bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpretable antibody-antigen interaction prediction by introducing route and priors guidance
Authors: Liu Yutian , Nie Zhiwei , Chen Jie , Zheng Xinhao , Fu Jie , Liu Zhihong , Liu Xudong , Xu Fan , Huang Xiansong , Zhang Wen-Bin , Ma Siwei , Gao Wen , Tian Yonghong
Published: March 2024

With the application of personalized and precision medicine, more precise and efficient antibody drug development technology is urgently needed. Identification of antibody-antigen interactions is crucial to antibody engineering. The time-consuming and expensive nature of wet-lab experiments calls for efficient computational methods. Taking into account the non-overlapping advantage of current structure-dependent and sequence-only computational methods, we propose an interpretable antibody-antigen interaction prediction method, S3AI. The introduction of structural knowledge, combined with explicit modeling of chemical rules, establishes a ‘sequence-to-function’ route in S3AI, thereby facilitating its perception of intricate molecular interactions through providing route and priors guidance. S3AI significantly and comprehensively outperforms the state-of-the-art models and exhibits excellent generalization when predicting unknown antibody-antigen pairs, surpassing specialized prediction methods designed for out-of-distribution generalization in fair comparisons. More importantly, S3AI captures the universal pattern of antibody-antigen interactions, which not only identifies the CDRs responsible for specific binding to the antigen but also unearths the importance of CDR-H3 for the interaction. Structure-free design and superior performance make S3AI ideal for large-scale, parallelized antibody optimization and screening, enabling the rapid and precise identification of promising candidates within the extensive antibody space.
PIGOME: An Integrated and Comprehensive Multi-omics Database for Pig Functional Genomics Studies
Authors: Han Guohao , Yang Peng , Zhang Yongjin , Li Qiaowei , Fan Xinhao , Chen Ruipu , Yan Chao , Zeng Mu , Yang Yalan , Tang Zhonglin
Published: March 2024

In addition to being a major source of animal protein, pigs are important model for the study of development and diseases in humans. During the past two decades, thousands of high-throughput sequencing studies in pigs have been performed using a variety of tissues from different breeds and developmental stages. However, the multi-omics database specifically used for pig functional genomic research is still limited. Here, we present a user-friendly database of pig multi-omics named PIGOME. PIGOME contains seven types of pig omics datasets, including whole-genome sequencing, RNA-seq, miRNA-seq, ChIP-seq, ATAC-seq, bisulfite-seq, and MeRIP-seq, from 6,901 samples and 392 projects with manually curated metadata, integrated gene annotation, and quantitative trait locus information. Furthermore, various ‘explore and browse’ functions have been established for user-friendly access to omics information. PIGOME implemented several tools to visualize genomic variants, gene expression, and epigenetic signals of a given gene in the pig genome, enabling efficient exploration of spatial-temporal expression/epigenetic pattern, function, regulatory mechanism, and associated economic traits. Collectively, PIGOME provides valuable resources for pig breeding and is helpful for human biomedical research. PIGOME is available athttps://pigome.com.
Dissociable representations of decision variables within subdivisions of macaque orbitofrontal and ventrolateral frontal cortex
Authors: Stoll Frederic M. , Rudebeck Peter H.
Published: March 2024

Ventral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subregions of VFC in macaque monkeys performing a two-choice probabilistic task for different fruit juices outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral subdivision 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within 12o, by contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subregions, while the properties of the reward, such as its flavor, were more strongly represented in areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates.

SIGNIFICANCE STATEMENT

Ventral frontal cortex (VFC) is essential for flexible decision-making and is composed of many anatomically defined subdivisions. How neural representations related to decision-making vary or not between these subdivisions is unclear. Here we recorded single neuron activity from eight anatomically distinct subdivisions of VFC while macaques made choices between stimuli based on the probability of receiving different flavored fruit juices. We report that neural representations across these subdivisions were dissociable. Area 12l exhibiting the most integrated representations of decision variables at the level of single neurons. By contrast, activity in area 12o was closely related to reward probability whereas activity in area 11m/l and 13m represented juice flavor. Thus, neural representations are distinct across anatomically separable parts of VFC.
Regenerative clustering of Enteroblasts in theDrosophilamidgut revealed by a morphometric analysis
Authors: Zhu Fionna , Murray Michael J.
Published: March 2024

