bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children
Authors: Spector Stephen A. , Brummel Sean S. , Chang Audrey , Wiznia Andrew , Ruel Theodore D. , Acosta Edward P. ,   for IMPAACT P1093 Team
Published: January 2024

Background:

Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined.

Methods:

Children defined by age and administered dolutegravir formulation had AUC24 at steady state, Cmax and C24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model.

Results:

The 59 children studied had a median age of 4.6 years, log10 plasma HIV RNA of 4.79 (copies/mm3), and CD4+ lymphocyte count of 1041 cells/mm3; 51% were female. For ABCG2, participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (−15.7, 95% CI: [−32.0 to 0.6], P = 0.06), and log10Cmax adjusted mean difference (−0.15, 95% CI: [−0.25 to −0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [−1.1 to 25.0], P = 0.07). For UGT1A1,poor metabolizers had nonsignificant higher concentrations (adjusted log10Cmax mean difference 11.8; 95% CI: [−12.3 to 36.0], P = 0.34) and lower mean log10 adjusted oral clearance −0.13 L/h (95% CI: [−0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4+ cell counts.

Conclusions:

Dolutegravir AUC24 for genetic variants in ABCG2, NR1l2, and UGT1A1 varied from −25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.
Ictal EEG Source Imaging
Authors: Knowlton Robert C.
Published: January 2024

Ictal EEG source imaging (ESI) is an advancing and growing application for presurgical epilepsy evaluation. For far too long, localization of seizures with scalp EEG has continued to rely on visual inspection of tracings arranged in a variety of montages allowing, at best, rough estimates of seizure onset regions. This most critical step is arguably the weakest point in epilepsy localization for surgical decision-making in clinical practice today. This review covers the methods and strategies that have been developed and tested for the performance of ictal ESI. It highlights practical issues and solutions toward sound implementation while covering differing methods to tackle the challenges specific to ictal ESI—noise and artifact reduction, component analysis, and other tools to increase seizure-specific signal for analysis. Further, validation studies to date—those with both high and low density numbers of electrodes—are summarized, providing a glimpse at the relative accuracy of ictal ESI in all types of focal epilepsy patients. Finally, given the added noninvasive information (greater degree of spatial resolution compared with standard ictal EEG review), the role of ictal ESI and its clinical utility in the presurgical evaluation is discussed.
Enhancing Antibody Language Models with Structural Information
Authors: Barton Justin , Galson Jacob D. , Leem Jinwoo
Published: January 2024

The central tenet of molecular biology is that a protein’s amino acid sequence determines its three-dimensional structure, and thus its function. However, proteins with similar sequences do not always fold into the same shape, and vice-versa, dissimilar sequences can adopt similar folds. In this work, we explore antibodies, a class of proteins in the immune system, whose local shapes are highly unpredictable, even with small variations in their sequence. Inspired by the CLIP method [1], we propose a multimodal contrastive learning approach, contrastive sequence-structure pre-training (CSSP), which amalgamates the representations of antibody sequences and structures in a mutual latent space. Integrating structural information leads both antibody and protein language models to show better correspondence with structural similarity and improves accuracy and data efficiency in downstream binding prediction tasks. We provide an optimised CSSP-trained model, AntiBERTa2-CSSP, for non-commercial use athttps://huggingface.co/alchemab.
Predictive coding in the auditory brainstem
Authors: de Cheveigné Alain
Published: January 2024

Predictive coding is an influential concept in sensory and cognitive neuroscience. It is often understood as involving top-down prediction of bottom-up sensory patterns, but the term also applies to feed-forward predictive mechanisms, for example in the retina. Here, I discuss a recent model of low-level predictive processing in the auditory brainstem that is of the feed-forward flavor. Past sensory input from the cochlea is delayed and compared with the current input, via a predictive model that is tuned with the objective of minimizing prediction error. This operation is performed independently within each peripheral channel, with parameters determined from information within that channel. The result is a sensory representation that is invariant to a certain class of interfering sounds (harmonic, quasi-harmonic, or spectrally sparse), thus contributing to Auditory Scene Analysis. The purpose of this paper is to discuss that model in the light of predictive coding, and examine how it might fit within a wider hierarchical model that supports the perceptual representation of objects and events in the world.
Rapid and specific detection of single nanoparticles and viruses in microfluidic laminar flow via confocal fluorescence microscopy
Authors: Drori Paz , Mouhadeb Odelia , Muñoz Gabriel G. Moya , Razvag Yair , Alcalay Ron , Klocke Philipp , Cordes Thorben , Zahavy Eran , Lerner Eitan
Published: January 2024

