bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating a conceptual consent permission model from the informed consent ontology for software application execution
Authors: Amith Muhammad “Tuan” , He Yongqun , Smith Elise , Harris Marceline , Manion Frank , Tao Cui
Published: February 2025

We developed a simulated process to show a software implementation to facilitate an approach to integrate the Informed Consent Ontology, a reference ontology of informed consent information, to express implicit description and implement conceptual permission from informed consent life cycle. An early study introduced an experimental method to use Semantic Web Rule Language (SWRL) to describe and represent permissions to computational deduce more information from the Informed Consent Ontology (ICO), demonstrated by the use of the All of Us informed consent documents. We show how incomplete information in informed consent documents can be elucidated using a computational model of permissions toward health information technology that integrates ontologies. Future goals entail applying our computational approach for specific sub-domains of the informed consent life cycle, specifically for vaccine informed consent.
Initial leads to combat streptogramin resistance generated from X-ray fragment screening against VatD
Authors: Asthana Pooja , Lee Sonya , MacDonald Christian M. , Seiple Ian , Fraser James S
Published: February 2025

Streptogramins are potent antibiotics targeting bacterial ribosome. The synergistic binding of group A and B streptogramins to 50S-ribosome, yields bactericidal effects. However, their efficacy is compromised by resistance mechanisms, including enzymatic acetylation of group A streptogramins by Virginiamycin Acetyl Transferase (Vat) enzymes, which reduces their affinity for ribosomes. Using fragment-based drug discovery we identified starting points for development of VatD inhibitors. X-ray crystallography screening revealed three primary fragment-binding sites on VatD. In the acetyl binding subsite, fragments stabilized distinct conformational states in critical residues, His82 and Trp121. In the antibiotic binding site, two fragments formed interactions that could be leveraged for competitive inhibition. Elaborations of these fragments showed weak inhibition of VatD activity, indicating potential for further optimization. These findings establish initial hits that could restore streptogramin efficacy by targeting VatD directly, providing a structural foundation for inhibitor development against resistant bacterial strains.
Multi-kinesin clusters impart mechanical stress that reveals mechanisms of microtubule breakage in cells
Authors: Geng Qi , Bonilla Andres , Sandwith Siara N. , Verhey Kristen J.
Published: February 2025

Microtubules are cytoskeletal filaments that provide structural support for numerous cellular processes. Despite their high rigidity, microtubules can be dramatically bent in cells and it is unknown how much force a microtubule can withstand before breaking. We find that liquid-liquid phase separation of the kinesin-3 motor KIF1C results in multi-kinesin clusters that entangle neighboring microtubules and impose a high level of mechanical stress that results in microtubule breakage and disassembly. Combining computational simulations and experiments, we show that microtubule fragmentation is enhanced by having a highly processive kinesin motor domain, a stiff clustering mechanism, and sufficient drag force on the microtubules. We estimate a rupture force for microtubules in cells of 70-120 pN, which is lower than previous estimates based onin vitrostudies with taxol-stabilized microtubules. These results indicate that the presence of multiple kinesins on a cargo has the potential to cause microtubule breakage. We propose that mechanisms exist to protect microtubule integrity by releasing either the motor-cargo or motor-microtubule interaction, thereby preventing the accumulation of mechanical stress upon the engagement of multi-motor clusters with microtubules.
New Species of Anthurium (Araceae) from Huánuco Department, Peru
Authors: Enikolopov Armen , Croat Thomas B.
Published: February 2025

Two new species are described as new, fully characterized and compared with all other related congeners.
Temporal dimensions of a microbial invader in a plant-microbiome feedback model
Authors: Parker William H. , Rakowski Chase J. , Yitbarek Senay
Published: February 2025

Plant-soil feedback (PSF) theory leverages the increasingly recognized ecological significance of microbiomes to provide insight into plant coexistence. However, PSF theory generally assumes that microbiomes have static composition and properties. In reality, plant communities are thought to experience high rates of colonization by new microbial strains.

