bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of high-resolution perfusion imaging using Arterial Spin Labelling MRI at 3 Tesla
Authors: Kashyap Sriranga , Oliveira ĺcaro Agenor Ferreira , Uludağ Kâmil
Published: August 2023

Cerebral blood flow (CBF) is a critical physiological parameter of brain health and it can be non-invasively measured with arterial spin labelling (ASL) MRI. In this study, we evaluated and optimised whole-brain, high-resolution ASL as an alternative to the low-resolution ASL employed in the routine assessment of CBF in both healthy participants and patients. Two high-resolution protocols (i.e., pCASL and FAIR-Q2TIPS (PASL) with 2 mm isotropic voxels) were compared to a default clinical pCASL protocol (3.4 × 3.4 × 4mm3), all of whom had an acquistion time of ≈ 5 min. We assessed the impact of high-resolution acquisition on reducing partial voluming and improving sensitivity to the perfusion signal, and evaluated the effectiveness of z-deblurring on the ASL data. We compared the quality of whole-brain ASL acquired using three available head coils with differing number of receive channels (i.e., 20, 32 and 64 ch). We found using higher coil counts (32 and 64 ch coils as compared to 20 ch) offer improved SNR and improved acceleration capabilities that are beneficial for ASL imaging at 3T. The inherent reduction in partial voluming effects with higher resolution acquisitions improves the resolving power of perfusion without impacting sensitivity. In conclusion, our results suggest that high-resolution ASL (2 - 2.5 mm isotropic) has the potential to become a new standard for perfusion imaging at 3 T and increase its adoption into clinical research and cognitive neuroscience applications.
Self-regulation of attention in children in a virtual classroom environment: a feasibility study
Authors: Guedj Carole , Tyrand Rémi , Badier Emmanuel , Planchamp Lou , Stringer Madison , Zimmermann Myriam Ophelia , Férat Victor , Leuchter Russia Ha-Vinh , Grouiller Frédéric
Published: August 2023

Attention is a crucial cognitive function that enables us to selectively focus on relevant information from the surrounding world to achieve our goals. When this sustained ability to direct attention is impaired, individuals face significant challenges in everyday life. This is the case for children with Attention Deficit Hyperactivity Disorder (ADHD), a complex neurodevelopmental disorder characterized by impulsive and inattentive behavior. While psychostimulant medications are currently the most effective treatment for ADHD, they often come with unwanted side effects, and sustaining the benefits can be difficult for many children. Therefore, it is imperative to explore non-pharmacological treatments that offer longer-lasting outcomes. Here, we proposed a groundbreaking protocol that combines electroencephalography-based neurofeedback (EEG-NFB) with virtual reality (VR) as an innovative approach to treating attention deficits. By integrating a virtual classroom environment, we aimed to enhance the transferability of attentional control skills while simultaneously increasing motivation and interest among children. The present study demonstrated the feasibility of this approach through an initial assessment involving a small group of healthy children, showcasing its potential for future evaluation in children diagnosed with ADHD. Encouragingly, the preliminary findings indicated high engagement rates and positive feedback from the children participating in the study. Additionally, the pre-and post-protocol assessments using EEG and fMRI recordings appeared to converge towards an improvement in attentional function. Although further validation is required to establish the efficacy of the proposed protocol, it represents a significant advancement in the field of neurofeedback therapy for ADHD. The integration of EEG-NFB and VR presents a novel avenue for enhancing attentional control and addressing behavioral challenges in children with ADHD.
Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity
Authors: Shi Wenqiang , Liu Nan , Liu Zexin , Yang Yuqi , Zeng Qiongya , Wang Yang , Song Luyao , Zhu Jianwei , Lu Huili
Published: August 2023

Immunocytokines, such as anti-PD-L1/IL-15, have shown promising efficacy in preclinical studies, but their clinical development still faces severe safety concerns, with the problem not easily overcome by simply reducing the cytokine activity. We proposed a next-generation immunocytokine concept of designing a tumor-conditional anti-PD-L1/IL-15 prodrug (LH05), which innovatively masks IL-15 with steric hindrance of its flanking moieties of anti-PD-L1 and IL-15Rα-sushi domain. The design successfully attenuated the ‘cytokine sink’ effect of IL-15 and resulted in a significantly reduced systemic toxicity when compared to wild-type anti-PD-L1/IL-15. LH05 would be specifically cleaved in the tumor microenvironment (TME) to release the active IL-15/IL-15Rα-sushi domain (ILR) in a proteolytic cleavage-dependent manner and exhibited potent antitumor effects in mouse syngeneic models. Mechanistically, the antitumor efficacy of LH05 was dependent on both innate and adaptive immunity, which altered the TME to Th1-type by recruiting and stimulating both NK and CD8+T cells and fired up cold tumors. LH05 also showed superior efficacy in restoring immunotherapy response in a refractory U251 xenograft model. Collectively, we introduced a novel next-generation immunocytokine strategy for tumor immunotherapy, contributing to the establishment of optimal treatment for patients with resistance to immune checkpoint inhibitors or cold tumors.
Hypothalamic CRH Neurons Modulate Sevoflurane Anesthesia and The Post-anesthesia Stress Responses
Authors: Jiang Shan , Chen Lu , Qu Wei-Min , Huang Zhi-Li , Chen Chang-Rui
Published: August 2023