Enteroblasts (EBs) are the cells responsible for the maintenance of the epithelium that lines the adult midgut inDrosophila. In response to cell death and damage, EBs undergo a Mesenchymal-Epithelial-Transition (MET) as they incorporate into the epithelium and differentiate into enterocytes (ECs). The morphogenetic mechanisms driving this MET process are not well understood. To improve phenotypic analysis of EBs, we established an analysis pipeline that uses machine learning segmentation to produce a reliable and automated quantification of cellular morphology and spatial distributions. EB morphology and fate is visualised using the Repressible Dual Differential stability cell Marker (ReDDM) approach. We show that wildtype EB cells exhibit a bimodal distribution pattern in which midguts fall into two categories: “quiescent” guts, in which EBs are evenly spaced out and newly formed ECs are uncommon, and “regenerative” guts, in which EBs are clustered and new ECs are prevalent. Using this system we first show that RNAi knockdown of Septate Junction proteins disrupts normal EB morphology and spatial distribution. With time-lapse imaging, we have also established that EBs are motile in nature, and when artificial tissue damage was introduced, exhibited increased cytoplasmic movements, and formed distinct clusters. We then demonstrate the utility of our pipeline in a small candidate screen for genes that might mediate EB clustering. Based on our results, we propose a working model that links the dynamic behaviour of EBs with midgut regeneration.
Monensin as potential drug for treatment of SLeX-positive tumors
Authors: Costa Ana F. , Senra Emanuel , Campos Diana , Faria-Ramos Isabel , Santos-Ferreira Liliana , Lamas Sofia , Gomes Joana , Pinto Filipe , Teixeira Andreia , Abrantes Rafaela , Duarte Henrique O. , Pacheco Mariana , Pinto Marta T. , Maia André F. , Pombinho António , Barros Rita , Fernandes Verónica , Casanova-Gonçalves Frederica , Sousa Fabiana , Barbosa José , Pereira Luísa , Carneiro Fátima , Reis Celso A. , Gomes Catarina
Published: March 2024

Colorectal (CRC) and gastric (GC) cancers remain the top lethal cancers and targeted therapies in this setting are still very limited. Sialyl Lewis X (SLeX), a cancer-associated glycan highly expressed in both CRC and GC, plays a crucial role in cancer cell dissemination and metastasis. Thus, presenting a promising but still underexplored therapeutic target. In this work, we performed a high-throughput screening (HTS) approach to identify potential inhibitors of SLeX expression on cancer cells. Two libraries including a total of 7836 compounds were screened and monensin emerged as a promising SLeX inhibitor. Monensin promoted structural alterations in the secretory pathway, particularly at the Golgi apparatus, impacting proteinO-glycosylation and secretion. RNAseq transcriptomic analysis uncovered significant alterations in Gene Ontology (GO) terms associated with protein misfolding, target to the membrane, as well as, epithelial cell-cell adhesion protein.In vitrostudies showed that, upon treatment with monensin, SLeX-positive cancer cells showed reduced viability, concomitant with decreased motility and invasive capacities. Usingin vivoxenograft models of chick embryo chorioallantoic membrane (CAM) and nude mice, revealed that monensin reduced tumor formation and invasion. Pre-clinical validation using gastric cancer patient-derived organoids (PDOs) and organoid xenotransplants in mice further underscored the clinical potential of monensin in suppressing the growth of SLeX- positive tumors. Overall, our findings set the ground for further evaluation of monensin as a novel therapeutic agent in GC and CRC in the clinical setting.
The PRIME-NL study: evaluating a complex healthcare intervention for people with Parkinson’s disease in a dynamic environment
Authors: Maas Bart R. , van den Bergh Robin , van den Berg Sanne W. , Hulstein Eveline , Stadhouders Niek , Jeurissen Patrick P.T. , de Vries Nienke M. , Bloem Bastiaan R. , Munneke Marten , Ben-Shlomo Yoav , Darweesh Sirwan K.L.
Published: March 2024

Background

An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants.

Objective

To describe which methodological adjustments were made to the study protocol because of these developments.

Methods

We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan.

Discussion

This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.
Effects of silver diamine fluoride on oral bacteriome and mycobiome: a randomized clinical trial
Authors: Manerkar Mayura , Cruz de Jesus Vivianne , Mittermuller Betty-Anne , Lee Victor H. K. , Singh Sarbjeet , Bertone Mary , Chelikani Prashen , Schroth Robert J.
Published: March 2024

Introduction

Silver diamine fluoride (SDF) is a simple and non-invasive agent used to arrest early childhood caries (ECC). This study aimed to investigate potential changes to the oral microbiome in children with ECC who were treated with SDF at three different frequency regimens.

