bluuebunny/crossref_metadata_2025 huggingface dataset:
The late onset Alzheimer’s disease risk factor iRhom2/RHBDF2 is a modifier of microglial TREM2 proteolysis
Authors: Jocher Georg , Müller Stephan A. , Hsia Hung-En , Lastra Osua Miranda , Özcelik Gözde , Hofmann Laura I. , Aßfalg Marlene , Dinkel Lina , Feng Xiao , Schlepckow Kai , Willem Michael , Haass Christian , Tahirovic Sabina , Blobel Carl P. , Lichtenthaler Stefan F.
Published: September 2024

The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimer’s disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, linked to AD risk, but the responsible protease in microglia is still unknown. Another microglia-expressed AD risk factor is catalytically inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and acts as a non-catalytic subunit of the metalloprotease ADAM17. A potential role in TREM2 proteolysis is not yet known. Using microglial-like BV2 cells, bone marrow-derived macrophages and primary murine microglia, we identify iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss of iRhom2 increased TREM2 in cell lysates and at the cell surface and enhanced TREM2 signaling and microglial phagocytosis of the amyloid β-peptide (Aβ). This study establishes ADAM17 as a physiological TREM2 protease in microglia, and suggests iRhom2 as a potential drug target for modulating TREM2 proteolysis in AD.
Mitochondrial superoxide acts in the intestine to extend longevity
Authors: Liontis Thomas , Senchuk Megan M. , Zhu Shusen , Jacob-Tomas Suleima , Anglas Ulrich , Traa Annika , Soo Sonja K. , Van Raamsdonk Jeremy M.
Published: September 2024

Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD genesod-2results in increased lifespan, indicating that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption ofsod-2is necessary for lifespan extension and the tissues in which disruption ofsod-2is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects ofsod-2deletion on lifespan. Knocking downsod-2expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown ofsod-2also increased resistance to heat stress and while decreasing resistance to oxidative stress. Combined, these results indicate that disruption ofsod-2in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasingsod-2expression in just the intestine extends lifespan. This work defines the conditions required for elevated mitochondrial superoxide to increase longevity.
Comprehensive mapping of the Interaction of levodopa and iron metabolism in Parkinson’s disease
Authors: Wang Jian , Ekambaram Srinivasan , Huang Xuemei , Mailman Richard B. , Proctor Elizabeth A. , Dokholyan Nikolay V.
Published: September 2024

Levodopa remains the primary treatment for Parkinson’s disease (PD), yet its long-term use has been associated with iron accumulation in the brain, a phenomenon linked to neurodegeneration. We utilize deep machine learning to determine plausible molecular mechanisms that may underlie the effects of levodopa on iron metabolism. Using the DRIFT platform, we performed a proteome-wide target identification of levodopa and uncovered significant interactions potentially involved in cellular iron transport. Pathway analysis revealed that levodopa may influence critical iron-related pathways, including the response of EIF2AK1 to heme deficiency, heme signaling, and ABC-family protein-mediated transport. These findings suggest that levodopa may contribute to iron dysregulation in PD by interacting with iron transporters and modulating iron-related pathways. Because levodopa is used at relatively high doses in PD, our findings provide new insight into secondary effects unrelated to being a precursor of dopamine. This highlights the need for careful consideration of its effects on iron metabolism as a consequence of use in the long-term management of PD. Further experimental validation is required to confirm these interactions, and also to explore potential strategies to mitigate iron-related side effects while preserving therapeutic efficacy.
A workflow for microclimate sensor networks: integrating geographic tools, statistics, and local knowledge
Authors: Klinges David H. , Lembrechts Jonas J. , Van de Vondel Stijn , Greenlee Eric , Hayles-Cotton Kian , Senior Rebecca A.
Published: September 2024

Wireless environmental sensors have become integral tools in environmental and conservation research, offering diverse data streams that complement traditional inventory-based surveys. Despite advancements in sensor technology, the ad-hoc nature of site selection for sensor deployment often limits the potential of collected data. In this paper, we argue for the importance of informed site selection to capture environmental variation effectively. We introduce a comprehensive step-by-step practical guide for environmental sensor site selection and network deployment, drawing on experiences from diverse geographic locations and focusing on microclimate monitoring as a representative environmental variable. The workflow integrates Geographic Information Systems (GIS) tools, local community-based knowledge, and statistical methods to provide adaptive and iterative guidelines for both new and expanded sensor deployments. We demonstrate the workflow’s applicability across three distinct settings: arid montane deserts in Oman, urban and rural gardens in Belgium, and humid forested landscapes in Madagascar. To facilitate the workflow’s implementation and reproducibility worldwide, we provide a modular software supplement with flexible user input for robust, data-driven and interactive site selection. Critically, our workflow underscores the importance of equitable collaboration with local stakeholders, addresses challenges in sensor deployment, and offers a practical tool to enhance the effectiveness and efficiency of environmental sensing across disciplines including ecology, meteorology, agriculture, and landscape design.
Plasma exosomes from individuals with type 2 diabetes drive breast cancer aggression in patient-derived organoids
Authors: Ennis Christina S. , Seen Michael , Chen Andrew , Kang Heejoo , Ilinski Adrian , Mahdaviani Kiana , Ko Naomi , Monti Stefano , Denis Gerald V.
Published: September 2024