General anesthesia is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with general anesthesia (GA) causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRHneurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRHneurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRHneurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRHneurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRHneurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

Impact statement

Discovery of critical brain nodes regulating sevoflurane general anesthesia and the post-anesthesia stress responses.
Highly scalable and standardized organ-on-chip platform with TEER for biological barrier modeling
Authors: Nguyen Hoang-Tuan , Rissanen Siiri-Liisa , Peltokangas Mimosa , Laakkonen Tino , Kettunen Jere , Barthod Lara , Sivakumar Ragul , Palojärvi Anniina , Junttila Pauliina , Talvitie Jussi , Bassis Michele , Nickels Sarah L. , Schwamborn Jens C. , Mosser Sebastien , Singh Prateek
Published: August 2023

The development of new therapies is hampered by the lack of predictive, and patient-relevant in vitro models. Organ-on-chip (OOC) technologies can potentially recreate physiological features and hold great promise for tissue and disease modeling. However, the non-standardized design of these chips and perfusion control systems has been a barrier to quantitative high-throughput screening (HTS).

Here we present a scalable OOC microfluidic platform for applied kinetic in vitro assays (AKITA) that is applicable for high, medium, and low throughput. Its standard 96-well plate and 384-well plate layouts ensure compatibility with existing laboratory workflows and high-throughput data collection and analysis tools. The AKITA plate is optimized for the modeling of vascularized biological barriers, primarily the blood-brain barrier, skin, and lung, with precise flow control on a custom rocker. The integration of trans-epithelial electrical resistance (TEER) sensors allows rapid and repeated monitoring of barrier integrity over long time periods.

Together with automated confocal imaging and compound permeability testing analyses, we demonstrate the flexibility of the AKITA platform for establishing human-relevant models for preclinical drug and precision medicine’s efficacy, toxicity, and permeability under physiological conditions.
The multi-Siglec inhibitor AL009 reprograms suppressive macrophages and activates innate and adaptive tumor immunity
Authors: Nalle Sam C. , Lam Helen , Leung Ling , Liang Spencer , Maslyar Daniel , Rosenthal Arnon
Published: August 2023

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are cell surface receptors that regulate innate and adaptive immunity, with inhibitory Siglecs promoting immune tolerance. In the tumor microenvironment, overexpression of sialic acid glycans exploits inhibitory Siglec signaling, leading to a cancer-permissive phenotype. AL009 is an engineered Siglec-9-Fc fusion molecule that functions as a sialic acid trap and reprograms suppressive macrophages to activate an anti-tumor immune response. AL009 treatment of human myeloid-derived suppressor cells, an in vitro model of tumor-associated macrophages, resulted in an increase in proinflammatory cytokines and chemokines, changes in cell surface markers, and potent relief of T cell inhibition in a co-culture assay. In syngeneic mouse (Mus musculus) tumor models, AL009 engineered with a mouse Fc (AL009m) reduced tumor growth as a monotherapy and in combination with the checkpoint inhibitor anti-PD-L1. In addition, AL009m synergized with the tumor-targeting therapy anti-TRP1 to reduce lung nodules in the B16-F10 intravenous model. Pharmacodynamic marker analysis in syngeneic and humanized mouse tumor models supported an AL009 mechanism of action based on reprogramming tumor-associated macrophages and enhanced T cell activation. Future clinical studies are warranted to further elucidate the safety and efficacy of AL009.
CellGO: A novel deep learning-based framework and webserver for cell type-specific gene function interpretation
Authors: Li Peilong , Wei Junfeng , Zhu Ying
Published: August 2023