Methods

Forty-five children (n=15 per group) with ECC were recruited into a randomized clinical trial testing three different treatment frequency regimens of SDF. A total of 195 carious lesions were treated with two applications of 38% SDF and 5% sodium fluoride varnish (NaFV) and assessed over three study visits (one month (Regimen 1M), four months (Regimen 4M), or six months (Regimen 6M) apart). Dental plaque samples were collected at each visit. Sequencing of the V4-16S rRNAandITS1 rRNAgenes were used to study the supragingival plaque microbiome.

Results

The overall arrest rates for treated carious lesions were 75.9% at Visit 2 and 92.8% at Visit 3. Arrest rates were higher for all lesions after two applications of SDF with NaFV, and applications one month and four months apart had higher arrest rates (95.9% and 98.5%) than six months (81.1%) apart. The microbial diversity analyses showed no significant differences in the overall microbiome after SDF treatment. However, significant changes in the abundance of specific bacteria and fungi, particularlyLactobacillus spp.,Bifidobacterium spp., and Candida spp.were observed after treatment. Furthermore, overabundance ofStreptococcus mutansandCandida dubliniensisat baseline was observed in children who had at least one caries lesion not arrested after one SDF application, compared to those who had 100% arrest rates.

Conclusion

SDF with NaFV applications were an effective modality for arresting ECC, with higher arrest rates after two SDF applications. No loss of diversity but significant changes in the abundance of specific bacteria and fungi were consequences of SDF treatment.
Symmetry breaking and fate divergence during lateral inhibition inDrosophila
Authors: Phan Minh-Son , Kim Jang-mi , Picciotto Cara , Couturier Lydie , Veits Nisha , Mazouni Khallil , Schweisguth François
Published: March 2024

Lateral inhibition by Notch mediates the adoption of alternative cell fates amongst groups of initially equipotent cells, leading to the formation of regular patterns of cell fates in many tissues across species. Genetic and molecular studies have established a model whereby an intercellular negative feedback loop serves to amplify small stochastic differences in Notch activity, thereby generating ordered salt-and-pepper patterns. InDrosophila, lateral inhibition selects Sensory Organ Precursor cells (SOPs) from clusters of proneural cells that are competent to become neural through the expression of proneural transcription factors. When and how symmetry breaking occurs during lateral inhibition remains, however, to be addressed. Here, we have used the pupal abdomen as an experimental model to study the dynamics of lateral inhibition inDrosophila. Using quantitative live imaging, we monitored the accumulation of the transcription factor Scute (Sc), used as a surrogate for proneural competence and adoption of the SOP fate. We found that fate symmetry breaking occurred at low Sc levels and that fate divergence was not preceded by a prolonged phase of low or intermediate level of Sc accumulation. The relative size of the apical area did not appear to bias this fate choice. Unexpectedly, we observed at low frequency (10%) pairs of cells that are in direct contact at the time of SB and that adopt the SOP fate. These lateral inhibition defects were corrected via cellular rearrangements. Analysis of Sc dynamics in wild-type and genetically mosaic pupae further revealed that cell-to-cell variations in Sc levels promoted fate divergence, thereby providing experimental support for the intercellular negative feedback loop model.
Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape
Authors: Wu Xinyu , Go Margareta , Nguyen Julie V. , Kuchel Nathan W. , Lu Bernadine G.C. , Lowes Kym N. , Calleja Dale J. , Mitchell Jeffrey P. , Lessene Guillaume , Komander David , Call Matthew E. , Call Melissa J.
Published: March 2024

SARS-CoV-2, the causative agent of COVID-19, is responsible for the recent global pandemic and remains a major source of mortality. Papain-like protease (PLpro) is a target for SARS-CoV-2 inhibitor development, as it is not only essential for viral replication through cleavage of the viral poly-proteins pp1a and pp1ab, but also has de-ubiquitylation and de-ISGylation activities, which can affect innate immune responses. To understand the features of PLpro that dictate activity and anticipate how emerging PLpro variants will affect function, we employed Deep Mutational Scanning to evaluate the mutational effects on enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify all mutations in neighboring residues that support or ablate activity. We characterize residues responsible for substrate binding and demonstrate that although the blocking loop is remarkably tolerant to nearly all mutations, its flexibility is important for enzymatic function. We additionally find a connected network of mutations affecting function but not structure that extends far from the active site. Using our DMS libraries we were able to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
Globally distributed bacteriophage genomes reveal mechanisms of tripartite phage-bacteria-coral interactions
Authors: Wallace Bailey A. , Varona Natascha S , Hesketh-Best Poppy , Silveira Cynthia
Published: March 2024