Women with obesity-driven diabetes are predisposed to more aggressive breast cancers. However, patient metabolic status does not fully inform the current standard of care. We previously identified plasma exosomes as functionally critical actors in intercellular communication and drivers of tumor progression. Here, we generated patient-derived organoids (PDOs) from breast tumor resections to model signaling within the tumor microenvironment (TME). Novel techniques and a short (1-week) culture preserved native tumor-infiltrating lymphocytes for the first time in breast tumor PDOs. After 3-day exosome treatment, we measured the impact of exosomal signaling on PDOs via single-cell RNA sequencing. Exosomes derived from Type 2 diabetic patient plasma significantly upregulated pathways associated with epithelial-to-mesenchymal transition, invasiveness, and cancer stemness, compared to non-diabetic exosome controls. Intratumoral heterogeneity and immune evasion increased in the diabetic context, consistent with enhanced tumor aggressiveness and metastatic potential of these PDOs. Our model of systemic metabolic dysregulation and perturbed transcriptional networks enhances understanding of dynamic interactions within the TME in obesity-driven diabetes and offers new insights into novel exosomal communication.
Ancient DNA reveals historical demographic decline and genetic erosion in the Atlantic bluefin tuna
Authors: Andrews Adam Jon , Eriksen Emma Falkeid , Star Bastiaan , Præbel Kim , Natale Antonio Di , Malca Estrella , Zapfe Glenn , Onar Vedat , Aniceti Veronica , Carenti Gabriele , Piquès Gäel , Nielsen Svein Vatsvåg , Persson Per , Piattoni Federica , Fontani Francesco , Atmore Lane M. , Kersten Oliver , Tinti Fausto , Cilli Elisabetta , Cariani Alessia
Published: September 2024

Overexploitation has depleted fish stocks during the past century, nonetheless its genomic consequences remain poorly understood. Characterising the spatiotemporal patterns of these consequences may provide baseline estimates of past diversity and productivity to aid management targets, help predict future dynamics, and facilitate the identification of evolutionary factors limiting fish population recovery. Here, we evaluate human impacts on the evolution of the iconic Atlantic bluefin tuna (Thunnus thynnus), one of the longest and most intensely exploited marine fishes, with a tremendous cultural and economic importance. We sequenced whole genomes from modern (n=49) and ancient (n=41) specimens dating up to 5000 years ago, uncovering several novel findings. First, we identify temporally stable patterns of population admixture, as bluefin tuna caught off Norway and in the eastern Mediterranean share a greater degree of ancestry with Gulf of Mexico bluefin tuna than western and central Mediterranean bluefin tuna. This suggests that Atlantic spawning areas are important mixing grounds for the genetic diversity of Mediterranean bluefin tuna. We model effective population size to show that Mediterranean bluefin tuna began to undergo a demographic decline by the year 1900 to an extent not observed across the previous millennia. Coinciding with this, we found that heterozygosity and nucleotide diversity was significantly lower in modern (2013-2020), than ancient (pre-1941) Mediterranean bluefin tuna, suggesting bluefin tuna underwent a genetic bottleneck. With this work we show how ancient DNA provides novel perspectives on ecological complexity with the potential to inform the management and conservation of fishes.

Significance

Achieving the aim of the current UN Ocean Decade to “protect and restore ecosystems and biodiversity” is stymied by a lack of historical knowledge on how human exploitation has impacted and therefore what should be restored. Here, we sequence DNA in ancient fish bones to evaluate the historical diversity of the Atlantic bluefin tuna; which has been of great commercial importance for centuries. We find that bluefin tuna began to undergo demographic decline by 1900, 70 years earlier than currently recognised. Correspondingly, we find modern bluefin tuna had lower levels of genetic diversity than historical ones. This suggests that human impacts on the diversity of marine fishes are likely to have begun earlier and be more complex than previously thought.
A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis
Authors: Ashkin Emily L , Tang Yuning J , Xu Haiqing , Hung King L , Belk Julia , Cai Hongchen , Lopez Steven S , Dolcen Deniz Nesli , Hebert Jess D , Li Rui , Ruiz Paloma A , Keal Tula , Andrejka Laura , Chang Howard Y , Petrov Dmitri A , Dixon Jesse R , Xu Zhichao , Winslow Monte M
Published: September 2024

The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and show that STAG2 is uniquely tumor suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility and 3D genome conformation that impact cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relates STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin mediated mechanisms of lung tumor suppression.
Cnes2bRegulates Host Resistance, Inflammatory Responses and Tissue Damage FollowingCryptococcus deneoformansInfection
Authors: Angers Isabelle , Beauchamp Annie , El Sheikh Marwa , Kaufmann Eva , Vinh Donald C. , Qureshi Salman T.
Published: September 2024

