bluuebunny/crossref_metadata_2025 huggingface dataset:
Food web context modifies predator foraging and weakens trophic interaction strength
Authors: Lemmen Kimberley D. , Pennekamp Frank
Published: March 2024

Trophic interaction modifications (TIM) are widespread in natural systems and occur when a third species indirectly alters the strength of a trophic interaction. Past studies have focused on documenting the existence and relative magnitude of TIMs, however the underlying processes and long-term consequences often remain elusive. To address this gap, we experimentally quantified the density-dependent effect of a third species on a predator’s functional response to identify the processes impacted by, and consequences of TIMs. To do so we conducted short-term experiments with two ciliate communities each composed of a predator, prey, and non-consumable ‘modifier’ species. In both communities, increasing modifier density weakened the trophic interaction strength, due to a negative effect on the predator’s search clearance rate, however the magnitude of the effect differed with prey species identity. Using parameters estimated from our experimental observation we simulated long-term dynamics and observed quantitative differences between models that account for TIMs or include only pairwise interactions. Our study is a clear demonstration that TIMs are important to understand and predict community dynamics and highlights the need to extend past pairs of focal species to understand the consequences of species interactions in communities.
Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges
Authors: Zhang Weigao , Liu Hu , Zhang Danyang , Yi Yuguo , Tao Liang , Huang Shuxian , Zhao Xunan , Shao Qianchao , Li Peiqi , Zhang Jianfa , Pan Yan , Lu Wei , Zhang Haibing , Chen Yuxin , Weng Dan
Published: March 2024

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1Δhep) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state inRipk1Δhepmice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver ofRipk1Δhepmice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury inRipk1Δhepmice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
Foundations of visual form selectivity in macaque areas V1 and V2
Authors: Oleskiw Timothy D. , Lieber Justin D. , Simoncelli Eero P. , Movshon J. Anthony
Published: March 2024

Neurons early in the primate visual cortical pathway generate responses by combining signals from other neurons: some from downstream areas, some from within the same area, and others from areas upstream. Here we develop a model that selectively combines afferents derived from a population model of V1 cells. We use this model to account for responses we recorded of both V1 and V2 neurons in awake fixating macaque monkeys to stimuli composed of a sparse collection of locally oriented features (“droplets”) designed to drive subsets of V1 neurons. The first stage computes the rectified responses of a fixed population of oriented filters at different scales that cover the visual field. The second stage computes a weighted combination of these first-stage responses, followed by a final nonlinearity, with parameters optimized to fit data from physiological recordings and constrained to encourage sparsity and locality. The fitted model accounts for the responses of both V1 and V2 neurons, capturing an average of 43% of the explainable variance for V1 and 38% for V2. The models fitted to droplet recordings predict responses to classical stimuli, such as gratings of different orientations and spatial frequencies, as well as to textures of different spectral content, which are known to be especially effective in driving V2. The models are less effective, however, at capturing the selectivity of responses to textures that include naturalistic image statistics. The pattern of afferents — defined by their weights over the 4 dimensions of spatial position, orientation, and spatial frequency — provides a common and interpretable characterization of the origin of many neuronal response properties in the early visual cortex.
Exploring the molecular structure of lipids in the design of artificial lipidated antifungal proteins
Authors: Saputra Hendra , Safaat Muhammad , Santoso Pugoh , Wakabayashi Rie , Goto Masahiro , Taira Toki , Kamiya Noriho
Published: March 2024

Fungal infections have been a concern for decades, yet effective and approved antifungal agents are limited. We recently developed a potential method to enhance the antifungal activity of a small chitin-binding domain (LysM) from Pteris ryukyuensis chitinase A (PrChiA) by the site-specific introduction of a palmitoyl (C16) group catalyzed by microbial transglutaminase (MTG). Herein, we attempted the conjugation of a series of lipid-peptide substrates with LysM genetically fused with a C-terminal MTG-reactive Q-tag (LysM-Q) to yield LysM-lipid conjugates (LysM-lipids) with different lengths (LysM-C12, -C14, and -C16) and different numbers of alkyl chains [LysM-(C12)2, - (C14)2, and -(C16)2]. The enzymatic conjugation proceeded smoothly for all LysM-lipids, except for LysM-(C16)2because of the low aqueous dispersibility of the hydrophobic (C16)2lipid-peptide substrate. The combination of amphotericin B (AmB) with LysM-C14 or LysM-C16 exhibited the highest antifungal performance against Trichoderma viride whereas alterations in the number of alkyl chains were not effective in enhancing the antifungal activity of the LysM-lipids. Fluorescent microscopic analysis showed that the fungal cell wall was stained with C14- and C16-modified LysM-muGFP fusion proteins when combined with AmB, suggesting a synergistic action of AmB and LysM-lipids with a suitable lipid length. All LysM-lipids showed minimum cytotoxicity toward mammalian cells, suggesting that LysM-lipids could be a safe additive in the development of new antifungal formulations.
Sarm1 is not necessary for activation of neuron-intrinsic growth programs yet required for the Schwann cell repair response and peripheral nerve regeneration
Authors: Schmitd Ligia B. , Hafner Hannah , Ward Ayobami , Adib Elham Asghari , Biscola Natalia P. , Kohen Rafi , Patel Manav , Williamson Rachel E. , Desai Emily , Bennett Julianna , Saxman Grace , Athaiya Mitre , Wilborn David , Shumpert Jaisha , Zhao Xiao-Feng , Kawaguchi Riki , Geschwind Daniel H. , Hoke Ahmet , Shrager Peter , Collins Catherine A. , Havton Leif A. , Kalinski Ashley L. , Giger Roman J.
Published: March 2024