Reef-building corals depend on an intricate community of microorganisms for functioning and resilience. Bacteriophages are the most abundant and diverse members of these communities, yet very little is known about their functions in the holobiont due to methodological limitations that have prevented the recovery of high-quality viral genomes and bacterial host assignment from coral samples. Here, we introduce a size-fractionation approach which increased bacterial and viral recovery in coral metagenomes by 9-fold and 3-fold, respectively, and enabled the assembly and binning of bacterial and viral genomes at relatively low sequencing coverage. We combined these viral genomes with those derived from 677 publicly available metagenomes, viromes, and bacterial isolates from stony corals to build a Global Coral Virome Database of over 20,000 viral genomes and genome fragments spanning four viral realms. The tailed bacteriophage families Kyanoviridae and Ackermannviridae were the most abundant, replacing the since-abolished groups Podoviridae and Siphoviridae. Prophage and CRISPR spacer linkages between these viruses and 626 bacterial metagenome-assembled genomes and bacterial isolates showed that most viruses infected Alphaproteobacteria, the most abundant class, and less abundant taxa like Halanaerobiia and Bacteroidia. A host-phage-gene network identified keystone viruses with the genomic capacity to eavesdrop and modulate bacterial quorum sensing, interfere with sulfur cycling, and direct molecular interactions with eukaryotic cells through the release of extracellular effectors. This study reveals the basis of bacteriophage roles in modulating ecological interactions not only among bacterial community members but also directly affecting tripartite interactions with the coral host and its endosymbiotic algae.
Neuroprotective role of Hippo signaling by microtubule stability control inC. elegans
Authors: Lee Hanee , Kang Junsu , Lee Sang-Hee , Lee Dowoon , Chung Christine H. , Lee Junho
Published: March 2024

The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons inC. elegans. Loss ofwts-1/LATS resulted in premature deformation of touch neurons and impaired touch responses in ayap-1/YAP-dependent manner. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule stabilizing genes alleviated the neuronal deformation ofwts-1mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzymespas-1also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in bothwts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
Construction of invariant features for time-domain EEG/MEG signals using Grassmann manifolds
Authors: Hindriks Rikkert , Rot Thomas O. , van Putten Michel J.A.M. , Tewarie Prejaas
Published: March 2024

A challenge in interpreting features derived from source-space electroencephalography (EEG) and magnetoencephalography (MEG) signals is residual mixing of the true source signals. A common approach is to use features that are invariant under linear and instantaneous mixing. In the context of this approach, it is of interest to know which invariant features can be constructed from a given set of source-projected EEG/MEG signals. We address this question by exploiting the fact that invariant features can be viewed as functions on the Grassmann manifold. By embedding the Grassmann manifold in a vector space, coordinates are obtained that serve as building blocks for invariant features, in the sense that all invariant features can be constructed from them. We illustrate this approach by constructing several new bivariate, higher-order, and multidimensional functional connectivity measures for static and time-resolved analysis of time-domain EEG/MEG signals. Lastly, we apply such an invariant feature derived from the Grassmann manifold to EEG data from comatose survivors of cardiac arrest and show its superior sensitivity to identify changes in functional connectivity.

Author Summary

Electroencephalography (EEG) and magnetoencephalography (MEG) are techniques to non-invasively measure brain activity in human subjects. This works by measuring the electric potentials on the scalp (EEG) or the magnetic fluxes surrounding the head (MEG) that are induced by currents flowing in the brains’ grey matter (the ”brain activity”). However, reconstruction of brain activity from EEG/MEG sensor signals is an ill-posed inverse problem and, consequently, the reconstructed brain signals are linear superpositions of the true brain signals. This fact complicates the interpretation of the reconstructed brain activity. A common approach is to only use features of the reconstructed activity that are invariant under linear superpositions. In this study we show that all invariant features of reconstructed brain signals can be obtained by taking combinations of a finite set of fundamental features. The fundamental features are parametrized by a high-dimensional space known as the Grass-mann manifold, which has a rich geometric structure that can be exploited to construct new invariant features. Our study advances the systematic study of invariant properties of EEG/MEG data and can be used as a framework to systematize and interrelate existing results. We use the theory to construct a new invariant connectivity measure and apply it to EEG data from comatose survivors of cardiac arrest. We find that this measure enables superior identification of affected brain regions.
Separate domains of theArabidopsisENHANCER OF PINOID drive its own polarization and recruit PIN1 to the plasma membrane
Authors: Matthes Michaela S. , Yun Nicole , Luichtl Miriam , Büschges Ulrich , Fiesselmann Birgit S. , Strickland Benjamin , Lehnardt Marietta S. , Ruiz Ramon A. Torres
Published: March 2024