The 32.1 MbCnes2chromosome 17 interval was shown to confer resistance to progressiveCryptococcus deneoformans52D infection. To refine the location ofCnes2host resistance genes, a subcongenic mouse strain (B6.CBA-Cnes2b) that contains 8.7 Mb from the telomeric region ofCnes2was created. At 28 days postinfection B6.CBA-Cnes2bmice had a lower lung fungal burden, increased lung injury, as well as mortality compared to C57BL/6N. B6.CBA-Cnes2bmice had increased pulmonary production of pro-inflammatory mediators, chemokines and Th1-type cytokines as well as increased recruitment of monocytes and neutrophils to the lungs.Cnes2balso regulated several elements of the host response toC. deneoformans52D infection in a sex-dependent manner. Specifically, male B6.CBA-Cnes2bmice had a lower lung fungal burden, increased brain injury and mortality relative to females. Taken together these findings demonstrate thatCnes2bregulates host inflammation in a manner that controls fungal burden and increases tissue damage. Precise identification of the genes encoded byCnes2bcould reveal key mechanisms of cryptococcal host resistance and immune reconstitution or postinfectious inflammatory syndromes.

Importance

The 32.1 MbCnes2congenic interval from chromosome 17 of resistant CBA/J mice regulates host resistance toC. deneoformans52D infection. This study characterizes the host response of B6.CBA-Cnes2bmice that carry an 8.7 Mb sub-congenic interval derived fromCnes2followingC. deneoformans52D infection. B6.CBA-Cnes2bmice had reduced lung fungal burden, increased lung and brain injury, and mortality. The effects ofCnes2bdiffered between male and female subcongenic mice and are consistent with known sex differences in human cryptococcal disease. The host response of B6.CBA-Cnes2bmice reflects a crucial balance between effective control of fungal burden and potentially deleterious consequences of enhanced inflammation during cryptococcal infection as predicted by the damage response framework. Further analysis of theCnes2bsub-congenic interval will lead to definitive identification of genes that confer resistance to progressive cryptococcal infection and/or contribute to deleterious inflammatory responses. Defining key mechanisms that regulate the immune response toCryptococcus sp.is an important step towards the development of host-directed therapeutics that could improve disease outcomes.
Variation in Biosynthetic Gene Clusters Among Lifestyles Across Kingdom Fungi
Authors: Allen Brooke M. , Drott Milton , Nickles Grant R , Hoeksema Jason D.
Published: September 2024

Biosynthetic gene clusters (BGCs) produce secondary metabolites, many of which are involved in trophic interactions and carbon acquisition lifestyles of fungi. As such, BGCs are hypothesized to exhibit evolutionary diversification across those lifestyles. We tested this hypothesis by analyzing predicted BGCs in more than 1000 fungal genomes, and their variation among fungal lineages and across putative fungal lifestyles (trophic modes). Analyses revealed that specific BGC classes, such as PKSI, RiPPs, and terpenes, exhibit significant phylogenetic signals, whereas others, like NRPS and PKS-NRPS Hybrids, do not. BGC abundance was associated with fungal lifestyles: pathotrophs generally had lower BGC abundance, while combined lifestyles such as saprotroph-symbiotrophs had higher BGC abundances. These findings suggest that both phylogenetic history and ecological strategies drive BGC distribution, highlighting their roles in fungal biochemical diversification. Understanding these patterns provides insights into fungal community ecology and the evolutionary processes shaping their biosynthetic potential.
Federated Multiple Imputation for Variables that Are Missing Not At Random in Distributed Electronic Health Records
Authors: Lian Yi , Jiang Xiaoqian , Long Qi
Published: September 2024

Large electronic health records (EHR) have been widely implemented and are available for research activities. The magnitude of such databases often requires storage and computing infrastructure that are distributed at different sites. Restrictions on data-sharing due to privacy concerns have been another driving force behind the development of a large class of distributed and/or federated machine learning methods. While missing data problem is also present in distributed EHRs, albeit potentially more complex, distributed multiple imputation (MI) methods have not received as much attention. An important advantage of distributed MI, as well as distributed analysis, is that it allows researchers to borrow information across data sites, mitigating potential fairness issues for minority groups that do not have enough volume at certain sites. In this paper, we propose a communication-efficient and privacy-preserving distributed MI algorithms for variables that are missing not at random.
Antibodies against the capsid induced after intracranial AAV administration limits second administration in a dose dependent manner
Authors: Xu Yuge , Bai Xiaoni , Lin Jianhua , Lu Kang , Weng Shihan , Wu Yiying , Liu Shanggong , Li Houlin , Chen Gong , Li Wen
Published: September 2024