Here we use a PSF model to study the conditions under which soil-associated fungi invade a community of two plant species and their associated microbiomes at different stages of assembly. We manipulate fungal colonization timing, initial plant and microbiome evenness, and properties of all actors, then analyze the resulting community structure.

Microbial invasion is most successful early in community assembly. However, invasion outcomes are highly variable across colonization timing. We derive an expression showing that the net support for the invader by the plants determines invasion success. When successful, the invader disrupts the negative feedback among the plants and their microbiomes that enables plant coexistence.

Our results highlight the importance of plant-microbial interactions in microbial invasion success, as well as the susceptibility of plant coexistence to soil-associated microbial invaders during transient dynamics. Broadly, our approach integrating a host-microbiome framework with time-dependent interactions is promising for predicting biodiversity dynamics in a changing world.
Worrisome Emergence of Pan-INSTI Resistance: A Systematic Scoping Review of Dolutegravir Resistance in INSTI-Naïve Patients Post-Therapy Failure
Authors: Arora Sumit , Raman Nishant , Anilkumar Anirudh , Ashta Kuldeep , Kisenjang N , Mohan Charu
Published: February 2025

Introduction

Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is widely used in HIV treatment, especially in low-resource settings. Despite its proven efficacy, concerns about DTG resistance mutations (DRMs) have emerged in patients failing dual NRTI + DTG-based ART regimens. This review examines the patterns and frequencies of these DRMs in INSTI-naïve patients.

Methods

A systematic scoping review was conducted, synthesizing data from 21 studies (2013–2024) involving 59 INSTI-naïve persons living with HIV-1 (PLH) who experienced virological failure (VF) on dual NRTI + DTG-based ART. Data extraction was undertaken by two independent reviewers, and key information included ART history, DRM profiles, duration of DTG-based ART, and viral load at failure. A qualitative synthesis identified common resistance patterns, geographic distributions, and HIV subtype correlations.

Results

The most prevalent DRMs were G118R (42.4%) and R263K (38.9%). G118R, when combined with T66I and E138K, was associated with high-level resistance and pan-INSTI resistance. R263K, frequently occurring alone or with minor mutations, also conferred modest resistance. Resistance patterns varied by HIV subtype, with non-B subtypes showing higher frequencies of G118R and Q148HRK mutations, while R263K predominated in subtype B.

Conclusion

Emerging DTG resistance in INSTI-naïve patients, particularly in resource-limited settings, is a cause for concern. G118R and R263K were the most prevalent mutations, with the former leading to pan-INSTI resistance. These findings stress the importance of monitoring resistance patterns, especially in non-HIV-B subtypes, to optimize ART strategies.
Class IV plant U-box proteins function redundantly to optimize protein accumulation of receptor-like cytoplasmic kinase BIK1
Authors: Dou Ruoqi , Miguel Virginia N. , Grubb Lauren E. , Rana Mansuba , Saltzman Brandon , Monaghan Jacqueline
Published: February 2025

InArabidopsis thaliana, the receptor-like cytoplasmic kinase BOTRYTIS INDUCED KINASE 1 (BIK1) is a direct substrate of multiple transmembrane immune receptor kinases and plays a crucial role in immune signal transduction. Inactive BIK1 is poly-ubiquitinated and degraded by the 26S proteasome, which is thought to optimize BIK1 levels in naive cells and may protect against inappropriately high immune responses. Here, we provide biochemical and genetic evidence that supports redundant roles between related Plant U-Box (PUB) proteins PUB22, PUB23, PUB24, PUB25, and PUB26 in BIK1 turnover.
Neuronal endolysosomal acidification relies on interactions between transmembrane protein 184B (TMEM184B) and the vesicular proton pump
Authors: Wright Elizabeth B. , Larsen Erik G. , Padilla-Rodriguez Marco , Langlais Paul R. , Bhattacharya Martha R.C.
Published: February 2025