TheArabidopsisENHANCER OF PINOID (ENP) protein and the AGC-kinase PINOID (PID) synergistically impact on polarization of the auxin transporter PIN-FORMED1 (PIN1) required for plant leaf and flower organ development. ENP offers a PID-independent input for PIN-polarity sinceenp piddouble mutants lead to cotyledon- and flower-less plants in contrast topidsingle mutants, which develop cotyledons and abnormal albeit fertile flowers. This indicated that ENP, which depicts a similar polar localization as PIN1, is a potential interactor of PINs especially PIN1.

Here we show that the modular structure of ENP predicted by AlphaFold separates the capability for its own cellular polarization and its function linked to polar PIN1 activity. The anterior part of ENP is subdivided into three structured domains. They are supportive and/or essential for cellular polarity. In contrast, the C-terminus, which is an intrinsically disordered region (IDR), is completely dispensable for polarity but essential for ENP-mediated PIN-function. FLIM-FRET shows ENP to be closely associated with the plasma membrane and its IDR to significantly interact with PINs. Moreover, the modification status of two prominent phosphorylation sites in the IDR determines ENPs stability and its capability in supporting PIN1. Our results show ENP to be an element in the assumed PIN-multiprotein complex and explain its impact on PID-independent PIN1 activity.
Large gradient of susceptibility to esca disease revealed by long-term monitoring of 46 grapevine cultivars in a common garden vineyard
Authors: Gastou Pierre , Destrac Irvine Agnès , Arcens Clarisse , Courchinoux Eva , This Patrice , van Leeuwen Cornelis , Delmas Chloé E. L.
Published: March 2024

Grapevine (Vitis viniferaL.) is prone to many fungal diseases, including esca, a severe vascular disease threatening the wine sector and for which there is no cost-effective cure. Susceptibility to esca varies between cultivars in different infection conditions. It may therefore be possible to use the genetic diversity of grapevine cultivars to mitigate disease impact. However, the genetic component of esca susceptibility has rarely been investigated in the vineyard, and the specific mechanisms and varietal traits underlying esca susceptibility remain unknown.

In this study, we monitored the incidence and severity of esca foliar symptoms and plant dieback (apoplexy and mortality) at plant level for seven years, on 46 cultivars planted in an experimental common garden, to separate the genetic component of esca susceptibility from the effects of environment and cropping practices. We observed a broad gradient of varietal susceptibility, with a mean incidence of 0 to 26% of vines expressing esca foliar symptoms depending on the variety. This gradient remained similar across years and, unlike the severity of foliar symptoms, the incidence of grapevine dieback was significantly correlated with that of foliar symptoms. We detected a significant but weak and very localised phylogenetic signal for the incidence of esca foliar symptoms in this panel of cultivars.

We then explored the relationships between epidemiological metrics and ecophysiological and phenological traits phenotyped on the same plot. Esca disease incidence was negatively correlated with δ13C across cultivars, suggesting that varieties with higher water use efficiency are less prone to the expression of esca symptoms on leaves. Moreover, the least vigorous cultivars were among the least susceptible, although this relationship was not significant. By contrast, neither phenological stages nor nitrogen status were significantly predictive of cultivar susceptibility to the disease.

Together, these results provide new insight into the potential of genetic resources for use in the sustainable management of grapevine trunk diseases and open up new perspectives for studying the pathological and physiological determinants of their incidence.
Setting Climate Targets: The Case of Higher Education and Research
Authors: Ligozat Anne-Laure , Brun Christophe , Demirdjian Benjamin , Gouget Guillaume , Jardé Emilie , Mialon Arnaud , Mouronval Anne-Sophie , Pagani Laurent , Vieu Laure
Published: March 2024

The carbon footprint and low-carbon strategies of higher education and research organizations have been the subject of scientific articles and reports. However, these provide few details on the reduction targets themselves, leaving the question of how should higher education and research organizations define and construct their climate targets and trajectories unanswered. The present paper fills this gap. We first review and analyze the documents describing the climate strategies of 53 higher education and research organizations coming from 11 countries, based on their detailed GreenHouse Gas emissions (GHGs) reporting. The selected reports include at least one target re-duction for at least one target year. Then, on the basis of this analysis we propose guidelines to encourage and help higher education and research organizations set rele-vant climate targets.
Karanjin alters gene expression through ERα: a preliminary study
Authors: Bhatt Gaurav , Rangan Latha , Limaye Anil Mukund
Published: March 2024