Recombinant adeno-associated virus (rAAV) is a widely used viral vector for gene therapy. However, a limitation of AAV-mediated gene therapy is that patients are typically dosed only once. In this study, we investigated the possiblility to deliver multiple rounds of AAV through intracerebral injections in the mouse brain. We discovered a dose-dependent modulation of the second round AAV infection by the first round AAV injection in the brain-wide scales besides the injection region. High-dose AAV infection increases chemokines CXCL9 and CXCL10 to recruit the parenchymal infiltration of lymphocytes. Surprisingly, the blood-brain-barrier was relatively intact. Brain-wide dissection discovered the likely rountes of the infiltrated lymphocytes through perivascular space and ventricles. Further analysis using B-cell depleted mice revealed that B lymphocytes, but not T lymphocytes, played a critical role in inhibiting the second round AAV infection. Strategies against neutralizing antibodies had limited effects, while reducing the dosage for the first injection or switching the second AAV to a different serotype appeared to be more effective in antagonizing the first round AAV inhibition. Together, these results suggest that mammalian brains are not immunoprivileged for AAV infection, but multiple rounds of AAV gene therapy are still possible if designed carefully with proper doses and serotypes.
Evaluating plant growth-defence trade-offs by modelling the interaction between primary and secondary metabolism
Authors: Zrimec Jan , Correa Sandra , Zagorščak Maja , Petek Marko , Bleker Carissa , Stare Katja , Schuy Christian , Sonnewald Sophia , Gruden Kristina , Nikoloski Zoran
Published: September 2024

Understanding the molecular mechanisms behind plant response to stress can enhance breeding strategies and help us design crop varieties with improved stress tolerance, yield and quality. To investigate resource redistribution from growth-to defence-related processes in an essential tuber crop, potato, here we generate a large-scale compartmentalised genome-scale metabolic model, Potato-GEM. Apart from a large-scale reconstruction of primary metabolism, the model includes the full known potato secondary metabolism, spanning over 600 reactions that facilitate the biosynthesis of 182 distinct potato secondary metabolites. Constraint-based modelling identifies that the activation of the largest amount of secondary (defence) pathways occurs at a decrease of the relative growth rate of potato leaf, due to the costs incurred by defence. We then obtain transcriptomics data from experiments exposing potato leaves to two biotic stress scenarios, a herbivore and a viral pathogen, and apply it as constraints to produce condition-specific models. We show that these models recapitulate experimentally observed decreases in relative growth rates under treatment, enabling us to pinpoint the metabolic rewiring underlying growth-defence trade-offs. Potato-GEM thus presents a useful resource to study and broaden our understanding of potato and general plant defence responses under stress conditions.
Employing Artificial Neural Networks for Optimal Storage and Facile Sharing of Molecular Dynamics Simulation Trajectories
Authors: Wasim Abdul , Schäfer Lars V. , Mondal Jagannath
Published: September 2024

With the remarkable stride in computing power and advances in Molecular Dynamics simulation programs, a crucial challenge of storing and sharing large biomolecular simulation datasets has emerged. By leveraging AutoEncoders, a type of artificial neural network, we developed a method to compress MD trajectories into significantly smaller latent spaces. Our method can save upto 98% in disk space compared to XTC, a highly compressed trajectory format from the widely used MD program package GROMACS, thus facilitating easier storage and sharing of simulation trajectories. Atomic coordinates are very accurately reconstructed from compressed data. The method was tested across a variety of biomolecular systems, including folded proteins, intrinsically disordered proteins (IDPs), and protein-ligand complexes, showing consistent accuracy in reconstruction. Notably, the compression efficiency was particularly beneficial for larger systems. This approach enables the scientific community to more efficiently store and share large-scale biomolecular simulation data, potentially enhancing collaborative research efforts. The workflow, termed “compressTraj”, is implemented in PyTorch and is publicly available athttps://github.com/SerpentByte/compressTrajfor use, offering a practical solution for managing the growing volumes of data generated in computational biomolecular studies.
Unexpected absence of a multiple-queen supergene haplotype from supercolonial populations ofFormicaants
Authors: Lagunas-Robles German , Alam Zul , Brelsford Alan
Published: September 2024

Ants exhibit many complex social organization strategies. One particularly elaborate strategy is supercoloniality, in which a colony consists of many interconnected nests (=polydomy) with many queens (=polygyny). In many species ofFormicaants, an ancient queen number supergene determines whether a colony is monogyne (=headed by single queen) or polygyne. The presence of the rearrangedPhaplotype typically leads colonies to be polygyne. However, the presence and function of this supergene polymorphism have not been examined in supercolonial populations. Here, we use genomic data from species in theFormica rufagroup to determine whether thePhaplotype leads to supercoloniality. In aFormica paralugubrispopulation, we find that nests are polygyne, despite the absence of thePhaplotype in workers. We find spatial genetic ancestry patterns in nests consistent with supercolonial organization. Additionally, we find that thePhaplotype is also absent in workers from supercolonialFormica aquilonia, andFormica aquiloniaxpolyctenahybrid populations, but is present in someFormica polyctenaworkers. We conclude that thePhaplotype is not necessary for supercoloniality in theFormica rufagroup, despite its longstanding association with non-supercolonial polygyny across theFormicagenus.
High Throughput Meta-analysis of Antimicrobial Peptides for Characterizing Class Specific Therapeutic Candidates: Anin-silicoApproach
Authors: Pandey Anwesh , Lenin Raji Rajesh , Patiyal Sumeet , Agrawal Piyush
Published: September 2024