Disruption of endolysosomal acidification is a hallmark of several neurodevelopmental and neurodegenerative disorders. Impaired acidification causes accumulation of toxic protein aggregates and disrupts neuronal homeostasis, yet the molecular mechanisms regulating endolysosomal pH in neurons remain poorly understood. A critical regulator of lumenal acidification is the vacuolar ATPase (V-ATPase), a proton pump whose activity depends on dynamic assembly of its V0 and V1 subdomains. In this study, we identify transmembrane protein 184B (TMEM184B) as a novel regulator of endolysosomal acidification in neurons. TMEM184B is an evolutionarily conserved 7-pass transmembrane protein required for synaptic structure and function, and sequence variation in TMEM184B causes neurodevelopmental disorders, but the mechanism for this effect is unknown. We performed proteomic analysis of TMEM184B-interacting proteins and identified enrichment of components involved in endosomal trafficking and function, including the V-ATPase. TMEM184B localizes to early and late endosomes, further supporting a role in the endosomal system. Loss of TMEM184B results in significant reductions in endolysosomal acidification within cultured mouse cortical neurons. This alteration in pH is associated with impaired assembly of the V-ATPase V0 and V1 subcomplexes in the TMEM184B mutant mouse brain, suggesting a mechanism by which TMEM184B promotes flux through the endosomal pathway. Overall, these findings identify a new contributor in maintaining endosomal function and provide a mechanistic basis for disrupted neuronal function in human TMEM184B-associated nervous system disorders.

Significance Statement

Endolysosomal acidification is essential for neuronal protein homeostasis, yet its regulation in neurons remains poorly understood. Here, we identify TMEM184B as a key regulator of this process, establishing its first known cellular role. We show that TMEM184B interacts with vacuolar ATPase (V-ATPase) components and promotes the assembly of its V0 and V1 subdomains, facilitating lumenal acidification. Loss of TMEM184B disrupts endolysosomal pH in neurons, potentially impairing proteostasis. These findings reveal a critical function for TMEM184B in neuronal maintenance and provide mechanistic insight into its link to neurological disorders. This work advances our understanding of endolysosomal regulation and suggests TMEM184B regulation could improve outcomes in diseases involving lysosomal dysfunction.
The dramatic impact of the PER-DBT interaction on circadian timekeeping and temperature compensation
Authors: Petersen E. Nicholas , Sullivan Camille , Ludewig Hannes , Kern Dorothee , Rosbash Michael
Published: February 2025

Circadian timekeeping depends on protein-protein interactions as well as post-translational modiﬁcations, yet the structural details that underlie these events remain largely uncharacterized. We used AlphaFold 2.3 to predict the interaction region between theDrosophilaPERIOD (PER) protein and the kinase Doubletime (DBT). The structure identiﬁed two conserved helical domains of PER, SYQ and LT, as critical for the interaction. We made mutations within these domains and used mutantperiodrescue constructs to assess their effects on circadian period and temperature compensation in vivo. A charge-reversal mutation (E to K) in the SYQ domain caused severe period lengthening and temperature sensitivity, which was rescued by a compensatory charge-reversal mutation in a predicted interacting LT domain residue (K to E); this validated an AlphaFold predicted interaction between two charged residues in SYQ and LT. Three additional mutations in the SYQ domain showed varying effects on period length and temperature compensation, with one uniquely displaying period shortening at higher temperatures. Most strikingly, two mutations in the LT domain (L770A, L775A) resulted in the longest recorded periods for single point mutations inperiod, with free-running periods > 44 hours at 25C. These also showed extreme temperature sensitivity with a magnitude of change >20 hrs. over the physiological temperatures tested. RNA-sequencing analysis of the L775A mutant shows that these behavioral changes are paralleled by altered molecular cycling. Our ﬁndings underscore the power of AlphaFold in predicting a crucial protein-protein interaction even with a largely disordered protein partner and reveal that the PER-DBT binding interface plays a crucial role in maintaining proper timekeeping and temperature-compensated circadian rhythms.
Telomerase mRNA Reduces Radiation-induced DNA Damage of human skin
Authors: Chang David F. , Li Shuang , Court Pinto Karem , Nguyen Thi Kim Cuc , Shah Vrutant V. , Morales Elisa , Carrier Jack , Ludlow Andrew T. , Brannan Kristopher W. , Spiegel Aldona J. , Olmsted-Davis  , Godin Biana , Mojiri Anahita , Cooke John P.
Published: February 2025