Karanjin is an abundant furanoflavonoid-constitutent of pongamia oil. Among several biological actions of karanjin, the antiproliferative effect of karanjin has gained traction in the recent years; raising speculations about its anticancer potential. In the backdrop of partial estrogen-like alteration of gene expression by karanjin in ERα positive MCF-7 breast cancer cells, we present preliminary evidences supporting of the role of ERα in karanjin-mediated effects.
The Kv2.2 channel mediates the inhibition of Prostaglandin E2 on glucose-stimulated insulin secretion in pancreatic β-cells
Authors: Pan Chengfang , Liu Ying , Wang Liangya , Fan Wengyong , Ni Yunzhi , Zhang Xuefeng , Wu Di , Li Chenyang , Li Jin , Li Zhaoyang , Liu Rui , Hu Changlong
Published: March 2024

Prostaglandin E2 (PGE2) is an endogenous inhibitor of glucose-stimulated insulin secretion (GSIS) and plays an important role in pancreatic β-cell dysfunction in type 2 diabetes mellitus (T2DM). This study aimed to explore the underlying mechanism by which PGE2 inhibits GSIS. Our results showed that PGE2 inhibited Kv2.2 channels via increasing PKA activity in HEK293T cells overexpressed with Kv2.2 channels. Point mutation analysis demonstrated that S448 residue was responsible for the PKA-dependent modulation of Kv2.2. Furthermore, the inhibitory effect of PGE2 on Kv2.2 was blocked by EP2/4 receptor antagonists, while mimicked by EP2/4 receptor agonists. The immune fluorescence results showed that EP1-EP4 receptors are expressed in both mouse and human β-cells. In INS-1(832/13) β-cells, PGE2 inhibited voltage-gated potassium currents and electrical activity through EP2/4 receptors and Kv2.2 channels. Knockdown of Kv2.2 reduced the action potential firing frequency and alleviated the inhibition of PGE2 on GSIS in INS-1(832/13) β-cells. PGE2 impaired glucose tolerance in wild-type mice but did not alter glucose tolerance in Kv2.2 knockout mice. Knockout of Kv2.2 reduced electrical activity, GSIS and abrogated the inhibition of PGE2 on GSIS in mouse islets. In conclusion, we have demonstrated that PGE2 inhibits GSIS in pancreatic β-cells through the EP2/4-Kv2.2 signaling pathway. The findings highlight the significant role of Kv2.2 channels in the regulation of β-cell repetitive firing and insulin secretion, and contribute to the understanding of the molecular basis of β-cell dysfunction in diabetes.
Association between gene expression plasticity and regulatory network topology
Authors: Petit Apolline J. R. , Genissel Anne , Le Rouzic Arnaud
Published: March 2024

Over the past two decades, numerous studies have been conducted with the aim of identifying the structures within regulatory networks responsible for gene expression patterns. Gene expression plasticity for instance has been associated with many network structures, but both theoretical results and empirical observations were often equivocal. Our objective was to decipher the regulatory causes of gene expression plasticity, with a particular focus on identifying the relevant structures in regulatory networks that might influence the sensitivity to environmental factors. We sought the common regulatory structures associated with gene expression plasticity between predictions from an evolutionary simulation model and the global regulatory network fromEscherichia coli. Congruent results from empirical and theoretical approaches confirmed that selection promotes more regulation towards plastic genes and, as a consequence, plastic genes were more often regulated by feedforward loops than non-plastic genes. Selection tends to bias the distribution of regulatory loop motifs towards positive feedforward and diamond loops, but this enrichment in specific structures was the same in plastic and non-plastic genes. The inability to predict gene expression plasticity from the network regulatory structure opens new questions about the nature of the missing information in current systems biology databases and the evolutionary causes of gene expression plasticity.
Islands promote diversification within the silvereye clade: a phylogenomic analysis of a great speciator
Authors: Estandía Andrea , Recalde Nilo Merino , Sendell-Price Ashley T. , Potvin Dominique , Robertson Bruce , Clegg Sonya
Published: March 2024