Mainstream virus detection relies on the specific amplification of nucleic acids via polymerase chain reaction, a process that is slow and requires extensive laboratory expertise and equipment. Other modalities, such as antigen-based tests, allow much faster virus detection but have reduced sensitivity. In this study, we report the development of a flow virometer for the specific and rapid detection of single nanoparticles based on confocal microscopy. The combination of laminar flow and multiple dyes enable the detection of correlated fluorescence signals, providing information on nanoparticle volumes and specific chemical composition properties, such as viral envelope proteins. We evaluated and validated the assay using fluorescent beads and viruses, including SARS-CoV-2. Additionally, we demonstrate how hydrodynamic focusing enhances the assay sensitivity for detecting clinically-relevant virus loads. Based on our results, we envision the use of this technology for clinically relevant bio-nanoparticles, supported by the implementation of the assay in a portable and user-friendly setup.
Orally delivered biodegradable targeted inflammation resolving pectin-coated nanoparticles induce anastomotic healing post intestinal surgery
Authors: Lee Jong Hyun , Reischl Stefan , Walter Robert Leon , Vieregge Vincent , Weber Marie-Christin , Xu Runxin , Chen Hao , Kasajima Atsuko , Friess Helmut , Neumann Philipp-Alexander , Kamaly Nazila
Published: January 2024

Although medical treatment is sucessful in most cases in patients with inflammatory bowel diseases (IBD), a percentage of patients require surgical resection of diseased bowel segments at least once in their lifetime. Healing success of the intestinal anastomosis is at high risk, especially in presence of acute inflammation. Failure of anastomotic healing is a life-threatening complication and causes high socioeconomic costs. Common anti-inflammatory medications can have detrimental effects on wound healing. Thus, targeted perioperative therapeutics supporting anastomotic healing during colitis are an urgent medical need. Here, we develop a novel basal membrane targeted controlled release, pectin-coated polymeric nanoparticle (NP) encapsulating a highly potent inflammation resolving mediator, the peptide Ac2-26. These NPs can undergo gastric passage and facilitate localized release of the therapeutic peptide in the colon via degradation of their pectin-chitosan coating by microbial pectinases, which subsequently exposes a collagen IV targeted NP surface, allowing for further binding and retention of the NPs at the intestinal wound. To test these NPs, we used a murine surgical model combining the formation of an intestinal anastomosis with the induction of a preoperative colitis by dextran sodium sulfate. In this model, perioperative administration of pectin-chitosan coated NPs containing Ac2-26 (P-C-Col IV-Ac2-26-NP) led to the reduction of colitis activity in the postoperative phase. Macroscopic wound closure was improved by P-C-Col IV-Ac2-26-NP treatment as evaluated by endoscopy and intraabdominal adhesion scoring. Microscopic analysis of the healing process showed an improved semiquantitative healing score in the treatment group. In this proof-of-concept study we demonstrate that novel P-C-Col IV-Ac2-26-NP could be a promising and clinically feasible perioperative treatment strategy for IBD patients.

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ExploreTurns: A web tool for the exploration, analysis, and classification of beta turns and structured loops in proteins; application to beta-bulge and Schellman loops, Asx helix caps, beta hairpins and other hydrogen-bonded motifs
Authors: Newell Nicholas E.
Published: January 2024

The most common type of protein secondary structure after the alpha helix and beta sheet is the four-residue beta turn, which plays many key structural and functional roles. Existing tools for the study of beta turns operate in backbone dihedral-angle (Ramachandran) space, which presents challenges for the visualization, comparison and analysis of the wide range of turn conformations. In this work, a new turn-local coordinate system and structural alignment, together with a set of geometric descriptors for turn backbone shape, are incorporated into ExploreTurns, a web facility for the exploration, analysis, geometric tuning and retrieval of beta turns and their contexts which combines the advantages of Ramachandran- and Euclidean-space representations. Due to the prevalence of beta turns in proteins, this facility, supported by its interpreter for a new general nomenclature which classifies H-bonded loop motifs and beta hairpins, serves as an exploratory browser and analysis tool for most loop structure. The tool is applied to the detection of new H-bonded loops, including short and “double” Schellman loops, a large family of beta-bulge loops with a range of geometries and H-bond topologies, and other motifs. Other applications presented here include the mapping of sequence preferences in Asx helix N-caps and an investigation of the depth dependence of beta-turn geometry. ExploreTurns, available atwww.betaturn.com, should prove useful in research, education, and applications such as protein design, in which an enhanced Euclidean-space picture of turn and motif structure and the ability to identify and tune structures suited to particular requirements may improve performance.
Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer
Authors: Bidgood Charles L. , Philp Lisa K. , Rockstroh Anja , Lehman Melanie , Nelson Colleen C. , Sadowski Martin C. , Gunter Jennifer H.
Published: January 2024