The increasing incidence of antimicrobial resistance (AMR) is becoming a serious concern worldwide and requires newer drugs. Recent evidence has shown growing interest in developing peptide-based therapeutics to tackle AMR. In the current study, we performed a meta-analysis of nearly 8.6 million predicted antimicrobial peptides (AMPs) and assessed their antibacterial, antiviral, and antifungal activity. We created high-quality, class-specific datasets and performed several analyses, including amino acid composition, motif preference, physiochemical properties, etc. We observed significant differences in the residue composition, charge, molecular weight, pI value, and instability index of peptides among 3 AMP classes. We further developed multiple machine learning models to predict peptide activity using the dataset. Our Extratree model developed using composition-based features achieved the highest AUROC of 0.98 for antibacterial peptide (ABP), 0.99 for antiviral peptide (AVP), and 0.99 for antifungal peptide (AFP) prediction when tested on an independent dataset. Subsequent filtering of peptides based on moonlighting properties (toxicity, allergenicity, cell-penetrating ability, half-life, and secondary structure) yielded a list of peptides that exhibit substantial therapeutic potential. We further selected the top 10 peptides in each category based on their half-lives, predicted their 3D structures using ColabFold, a feature built into ChimeraX1.8 software, and used HDock to perform molecular docking analysis with a pathogenic protein selected from an organism in each class. Docking studies demonstrated strong interaction between peptides and proteins, and based on free energy, we ranked the peptides. Overall, we have put forth class-specific peptides with high therapeutic potential based on rigorous meta-analysis encompassing ∼8.6 million AMPs.
Climate Change and Malaria: A Call for Robust Analytics
Authors: Laydon Daniel J , Smith David L , Chakradeo Kaustubh , Khurana Mark P , Okiring Jaffer , Duchene David A , Bhatt Samir
Published: September 2024

Mosquito ecology and behavior and malaria parasite development display marked sensitivity to weather, in particular to temperature and precipitation. Therefore, climate change is expected to profoundly affect malaria epidemiology in its transmission, spatiotemporal distribution and consequent disease burden. However, malaria transmission is also complicated by other factors (e.g. urbanization, socioeconomic development, genetics, drug resistance) which together constitute a highly complex, dynamical system, where the influence of any single factor can be masked by others.

In this study, we therefore aim to re-evaluate the evidence underlying the widespread belief that climate change will increase worldwide malaria transmission. We review two broad types of study that have contributed to this evidence-base: i) studies that project changes in transmission due to inferred relationships between environmental and mosquito entomology, and ii) regression-based studies that look for associations between environmental variables and malaria prevalence. We then employ a simple statistical model to show that environmental variables alone do not account for the observed spatiotemporal variation in malaria prevalence.

Our review raises several concerns about the robustness of the analyses used for advocacy around climate change and malaria. We find that, while climate change’s effect on malaria is highly plausible, empirical evidence is much less certain. Future research on climate change and malaria must become integrated into malaria control programs, and understood in context as one factor among many. Our work outlines gaps in modelling that we believe are priorities for future research.
ArabidopsisAtGELP53 modulates polysaccharide acetylation and defense response through oligosaccharide-mediated signaling
Authors: Rastogi Lavi , Hussain Muhammad-Moazzam , Tyagi Shivangi , Kabyashree Kristi , Kharbanda Naman , Maiti Tushar Kanti , Krishnan Vengadesan , Jha Gopaljee , Voxeur Aline , Pawar Prashant Anupama-Mohan
Published: September 2024

O-acetylation is a crucial substitution found in hemicelluloses and pectin which are necessary for maintaining the flexibility and structural integrity of the cell. A balanced polysaccharideO-acetylation level is maintained by cell wall acetyl transferases and esterases present in different cell organelles. Specifically, the role of esterases in cell wall acetylation metabolism is less explored. Therefore, we investigated the role ofAtGELP53 from the GELP family of esterases or lipases. Here, we show thatAtGELP53 is localized in the plasma membrane. Analysis ofAtGELP53 overexpressing independent transgenic lines revealed a decrease in xyloglucan acetylation, changes in other polysaccharide acetylation and alteration in cell wall composition. The series of elicitor-based, transcriptomic and proteomic analyses inAtGELP53 overexpressing lines suggested that oligosaccharide-mediated signalling activates the cell wall and defence-related genes primarily because of xyloglucan deacetylation. Furthermore,AtGELP53 overexpression plants showed resistance againstPseudomonas syringaeandRalstonia solanacearumthrough activation of elicitor-mediated defense response. Overall, our findings outline the role ofAtGELP53 in polysaccharide acetylation, cell wall remodelling and defense through the activation of plant cell wall integrity.
Negative Charges, Not Necessary Phosphorylation, are Required for Ligand Recognition by 14-3-3 Proteins
Authors: Kamayirese Seraphine , Hansen Laura A. , Lovas Sándor
Published: September 2024