Interpreting the function of genes and gene sets identified from omics experiments remains a challenge, as current pathway analysis tools often fail to account for complex interactions across genes and pathways under specific tissues and cell types. We introduce CellGO, a tool for cell type-specific gene functional analysis. CellGO employs a deep learning model to simulate signaling propagation within a cell, enabling the development of a heuristic pathway activity measuring system to identify cell type-specific active pathways given a single gene or a gene set. It is featured with additional functions to uncover pathway communities and the most active genes within pathways to facilitate mechanistic interpretation. This study demonstrated that CellGO can effectively capture cell type-specific pathways even when working with mixed cell-type markers. CellGO’s performance was benchmarked using gene knockout datasets, and its implementation effectively infers the cell type-specific pathogenesis of risk genes associated with neurodevelopmental and neurodegenerative disorders, suggesting its potential in understanding complex polygenic diseases. CellGO is accessible through a python package and a four-mode web interface for interactive usage with pretrained models on 71 single-cell datasets from human and mouse fetal and postnatal brains.
SCD inhibition preferentially eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy
Authors: Dembitz Vilma , Lawson Hannah , Burt Richard , Philippe Céline , James Sophie C. , Atkinson Samantha , Durko Jozef , Wang Lydia M. , Campos Joana , Magee Aoife M. S. , Woodley Keith , Austin Michael , Rio-Machin Ana , Casado-Izquierdo Pedro , Bewicke-Copley Findlay , Blanco Giovanny Rodriguez , Martins Diego Pereira , Oudejans Lieve , Boet Emeline , von Kriegsheim Alex , Schwaller Juerg , Finch Andrew J. , Patel Bela , Sarry Jean-Emmanuel , Tamburini Jerome , Schuringa Jan Jacob , Hazlehurst Lori , Copland John A. , Yuneva Mariia , Peck Barrie , Cutillas Pedro , Fitzgibbon Jude , Rouault-Pierre Kevin , Kranc Kamil , Gallipoli Paolo
Published: August 2023

Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients’ outcome. These features should be ideally present in many patients independently of mutational background. Here we identifyde novofatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML modelsin vitroandin vivo. We use the novel clinical grade SCD inhibitor SSI-4 to show that SCD inhibition induces AML cell deathviapleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. SSI-4 efficacy is enhanced by driving FA biosynthesisin vitrowhile stroma confers protective effects that extend toin vivomodels. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential.

One Sentence Summary

SCD inhibition is toxic to AML cells with high rates of fatty acid desaturation and in combination with chemotherapy prolongs survival in murine AML models.
Constraint and innovation in color evolution among species and among plumage patches in five avian radiations
Authors: Eliason Chad M. , Marcondes Rafael S. , Eaton Muir D. , Maia Rafael , Burns Kevin J. , Shultz Allison J.
Published: August 2023

Understanding the causes and limits of phenotypic diversification remains a key challenge in evolutionary biology. Color patterns are some of the most diverse phenotypes in nature. In birds, recent work within families has suggested that plumage complexity might be a key innovation driving color diversity. Whether these patterns hold at larger taxonomic scales remains unknown. Here, we assemble a large database of UV-Vis spectral data across five diverse clades of birds (45791 spectra, 1135 species). Using multivariate phylogenetic comparative methods, we compare evolutionary rates and color space occupancy (i.e., quantification of observed colors) among these clades. Novel color-producing mechanisms have enabled clades to occupy new regions of color space, but using more coloration mechanisms did not result in overall more color space occupancy. Instead, the use of more color-producing mechanisms resulted in faster rates of color evolution and less integrated color among plumage regions. Flexible Bayesian modeling further allowed us to assess the relationship between interpatch and interspecific directions of color variation. We find that interpatch variation generally diverges from interspecies cladewise trends in males but not females, suggesting developmental or selective constraints operating in females across evolutionary scales. By comparing rates among clades and assessing both interpatch and interspecies color variation, we reveal how innovations and constraints operate across evolutionary and developmental scales.
Pathogen lifestyle determines host genetic signature of quantitative disease resistance loci in oilseed rape (Brassica napus)
Authors: Jacott Catherine N. , Schoonbeek Henk-jan , Sidhu Gurpinder Singh , Steuernagel Burkhard , Kirby Rachel , Zheng Xiaorong , von Tiedermann Andreas , Macioszek Violetta K. , Kononowicz Andrzej K. , Fell Heather , Fitt Bruce D.L. , Mitrousia Georgia K. , Stotz Henrik U. , Ridout Christopher J. , Wells Rachel
Published: August 2023

Crops are affected by several pathogens, but these are rarely studied in parallel to identify common and unique genetic factors controlling diseases. Broad-spectrum quantitative disease resistance (QDR) is desirable for crop breeding as it confers resistance to several pathogen species.