Metabolic reprogramming is a hallmark of cancer and fundamental for disease progression. The remodelling of oxidative phosphorylation and enhanced lipogenesis are key characteristics of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours with upregulation of enzymes associated with branched-chain amino acid (BCAA) catabolism. We hypothesised that the degradation of BCAAs, particularly valine may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool. Through suppression of valine availability, we report strongly reduced lipid content despite compensatory upregulation of fatty acid uptake, indicating valine is an important lipogenic fuel in PCa. Inhibition of the enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) also resulted in selective inhibition of cellular proliferation of malignant but not benign prostate cells and impaired succinate production. In combination with a comprehensive multi-omic investigation of patient and cell line data, our work highlights a therapeutic target for selective inhibition of metabolic reprogramming in PCa.
Long-Term Monolayer Cultivation Captures Homeostatic and Regenerative Features of Human Colonic Epithelial Cells
Authors: Fujii Satoru , Wang Yi , Meng Shanshan , Musich Ryan J. , Espenschied Scott T. , Newhall Kevin , Han Yi , Sekiguchi Shuhei , Matsumoto Ryoma , Ciorba Matthew A. , Sibley L. David , Okamoto Ryuichi , Stappenbeck Thaddeus S.
Published: January 2024

While organoid culture technique has significantly advanced research on intestinal epithelial cells (IECs), reproducing the homeostatic and regenerative processes of human IECs in vitro remains challenging. We previously established a unique long-term 2-dimensional (2D) cultivation for mouse IECs using the air-liquid interface (ALI) technique, successfully recapitulating homeostasis and regeneration. Here, applying this to human IECs, we developed a long-term, self-organizing 2D cultivation for human IECs. During the culture, we observed a dynamic transition in cellular shape from squamous to columnar, resembling in vivo regeneration. RNA sequencing indicated that intestinal stem cells (SCs) with canonical SC markers like LGR5 may play a main role in both homeostasis and regeneration. Moreover, we identified minor populations, including deep crypt secretory (DCS)-like cells, CA7-positive cells, and non-canonical Goblet cells, previously overlooked in vitro. This novel technique holds promise for not only broadening our understanding of homeostasis, regeneration, and the functions of minor populations as well as SCs in human intestinal mucosa, but also facilitating future studies such as analyzing host-microbe interactions.
Structural Basis of Conformational Dynamics in the PROTAC-Induced Protein Degradation
Authors: Zhao Hongtao
Published: January 2024

Pronounced conformational dynamics is unveiled upon analyzing multiple crystal structures of the same proteins recruited to the same E3 ligases by PROTACs, and yet, is largely permissive for targeted protein degradation due to the intrinsic mobility of E3 assemblies creating a large ubiquitylation zone. Mathematical modelling of ternary dynamics on ubiquitylation probability confirms the experimental finding that ternary complex rigidification need not correlate with enhanced protein degradation. Salt bridges are found to prevail in the PROTAC-induced ternary complexes, and may contribute to a positive cooperativity and prolonged half-life. The analysis highlights the importance of presenting lysines close to the active site of the E2 enzyme while constraining ternary dynamics in PROTAC design to achieve high degradation efficiency.

Abstract Figure
Macrophage- and CD4+T cell-derived SIV differ in glycosylation, infectivity and neutralization sensitivity
Authors: Karsten Christina B. , Buettner Falk F.R. , Cajic Samanta , Nehlmeier Inga , Roshani Berit , Klippert Antonina , Sauermann Ulrike , Stolte-Leeb Nicole , Reichl Udo , Gerardy-Schahn Rita , Rapp Erdmann , Stahl-Hennig Christiane , Pöhlmann Stefan
Published: January 2024

The human immunodeficiency virus (HIV) envelope protein (Env) mediates viral entry into host cells and is the primary target for the humoral immune response. Env is extensively glycosylated, and these glycans shield underlying epitopes from neutralizing antibodies. The glycosylation of Env is influenced by the type of host cell in which the virus is produced. Thus, HIV is distinctly glycosylated by CD4+T cells, the major target cells, and macrophages. However, the specific differences in glycosylation between viruses produced in these cell types have not been explored at the molecular level. Moreover, the impact of these differences on viral spread and neutralization sensitivity remains largely unknown. To address these questions, we employed the simian immunodeficiency virus (SIV) model. Glycan analysis revealed higher relative levels of oligomannose-typeN-glycans in SIV from CD4+T cells (T-SIV) compared to SIV from macrophages (M-SIV), and the complex-typeN-glycans profiles differed between the two viruses. Notably, M-SIV demonstrated greater infectivity than T-SIV, even when accounting for Env incorporation, suggesting that host cell-dependent factors influence infectivity. Further, M-SIV was more efficiently disseminated by HIV binding cellular lectins. We also evaluated the influence of cell type-dependent differences on SIV’s vulnerability to carbohydrate binding agents (CBAs) and neutralizing antibodies. T-SIV demonstrated greater susceptibility to mannose-specific CBAs, possibly due to its elevated expression of oligomannose-typeN-glycans. In contrast, M-SIV exhibited higher susceptibility to neutralizing sera in comparison to T-SIV. These findings underscore the importance of host cell-dependent attributes of SIV, such as glycosylation, in shaping both infectivity and the potential effectiveness of intervention strategies.
PCA-Plus: Enhanced principal component analysis with illustrative applications to batch effects and their quantitation
Authors: Zhang Nianxiang , Casasent Tod D. , Casasent Anna K. , Kumar Shwetha V. , Wakefield Chris , Broom Bradley M. , Weinstein John N. , Akbani Rehan
Published: January 2024