Protein-protein interactions involving 14-3-3 proteins regulate various cellular activities in normal and pathological conditions. These interactions have mostly been reported to be phosphorylation-dependent, but the 14-3-3 proteins also interact with unphosphorylated proteins. In this work, we investigated whether phosphorylation is required, or, alternatively, whether negative charges are sufficient for 14-3-3ε binding. We substituted the pThr residue of pT(502-510) peptide by residues with varying number of negative charges, and investigated binding of the peptides to 14-3-3ε using MD simulations and biophysical methods. We demonstrated that at least one negative charge is required for the peptides to bind 14-3-3ε while phosphorylation is not necessary, and that two negative charges are preferable for high affinity binding.
Metagenomic detection of Mimiviridae reads in upper respiratory tract samples of SARS-CoV-2 patients
Authors: Tomar Siddharth Singh , Khairnar Krishna
Published: September 2024

The upper respiratory tract (URT) virome is crucial in respiratory health and response to pathogens. While common respiratory viruses are well-studied, the presence and potential impact of giant DNA viruses, such as Mimiviridae, in the human URT remain underexplored. This study employed a whole genome metagenomics approach to profile the URT virome of 48 SARS-CoV-2-positive patients from central India. Mimiviridae reads were detected in two elderly male patients with severe acute respiratory infection (SARI) or influenza-like illness (ILI), contributing to 24% and 44% of the total virome in their samples. The dominant species wereAcanthamoeba polyphaga mimivirusandMoumouvirus. Although Mimiviridae are not traditionally associated with human respiratory infections, their presence in SARS-CoV-2 patients raises questions about their potential role in co-infections and disease severity, particularly in individuals with ongoing respiratory infections. These findings underscore the need to investigate further giant viruses’ clinical significance, transmission, and pathogenicity in humans. Future research should focus on their epidemiology and the development of improved diagnostic tools to assess their contribution to human health.
Glucagon-Like Peptide 1 Receptor Agonists and Cardiovascular Disease Risk: Findings from Real-World Data using AI-Powered Outcomes
Authors: Prakash Shivaani , Coleman Jeffrey , Steinfeldt Jakob
Published: September 2024

Background

The SELECT trial showed cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in obese patients with cardiovascular disease; however, real-world data (RWD) on this benefit remain limited. This study used an artificial intelligence (AI)-generated algorithm and multimodal RWD to evaluate the impact of GLP-1 RAs on cardiovascular disease risk in a population of obese patients with and without preexisting cardiovascular disease.

Methods

Using data from the Dandelion Health RWD library, an Emulated SELECT Cohort was created to include obese patients similar to those in the SELECT trial, but with and without preexisting cardiovascular disease. An AI algorithm developed by Pheiron that used 12-lead electrocardiograms (ECGs) as a predictive biomarker for the risk of major adverse cardiovascular events (MACE) was validated and used to derive MACE risk scores for the Emulated SELECT Cohort. These outcomes were compared over time between patients who used GLP-1 RAs and non-users using inverse-probability weighted linear regression models, adjusting for key covariates.

Results

Out-of-sample validation showed high predictive accuracy of the AI algorithm, with ROC AUCs of 0.81 for myocardial infarction (MI) and 0.75 for stroke. Increased risk scores from the algorithm were correlated with higher MACE incidence in RWD. In the Emulated SELECT Cohort of 20,795 patients, GLP-1 RA use was associated with significant attenuation of MACE risk, with reductions observed in percentile risk score for MI (4%; p<0.001) and stroke (3.6%; p<0.001) per year of use. Differences in GLP-1 RA and non-GLP-1 users were evident as early as 1.7 years, with a 15-20% difference in absolute MACE risk scores between GLP-1 RA users and non-users observed by the end of the study.

Conclusion

An AI algorithm using 12-lead ECGs accurately predicted MACE risk and could be used to model risk attenuation associated with GLP-1 RA use. Using this outcome, we find that GLP-1 RA use was associated with significant reductions in MI and stroke risk, in a broader population and within a shorter timeframe than the SELECT trial. These findings suggest potentially significant cardioprotective benefits of GLP-1 RAs in real-world settings and demonstrate a proof-of-concept for utilizing clinical AI to understand these benefits.
Public communication and outreach by mosquito programs in the United States
Authors: Thomas Nicole , Balanay Jo Anne G. , Shearman Sachiyo , Richards Stephanie L.
Published: September 2024