Over four million people undergo radiation therapy annually in the United States. Among these, more than 90% experience varying degrees of radiation-induced skin injury. Despite the enormity of the problem, there is currently no FDA-approved agent to prevent or treat skin damage caused by ionizing radiation. In the current study, ionizing radiation induced dose-dependent genomic and mitochondrial DNA damage, leading to apoptosis in primary cutaneous cells. Prior treatment with mRNA encoding telomerase reverse transcriptase (TERT) substantially reduced radiation-induced DNA damage in human primary skin cells and tissues. Mechanistically, TERT mRNA pretreatment enhances DNA repair, reduces mitochondrial ROS, and decreases apoptosis without extending telomere length during the experimental period, suggesting a non-canonical function of TERT to accelerate the cellular recovery from radiation. These findings highlight a potential therapeutic approach for preventing radiation-induced skin injury.

Graphic abstract
Extended Modelling of Platelet Calcium Signaling by Combined Recurrent Neural Network and Partial Least Squares Analyses
Authors: Tantiwong Chukiat , Cheung Hilaire Yam Fung , Dunster Joanne L , Gibbins Jonathan M. , Heemskerk Johan W. M. , Cavill Rachel
Published: February 2025

Platelets play critical roles in hemostasis and thrombosis. The platelet activation process is driven by agonist-induced rises in cytosolic [Ca2+]i, where the patterns of Ca2+responses are still incompletely understood. In this study, we developed a number of techniques to model the [Ca2+]icurves of platelets from a single blood donor. Using a fluorescence ratio probe, the platelets were stimulated with a panel of agonists, i.e. thrombin, collagen, or CRP under various conditions, preventing extracellular Ca2+entry, secondary mediator effects or Ca2+reuptake into intracellular stores. To analyze the data, we developed two non-linear models, a multilayer perceptron (MLP) network and an autoregressive network with exogenous inputs (NARX). The trained networks accurately predicted the platelet [Ca2+]icurves in the presence of combinations of agonists and inhibitors, with the NARX model achieving an R2up to 0.64 for trend prediction of unforeseen data. In addition, we used the same dataset for construction of a partial least square (PLS) linear regression model, which estimated the explained variance of each input. The NARX model demonstrated that good fits could be obtained for the calcium curves modelled, whereas the PLS model gave useful interpretable information on the importance of each variable. These modelling results can be used for the development of novel platelet [Ca2+]i-inhibiting drugs.
Mitophagy at the oocyte-to-zygote transition promotes species immortality
Authors: Balachandar Thendral Siddharthan , Bacot Sasha , Morton Katherine S. , Chi Qiuyi , Kenny-Ganzert Isabel W. , Meyer Joel N. , Sherwood David R.
Published: February 2025

The quality of inherited mitochondria determines embryonic viability1, metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria2, and mitochondrial health is under strict developmental regulation during early oogenesis3–5. Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA)6,7and mitochondrial dysfunction from high levels of endogenous reactive oxygen species8and exogenous toxicants9. How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.
MOLECULAR AND MORPHOMETRIC APPROACHES IN RECENTLY RADIATED SPECIES:Inga subnudaSALZM. EX BENTH ANDInga veraWILLD. (LEGUMINOSAE, MIMOSOID CLADE)
Authors: Badia Clara da Cruz Vidart , Garcia Flávia Cristina Pinto , Muller Larissa Areal , Fregonezi Jèferson Nunes
Published: February 2025