Background

Principal component analysis (PCA), a standard approach to analysis and visualization of large datasets, is commonly used in biomedical research for detecting similarities and differences among groups of samples. We initially used conventional PCA as a tool for critical quality control of batch and trend effects in multi-omic profiling data produced by The Cancer Genome Atlas (TCGA) project of the NCI. We found, however, that conventional PCA visualizations were often hard to interpret when inter-batch differences were moderate in comparison with intra-batch differences; it was also difficult to quantify batch effects objectively. We, therefore, sought enhancements to make the method more informative in those and analogous settings.

Results

We have developed algorithms and a toolbox of enhancements to conventional PCA that improve the detection, diagnosis, and quantitation of differences between or among groups, e.g., groups of molecularly profiled biological samples. The enhancements include (i) computed group centroids; (ii) sample-dispersion rays; (iii) differential coloring of centroids, rays, and sample data points; (iii) trend trajectories; and (iv) a novel separation index (DSC) for quantitation of differences among groups.

Conclusions

PCA-Plus has been our most useful single tool for analyzing, visualizing, and quantitating batch effects, trend effects, and class differences in molecular profiling data of many types: mRNA expression, microRNA expression, DNA methylation, and DNA copy number. An early version of PCA-Plus has been used as the central graphical visualization in our MBatch package for near-real-time surveillance of data for analysis working groups in more than 70 TCGA, PanCancer Atlas, PanCancer Analysis of Whole Genomes, and Genome Data Analysis Network projects of the NCI. The algorithms and software are generic, hence applicable more generally to other types of multivariate data as well. PCA-Plus is freely available in a down-loadable R package at our MBatch website.
Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging
Authors: Lanzillotta Chiara , Baniowska Monika Rataj , Prestia Francesca , Sette Chiara , Nalesso Valérie , Perluigi Marzia , Barone Eugenio , Duchon Arnaud , Tramutola Antonella , Herault Yann , Di Domenico Fabio
Published: January 2024

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy ofHomo sapienschromosome 21 (HSA21). The increased dosage of genes on HSA21 is the cause for the initial neurodevelopmental disorder and for further development of cognitive decline, however the molecular mechanisms promoting brain pathology along ageing are still missing. One of the major challenges in the study of DS is the lack of reliable murine model able to accurately replicate genotypic and phenotypic aspects observed in humans along ageing. Preclinical studies in DS were pioneered using the Ts65Dn murine model, which despite its genetic limitations, has been extremely helpful in characterising the progression of brain degeneration. The novel Ts66Yah model represents an evolution of the Ts65Dn, with phenotypes only induced by trisomic HSA21 homologous genes, closer to human DS condition. In this study, we confirmed the behavioural features of Ts66Yah mice with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The molecular characterisation of Ts66Yah demonstrated the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-related alterations of those pathways occur early promoting the alteration of brain development and the onset of a condition of premature aging. Overall, data collected in Ts66Yah provide novel and consolidated insights, devoid of genome bias, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.
3D-Printable Non-invasive Head Immobilization System for Non-Human Primates
Authors: Shahbazi Elia , Nguyen Drew , Swedan Tyler , Ma Timothy , Lafer-Sousa Rosa , Dinh Alvin , Azadi Reza , Ryan Amy M. , Afraz Arash
Published: January 2024

A critical contribution to understanding the primate brain is our ability to directly record, manipulate, or image the brain in awake, behaving monkeys. A challenge with carrying out these studies is that typically the monkey’s head must be fixed in place. While non-invasive head immobilization systems (NHIS) have been demonstrated to be effective, they have not fully replaced the use of surgically applied headposts. Here, we introduce a novel NHIS, with an option for voluntary engagement, for macaques using a widely available resource: the 3D printer. We designed customized 3D-printable head-immobilization masks for monkeys and a docking system using standard CT scans and user-friendly open-source software packages (FLoRIN, Blender, Python). We examined the efficacy and stability of our mask system for collecting eye fixation data by measuring trial-by-trial gaze precision and accuracy in two mask-immobilized monkeys and three headposted monkeys, including a within-subjects comparison. Our results demonstrate that monkeys stabilized by the mask maintain gaze precision and accuracy comparable with their headposted counterparts. While the headpost outperformed the mask, the difference in precision was 0.03° of visual angle, and the difference in accuracy was less than 0.2°, well within the acceptable range for most use-cases. Our process allows for the production of 3D-printable masks based on CT or MRI scans with the flexibility to incorporate design modifications for experimental equipment and resizing, potentially serving as a promising and more easily accessible alternative to headposts and other NHISs for primate neuroscience research.
G-quadruplexes as pivotal components ofcis-regulatory elements in the human genome
Authors: Zhang Rongxin , Wang Yuqi , Wang Cheng , Sun Xiao , Mergny Jean-Louis
Published: January 2024