Blood feeding female mosquitoes cause itchy welts and can transmit pathogens that cause diseases such as chikungunya, malaria, West Nile encephalitis, and Zika. Mosquito control programs conduct mosquito, pathogen, and epidemiological surveillance, carry out source reduction, treat mosquito habitats with larvicides or adulticides, and disseminate information to the public. Here, 100 organizations (e.g., private/public mosquito control programs, national professional mosquito/pest control associations) in the United States were asked to complete a survey (N=39 respondents) about their public communication and outreach efforts. Results indicate most programs (N=27, 69%) have dedicated personnel for public communication. A checklist was constructed to compare communication strategies between a subset of program websites and Facebook pages. Recommendations for improving public communication and outreach strategies for mosquito control programs are discussed.
The Gq/11 family of Gα subunits is necessary and sufficient for lower jaw development
Authors: Kanai Stanley M. , Garcia Chloe R. , Augustus MaCalia R. , Sharafeldeen Shujan A. , Brooks Elliott P. , Sucharov Juliana , Lencer Ezra S. , Nichols James T. , Clouthier David E.
Published: September 2024

Vertebrate jaw development is coordinated by highly conserved ligand-receptor systems such as the peptide ligand Endothelin 1 (Edn1) and Endothelin receptor type A (Ednra), which are required for patterning of lower jaw structures. The Edn1/Ednra signaling pathway establishes the identity of lower jaw progenitor cells by regulating expression of numerous patterning genes, but the intracellular signaling mechanisms linking receptor activation to gene regulation remain poorly understood. As a first step towards elucidating this mechanism, we examined the function of the Gq/11 family of Gα subunits in zebrafish using pharmacological inhibition and genetic ablation of Gq/11 activity and transgenic induction of a constitutively active Gq protein inedn1-/-embryos. Genetic loss of Gq/11 activity fully recapitulated theedn1-/-phenotype, with genes encoding G11 being most essential. Furthermore, inducing Gq activity inedn1-/-embryos not only restored Edn1/Ednra-dependent jaw structures and gene expression signatures but also caused homeosis of the upper jaw structure into a lower jaw-like structure. These results indicate that Gq/11 is necessary and sufficient to mediate the lower jaw patterning mechanism for Ednra in zebrafish.

Summary statement

Gq/11 is the signaling mediator downstream of Endothelin 1 and Endothelin Receptor Type A that drives tissue patterning for all lower jaw structures in zebrafish.
Fine-TuningTAWAWA1-Mediated Panicle Architecture by Genome Editing of a Downstream Conserved Noncoding Sequence in Rice
Authors: Kuroha Takeshi , Lombardo Fabien , Iwasaki Watal M , Chechetka Svetlana , Kawahara Yoshihiro , Yoshida Akiko , Kyozuka Junko , Makino Takashi , Yoshida Hitoshi
Published: September 2024

Genome editing is a promising tool to enhance plant breeding, particularly for the generation of practical quantitative traits. We focused on the rice yield-related geneTAWAWA1(TAW1) and produced various degrees of increased panicle branching phenotypes by modifying its downstream conserved noncoding sequence (CNS). Differential modification of two highly conserved regions containing putative repressive elements in this CNS caused transcriptional upregulation ofTAW1, resulting in diverse phenotypes.
Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory
Authors: Alam El Din Dowlette-Mary , Moenkemoeller Leah , Loeffler Alon , Habibollahi Forough , Schenkman Jack , Mitra Amitav , van der Molen Tjitse , Ding Lixuan , Laird Jason , Schenke Maren , Johnson Erik C. , Kagan Brett J. , Hartung Thomas , Smirnova Lena
Published: September 2024

Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, also known as Organoid Intelligence by quantifying immediate early gene expression, synaptic plasticity, neuronal network dynamics, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation and short-term potentiation, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases.

Graphical Abstract

Overview of the main components of the experiments conducted. Figure created using BioRender.com.
Identification and comparison ofN-glycome profiles from common dietary protein ingredients
Authors: Bolino Matthew , Avcı İzzet , Kayili Hacı Mehmet , Duman Hatice , Salih Bekir , Karav Sercan , Frese Steven A.
Published: September 2024

TheN-glycome profiles purified from dietary bovine whey, egg white, pea, soy protein isolates and a recently commercialized animal-free whey is described. Purified glycoproteins resulting from centrifugation and ethanol precipitation of protein powder supplements were treated with peptide-N-glycosidase F (PNGase F) to release protein-boundN-glycans. Once released from the protein,N-glycans were labeled by procainamide labeling, purified via cotton-hydrophilic interaction liquid chromatography (HILIC), and analyzed using HILIC high performance liquid chromatography equipped with a fluorescence detector and a quadrupole time-of-flight tandem mass spectrometry (HILIC-FLD-QTOF-MS/MS). A total of 33, 33, 10, and 10N-glycan structures were identified from bovine whey, egg, soy, and pea glycoprotein isolates, respectively. The type ofN-glycans per glycoprotein source were highly predictable, likely attributed to differences in biosynthetic glycosylation pathways. Mammalian glycoprotein sources favored a combination of complex and hybrid glycan configurations while the plant proteins were dominated by oligomannosidicN-glycans. Bovine whey glycoprotein isolate contained the most diverseN-glycans by monosaccharide composition as well as structure, while plant sources such as pea and soy glycoprotein isolates contained an overlap of oligomannosidicN-glycans. The results suggestN-glycan structure and composition is dependent on the host organism rather than protein sequence homology, likely driven by the differences inN-glycan biosynthetic pathways.
Mendelian randomization suggests a causal link between glycemic traits and thoracic aortic structures and diseases
Authors: Daria Tselmen , Iyer Kruthika , Alkhairo Hasan , Fang Kho Pik , Suzuki Ken , Hatzikotoulas Konstantinos , Southam Lorraine , Taylor Henry J , Yin Xianyong , Mandla Ravi , Huerta-Chagoya Alicia , Rayner Nigel W , Levin Michael G. , Damrauer Scott M , Tsao Philip S , Priest James R , Pirruccello James , Echouffo Tcheugui Justin B , Tcheandjieu Catherine
Published: September 2024