Upon peripheral nervous system (PNS) injury, severed axons undergo rapid SARM1-dependent Wallerian degeneration (WD). In mammals, the role of SARM1 in PNS regeneration, however, is unknown. Here we demonstrate thatSarm1is not required for axotomy induced activation of neuron-intrinsic growth programs and axonal growth into a nerve crush site. However, in the distal nerve,Sarm1is necessary for the timely induction of the Schwann cell (SC) repair response, nerve inflammation, myelin clearance, and regeneration of sensory and motor axons. InSarm1-/-mice, regenerated fibers exhibit reduced axon caliber, defective nerve conduction, and recovery of motor function is delayed. The growth hostile environment ofSarm1-/-distal nerve tissue was demonstrated by grafting ofSarm1-/-nerve into WT recipients. SC lineage tracing in injured WT andSarm1-/-mice revealed morphological differences. In theSarm1-/-distal nerve, the appearance of p75NTR+, c-Jun+ SCs is significantly delayed.Ex vivo, p75NTRand c-Jun upregulation inSarm1-/-nerves can be rescued by pharmacological inhibition of ErbB kinase. Together, our studies show thatSarm1is not necessary for the activation of neuron intrinsic growth programs but in the distal nerve is required for the orchestration of cellular programs that underlie rapid axon extension.
Long-read sequencing and genome assembly of natural history collection samples and challenging specimens
Authors: Bein Bernhard , Chrysostomakis Ioannis , Arantes Larissa , Brown Tom , Gerheim Charlotte , Schell Tilman , Schneider Clement , Leushkin Evgeny , Chen Zeyuan , Sigwart Julia , Gonzalez Vanessa , Wong Leena , Santos Fabricio , Blom Mozes , Mayer Frieder , Mazzoni Camila , Boehne Astrid , Winkler Sylke , Greve Carola , Hiller Michael
Published: March 2024

Museum collections harbor millions of samples, largely unutilized for long-read sequencing. Here, we use ethanol-preserved samples containing kilobase-sized DNA to show that amplification-free protocols can yield contiguous genome assemblies. Additionally, using a modified amplification-based protocol, employing an alternative polymerase to overcome PCR bias, we assembled the 3.1 Gb maned sloth genome, surpassing the previous 500 Mb protocol size limit. Our protocol also improves assemblies of other difficult-to-sequence molluscs and arthropods, including millimeter-sized organisms. By highlighting collections as valuable sample resources and facilitating genome assembly of tiny and challenging organisms, our study advances efforts to obtain reference genomes of all eukaryotes.
Beyond homogeneity: Charting the landscape of heterogeneity in psychiatric electroencephalography
Authors: Ebadi Aida , Allouch Sahar , Mheich Ahmad , Tabbal Judie , Kabbara Aya , Robert Gabriel , Lefebvre Aline , Iftimovici Anton , Rodríguez-Herreros Borja , Chabane Nadia , Hassan Mahmoud
Published: March 2024

Electroencephalography (EEG) has been thoroughly studied for decades in psychiatry research. Yet its integration into clinical practice as a diagnostic/prognostic tool remains unachieved. We hypothesize that a key reason is the underlying patient’s heterogeneity, overlooked in psychiatric EEG research relying on a case-control approach. We combine HD-EEG with normative modeling to quantify this heterogeneity using two well-established and extensively investigated EEG characteristics -spectral power and functional connectivity-across a cohort of 1674 patients with attention-deficit/hyperactivity disorder, autism spectrum disorder, learning disorder, or anxiety, and 560 matched controls. Normative models showed that deviations from population norms among patients were highly heterogeneous and frequency-dependent. Deviation spatial overlap across patients did not exceed 40% and 24% for spectral and connectivity, respectively. Considering individual deviations in patients has significantly enhanced comparative analysis, and the identification of patient-specific markers has demonstrated a correlation with clinical assessments, representing a crucial step towards attaining precision psychiatry through EEG.
AlGrow: a graphical interface for easy, fast and accurate area and growth analysis of heterogeneously colored targets
Authors: McHale Marcus , Sulpice Ronan
Published: March 2024