Cis-regulatory elements have the ability to precisely regulate gene expression in cells, and G-quadruplexes (G4s), as non-canonical secondary structures, may potentially play a role in this regulation. However, a lack of systematic studies exists to uncover the connection between these two elements. Here, we comprehensively characterized the associations between G4s and human candidatecis-regulatory elements (cCREs) inferred from the Encyclopedia of DNA Elements (ENCODE) data. Our findings demonstrate that G4s are prominently enriched in most types of cCREs, particularly in elements with promoter-like signatures (PLS). Furthermore, we observed that the co-occurrence of CTCF signals with H3K4me3 or H3K27ac signals significantly strengthens the association between cCREs and G4s. This association becomes more pronounced when examining cell type-specific cCREs and G4s. Interestingly, compared to cCREs, genetic variants occurring in G4s, especially within their G-runs, often exhibit higher regulatory potential and deleterious effects. Runs of several consecutive guanines (G-runs) in the vicinity of transcriptional start sites tend to be more constrained in mammalian evolution than cCREs’s G-runs. Besides, the presence of G4s, is often linked to a more favorable local chromatin environment for the activation and execution of regulatory functions of cCREs, potentially attributable to the formation of G4 secondary structures. Finally, we discovered that G4-associated cCREs exhibit widespread activation in a variety of cancers. Altogether, our study suggests that G4s are integral components of humancis-regulatory elements, and the G4 primary sequences are associated with the localization of the cCREs, while the G4 structures are linked to the activation of the cCREs. Therefore, we propose to define G4s as pivotal regulatory elements in the human genome.
Beyond Antibiotics: Cinnamic Acid’s role in combatting complex biofilms in the oral cavity
Authors: Al_Darwish Lama , Alajlani Muaaz , Alashkar Sharif
Published: January 2024

Traditional antibiotic therapy has become inefficient in treating oral plaques, due to the the presence of highly adherent bacteria in complex infections of oral cavities. Our study aimed to evaluate the anti-biofilm activity of Cinnamic Acid against single and multispecies bacteria causing dental plaques. Different concentrations of cinnamic acid (1-1000 mg/L) were tested using Biofilm assays, EPS analysis, and biomass quantification. To gain insight, a drug-likeness chemoinformatics study of cinnamic acid was conducted.

We found that lower concentrations (1-400mg/L) of Cinnamic Acid had a minor effect on biofilm formation inhibition. Whilst concentrations of 600mg/L and above had shown significant biofilm production, EPS production and biomass production reduced down to 80%.Cinnamic Acid has proven to contain antibacterial, antibiofilm, and drug-likeness properties and is a prominent compound in combating oral biofilm.

Authors Summary

Combating oral pathogenic biofilm is an important approach in treating polymicrobial oral infections, We have tested the anti-biofilm activity of cinnamic acid at different connections (1-1000 mg/L) and against single and multispecies biofilm forming bacteria. We found that cinnamic acid had a notable reduction in biofilm formation and EPS production, and reduced total biofilm biomass. Cinnamic Also fulfills the lipinski ROFs criteria for drug-likeness.

Due to its antibacterial, anti-biofilm, and drug-likeness properties, a plant-derived compound such as Cinnamic Acid can be a new prominent approach to defecting the global risk of oral pathogenic biofilms. And serve as an alternative to conventional oral care methods which have been rendered inefficient by biofilm-forming pathogens.
The role of transposon activity in shaping cis-regulatory element evolution after whole genome duplication
Authors: Monsen Øystein , Grønvold Lars , Datsomor Alex , Harvey Thomas , Kijas James , Suh Alexander , Hvidsten Torgeir R. , Sandve Simen Rød
Published: January 2024

Two of the most potent drivers of genome evolution in eukaryotes are whole genome duplications (WGD) and transposable element (TE) activity. These two mutational forces can also play synergistic roles; WGDs result in both cellular stress and functional redundancy, which would allow TEs to escape host-silencing mechanisms and effectively spread with reduced impact on fitness. As TEs can function as, or evolve into, TE-derived cis-regulatory elements (TE-CREs), bursts of TE-activity following WGD are likely to impact evolution of gene regulation. However, the role of TEs in genome regulatory remodelling after WGDs is unclear. Here we used the genome of Atlantic salmon, which is known to have experienced massive expansion of TEs after a WGD ∼100 Mya, as a model system to explore the synergistic roles of TEs and WGDs on genome regulatory evolution.