The species-rich genusInga(Leguminosae) presents ca. 300 species widespread throughout the Neotropics and is recognized by its recent and rapid diversification. Forty-eight species ofIngaare endemic of the Brazilian Atlantic Forest. Among them,Inga subnuda, with two subspecies: subsp.subnuda, which occurs from the state of Paraíba to Rio de Janeiro; and subsp.luschnathiana, which occurs from Espírito Santo to the state of Santa Catarina. Both subspecies occur in sympatry in the southeastern region and share floral and leaf characters, which hampers the morphological delimitation. The co-occurrence ofInga verasubsp.affinis. with bothI. subnudasubspecies results in intermediate morphologies betweenI. verasubsp.affinisandI. subnudasubsp.luschnathiana, making the distinction between the latter species even harder. We sampled 94 individuals from 8 natural populations and evaluated morphological characters previously described as distinctive among the subspecies ofI. subnudain addition to others not measured yet. We used 84 plastid (trnD-trnTspacer) and 58 nuclear (ITS 1 and 2) sequences to characterize the phylogenetic relationships between the taxa. The results obtained point outI. subnudasubsp.subnudaas a more structured taxon in relation to the other subspecies, whilstI. subnudasubsp.luschnathianaandI. verasubsp.affinisconstituted a cohesive group. The apportionment of haplotypes differed between the markers used, thus evincing a retention of ancestral polymorphism between the subspecies, given their recent diversification. This paper explores different lines of evidence, thus contributing to the delimitation of these species. Demographic and biogeographic scenarios are also discussed. A new status of for the taxon currently circumscribed asInga subnudasubsp.luschnathianais suggested.
Platelet endocytosis and α-granule cargo packaging are essential for normal skin wound healing
Authors: Coenen Daniëlle M. , Alfar Hammodah R. , Whiteheart Sidney W.
Published: February 2025

The high prevalence of chronic wounds,i.e.,2.5-3% of the US population, causes a large social and financial burden. Physiological wound healing is a multi-step process that involves different cell types and growth factors. Platelet-rich plasma or platelet-derived factors have been used to accelerate wound repair, but their use has been controversial with mixed results. Thus, a detailed functional understanding of platelet functions in wound healing beyond hemostasis is needed. This study investigated the importance of platelet α-granule cargo packaging and endocytosis in a dorsal full-thickness excisional skin wound model using mice with defects in α-granule cargo packaging (Nbeal2-/-mice) and endocytosis (platelet-specific Arf6-/-and VAMP2/3Δmice). We found that proper kinetic and morphological healing of dorsal skin wounds in mice requires bothde novoas well as endocytosed platelet α-granule cargo. Histological and morphometric analyses of cross-sectional wound sections illustrated that mice with defects in α-granule cargo packaging or platelet endocytosis had delayed (epi)dermal regeneration in both earlier and advanced healing. This was reflected by reductions in wound collagen and muscle/keratin content, delayed scab formation and/or resolution, re-epithelialization, and cell migration and proliferation. Molecular profiling analysis of wound extracts showed that the impact of platelet function extends beyond hemostasis to the inflammation, proliferation, and tissue remodeling phases via altered expression of several bioactive molecules, including IL-1β, VEGF, MMP-9, and TIMP-1. These findings provide a basis for advances in clinical wound care through a better understanding of key mechanistic processes and cellular interactions in (patho)physiological wound healing.

Key points

De novoand endocytosed platelet α-granule cargo support physiological skin wound healing

Platelet function in wound healing extends to the inflammation, proliferation, and tissue remodeling phases
The Psychological Impact of the COVID-19 Pandemic, A Meta-Analysis and General Population Study
Authors: Korff-Korn Derek C. , Trauben Andrew , Rayfield Elliot J.
Published: February 2025