Image analysis is widely used in plant biology to determine growth rates and other phenotypic characters, with segmentation into foreground and background being a primary challenge. Statistical clustering and learning approaches can reduce the need for user input into this process, though these are computationally demanding, can generalise poorly and are not intuitive to end users. As such, simple strategies that rely on the definition of a range of target colors are still frequently adopted. These are limited by the geometries in color space that are implicit to their definition; i.e. thresholds define cuboid volumes and selected colors with a radius define spheroid volumes. A more comprehensive specification of target color is a hull, in color space, enclosing the set of colors in the image foreground. We developed AlGrow, a software tool that allows users to easily define hulls by clicking on the source image or a three-dimensional projection of its colors. We implemented convex hulls and then alpha-hulls, i.e. a limit applied to hull edge length, to support concave surfaces and disjoint color volumes. AlGrow also provides automated annotation by detecting internal circular markers, such as pot margins, and applies relative indexes to support movement. Analysis of publicly available Arabidopsis image series and metadata demonstrated effective automated annotation and mean Dice coefficients of >0.95 following training on only the first and last images in each series. AlGrow provides both graphical and command line interfaces and is released free and open-source with compiled binaries for the major operating systems.
EDC-3 and EDC-4 Regulate Embryonic mRNA Clearance and Biomolecular Condensate Specialization
Authors: Vidya Elva , Jami-Alahmadi Yasaman , Mayank Adarsh K. , Rizwan Javeria , Xu Jia Ming Stella , Cheng Tianhao , Leventis Rania , Sonenberg Nahum , Wohlschlegel James A. , Vera Maria , Duchaine Thomas F.
Published: March 2024

Animal development is dictated by the selective and timely decay of mRNAs in developmental transitions, but the impact of mRNA decapping scaffold proteins in development is unknown. This study unveils the roles and interactions of the DCAP-2 decapping scaffolds EDC-3 and EDC-4 in the embryonic development ofC. elegans. EDC-3 facilitates the timely removal of specific embryonic mRNAs, includingcgh-1, car-1,andifet-1by reducing their expression, and preventing excessive accumulation of DCAP-2 condensates in somatic cells. We further uncover a novel role for EDC-3 in defining the boundaries between P-bodies, germ granules, and stress granules. Lastly, we show that EDC-4 counteracts EDC-3 and engenders the assembly of DCAP-2 with the GID (CTLH) complex, a ubiquitin ligase involved in maternal-to-zygotic transition (MZT). Our findings support a model wherein multiple RNA decay mechanisms temporally partake in the clearance of maternal and zygotic mRNAs throughout embryonic development.
Targeted Long-Read Bisulfite Sequencing for Promoter Methylation Analysis in Severe Preterm Birth
Authors: Pereyra Silvana , Sardina Angela , Neumann Rita , May Celia , Sapiro Rossana , Bertoni Bernardo , Cappetta Mónica
Published: March 2024

DNA methylation plays a critical role in the dynamics of gene expression regulation and the development of various disorders. Whole-genome bisulfite sequencing can provide single base resolution of CpG methylation levels and is the “gold standard” for DNA methylation quantification, but it also has a high cost. In contrast, targeted sequencing is optimal when focusing on specific candidate regions, while providing sufficient sequencing depth. Here, we present a targeted bisulfite sequencing approach to study the methylation status of regions of interest. We amplify selected regions from bisulfite-treated DNA and sequence them using Nanopore sequencing. In this work, we applied this workflow to candidate gene promoters for severe premature labor in a Latin American population.

We successfully amplified fragments over 1 Kb in length using long PCR conditions for 12 genes that were barcoded per sample and pooled to be sequenced on MinION flow cells. This approach achieved high sequencing depths, ensuring reliable DNAm estimation. We found significant hypomethylation of theMIR155HGgene promoter in severe preterm birth samples, which is concordant with reported gene expression changes.

We demonstrate that combining bisulfite DNA treatment with pooled long-read sequencing is a cost- and time-effective method to evaluate DNAm in several targeted regions and several samples in parallel. This study provides proof-of-concept for larger studies, demonstrating the applicability and high scalability of our assay to any locus of interest. Our experience suggests that this approach can be easily transferred to other diagnostic questions.
GP-HTNLoc: A Graph Prototype Head-Tail Network-based Model for Multi-label Subcellular Localization Prediction of ncRNAs
Authors: Han Shuangkai , Liu Lin
Published: March 2024