We identified 55,080 putative TE-CREs in Atlantic salmon using chromatin accessibility data from brain and liver. Of these, 80% were tissue specific to liver (43%) or brain (37%) and TE-CREs originating from retroelements were twice as common as those originating from DNA elements. Signatures of selection shaping TE-CRE evolution were evident from depletion of TEs in open chromatin, a bias in tissue-shared TE-CREs towards older TE-insertions, as well as tissue-specific processes shaping the TE-CRE repertoire. A minority of TE-families (16%) accounted for the origin of 46% of all TE-CREs, but the transposition activity of these ‘CRE-superspreader’ families happened mostly prior to the WGD. Analyses of individual TE-CREs do however support a significantly higher rate of TE-CRE evolution from insertions happening around the time of the salmonid WGD. This pattern was particularly striking for the DTT elements, despite having generally low propensity to evolve into TE-CREs and impact transcription. Furthermore, co-expression based analyses supported the presence of TE-driven gene regulatory network evolution, including DTT elements active at the time of WGD.

In conclusion, we find a strong association between TE insertions at the time of WGD and TE-CRE evolution. This association was not driven by particular TE-families with high capability to evolve into TE-CREs but likely a consequence of the concurrent surge of novel TE insertions, mostly from DTT elements, in combination with a shift in selective pressure on genome regulation following the WGD.
Ancestral Sequence Reconstruction as a tool to detect and study de novo gene emergence
Authors: Vakirlis Nikolaos , Acar Omer , Cherupally Vijay , Carvunis Anne-Ruxandra
Published: January 2024

New protein-coding genes can evolve from previously non-coding genomic regions through a process known as de novo gene emergence. Evidence suggests that this process has likely occurred throughout evolution and across the tree of life. Yet, confidently identifying de novo emerged genes remains challenging. Ancestral Sequence Reconstruction (ASR) is a promising approach for inferring whether a gene has emerged de novo or not, as it can enable us to inspect whether a given genomic locus ancestrally harbored protein-coding capacity. However, the use of ASR in the context of de novo emergence is still in its infancy and its capabilities, limitations, and overall potential are largely unknown. Notably, it is difficult to formally evaluate the protein-coding capacity of ancestral sequences, particularly when new gene candidates are short. How well-suited is ASR as a tool for the detection and study of de novo genes? Here, we address this question by designing an ASR workflow incorporating different tools and sets of parameters and by introducing a formal criterion that allows to estimate, within a desired level of confidence, when protein-coding capacity originated at a particular locus. Applying this workflow on ∼2,600 short, annotated budding yeast genes (<1,000 nucleotides), we found that ASR robustly predicts an ancient origin for most widely conserved genes, which constitute “easy” cases. For less robust cases, we calculated a randomization-based empirical P-value estimating whether the observed conservation between the extant and ancestral reading frame could be attributed to chance. This formal criterion allowed us to pinpoint a branch of origin for most of the less robust cases, identifying 33 genes that can unequivocally be considered de novo originated since the split of theSaccharomycesgenus, including 20S. cerevisiae-specific genes. We find that the remaining, equivocal cases, may be explained by different evolutionary scenarios including rapid evolution and multiple losses, as well as a very recent de novo origin. Overall, our findings suggest that ASR is a valuable tool to study de novo gene emergence but should be applied with caution and awareness of its limitations.
CDR Proteins ofC.elegansand Related Species: Relationship to Metaxin and FAXC Proteins
Authors: Adolph Kenneth W.
Published: January 2024

CDR (cadmium-responsive) proteins of the nematodeC. elegansand related species are shown to have structural homology to metaxin proteins and FAXC (failed axon connections) proteins of vertebrates and invertebrates. Unlike the metaxin and FAXC proteins, however, the predicted CDR proteins are only encoded in the genomes of nematodes, and not in vertebrates or other invertebrates. Metaxin-like structural features of CDR proteins are shown in this report to include: (1) GST_N_Metaxin and GST_C_Metaxin conserved protein domains, (2) metaxin-like patterns of α-helical secondary structure, and (3) a special 4-stranded β-sheet motif shared with the metaxins. FAXC proteins also possess these structural features. Phylogenetic analysis revealed that CDR proteins are related to metaxins 1, 2, and 3 and to FAXC proteins, although more closely to FAXC proteins. Nevertheless, all three types of proteins – CDR, FAXC, and metaxin – are related by evolution. Although CDR proteins have structural homology to metaxin and FAXC proteins, pairwise alignments of CDR proteins with metaxins and FAXCs demonstrated only low percentages of identical amino acids. CDR proteins can therefore be considered a separate category of proteins, distinct from metaxin and FAXC proteins. The CDR genes ofC. elegansconsist of a family of seven genes,cdr-1tocdr-7, which form a cluster of closely adjacent genes on chromosome V. Multiple genes were also found for the related speciesC. briggsaeandC. remanei. Alignment of pairs ofC. elegansCDR protein sequences encoded by differentcdrgenes demonstrated a high level of sequence homology. The neighboring genes of theC.elegans cdrgenes are different than the genes adjacent to theC.elegans faxcgenes and themtx-1andmtx-2metaxin genes.
Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy
Authors: Bar Jair , Leibowitz Raya , Reinmuth Niels , Ammendola Astrid , Jacob Eyal , Moskovitz Mor , Levy-Barda Adva , Lotem Michal , Katzenelson Rivka , Agbarya Abed , Abu-Amna Mahmoud , Gottfried Maya , Harkovsky Tatiana , Wolf Ido , Tepper Ella , Loewenthal Gil , Yellin Ben , Brody Yehuda , Dahan Nili , Yanko Maya , Lahav Coren , Harel Michal , Shoval Shani Raveh , Elon Yehonatan , Sela Itamar , Dicker Adam P. , Shaked Yuval
Published: January 2024

