: Mwamasangula Johnson W. , Gibore Nyasiro S.
Published: June 2024

Background

The health sector is a key stakeholder in GBV national response network however, delivery of quality healthcare services for GBV survivors is highly neglected.

Methods

This study will use a mixed-research approach by employing an explanatory sequential study design. Phase one will involve a cross-sectional survey of 61 primary healthcare facilities to examine availability and readiness of GBV survivor’s services. The second phase will involve a descriptive qualitative study among healthcare providers, community healthcare workers and clients to examine the health-seeking behavior and challenges in providing and receiving GBV survivor’s services in primary healthcare facilities. The study will be conducted between March-April 2024 in Dodoma City Council, Tanzania.

Discussion

This study will have potential implications to program managers, policy makers and healthcare providers to tailor interventions that will improve the quality of healthcare service delivery especially towards integrated GBV survivor’s services. But also, understanding the health-seeking behavior and challenges associated with access and provision of GBV survivor’s services will help unveiling gaps in the clients’ point of view and the community, their needs for the GBV survivor’s services and enhancing client-healthcare provider relationship.
Effects of selection stringency on the outcomes of directed evolution
Authors: Alpay Berk A. , Desai Michael M.
Published: June 2024

Directed evolution makes mutant lineages compete in climbing complicated sequence-function landscapes. Given this underlying complexity it is unclear how selection stringency, a ubiquitous parameter of directed evolution, impacts the outcome. Here we approach this question in terms of the fitnesses of the candidate variants at each round and the heterogeneity of their distributions of fitness effects. We show that even if the fittest mutant is most likely to yield the fittest mutants in the next round of selection, diversification can improve outcomes by sampling a larger variety of fitness effects. We find that heterogeneity in fitness effects between variants, larger population sizes, and evolution over a greater number of rounds all encourage diversification.
Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System
Authors: Kurapati Sravya , Shin Changsik , Szabo Krisztina , Liu Yu , Ashraf Azree Zaffran , Koscso Balazs , Dash Chinmayee , Navarro Leonardo , Saha Monalee , Nagaraj Sushma , Wang Wenhui , Zhu Jun , Shulzhenko Natalya , Baer Christina E. , Srinivasan Shanthi , Kulkarni Subhash , Pasricha Pankaj Jay , Peters Lauren A. , Bogunovic Milena
Published: June 2024

The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology, including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2+monocytes into the neural myenteric plexus within the intestinal muscle. This is followed by the expansion of monocyte-derived macrophages and their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes results in disproportionate ENS remodeling and PI-GID. The expansion of inflammatory cells is known to promote tissue hypoxia. We find that enteric neurons become hypoxic upon colitis, but hypoxia-induced signaling via HIF1α initiates an adaptation program in enteric neurons to attenuate CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1α signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and protecting against ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention.

One Sentence Summary

Intestinal mucosal inflammation engages enteric neurons in the inflammatory response leading to neurogenic recruitment of monocytes into the extra-mucosal myenteric plexus followed by pathological structural remodeling of the enteric nervous system by monocyte-derived macrophages.
WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling
Authors: Jaykumar Ankita B. , Binns Derk , Taylor Clinton A. , Anselmo Anthony , Birnbaum Shari G. , Huber Kimberly M. , Cobb Melanie H.
Published: June 2024

Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhancesin vivohippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.
The zebrafish as a new model for studying chaperone-mediated autophagy unveils its role in spermatogenesis
Authors: Goguet Maxime , Vélez Emilio J , Schnebert Simon , Dias Karine , Véron Vincent , Depincé Alexandra , Beaumatin Florian , Herpin Amaury , Seiliez Iban
Published: June 2024

Chaperone-Mediated Autophagy (CMA) is a major pathway of lysosomal proteolysis involved in numerous cellular processes, and whose dysfunction is associated to several pathologies. Initially studied in mammals and birds, recent findings have identified CMA in fish, reshaping our understanding of its evolution across metazoans. Given the exciting perspectives this finding offered, we have now developed the required tools to investigate and functionally asses that CMA function in a powerful fish genetic model: the zebrafish (Danio rerio). After adapting and validating a fluorescent reporter (KFERQ-Dendra2; previously used to track CMA in mammalian cells) in zebrafish primary embryonic cells, we first demonstrated CMA functionality in this fish species. Then, we developed a transgenic zebrafish line expressing the KFERQ-Dendra2 CMA reporter, enabling the real-time tracking of CMA activityin vivo. This model revealed heterogeneous CMA responses within tissues, highlighting the zebrafish as a valuable model for investigating tissue-specific and cell-scale variations in CMA. Moreover, a novel role for CMA has been uncovered, acting as a gatekeeper of sperm cell proteostasis, thereby playing a crucial role in the production of active and high-quality spermatozoa. Overall, these findings emphasize the zebrafish as a pivotal model for advancing our comprehension of the fundamental mechanisms underlying CMA.
A Nonsecretory Antimicrobial Peptide Mediates Inflammatory Organ Damage inDrosophilaRenal Tubules
Authors: Oi Ayano , Nagashima Shun , Shinoda Natsuki , Miura Masayuki , Obata Fumiaki
Published: June 2024

An excessive immune response damages organs, yet its molecular mechanism is incompletely understood. In this study, we usedDrosophilarenal tubules as a model to screen a factor mediating organ damage upon genetic activation of an innate immune Imd signalling pathway. We identified an antimicrobial peptide, Attacin-D (AttD), which causes organ damage upon Imd activation in the Malpighian tubules. Loss of AttD function suppresses most of the pathological phenotypes induced by Imd activation, such as cell death, compensatory stem cell proliferation, bloating of whole animal, susceptibility to a high salt diet, elevation of purine levels, and mortality, without compromising the immune activation. AttD is required for the immune-induced damage specifically in the Malpighian tubules but not the midgut. Interestingly, AttD uniquely lacks the signal peptide and is not secreted out from cells. Suppression of AttD almost completely attenuates mortality induced by gut tumour-induced immune activation. Our study elucidates the mechanistic effector of immune-induced organ damage.