Here, we use associative transcriptomics (AT) to identify candidate gene loci associated withBrassica napusQDR to four contrasting fungal pathogens:Alternaria brassicicola,Botrytis cinerea,Pyrenopeziza brassicaeandVerticillium longisporum.

We did not identify any loci associated with broad-spectrum QDR to fungal pathogens with contrasting lifestyles. Instead, we observed QDR dependent on the lifestyle of the pathogen—hemibiotrophic and necrotrophic pathogens had distinct QDR responses and associated loci, including some loci associated with early immunity. Furthermore, we identify a genomic deletion associated with resistance toV. longisporumand potentially broad-spectrum QDR.

This is the first time AT has been used for several pathosystems simultaneously to identify host genetic loci involved in broad-spectrum QDR.

We highlight candidate loci for broad-spectrum QDR with no antagonistic effects on susceptibility to the other pathogens studies as candidates for crop breeding.
Seasonally migratory songbirds have different historic population size characteristics than resident relatives
Authors: Winker Kevin , Delmore Kira
Published: August 2023

Modern genomic methods enable estimation of a lineage’s long-term effective population sizes back to its origins. This ability allows unprecedented opportunities to determine how adoption of a major life-history trait affects lineages’ populations relative to those without the trait. We used this novel approach to study the population effects of the life-history trait of seasonal migration across evolutionary time. Seasonal migration is a common life-history strategy, but its effects on long-term population sizes relative to lineages that don’t migrate are largely unknown. Using whole-genome data, we estimated effective population sizes over millions of years in closely related seasonally migratory and resident lineages in a group of songbirds. Our main predictions were borne out: Seasonal migration is associated with larger effective population sizes (Ne), greater long-term variation inNe, and a greater degree of initial population growth than among resident lineages. Initial growth periods were remarkably long (0.63-4.29 Myr), paralleling the expansion and adaptation phases of taxon cycles, a framework of lineage expansion and eventual contraction over time encompassing biogeography and evolutionary ecology. Heterogeneity among lineages is noteworthy, despite geographic proximity (including overlap) and close relatedness. Seasonal migration imbues these lineages with fundamentally different population size attributes through evolutionary time compared to closely related resident lineages.
Lack of early animal fossils: insights from taphonomic experiments on placozoans and their traces
Authors: Naimark E.B. , Lyupina Yu.V. , Nikitin M.A. , Finoshin A.D.
Published: August 2023

Placozoa are simple two-layered multicellular animals. Can such a simple animal preserve in the fossil record? The results of our taphonomic experiments showed that it is chemically possible; however, the chances of the presevation are negligible for two reasons. Firstly, the resistance of livingTrichoplaxto lethal factors turned out to be quite high. Secondly, post-mortem changes in the body ofTrichoplaxpreclude preservation. We observed these changes for the first time: their bodies immediately disintegrated into a cloud of individual dead cells, apparently unrecognizable in the fossil record. We hypothesized that the absence of a basement membrane, which unites each cell layer into the epithelia, is a key factor in this dramatic disintegration. This hypothesis adds an option to the explainations of the gap between the time of emergence of metazoan body fossils and the reconstructed time of metazoan divergence from a single-celled ancestor. However, it is theoretically possible to find ichnofossils ofTrichoplax-like locomotion. For the first time, we observed traces ofTrichoplaxon a soft substrate and identified a previously unknown type of traces. They were 3D chains of compacted round lumps of the substrate, similar in some features to the Precambrian meniscus ichnofossils.
An Integrated Platform for in vivo Electrophysiology in Spatial Cognition Experiments
Authors: Brea Guerrero A. , Oijala M. , Moseley S. C. , Tang T. , Fletcher F. , Zheng Y. , Sanchez L.M. , Clark B. J. , Mcnaughton B. L. , Wilber A. A.
Published: August 2023

Spatial cognition research requires behavioral paradigms that can distinguish between different navigational elements, such as allocentric (map-like) navigation and egocentric (e.g., body centered) navigation. To fill this need, we developed a flexible experimental platform that can be quickly modified without the need for significant changes to software and hardware. In this paper, we present this inexpensive and flexible behavioral platform paired with software which we are making freely available.

Our behavioral platform serves as the foundation for a range of experiments, and though developed for assessing spatial cognition, it also has applications in the non-spatial domain of behavioral testing. There are two components of the software platform, ‘Maze’ and ‘Stim Trigger’. Both programs can work in conjunction with electrophysiology acquisition systems, allowing for precise time stamping of neural events with behavior. The Maze program includes functionality for automatic reward delivery based on user defined zones. ‘Stim Trigger’ permits control of brain stimulation via any equipment that can be paired with an Arduino board. We seek to share our software and leverage the potential by expanding functionality in the future to meet the needs of a larger community of researchers.