Introduction

Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.

Methods

Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes.

Results

The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network with CD8A serving as a central hub, suggesting T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage.

Conclusions

Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and potential biomarkers for outcome.
Musicians’ brains at rest: Multilayer network analysis of MEG data
Authors: Mandke Kanad N , Tewarie Prejaas , Adjamian Peyman , Schürmann Martin , Meier Jil
Published: January 2024

The ability to proficiently play a musical instrument requires a fine-grained synchronisation between several sensorimotor and cognitive brain regions. Previous studies have demonstrated that the brain undergoes functional changes with musical training, identifiable also in resting-state data. These studies analysed fMRI or electrophysiological frequency-specific brain networks in isolation. While the analysis of such “mono-layer” networks has proven useful, it fails to capture the complexities of multiple interacting networks. To this end, we applied a multilayer network framework for analysing publicly available data (Open MEG Archive) obtained with magnetoencephalography (MEG). We investigated resting-state differences between participants with musical training (n=31) and those without (n=31). While single-layer analysis did not demonstrate any group differences, multilayer analysis revealed that musicians show a modular organisation that spans visuomotor and frontotemporal areas, known to be involved in musical performance execution, which is significantly different from non-musicians. Differences between the two groups are primarily observed in the theta (6.5-8Hz), alpha1 (8.5-10Hz) and beta1 (12.5-16Hz) frequency bands.

We demonstrate that the multilayer method provides additional information that single-layer analysis cannot. Overall, the multilayer network method provides a unique opportunity to explore the pan-spectral nature of oscillatory networks, with studies of brain plasticity as a potential future application.
ABCA7-dependent Neuropeptide-Y signalling is a resilience mechanism required for synaptic integrity in Alzheimer’s disease
Authors: Tayran Hüseyin , Yilmaz Elanur , Bhattarai Prabesh , Min Yuhao , Wang Xue , Ma Yiyi , Nelson Nastasia , Kassara Nada , Cosacak Mehmet Ilyas , Dogru Ruya Merve , Reyes-Dumeyer Dolly , Reddy Joseph S , Qiao Min , Flaherty Delaney , Teich Andrew F. , Gunasekaran Tamil Iniyan , Yang Zikun , Tosto Giuseppe , Vardarajan Badri N , İş Özkan , Ertekin-Taner Nilüfer , Mayeux Richard , Kizil Caghan
Published: January 2024

Alzheimer’s disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for a better understanding of the disease mechanisms; yet the specific mechanism of action for those genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Using CRISPR/Cas9 gene editing, we generated a knockout model forabca7,orthologous to humanABCA7 –an established AD-risk gene. Theabca7+/-zebrafish showed reduced astroglial proliferation, synaptic density, and microglial abundance in response to amyloid beta 42 (Aβ42). Single-cell transcriptomics revealedabca7-dependent neuronal and glial cellular crosstalk through neuropeptide Y (NPY) signaling. Theabca7knockout reduced the expression ofnpy, bdnfandngfra, which are required for synaptic integrity and astroglial proliferation. With clinical data in humans, we showed reducedNPYin AD correlates with elevated Braak stage, predicted regulatory interaction betweenNPYandBDNF, identified genetic variants inNPYassociated with AD, found segregation of variants inABCA7, BDNFandNGFRin AD families, and discovered epigenetic changes in the promoter regions ofNPY, NGFRandBDNFin humans with specific single nucleotide polymorphisms inABCA7. These results suggest that ABCA7-dependent NPY signaling is required for synaptic integrity, the impairment of which generates a risk factor for AD through compromised brain resilience.