Numerous research findings demonstrated that understanding the subcellular localization of non-coding RNAs (ncRNAs) is pivotal in elucidating their roles and regulatory mechanisms in cells. Despite the existence of over ten computational models dedicated to predicting the subcellular localization of ncRNAs, a majority of these models are designed solely for single-label prediction. In reality, ncRNAs often exhibit localization across multiple subcellular compartments. Furthermore, the existing multi-label localization prediction models are insufficient in addressing the challenges posed by the scarcity of training samples and class imbalance in ncRNA dataset. This study addresses the limitations of existing models by introducing a novel multi-label localization prediction model for ncRNAs, termed GP-HTNLoc. To alleviate class imbalance, the model adopts a separate training approach for head and tail class labels. In GP-HTNLoc, a pioneering graph prototype module is introduced for capturing potential association of ncRNA samples with labels. This module efficiently learns the graph structure and aggregates sample features. Notably, only few samples are required to obtain label prototypes containing rich information. These prototypes are then utilized to train a transfer learner, facilitating the transfer of meta-knowledge from the head class to the tail class. Experimental results demonstrate that GP-HTNLoc surpasses current state-of-the-art models across all datasets. Ablation study underscore the vital role played by the graph prototype module in enhancing the performance of GP-HTNLoc. The user-friendly online GP-HTNLoc web server can be accessed athttps://56s8y85390.goho.co.
Testing a Method for Quantifying Microplastic Content inMytilus californianus
Authors: Sidhu Ajeetesh S. , Sun William , Helal Mariam B. , Gupta Aryaman , Mittal Aarsh , Ramanathan Serena , Thakur Manu , Jain Bhoomi , Wang Dylan , Benson Andrew , Adams Connor T.
Published: March 2024

With the proliferation of microplastics within the environment, there has been an increased need to quantify them within organic tissues of aquatic species. Several studies have examined the potential role of mussels in filtering these contaminants, prompting interest in characterizing uptake and retention of microplastics in these species. There are a variety of methods to isolate and quantify microplastics, including density separation, enzymatic digestion, and filtration. The applicability of a combined digestion and ultrasonic bath methodology in isolating microplastics from the California mussel (Mytilus californianus Conrad, 1837) was investigated. Microplastics were added to 20-gallon tanks at 0 g (control) 8 mg. Mussel tissues from each tank were digested using potassium hydroxide solutions. These digestions were subjected to vacuum filtration and a sonication bath, then treated with a mixture of sodium hypochlorite and nitric acid. It was found that this method successfully removed organic tissue from the mussels while leaving dyed microplastics intact. The latter were quantified using fluorescent microscopy. This proof-of-principle experiment indicates that this technique can be applied to further studies on environmental impact and retention of microplastics in mussels and may also have utility for other shellfish.
Sensing of dietary amino acids and regulation of calcium dynamics in adipose tissues through Adipokinetic hormone inDrosophila
Authors: Ahmad Muhammad , Wu Shang , Guo Xuan , Perrimon Norbert , He Li
Published: March 2024

Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various obesity-related diseases.Drosophila melanogasterhas emerged as an excellent model for investigating metabolism and its associated disorders. In this study, we used live-cell imaging to demonstrate that the fly functional homolog of mammalian glucagon, Adipokinetic hormone (AKH), secreted from AKH hormone-producing cells (APCs) in the corpora cardiaca, stimulates intracellular Ca2+waves in the larval fat body/adipose tissue to promote lipid metabolism. Further, we show that specific dietary amino acids activate the APCs, leading to increased intracellular Ca2+and subsequent AKH secretion. Finally, a comparison of Ca2+dynamics in larval and adult fat bodies revealed different mechanisms of regulation, highlighting the interplay of pulses of AKH secretion, extracellular diffusion of the hormone, and intercellular communication through gap junctions. Our study underscores the suitability ofDrosophilaas a powerful model for exploring real-time nutrient sensing and inter-organ communication dynamics.
Unraveling the Genetic Comorbidity Landscape of Alzheimer’s Disease
Authors: Zhang Xueli , Li Dantong , Ye Siting , Liu Shunming , Ma Shuo , Li Min , Peng Qiliang , Hu Lianting , Shang Xianwen , He Mingguang , Zhang Lei
Published: March 2024

Alzheimer’s disease (AD) has emerged as the most prevalent and complex neurodegenerative disorder among the elderly population. However, the genetic comorbidity etiology for AD remains poorly understood. In this study, we conducted pleiotropic analysis for 41 AD phenotypic comorbidities, identifying ten genetic comorbidities with 16 pleiotropy genes associated with AD. Through biological functional and network analysis, we elucidated the molecular and functional landscape of AD genetic comorbidities. Furthermore, leveraging the pleiotropic genes and reported biomarkers for AD genetic comorbidities, we identified 50 potential biomarkers for AD diagnosis. Our findings deepen the understanding of the occurrence of AD genetic comorbidities and provide new insights for the search for AD diagnostic markers.