Significance Statement

This paper presents an innovative and cost-effective behavioral platform designed to distinguish between different navigational elements, addressing the crucial need for better spatial cognition research paradigms. The platform’s flexibility allows for quick modifications without major software or hardware changes. Additionally, the freely available software, comprising ‘Maze’ and ‘Stim Trigger’ components, enables precise time stamping of neural events with behavior, while facilitating automatic reward delivery and brain stimulation control. Beyond spatial cognition assessment, the platform’s adaptability extends to non-spatial behavioral testing. By openly sharing this software, the authors aim to foster collaboration and encourage future developments, promoting its application to a broader community of researchers. This platform represents a significant advancement in spatial cognition research and behavioral experimentation methods.
Ciliary ARL13B prevents obesity in mice
Authors: Terry Tiffany T. , Gigante Eduardo D. , Alexandre Coralie M. , Brewer Kathryn M. , Engle Staci E. , Yue Xinyu , Berbari Nicolas F. , Vaisse Christian , Caspary Tamara
Published: August 2023

Cilia are near ubiquitous small, cellular appendages critical for cell-to-cell communication. As such, they are involved in diverse developmental and homeostatic processes, including energy homeostasis. ARL13B is a regulatory GTPase highly enriched in cilia. Mice expressing an engineered ARL13B variant, ARL13BV358Awhich retains normal biochemical activity, display no detectable ciliary ARL13B. Surprisingly, these mice become obese. Here, we measured body weight, food intake, and blood glucose levels to reveal these mice display hyperphagia and metabolic defects. We showed that ARL13B normally localizes to cilia of neurons in specific brain regions and pancreatic cells but is excluded from these cilia in theArl13bV358A/V358Amodel. In addition to its GTPase function, ARL13B acts as a guanine nucleotide exchange factor (GEF) for ARL3. To test whether ARL13B’s GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing ARL13BR79Q, a variant that lacks ARL13B GEF activity for ARL3. We found no difference in body weight. Taken together, our results show that ARL13B functions within cilia to control body weight and that this function does not depend on its role as a GEF for ARL3. Controlling the subcellular localization of ARL13B in the engineered mouse model, ARL13BV358A, enables us to define the cilia-specific role of ARL13B in regulating energy homeostasis.
Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts
Authors: Sychev Zoi E. , Day Abderrahman , Bergom Hannah E. , Larson Gabrianne , Ali Atef , Ludwig Megan , Boytim Ella , Coleman Ilsa , Corey Eva , Plymate Stephen R. , Nelson Peter S. , Hwang Justin H. , Drake Justin M.
Published: August 2023

Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
The interplay of cortical magnification and perceptual load in the visual processing of task-irrelevant biological motion across the visual field
Authors: Tunca Murat Batu , Rezaki Ada Dilek , Nizamoğlu Hilal , Urgen Burcu A.
Published: August 2023

Perceptual load theory argues that attention is a limited resource and stimuli cannot be processed if there is insufficient perceptual capacity available. Although attention is known to modulate biological motion processing, whether this modulation differs among different perceptual loads remains unknown. To answer this question, three experiments are conducted in which biological motion is utilized as a task-irrelevant distractor. The first experiment showed that biological motion is processed differently than non-biological motion across different perceptual load conditions. The second experiment investigated the effect of attention on biological motion processing, revealing that higher eccentricities enhance biological motion processing but only when the perceptual load is low. The last experiment investigated the same question but with cortically magnified stimuli. It found that when the stimuli are cortically magnified, the enhancement effect of eccentricity is present regardless of the perceptual load. Overall, the results suggest that perceptual load modulates the processing of task-irrelevant biological motion and interacts with other factors (such as eccentricity) that modulate this processing.
Genetic Dependence and Genetic Diseases
Authors: Li Bin , Bian Wen-Jun , Zhou Peng , Wang Jie , Fan Cui-Xia , Xu Hai-Qing , Yu Lu , He Na , Shi Yi-Wu , Su Tao , Yi Yong-Hong , Liao Wei-Ping
Published: August 2023

The human life depends on the function of proteins that are encoded by about twenty-thousand genes. The gene-disease associations in majority genes are unknown and the mechanisms underlying pathogenicity of genes/variants and common diseases remain unclear. We studied how human life depends on the genes, i.e., the genetic-dependence, which was classified as genetic-dependent nature (GDN, vital consequence of abolishing a gene), genetic-dependent quantity (GDQ, quantitative genetic function required for normal life), and genetic-dependent stage (GDS, temporal expression pattern). Each gene differs in genetic-dependent features, which determines the gene-disease association extensively. The GDN is associated with the pathogenic potential/feature of genes and the strength of pathogenicity. The GDQ-damage relation determines the pathogenicity of variants and subsequently the pathogenic genotype, phenotype spectrum, and inheritance of variants. The GDS is mainly associated with the onset age/evolution/outcome and the nature of genetic disorders (disease/susceptibility). The varied and quantitative genetic-dependent feature of genome explains common mild phenotype/susceptibility. The genetic-dependence discloses the mechanisms underlying pathogenicity of gene/variants and common diseases.