This study assessed the impact of the financial, social and health disruptions due to the pandemic on increased rates of depression, anxiety, obsessiveness and substance abuse tendencies. In the meta-analysis portion of the study, a systematic search was performed and resulted in twenty studies which met the appropriate relevance and quality. The degree of symptoms was assessed in comparison to certain variables such as sex, age and income. Given the diversity of countries in which these studies were sourced, a varying severity of pandemic and subsequent restrictions were observed which allowed for a more expansive comprehension of the correlation to mental health risks. The complementary aspect of the meta-analysis was a general population study performed in the later months of 2020, which surveyed New York City residents. The provided questionnaire included sociodemographic background, previous mental health issues as well as associated factors such as social isolation, financial burdens and health concerns. The investigated levels of depression, anxiety and traumatic stress exposed positive correlations between younger age and mental health symptoms, a greater impact on one’s mental health due to social isolation than health exposure, a significance of news exposure, a fluctuation in various issues of anxiety, depression and stress when assessing participants who had been infected, and a difference in time from change in lifestyle to expressed mental health symptoms.
Anionic polymers stabilize Cas9 ribonucleoprotein nanoparticles to improve direct protein delivery and genome editing efficiencies in plant protoplasts
Authors: Hubbard Joshua D. , Tomatz Sophia , Carll Nicole , Matos Juliana , Hassan Danya , Ly Tong , Landry Markita P.
Published: February 2025

The application of CRISPR-based genome editing tools in plants is often challenged by low editing efficiencies, requiring most plant editing workflows to proceed through the delivery of pre-formed ribonucleoprotein (RNP) complexes to protoplasts. Here, we report increases in protoplast-based RNP delivery and genome editing efficiencies through the addition of anionic polymers to standard protoplast transfection protocols. We test addition of various polymers and peptides for their ability to increase genome editing efficiencies in bothNicotiana benthamianaandArabidopsis thalianaprotoplasts, by adding these components to standard PEG-based protoplast transfection protocols:i)non-covalent addition of charged polymers,ii)non-covalent addition of amphiphilic peptide A5K, andiii)tyrosinase-mediated covalent conjugation of various relevant peptide motifs directly to the RNP. Incorporation of the amphiphilic peptide A5K or covalent attachment of peptides to the RNP had no positive effect on editing efficiencies. However, we found that addition of anionic polymer polyglutamic acid to standard PEG transfection protocols significantly improved editing efficiencies in bothNicotiana benthamianaandArabidopsis thalianaprotoplasts relative to RNPs alone without negatively impacting protoplast viability. Our results suggest anionic polymers stabilize the RNP and increase the colloidal stability of the protoplast transfection workflow. This simple and straightforward method of stabilizing Cas9 RNPs can be easily adopted by others working on direct protein delivery to plant protoplasts to increase genome editing efficiencies.

Key message

The addition of anionic polymer polyglutamic acid to standard protoplast PEG transfection workflows enhance CRISPR-Cas9-mediated gene editing in plant protoplasts. Our results suggest the mechanism of increased transfection efficiency is due to colloidal stabilization of RNPs.

Graphical Abstract
AKAP12 variant 1 knockout enhances vascular endothelial cell motility
Authors: Ali Ashrifa , Roy Bhaskar , Schott Micah B. , Grove Bryon D.
Published: February 2025

In this study, we examined the role of AKAP12, in endothelial cell motility, with a specific focus on AKAP12 variants AKAP12v1 and AKAP12v2. Previous work has shown that AKAP12, a multivalent A-kinase anchoring protein that binds to PKA and several other proteins regulating protein phosphorylation, is expressed at low levels in most endotheliain vivobut at higher levels in cellsin vitro. Here, we found that AKAP12 expression in endothelial cell (HUVEC) cultures was cell density-dependent, with the expression being highest in subconfluent cultures and lowest in confluent cultures. AKAP12 expression was also elevated in cells at the wound edge of wounded endothelial cell monolayers. Knockdown of variants 1 and 2 inhibited cell migration, whereas CRISPR/Cas9 knockout of AKAP12v1 enhanced migration, indicating that the absence of this variant and the presence of AKAP12v2 may shift the signaling pathways. Further analysis using bulk RNA sequencing revealed that the loss of AKAP12v1 affects genes associated with cell migration and intercellular junctions. We propose that AKAP12v1 and AKAP12v2 work together to modulate endothelial cell migration, providing insights into their distinct yet complementary roles in endothelial function and potential implications for cardiovascular health.
An Open-Source Image Analysis Method for Quantifying Reporter Fluorescence
Authors: Ball Kathryn F. , Perez Jacob A. , Cooper Allen M. , Pira Charmaine U. , Oberg Kerby C. , Wilson Christopher G.
Published: February 2025