Highlights

The present study has focused on the comorbidities associated with Alzheimer’s disease (AD) by constructing a landscape of these comorbidities at various levels, including diseases, genetics, and pathways.

The study findings reveal novel and significant pathways that contribute to the etiology of AD and its comorbidities.

By exploring pleiotropic genes and reported biomarkers of AD comorbidities, the study has identified several potential diagnostic biomarker candidates for AD.

Abstract Figure

Graphic abstract.

Study pipeline.
Biochemical properties of chromatin domains define genome compartmentalization
Authors: Lucini Federica , Petrini Cristiano , Salviato Elisa , Pal Koustav , Rosti Valentina , Gorini Francesca , Santarelli Philina , Quadri Roberto , Lembo Giovanni , Graziano Giulia , Di Patrizio Soldateschi Emanuele , Tagliaferri Ilario , Pinatel Eva , Sebestyén Endre , Rotta Luca , Gentile Francesco , Vaira Valentina , Lanzuolo Chiara , Ferrari Francesco
Published: March 2024

Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility.

Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10,000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states.

A key novelty is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their 3D compartmentalization in one single experiment.
Visualization of endogenous G proteins on endosomes and other organelles
Authors: Jang Wonjo , Senarath Kanishka , Feinberg Gavin , Lu Sumin , Lambert Nevin A.
Published: March 2024

Classical G protein-coupled receptor (GPCR) signaling takes place in response to extracellular stimuli and involves receptors and heterotrimeric G proteins located at the plasma membrane. It has recently been established that GPCR signaling can also take place from intracellular membrane compartments, including endosomes that contain internalized receptors and ligands. While the mechanisms of GPCR endocytosis are well understood, it is not clear how well internalized receptors are supplied with G proteins. To address this gap we use gene editing, confocal microscopy, and bioluminescence resonance energy transfer to study the distribution and trafficking of endogenous G proteins. We show here that constitutive endocytosis is sufficient to supply newly internalized endocytic vesicles with 20-30% of the G protein density found at the plasma membrane. We find that G proteins are present on early, late, and recycling endosomes, are abundant on lysosomes, but are virtually undetectable on the endoplasmic reticulum, mitochondria, and the medial Golgi apparatus. Receptor activation does not change heterotrimer abundance on endosomes. Our findings provide a subcellular map of endogenous G protein distribution, suggest that G proteins may be partially excluded from nascent endocytic vesicles, and are likely to have implications for GPCR signaling from endosomes and other intracellular compartments.
Atypical Cell Cycle Regulation Promotes Mammary Stem Cell Expansion and Therapeutic Resistance
Authors: Fifield Bre-Anne , Vusich John , Haberfellner Erika , Andrechek Eran R. , Porter Lisa A.
Published: March 2024

Background

The cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours.

Methods

Using a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis.

Results

We show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population.

Conclusions

This data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, drug resistant breast cancers with increased cancer stem cell populations.
Frequency-specific cortico-subcortical interaction in continuous speaking and listening
Authors: Abbasi Omid , Steingräber Nadine , Chalas Nikos , Kluger Daniel S. , Gross Joachim
Published: March 2024

Speech production and perception involve complex neural dynamics in the human brain. Using magnetoencephalography (MEG), our study explores the interaction between cortico-cortical and cortico-subcortical connectivities during these processes. Our connectivity findings during speaking revealed a significant connection from the right cerebellum to the left temporal areas in low frequencies, which displayed an opposite trend in high frequencies. Notably, high-frequency connectivity was absent during the listening condition. These findings underscore the vital roles of cortico-cortical and cortico-subcortical connections within the speech production and perception network. The results of our new study enhance our understanding of the complex dynamics of brain connectivity during speech processes, emphasizing the distinct frequency-based interactions between various brain regions.
Frontoparietal network integrity supports cognitive function despite atrophy and hypoperfusion in pre-symptomatic frontotemporal dementia: multimodal analysis of brain function, structure and perfusion
Authors: Liu Xulin , Jones P Simon , Pasternak Maurice , Masellis Mario , Bouzigues Arabella , Russell Lucy L , Foster Phoebe H. , Ferry-Bolder Eve , van Swieten John , Jiskoot Lize , Seelaar Harro , Sanchez-Valle Raquel , Laforce Robert , Graff Caroline , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Tiraboschi Pietro , Santana Isabel , Gerhard Alexander , Levin Johannes , Sorbi Sandro , Otto Markus , Pasquier Florence , Ducharme Simon , Butler Chris , Le Ber Isabelle , Finger Elizabeth , Tartaglia Maria Carmela , Synofzik Matthis , Moreno Fermin , Borroni Barbara , Rohrer Jonathan D. , Tsvetanov Kamen A. , Rowe James B. ,   The GENFI consortium
Published: March 2024

INTRODUCTION

Genetic mutation carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion and functional patterns in pre-symptomatic stage could inform accurate staging and potential mechanisms.