One sentence summary

Genetic dependent feature differs in genes and determines pathogenicity of genes/variants and the clinical features of genetic diseases.
piikun: An Information Theoretic Toolkit for Analysis and Visualization of Species Delimitation Metric Space
Authors: Sukumaran Jeet , Meila Marina
Published: August 2023

Background

Existing software for comparison of species delimitation models do not provide a (true) metric or distance functions between species delimitation models, nor a way to compare these models in terms of relative clustering differences along a lattice of partitions.

Results

piikunis a Python package for analyzing and visualizing species delimitation models in an information theoretic framework that, in addition to classic measures of information such as the entropy and mutual information [1], provides for the calculation of the variation of information criterion [2], a true metric or distance function for species delimitation models that is aligned with the lattice of partitions.

Conclusions

piikunis available under the MIT license from its public repository (https://github.com/jeetsukumaran/piikun), and can be installed locally using the Python package manager ‘pip’.
Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2
Authors: Ibtisam Ibtisam , Kisselev Alexei F.
Published: August 2023

Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.
Estimating the reproduction number,R0, from agent-based models of tree disease spread
Authors: Wadkin Laura E , Holden John , Ettelaie Rammile , Holmes Melvin J , Smith James , Golightly Andrew , Parker Nick G , Baggaley Andrew W
Published: August 2023

Tree populations worldwide are facing an unprecedented threat from a variety of tree diseases and invasive pests. Their spread, exacerbated by increasing globalisation and climate change, has an enormous environmental, economic and social impact. Computational agent-based models are a popular tool for describing and forecasting the spread of tree diseases due to their flexibility and ability to reveal collective behaviours. In this paper we present a versatile agentbased model with a Gaussian infectivity kernel to describe the spread of a generic tree disease through a synthetic treescape. We then explore several methods of calculating the basic reproduction numberR0, a characteristic measurement of disease infectivity, defining the expected number of new infections resulting from one newly infected individual throughout their infectious period. It is a useful comparative summary parameter of a disease and can be used to explore the threshold dynamics of epidemics through mathematical models. We demonstrate several methods of estimatingR0through the agent-based model, including contact tracing, inferring the Kermack-McKendrick SIR model parameters using the linear noise approximation, and an analytical approximation. As an illustrative example, we then use the model and each of the methods to calculate estimates ofR0for the ash dieback epidemic in the UK.
AAontology: An ontology of amino acid scales for interpretable machine learning
Authors: Breimann Stephan , Kamp Frits , Steiner Harald , Frishman Dmitrij
Published: August 2023

Amino acid scales are crucial for protein prediction tasks, many of them being curated in the AAindex database. Despite various clustering attempts to organize them and to better understand their relationships, these approaches lack the fine-grained classification necessary for satisfactory interpretability in many protein prediction problems.

To address this issue, we developed AAontology—a two-level classification for 586 amino acid scales (mainly from AAindex) together with an in-depth analysis of their relations—using bag-of-word-based classification, clustering, and manual refinement over multiple iterations. AAontology organizes physicochemical scales into 8 categories and 67 subcategories, enhancing the interpretability of scale-based machine learning methods in protein bioinformatics. Thereby it enables researchers to gain a deeper biological insight. We anticipate that AAontology will be a building block to link amino acid properties with protein function and dysfunctions as well as aid informed decision-making in mutation analysis or protein drug design.
Functional Adaptations of Endogenous Retroviruses to theDrosophilaHost Underlie their Evolutionary Diversification
Authors: Senti Kirsten-Andre , Handler Dominik , Rafanel Baptiste , Kosiol Carolin , Schlötterer Christian , Brennecke Julius
Published: August 2023