Geographic isolation plays a pivotal role in speciation by restricting gene flow between populations through distance or physical barriers. However, the speciation process is complex, influenced by the interplay between dispersal ability and geographic isolation, especially in “great speciators” – bird species present on multiple islands that, at the same time, have many subspecies. Comparing population differentiation in both continental and insular settings can help us to understand the importance of geographical context in the emergence of great speciators. The highly diverse white-eye family Zosteropidae includes several great speciators, including the silvereye (Zosterops lateralis) which consists of 16 subspecies, 11 occurring on islands. The distribution of the silvereye on the Australian continent and numerous southwest Pacific islands allows us to explore the influence of different forms of geographic isolation on population divergence. To do this, we conducted a comprehensive phylogenomic analysis of the silvereye and compared patterns of population divergence in insular versus continental silvereye populations. We estimate that the silvereye lineage emerged approximately 1.5 million years ago, followed by the split of the two main silvereye clades: Southern Melanesia and the broader South Pacific (encompassing Australia, New Zealand, and outlying islands). Continental populations show low genetic population structure, which suggests that they can overcome multiple forms of geographic barriers across long distances. In contrast, most island populations are highly structured even over relatively short distances. Divergence statistics further support the idea that water barriers lead to a higher population differentiation when compared to continental distances. Our results indicate that islands promote divergence and provide an empirical example of the geographical conditions that result in the emergence of great speciators.
Root exudation and rhizosphere microbial recruitment are influenced by novel plant trait diversity in carrot genotypes
Authors: Anderson Hannah M. , Cagle Grace A. , Majumder Erica L.-W. , Silva Erin , Dawson Julie , Simon Philipp , Freedman Zachary B.
Published: March 2024

Root exudate composition can influence rhizosphere microbial recruitment and is tightly controlled by plant genetics. However, little research has profiled root exudate in vegetable crops or determined their role in rhizosphere microbial community and metabolite composition. It is also not well understood how root exudates and resulting rhizosphere dynamics shift across plant trait diversity and with the development of novel crop genotypes. To address these knowledge gaps, this study paired metabolomics and microbiome analyses to evaluate associations between the composition of exudates, soil bacterial and fungal communities, and soil metabolites across four genotypes of organically produced carrot of differential breeding histories, including two experimental genotypes. Plant genotypes modified soil microbial diversity and composition, and differentially recruited bacterial taxa with demonstrated potential for plant-growth related functions including ammonia oxidation, nitrogen fixation, and phytohormone production. Bacterial rhizosphere recruitment from bulk soil was genotype and root exudate-mediated, while fungal recruitment was not. Moreover, root exudate composition was distinct in an heirloom genotype and a novel nematode resistant genotype, compared to other genotypes tested. Root exudate and rhizosphere metabolite composition was decoupled, and soil metabolites strongly associated with fungal, but not bacterial communities. Taken together, the results of this study suggest that novel crop trait diversity and breeding histories hold consequences for the functional potential of soils through the diversification of root exudate mediated plant-microbe interactions.
PRMT5 maintains tumor stem cells to promote pediatric high-grade glioma tumorigenesis
Authors: DeSisto John , Balakrishnan Ilango , Knox Aaron J. , Link Gabrielle , Venkataraman Sujatha , Vibhakar Rajeev , Green Adam L.
Published: March 2024

Background

Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a screen for epigenetic regulators, we identifiedPRMT5as essential for PHGG growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth.Methods. We conductedin vitroassays, including limiting dilution studies of self-renewal, to determine the phenotypic effects ofPRMT5KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting fromPRMT5KD or administration of a PRMT5 inhibitor ± radiation therapy (RT).

Results

In vitro,PRMT5KD slowed cell cycle progression, tumor growth and self-renewal.PRMT5KD reduced H3K4me3 occupancy at genes associated with self-renewal, tumor formation and growth.In vivo,PRMT5KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival.

Conclusion

PRMT5KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failedin vivodue to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant.

Implications

Our findings show the importance ofPRMT5to maintain and promote the growth of stemlike cells that initiate and drive tumorigenesis in pediatric high grade glioma.
playOmics: A multi-omics pipeline for interpretable predictions and biomarker discovery
Authors: Głowacka-Walas Jagoda , Sijko Kamil , Wojdan Konrad , Gambin Tomasz
Published: March 2024

Background

Multi-omics analysis is increasingly popular in biomedical research. While promising, these analyses confront challenges in data integration, management, and interpretation due to their complexity, diversity, and volume. Moreover, achieving transparency, reproducibility, and repeatability in multi-omics analyses is essential for facilitating scientific collaboration and validation of complex datasets.

Results

We introduce playOmics, an open-source R package tailored for omics data analysis. It facilitates data management and biomarker discovery through various visualizations, statistics and explanations for boosted interpretability. playOmics identifies significant prognostic markers and iteratively constructs logistic regression models, identifying combinations with high predictive performance. Our tool enables users to make direct, model-driven predictions by inputting new data into the selected pre-trained model. playOmics performed well in handling extensive datasets and missing data, showing a mean validation MCC of 0.773.