METHODS

We included 207 pre-symptomatic genetic mutation carriers and 188 relatives without mutations. The grey matter volume, cerebral perfusion, and resting-state functional network maps were co-analyzed using linked independent component analysis (LICA). Multiple regression analysis was used to investigate the relationship of LICA components to genetic status and cognition.

RESULTS

Pre-symptomatic mutation carriers showed an age-related decrease in the left frontoparietal network integrity while non-carriers did not. Executive functions of mutation carriers became dependent on the left frontoparietal network integrity in older age.

DISCUSSION

The frontoparietal network integrity of pre-symptomatic mutation carriers showed a distinctive relationship to age and cognition compared to non-carriers, suggesting a contribution of the network integrity to brain resilience, despite atrophy and hypoperfusion.
High-throughput metabolome comparison of cutaneous squamous cell carcinoma, basal cell carcinoma, and healthy skin with e-biopsy sampling
Authors: Louie Leetal , Wise Julia , Berl Ariel , Shir-az Ofir , Kravtsov Vladimir , Yakhini Zohar , Shalom Avshalom , Golberg Alexander , Vitkin Edward
Published: March 2024

A standard histopathology-slides based diagnostics becomes a serious process bottleneck due to rising incidence rates of cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Leveraging tissue molecular information for diagnostics can be a beneficial alternative in certain cases. Sampling and processing of a constantly growing number of tumors can be enhanced with faster specimen collection methods together with high-throughput molecular identification approaches. Tumor specimens can be collected with electroporation-based biopsy (e-biopsy), a minimally invasive sampling collection tool with a proven ability, while mass spectrometry can be used for molecular identification.

The aim of this study was (i) to confirm the ability of e-biopsy technique to harvest metabolites, (ii) to obtain high-resolution metabolomic profiles of cSCC, BCC, and healthy skin tissues, and (iii) to perform a comparative analysis of the collected profiles.

Data, collected with e-biopsy coupled with ultra performance liquid chromatography and tandem mass spectrometry (UPLC-MS-MS), expands the current metabolomic profiles reported for cSCC, BCC, and healthy skin. Here we report measurements of 2325 small metabolites identified (301 with high confidence) in 13 tissue samples from 12 patients. Comparative analysis identified 34 significantly (p<0.05) differentially expressed high-confidence metabolites. Generally, we observed a greater number of metabolites with higher expression, in cSCC and in BCC compared to healthy tissues, belonging to the subclass amino acids, peptides, and analogues.
How to mitigate selection bias in COVID-19 surveys: evidence from five national cohorts
Authors: Narayanan Martina K. , Dodgeon Brian , Katsoulis Michail , Ploubidis George B. , Silverwood Richard J.
Published: March 2024

Background

Non-response is a common problem, and even more so during the COVID-19 pandemic where social distancing measures challenged data collections. As non-response is often systematic, meaning that respondents are usually healthier and from a better socioeconomic background, this potentially introduces serious bias in research findings based on COVID-19 survey data. The goal of the current study was to see if we can reduce bias and restore sample representativeness despite systematic non-response in the COVID-19 surveys embedded within five UK cohort studies using the rich data available from previous time points.

Methods

A series of three surveys was conducted during the pandemic across five UK cohorts: National Survey of Health and Development (NSHD, born 1946), 1958 National Child Development Study (NCDS), 1970 British Cohort Study (BCS70), Next Steps (born 1989-90) and Millennium Cohort Study (MCS, born 2000-02). We applied non-response weights and utilised multiple imputation, making use of covariates from previous waves which have been commonly identified as predictors of non-response, to attempt to reduce bias and restore sample representativeness.

Results

Response rates in the COVID-19 surveys were lower compared to previous cohort waves, especially in the younger cohorts. We identified bias due to systematic non-response in the distributions of variables including parental social class and childhood cognitive ability. In each cohort, respondents of the COVID-19 survey had a higher percentage of parents in the most advantaged social class, and a higher mean of childhood cognitive ability, compared to the original (full) cohort sample. The application of non-response weights and multiple imputation was successful in reducing bias in parental social class and childhood cognitive ability, nearly eliminating it for the former.