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Graphical abstract
Dissecting the heat stress altering immune responses and skin microbiota in fish in a recirculating aquaculture system in Singapore
Authors: Ng Tze Hann , Sobana M , Chew Xian Zhe , Nair D/O Madhaven Thiviya , Chow Jing Wen , Low Adrian , Seedorf Henning , Bastos Gomes Giana
Published: January 2024

Environmental factors, probiotics and feed additives affect microbiota diversity in fish. Water temperature disrupts the composition and diversity of microbiota, with temperature changes triggering stress and immune responses in fish. In Singapore, water heat treatment is used to control and prevent disease outbreaks in farmed fish. Although gut microbiota responses to heat stress have been reported, little is known about the effects of heat treatment on fish immune responses and fish skin microbiota dynamics. Over a 3-mo interval, we investigated microbiota dynamics and fish immune responses associated with a heat treatment practice in a commercial fish farm with a recirculating aquaculture system (RAS). Tank water temperature was raised to 37-39 °C for 1 hour, every 2 weeks. Tank water and fish microbial communities were analysed by 16S amplicon sequencing, and host molecular expressions were determined by qPCR. We inferred that heat treatment increased stress and immune responses that protected fish from opportunistic infections. However, overreaction to temperature stress can cause dysbiosis of the skin microbiota and death. We also suggested the value of the skin microbiota Pseudomonadota: Bacteroidota (P:B) ratio as a biomarker for aquaculture fish health.

IMPORTANCE

Aquaculture is an emerging economic activity to supply high-quality animal protein and reduce reliance on wild-caught fish products. Recently, there has been emphasis on intensive aquaculture, using a Recirculating Aquaculture System (RAS). In RAS, management of pathogens/parasites prevalence is a major challenge. Developing practical solutions for producing healthy juveniles in nursery systems will make profound contributions to sustainable aquaculture. In this study, we used an unconventional strategy, exposing juveniles to the pathobiome in the environment, followed by non-lethal heat shock treatments to enhance immunity. Short-term stress induced heat shock proteins that protected fish from opportunistic infections. We concluded that manipulating environmental-microbial-host interactions, together with enhanced functional capacity of fish immune response, has potential for disease control in aquaculture.
Offspring size resolves a latitudinal population growth rate paradox in rays and skates
Authors: Barrowclift Ellen , Bigman Jennifer S. , Digel Eric D. , Berggren Per , Dulvy Nicholas K.
Published: January 2024

As animal populations continue to decline, understanding global patterns of life histories will improve our predictions of species vulnerability and extinction risk to prioritise management. Sharks and rays are threatened with extinction due to overfishing, particularly in the tropics and sub-tropics. Metabolic theory suggests that warm-water species and populations will have a higher maximum intrinsic rate of population increase (rmax) and therefore will be less intrinsically sensitive to exploitation. However, recent empirical work has highlighted a paradox and shown that warm, shallow-water tropical rays have lowerrmaxthan cold, deep-water temperate skates. We test whether the different reproductive strategies of live-bearing rays and egg-laying skates explain this observed paradox by comparing variation inrmaxwith adult body mass, offspring size, temperature, and depth across 85 species of rays and skates. Our results show that the large relative offspring size of warm, shallow-water tropical rays better explains their greater intrinsic sensitivity (lowerrmax) compared to cold, deep-water temperate skates. This is consistent with life history theory that suggestsrmaxis greater in species with smaller relative offspring size. We hypothesise that the larger relative offspring size may be driven by greater predation risk in the tropics and may help explain global patterns of intrinsic sensitivity to overexploitation.
Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition
Authors: Tenge Victoria , Vijayalakshmi Ayyar B. , Ettayebi Khalil , Crawford Sue E. , Shen Yi-Ting , Neill Frederick H. , Atmar Robert L. , Estes Mary K.
Published: January 2024

Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause both endemic and pandemic acute viral gastroenteritis. Previously we reported that many strains of HuNoV require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. Of note, BA was not essential for replication of a pandemic-causing GII.4 HuNoV strain. Using the BA-requiring strain GII.3, we found that the hydrophobic BA GCDCA induces multiple cellular responses that promote replication in jejunal enteroids. Further, we found that chemical inhibition of the G-protein coupled receptor, sphingosine-1- phosphate receptor 2 (S1PR2), by JTE-013 reduced both GII.3 infection in a dose- dependent manner and cellular uptake in enteroids. Herein, we sought to determine if S1PR2 is required by other BA-dependent HuNoV strains and BA-independent GII.4, and if S1PR2 is required for BA-dependent HuNoV infection in other segments of the small intestine. We found JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not the GII.4 Sydney variant (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. GII.3 infection of duodenal, jejunal and ileal lines derived from the same individual was also reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoV exploit the activation of S1PR2 by BA to infect the entire small intestine.

Importance

Human noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA- independent strain, all required S1PR2 for infection. Additionally, BA-dependent infection required S1PR2 in multiple segments of the small intestine. Together these results indicate S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.