Conclusions

playOmics demonstrates the balance between model complexity and interpretability, crucial in biomedical research for understanding model decisions. playOmics’ approach promotes a flexible model selection process, encouraging exploration and hypothesis generation in biomarker discovery. The dockerized setup and intuitive graphical interface of playOmics support its adoption in a wide range of research and clinical settings, adhering to principles of open science, enhancing reproducibility and transparency.
Magnetic particle imaging reveals that iron-labeled extracellular vesicles accumulate in brains of mice with metastases
Authors: Toomajian Victoria A , Tundo Anthony , Ural Evran E , Greeson Emily M , Contag Christopher H , Makela Ashley V
Published: March 2024

The incidence of breast cancer remains high worldwide and is associated with a significant risk of metastasis to the brain that can be fatal; this is due, in part, to the inability of therapeutics to cross the blood brain barrier (BBB). Extracellular vesicles (EVs) have been found to cross the BBB and further, have been used to deliver drugs to tumors. EVs from different cell types appear to have different patterns of accumulation and retention as well as efficiency of bioactive cargo delivery to recipient cells in the body. Engineering EVs as delivery tools to treat brain metastases, therefore, will require an understanding of the timing of EV accumulation, and their localization relative to metastatic sites. Magnetic particle imaging (MPI) is a sensitive and quantitative imaging method that directly detects superparamagnetic iron. Here, we demonstrate MPI as a novel tool to characterize EV biodistribution in metastatic disease after labeling EVs with superparamagnetic iron oxide (SPIO) nanoparticles. Iron-labeled EVs (FeEVs) were collected from iron-labeled parental primary 4T1 tumor cells and brain-seeking 4T1BR5 cells, followed by injection into mice with orthotopic tumors or brain metastases. MPI quantification revealed that FeEVs were retained for longer in orthotopic mammary carcinomas compared to SPIOs. MPI signal due to iron could only be detected in brains of mice bearing brain metastases after injection of FeEVs, but not SPIOs, or FeEVs when mice did not have brain metastases. These findings indicate the potential use of EVs as a therapeutic delivery tool in primary and metastatic tumors.

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ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer
Authors: Moreno Paloma , Ohara Yuuki , Craig Amanda J , Liu Huaitian , Yang Shouhui , Zhang Lin , Panigrahi Gatikrushna , Dorsey Tiffany H , Cawley Helen , Azizian Azadeh , Gaedcke Jochen , Ghadimi Michael , Hanna Nader , Hussain S. Perwez
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatADRA2Atransgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.
An array ofZymoseptoria triticieffectors suppress plant immune responses
Authors: Thynne E. , Ali H. , Seong K. , Abukhalaf M. , Guerreiro M. A. , Flores-Nunez V. M. , Hansen R. , Bergues A. , Salman M. J. , Rudd J. J. , Kanyuka K. , Tholey A. , Krasileva K. V. , Kettles G. J. , Stukenbrock E. H.
Published: March 2024

Zymoseptoria triticiis the most economically significant fungal pathogen of wheat in Europe. However, despite the importance of this pathogen, the molecular interactions between pathogen and host during infection are not well understood. Herein, we describe the use of two libraries of clonedZ. triticieffectors that were screened to identify effector candidates with putative pathogen associated molecular pattern (PAMP) triggered immunity (PTI)-suppressing activity. The effectors from each library were transiently expressed inNicotiana benthamiana, and expressing leaves were treated with bacterial or fungal PAMPs to assess the effectors’ ability to suppress reactive oxygen species (ROS) production. From these screens, numerous effectors were identified with PTI-suppressing activity. In addition, some effectors were able to suppress cell death responses induced by otherZ. triticisecreted proteins. We used structural prediction tools to predict the putative structures of all of theZ. triticieffectors, and used these predictions to examine whether there was enrichment of specific structural signatures among the PTI-suppressing effectors. From among the libraries, multiple members of the killer protein-like 4 (KP4) and killer protein-like 6 (KP6) effector families were identified as PTI-suppressors. This observation is intriguing, as these protein families were previously associated with antimicrobial activity rather than virulence or host manipulation. This data provides mechanistic insight into immune suppression byZ. triticiduring infection, and suggests that similar to biotrophic pathogens, this fungus relies on a battery of secreted effectors to suppress host immunity during early phases of colonisation.