Importance

Type 2 diabetes mellitus (T2DM) and elevated glucose levels have been inversely associated with aortic aneurysms. However, the causality of this relationship remains uncertain. Additionally, there is a lack of studies investigating the association between glycemic traits and imaging-based thoracic aortic phenotypes.

Objective

We investigated whether T2DM and glycemic measures (fasting glucose (FG), fasting insulin (FI), glycated hemoglobin (HbA1c), and 2-hour post-load glucose (2hPG)) are causally associated with various imaging and clinical thoracic aortic phenotypes.

Design, setting, and participants

We performed Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies of glycemic traits (GT) and aortic phenotypes. We employed a two-sample univariate MR (UVMR) followed by a multivariable MR and MR analysis using a cluster-based approach.

Main Outcomes and Measures

The outcome includes imaging-based ascending and descending aortic diameters (AAoD and DAoD), aortic distensibility (AoDist) and strain (AoStr), and thoracic aortic aneurysm and dissection (TAAD). The GT include FI, FG, HbA1c, 2hPG and T2DM.

Results

We observed an inverse association between 2hPG, FG, HbA1c, and T2DM and AAoD, DAoD. For instance, the genetically predicted increases levels of 2hPG, FG, HbA1c, and T2DM were associated with decreased AAoD (2hPG β= -0.2, p=3x10-08; FG β= -0.21, p=5x10-05; HbA1c β= -0.36, p=2x10-07; T2DM β=-0.04, p=2x10-04) and reduce risk TAAD (2hPG decreased TAAD (2hPG OR= 0.70, p=4x10-04; FG OR= 0.58, p=3x10-05; HbA1c OR= 0.62, p=5x10-03; T2DM OR= 0.90, p=6x10-6). Further investigation showed that the inverse association between T2DM and aortic phenotypes is driven by genetic predictors of T2DM beta cell proinsulin clusters. UVMR and Proteomic MR showed a strong association with aortic phenotypes for genes, suchas AGER, GLRX, TCF7L2, andGCK, which are known to play an important role in glucose regulation.

Conclusion and relevance

Our findings suggest a potentially causal impact of GT on the aortic vasculature. Furthermore, specific glucose regulation genes such asGCK,AGER, andTCF7L2appear to contribute to this process, opening avenues for potentially leveraging the druggability of these genes for treatment or preventions of TAAD.
Health Data Reporting Challenges in the Age of DHIS2: a Mixed-Methods Review in the Teso Sub-Region of Uganda
Authors: Lawrence Margaret R. , Fuller Benjamin P. , Isabirye Herbert Kirya , Kyozira Carol , Makumbi Issa , Bakainaga Andrew , Moore Christopher C. , Ssekitoleko Richard
Published: September 2024

In Uganda, the complete and timely reporting of priority disease data by health centers is critical for detecting outbreaks. However, health centers face significant reporting challenges, which compromise data fidelity and public health. To assess the efficacy of existing systems, we aimed to (1) compare reporting performance among districts in the Teso region of Eastern Uganda, (2) ascertain the association between volume of outpatient department (OPD) visits and reporting rates at facilities, and (3) characterize reporting challenges. We queried Uganda’s Electronic Health Management Information System database, DHIS2, regarding the completeness (reporting rate) and timeliness (reporting rate on time) of priority disease data submission within Teso from January-April 2024. We selected the 3 lowest-performing districts in both metrics and assessed reporting at all health centers within these districts. We used linear regression to determine the relationship between the aggregate number of outpatient visits per health facility and their mean reporting rates. At 7 health facilities across the 3 districts, we interviewed staff to enumerate reporting challenges. Of all 11 districts in Teso, 7 (64%) scored >80% for completeness and 2 (18%) scored >80% for submission timeliness across health facilities. The median (IQR) scores for completeness and timeliness were 83% (75-93%) and 69% (55-75%), respectively. The 3 lowest performing districts in both metrics were Soroti City, Soroti district, and Ngora district. In Soroti City, increasing number of OPD visits was associated with higher reporting rate percentages (b [slope]=0.005, p=0.01). The main reasons given for low reporting rates included limited staff trained on data entry protocols, competing responsibilities among reporting personnel, and lack of reliable internet access. The implementation of DHIS2 has improved public health and disease surveillance in Uganda, but institutional-level data reporting challenges continue to impair disease tracking. Targeted interventions to relieve such barriers is possible.