Image analysis is a rapidly developing field that provides unique opportunities to characterize and quantify spatial information in images. We studycis-regulatory modules (CRMs), non-coding DNA regions that regulate gene expression, during development using fluorescent reportersin vivo.Characterizing CRM activity during development presents challenges including image segmentation into biologically relevant regions of interest that are not easily distinguishable via common segmentation methods, fluorophore band passing, and variable transfection undermine standardized analysis. To quantify and compare CRM activity levels, we compiled an open-source computer vision tool stack in the form of aPython-basedJupyternotebook and tested four analysis methods to assess their efficacy in quantifying CRM expression in limb development. ThisJupyternotebook provides a reproducible, standardized workflow that can be adapted to numerous image analysis applications.
SBIS, a new orange fluorescent vital probe for the 4D imaging of brown algal cells
Authors: Zilliox Marie , Collot Mayeul , Charrier Bénédicte
Published: February 2025

Living cells of brown algae are difficult to observe in 3D due to the presence of pigments such as fucoxanthin and chlorophyll that diffract light. Furthermore, they grow slowly in seawater. To gain insight into the shape and size of brown alga cells in 3D during the development of these multicellular photosynthetic organisms, we designed a fluorescence probe that efficiently and selectively labels the plasma membrane. Styryl benzoIndoleninium sulfonate (SBIS) is a bright orange fluorogenic probe that is soluble and virtually non-emissive in seawater; it accumulates in the plasma membrane of brown algal cells, where it activates upon binding. SBIS enabled the 3D observation of cells of different shapes and sizes in several brown alga species, over a period of up to seven days and in a medium mimicking natural growth conditions. More importantly, SBIS makes it possible to observe cells at thicknesses of up to 20 µm, in contrast to Calcofluor White. These properties resulted in the visualization of the entire contour of the cells in the Z-axis of uniseriate filaments ofEctocarpus,polystichous filaments ofSphacelariaand cellular monolayered lamina ofSaccharina. Altogether, SBIS now makes the study of embryogenesis and early development possible in 4D in these brown algae.
TheNeflE397Kmouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E
Authors: Pérez-López Dennis O. , Shively Audrey A. , Torres F. Javier Llorente , Muchow Roxanne , Abu-Salah Zaid , Abu-Salah Mohammed T. , Garcia Michael L. , Smith Catherine L. , Nichols Nicole L. , Lorson Monique A. , Lorson Christian L.
Published: February 2025

Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2,500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. SeveralNeflmouse models exist that either alter the mouseNeflgene or overexpress a mutated humanNEFLtransgene, each recapitulating various aspects of CMT2E disease. We generated the orthologousNEFLE396Kmutation in the mouse C57BL/6 background,NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology inNeflE397Kmice. In this manuscript, we report our characterization ofNeflE397Kmotor function deficits, muscle pathology and changes in breathingNefl+/E397KandNeflE397K/E397Kmice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally,Nefl+/E397KandNeflE397K/E397Kmice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly,Neflmutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions.NeflE397K/E397Kmice phenotypes and pathology were consistently more severe thanNefl+/E397Kmice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.
Post-Ictal Gamma Oscillations Predict Hippocampal Structural Integrity in Mesial Temporal Lobe Epilepsy
Authors: Valdivia Daniel J. , Tescarollo Fabio Cesar , Ercan Koray , Huang Isaac , Vasquez Betsy , Parsonnet Lauren , Chung Sangmi , Boison Detlev , Gross Robert , Gleichgerrcht Ezequiel , Chen Spencer C. , Sun Hai
Published: February 2025