Transposable elements profoundly affect the biology and evolution of their hosts, yet their own evolutionary dynamics remain poorly understood. Here, we investigate insect endogenous retroviruses (iERVs), a monophyletic group of LTR retrotransposons that have acquired the trait of infectivity, likely through capture of a Baculovirusenvelopegene. InDrosophilaovaries, iERVs with functionalenvelopehave adapted theircis-regulatory sequences to be expressed in any somatic cell type, from where they infect the germline. Strikingly, related retroviruses show distinct expression patterns, indicating niche partitioning. In contrast, all non-infectious iERVs that emerged through secondaryenvelope-loss are specifically expressed in the germline. Co-evolving with iERVs, the genome-protecting piRNA pathway has assimilated iERV promoter and sequence information into piRNA clusters, underscoring the functional significance of iERV expression in somatic niches. We propose that the evolutionary innovation of cell-to-cell infectivity has triggered the adaptive radiation of iERVs through trait diversification and antagonistic virus-host interactions, processes that likely underpin niche-specific expression of endogenous retroviruses in vertebrates as well.
TIM3 is a context-dependent co-regulator of cytotoxic T cell function
Authors: Alamir Hanin , Wong Carissa C.W. , Alsubaiti Amal , Edmunds Grace L. , Grant Tressan , Alsulaimani Safaa , Boyd James , Holland Christopher J. , Morgan David J. , Gallimore Awen M. , Wülfing Christoph
Published: August 2023

TIM3 is a co-regulatory receptor that is highly expressed on multiple immune cell types, including on T cells after prolonged exposure to antigen. It marks functionally suppressed cytotoxic T lymphocytes (CTL) in the tumor microenvironment. However, it is unresolved whether TIM3 acts directly on suppressed CTL. Moreover, the nature of TIM3 ligands remains controversial. Paradoxically, TIM3 combines inhibitory function in vivo with costimulatory signaling capability in vitro. Here we have investigated TIM3 in the direct interaction of suppressed murine and human CTL with tumor target cell using spheroids. TIM3 directly inhibited the function of such CTL. TIM3 regulated the ability of suppressed CTL to polarize their cytoskeleton as a required step in cytolysis. Expression of CEACAM1 in cis, on the CTL, blocked TIM3 function, expression of CEACAM1 and galectin9 in trans, on the tumor target cells, enhanced TIM3 function. TIM3 only functioned as an inhibitory receptor on the spheroid-suppressed CTL, not on active CTL in a two-dimensional tissue culture model. These data suggest that TIM3 amplifies T cell function, serving as a co-inhibitory or co-stimulatory receptor depending on the functional context of the T cell it is expressed on.
Optogenetic strategies for optimizing the performance of biosensors of membrane phospholipids in live cells
Authors: Yao Yuanfa , Lou Xiayan , Jin Luhong , Sun Weiyun , Liu Jingfang , Chen Yunyue , Cheng Sunying , Zhao Tengjiao , Ke Shuwei , Zhang Luhao , Xu Yingke , He Lian , Li Hanbing
Published: August 2023

High-performance biosensors play a crucial role in elucidating the intricate spatiotemporal regulatory roles and dynamics of membrane lipids. However, enhancing their sensitivity and substrate-detecting capabilities remains a significant challenge. Here, we presented optogenetic-based strategies to optimize phospholipid biosensors. These strategies involved pre-sequestering unbound probes in the cell nucleus to minimize background signals in the cytoplasm. These stored probes could be released from the nucleus in response to blue light according to experimental requirements. Furthermore, we employed optically-controlled phase separation to generate punctate probes that amplified signals and facilitated the visualization of phospholipids in cells. These improved phospholipid biosensors hold great potential for enhancing our understanding of the spatiotemporal dynamics and regulatory roles of membrane lipids in live cells and this methodological insights might be valuable for developing other high-performance biosensors.
Comparing auditory and visual aspects of multisensory working memory using bimodally matched feature patterns
Authors: Turpin Tori , Uluç Işıl , Kotlarz Parker , Lankinen Kaisu , Mamashli Fahimeh , Ahveninen Jyrki
Published: August 2023