Conclusions

The current paper demonstrates that it is possible to reduce bias from non-response and to a large degree restore sample representativeness in multiple waves of a COVID-19 survey embedded within long running longitudinal cohort studies through application of non-response weights or multiple imputation. Such embedded COVID-19 surveys therefore have an advantage over cross-sectional COVID-19 surveys, where non-response bias cannot be handled by leveraging previously observed information on non-respondents. Our findings suggest that, if non-response is appropriately handled, analyses based on the COVID-19 surveys within these five cohorts can contribute significantly to COVID-19 research, including studying the medium and long-term effects of the pandemic.
Nephroprotective effects of cilastatin in people at risk of acute kidney injury: A systematic review and meta-analysis
Authors: Acharya Dilaram , Ghanim Fanar , Harrison Tyrone G. , Scory Tayler Dawn , Shommu Nusrat , Ronksley Paul E. , Elliott Meghan J. , Collister David , Pannu Neesh , James Matthew T.
Published: March 2024

Rationale & Objective

Cilastatin is an inhibitor of drug metabolism in the proximal tubule that demonstrates nephroprotective effects in animals. It has been used in humans in combination with the antibiotic imipenem to prevent imipenem’s degradation. This systematic review and meta-analysis evaluated the nephroprotective effects of cilastatin in humans.

Study Design

Systematic review and meta-analysis of observational (comparative effectiveness) studies or randomized clinical trials (RCTs)

Setting & Study Populations

People of any age at risk of acute kidney injury (AKI).

Selection Criteria for Studies

We systematically searched MEDLINE, Embase, Web of Science, and the Cochrane Controlled Trials registry from database inception to November 2023 for observational studies or RCTs that compared kidney outcomes among groups treated with cilastatin, either alone or as combination imipenem-cilastatin, versus an inactive or active control group not treated with cilastatin.

Data Extraction

Two reviewers independently evaluated studies for inclusionand risk of bias.

Analytical Approach

Treatment effects were estimated using random effects models and heterogeneity was quantified using the I2statistic.

Results

We identified 10 studies (five RCTs, n=531 patients; 5 observational studies, n=6,321 participants) that met the inclusion criteria, including 6 studies with comparisons of imipenem-cilastatin to an inactive control and 4 studies with comparisons to alternate antibiotics. Based on pooled results from 5 studies, the risk of AKI was lower with imipenem-cilastatin (risk ratio [RR] 0.53 [95% CI, 0.38 to 0.74]; I2=42.2%), with consistent results observed from randomized trials (two trials, RR 0.30 [95% CI, 0.09 to 1.00]; I2=62.8%) and observational studies (three studies, RR 0.55 [95% CI, 0.38 to 0.81]; I2=62.8%). Based on results from six studies, kidney function was also better with imipenem-cilastatin than comparators (weighted mean difference [WMD] in serum creatinine -0.14 mg/dL [95% CI, -0.21 to -0.07]; I2=0%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies.

Limitations

Clinical and statistical heterogeneity could not be fully explained due to a limited number of studies.

Conclusion

Patients treated with imipenem-cilastatin developed AKI less frequently and had better short-term kidney function than control groups or those receiving comparator antibiotics. Larger clinical trials with less risk of detection bias due to lack of allocation concealment and blinding are needed to establish the efficacy of cilastatin for AKI prevention.

Registration

International Prospective Register of Systematic Reviews (PROSPERO) database (ID: CRD42023488809)
Comparison of Deep Learning Approaches for Conversion of International Classification of Diseases Codes to the Abbreviated Injury Scale
Authors: Doshi Ayush , Marche Charbel , Chernyavskiy Pavel , Glass George , Hartka Thomas
Published: March 2024

The injury severity classifications generated from the Abbreviated Injury Scale (AIS) provide information that allows for standardized comparisons in the field of trauma injury research. However, the majority of injuries are coded in International Classification of Diseases (ICD) and lack this severity information. A system to predict injury severity classifications from ICD codes would be beneficial as manually coding in AIS can be time-intensive or even impossible for some retrospective cases. It has been previously shown that the encoder-decoder-based neural machine translation (NMT) model is more accurate than a one-to-one mapping of ICD codes to AIS. The objective of this study is to compare the accuracy of two architectures, feedforward neural networks (FFNN) and NMT, in predicting Injury Severity Score (ISS) and ISS ≥16 classification. Both architectures were tested in direct conversion from ICD codes to ISS score and indirect conversion through AIS for a total of four models. Trauma cases from the U.S. National Trauma Data Bank were used to develop and test the four models as the injuries were coded in both ICD and AIS. 2,031,793 trauma cases from 2017-2018 were used to train and validate the models while 1,091,792 cases from 2019 were used to test and compare them. The results showed that indirect conversion through AIS using an NMT was the most accurate in predicting the exact ISS score, followed by direct conversion with FFNN, direct conversion with NMT, and lastly indirect conversion with FFNN, with statistically significant differences in performance on all pairwise comparisons. The rankings were similar when comparing the accuracy of predicting ISS ≥16 classification, however the differences were smaller. The NMT architecture continues to demonstrate notable accuracy in predicting exact ISS scores, but a simpler FFNN approach may be preferred in specific situations, such as if only ISS ≥16 classification is needed or large-scale computational resources are unavailable.
Normative modeling of thalamic nuclear volumes
Authors: Young Taylor R , Kumar Vinod Jangid , Saranathan Manojkumar
Published: March 2024

Thalamic nuclei have been implicated in neurodegenerative and neuropsychiatric disorders. Normative models for thalamic nuclear volumes have not been proposed thus far. The aim of this work was to establish normative models of thalamic nuclear volumes and subsequently investigate changes in thalamic nuclei in cognitive and psychiatric disorders. Volumes of the bilateral thalami and 12 nuclear regions were generated from T1 MRI data using a novel segmentation method (HIPS-THOMAS) in healthy control subjects (n=2374) and non-control subjects (n=695) with early and late mild cognitive impairment (EMCI, LMCI), Alzheimers disease (AD), Early psychosis and Schizophrenia, Bipolar disorder, and Attention deficit hyperactivity disorder. Three different normative modelling methods were evaluated while controlling for sex, intracranial volume, and site. Z-scores and extreme z-score deviations were calculated and compared across phenotypes. GAMLSS models performed the best. Statistically significant shifts in z-score distributions consistent with atrophy were observed for most phenotypes. Shifts of progressively increasing magnitude were observed bilaterally from EMCI to AD with larger shifts in the left thalamic regions. Heterogeneous shifts were observed in psychiatric diagnoses with a predilection for the right thalamic regions. Here we present the first normative models of thalamic nuclear volumes and highlight their utility in evaluating heterogenous disorders such as Schizophrenia.
Neuroanatomical variability associated with early substance use initiation: Results from the ABCD Study
Authors: Miller Alex P. , Baranger David A. A. , Paul Sarah E. , Garavan Hugh , Mackey Scott , Tapert Susan F. , LeBlanc Kimberly H. , Agrawal Arpana , Bogdan Ryan
Published: March 2024

The extent to which neuroanatomical variability associated with substance involvement reflects pre-existing risk and/or consequences of substance exposure remains poorly understood. In the Adolescent Brain Cognitive DevelopmentSM(ABCD®) Study, we identify associations between global and regional differences in brain structure and early substance use initiation (i.e., occurring <15 years of age; nsanalytic=6,556-9,804), with evidence that associations precede initiation. Neurodevelopmental variability in brain structure may confer risk for substance involvement.
Immune history influences SARS-CoV-2 booster impacts: the role of efficacy and redundancy
Authors: Larsen Sophie L. , Noor Iffat , West Haylee , Chandra Eliana , Martinez Pamela P. , Kraay Alicia N. M.
Published: March 2024

Given the continued emergence of SARS-CoV-2 variants of concern as well as unprecedented vaccine development, it is crucial to understand the effect of the updated vaccine formulations at the population level. While bivalent formulations have higher efficacy in vaccine trials, translating these findings to real-world effectiveness is challenging due to the diversity in immune history, especially in settings with a high degree of natural immunity. Known socioeconomic disparities in key metrics such as vaccine coverage, social distancing, and access to healthcare have likely shaped the development and distribution of this immune landscape. Yet little has been done to investigate the impact of booster formulation in the context of host heterogeneity. Using two complementary mathematical models that capture host demographics and immune histories over time, we investigated the potential impacts of bivalent and monovalent boosters in low– and middle-income countries (LMICs). These models allowed us to test the role of natural immunity and cross-protection in determining the optimal booster strategy. Our results show that to avert deaths from a new variant in populations with high immune history, it is more important that a booster is implemented than which booster is implemented (bivalent vs. monovalent). However, in populations with low preexisting immunity, bivalent boosters can become optimal. These findings suggest that for many LMICs – where acquiring a new vaccine stock may be economically prohibitive – monovalent boosters can still be implemented as long as pre-existing immunity is high.
Recommendations for implementing the INTERACT3 care bundle for intracerebral hemorrhage in Latin America: a Delphi Study
Authors: Allende Ma.Ignacia , Muñoz-Venturelli Paula , Gonzalez Francisca , Bascur Francisca , Anderson Craig S. , Ouyang Menglu , Cabieses Báltica , Obach Alexandra , Cano-Nigenda Vanessa , Arauz Antonio
Published: March 2024

Background and aims

The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC).

Methods

A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank various statements that commenced with 43 statements relevant to 7 domains (training, resources and infrastructure, education of patients, blood pressure, temperature, glycemic control, and reversal of anticoagulation). The pre-defined consensus threshold was 75%.

Results

A total of 55 statements reached consensus by the third round, which included 12 new statements that emerged through rounds. The highest-ranked statements in each domain emphasized critical aspects with successful implementation requiring a minimum level of resources to be made available. Key priorities included the continuous training of all healthcare workers involved in the management of ICH, establishing protocols aligned with available resources, and a collaborative inter-disciplinary approach to care being supported by institutional networks. Statements related to anticoagulation reversal were given the highest priority, which highlighted interest in the topic but limited availability of treatment in the region.

Conclusions

Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.