Working memory (WM) reflects the transient maintenance of information in the absence of external input, which can be attained via multiple senses separately or simultaneously. Pertaining to WM, the prevailing literature suggests the dominance of vision over other sensory systems. However, this imbalance may be stemming from challenges in finding comparable stimuli across modalities. Here, we addressed this problem by using a balanced multisensory retro-cue WM design, which employed combinations of auditory (ripple sounds) and visuospatial (Gabor patches) patterns, adjusted relative to each participant’s discrimination ability. In three separate experiments, the participant was asked to determine whether the (retro-cued) auditory and/or visual items maintained in WM matched or mismatched the subsequent probe stimulus. In Experiment 1, all stimuli were audiovisual, and the probes were either fully mismatching, only partially mismatching, or fully matching the memorized item. Experiment 2 was otherwise same as Experiment 1, but the probes were unimodal. In Experiment 3, the participant was cued to maintain only the auditory or visual aspect of an audiovisual item pair. In two of the three experiments, the participant matching performance was significantly more accurate for the auditory than visual attributes of probes. When the perceptual and task demands are bimodally equated, auditory attributes can be matched to multisensory items in WM at least as accurately as, if not more precisely than, their visual counterparts.
Evaluating vaccine-elicited antibody activities againstNeisseria gonorrhoeae:cross-protective responses elicited by the 4CMenB meningococcal vaccine
Authors: Gray Mary C. , Thomas Keena S. , Lamb Evan R. , Werner Lacie M. , Connolly Kristie L. , Jerse Ann E. , Criss Alison K.
Published: August 2023

The bacterial pathogenNeisseria gonorrhoeaeis an urgent global health problem due to increasing numbers of infections, coupled with rampant antibiotic resistance. Vaccines against gonorrhea are being prioritized to combat drug-resistantN. gonorrhoeae.Meningococcal serogroup B vaccines such as 4CMenB are predicted by epidemiology studies to cross-protect individuals from natural infection withN. gonorrhoeaeand elicit antibodies that cross-react withN. gonorrhoeae.Evaluation of vaccine candidates for gonorrhea requires a suite of assays for predicting efficacy in vitro and in animal models of infection, including the role of antibodies elicited by immunization. Here we present assays to evaluate antibody functionality after immunization: antibody binding to intactN. gonorrhoeae,serum bactericidal activity, and opsonophagocytic killing activity using primary human neutrophils (polymorphonuclear leukocytes). These assays were developed with purified antibodies againstN. gonorrhoeaeand used to evaluate serum from mice that were vaccinated with 4CMenB or given alum as a negative control. Results from these assays will help prioritize gonorrhea vaccine candidates for advanced preclinical to early clinical study and will contribute to identifying correlates and mechanisms of immune protection againstN. gonorrhoeae.
Retinoid X Receptor activation prevents diabetic retinopathy in murine models
Authors: Dorofeeva Iuliia , Zhylkibayev Assylbek , Saltykova Irina V. , Atigadda Venkatram , Adhikari Bibek , Gorbatyuk Oleg , Grant Maria B. , Gorbatyuk Marina
Published: August 2023

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess UAB126 effect in progression of diabetic retinopathy (DR) in rodent models of Type1 diabetes (T1D), streptozotocin-induced, and Type2 diabetes (T2D), the db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar, and expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.
Identification of omega-3 oxylipins in human milk-derived extracellular vesicles with pro-resolutive actions in gastrointestinal inflammation
Authors: Gómez-Ferrer Marta , Amaro-Prellezo Elena , Albiach-Delgado Abel , Ten-Domenech Isabel , Kuligowski Julia , Sepúlveda Pilar
Published: August 2023

Premature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. We isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and and in a murine model of inflammatory bowel disease (IBD). HM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA (ω3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both ω3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis. Incorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.
Reconstitution of ORP-mediated lipid exchange process coupled to PI(4)P metabolism
Authors: Fuggetta Nicolas , Rigolli Nicola , Magdeleine Maud , Seminara Agnese , Drin Guillaume
Published: August 2023

Lipid distribution in the eukaryotic cells depends on tight couplings between lipid transfer and lipid metabolism. Yet these couplings remain poorly described. Notably, it is unclear to what extent lipid exchangers of the OSBP-related proteins (ORPs) family, coupled to PI(4)P metabolism, contribute to the formation of sterol and phosphatidylserine gradient between the endoplasmic reticulum (ER) and other cell regions. To address this question, we have examinedin vitrothe activity of Osh4p, a representative ORP, between Golgi mimetic membranes in which PI(4)P is produced by a PI 4-kinase and ER mimetic membranes in which PI(4)P is hydrolyzed by the phosphatase Sac1p. Using quantitative, real-time assays, we demonstrate that Osh4p creates a sterol gradient between the two membranes by sterol/PI(4)P exchange as soon as a PI(4)P gradient is generated at this interface following ATP addition, and define how much PI(4)P must be synthesized for this process. Then, using a kinetic model supported by ourin vitrodata, we estimate to what extent PI(4)P metabolism can drive lipid transfer in cells. Finally, we show that Sec14p, by transferring phosphatidylinositol between membranes, can support the synthesis of PI(4)P and the creation of a sterol gradient by Osh4p. These results indicate to what extent ORPs, under the control of PI(4)P metabolism, can distribute lipids in the cell.