The underlying histopathology and epileptic network of patients with mesial temporal lobe epilepsy (mTLE) are difficult to ascertain. Here, we report a novel electrical activity following seizure termination, termed post-ictal gamma oscillations (PIGOs), recorded in mice with intrahippocampal kainic acid injection and a patient with mTLE. PIGOs are characterized by a spectral shift of increased power in gamma frequencies relative to decreased power in other frequencies, generating a gamma peak. PIGOs are accompanied by increased intracellular calcium levels among parvalbumin-positive interneurons and a direct current shift. Only a subgroup of animals in the study had PIGOs. These animals had less pronounced hippocampal sclerosis (HS) than those without PIGOs. To illustrate the translational potential of these findings, we analyzed data from two patients with unilateral mTLE, one with PIGOs and the other without. The patient with PIGOs had symmetrical hippocampi on neuroimaging, whereas the other exhibited overly decreased interictal glucose uptake in left hippocampus, suggesting left-sided HS. After receiving laser ablation of mesial temporal regions, the patient with PIGOs became seizure-free, whereas the other did not. Our results suggest that PIGOs may serve as a biomarker for a milder form of HS in patients with mTLE and for predicting treatment outcomes.
Regulation of hippocampal excitatory synapse development by the adhesion G-protein coupled receptor Brain-specific angiogenesis inhibitor 2 (BAI2/ADGRB2)
Authors: Meyer Christina M. , Vafaeva Olga , Low Henry , Speca David J. , Díaz Elva
Published: February 2025

Glutamatergic synapses and their associated dendritic spines are critical information processing sites within the brain. Proper development of these specialized cellular junctions is important for normal brain functionality. Synaptic adhesion G protein-coupled receptors (aGPCRs) have been identified as regulators of synapse development and function. While two members of the Brain-specific angiogenesis inhibitor (BAI/ADGRB) subfamily of synaptic aGPCRs, BAI1/ADGRB1 and BAI3/ADGRB3, have been found to mediate synapse and spine formation, BAI2/ADGRB2 function remains uncharacterized at the synapse. Here, we show that endogenous BAI2 is expressed throughout the nervous system with prominent expression in synapse dense regions of the hippocampus. In dissociated hippocampal cultures, BAI2 is highly enriched at large postsynaptic sites, defined by the size of the postsynaptic scaffold PSD95. Loss of BAI2 negatively impacts glutamatergic synapses across development in dissociated hippocampal cultures. In contrast, GABAergic synapse density is unchanged. Furthermore, BAI2 deficient neurons have significant alterations in spine morphology with decreased density of mature PSD95-containing mushroom-shaped spines compared with wild-type neurons. Interestingly, no major alterations in dendritic complexity were observed in BAI2 deficient neurons, in contrast to previous results for the other BAIs. The reduction in mature mushroom-shaped spine is commensurate with a reduction in spine volume and head diameter. Altogether, these results demonstrate that the aGPCR BAI2 is an important regulator of glutamatergic synapse and PSD95-associated spine development in cultured hippocampal neurons. These results expand the knowledge of the BAI subfamily of aGPCRs in mediating excitatory synapse and spine development and highlight differences unique to BAI2.

Highlights

- BAI2 expression is upregulated during postnatal development in the hippocampus

- BAI2 is enriched at postsynaptic sites, particularly large synapses

- Loss of BAI2 results in decreased density of glutamatergic synapses with no change in GABAergic synapse density

- Loss of BAI2 results in decreased density of mushroom spines
Shared Alteration of Whole-Brain Connectivity and Olfactory Deficits in Multiple Autism Mouse Models
Authors: Hsu Tsan-Ting , Chen Chih-Ping , Lin Ming-Hui , Haung Tzyy-Nan , Wang Chung-Yu , Lee Chia-Ming , Chen Bi-Chang , Wang Chien-Yao , Hsueh Yi-Ping
Published: February 2025

Autism spectrum disorder (ASD) is a disconnection condition influenced by both heterogeneous genetic and environmental factors, yet it remains unclear whether common connectivity deficits exist. Here, we demonstrate that different ASD-linked mutations lead to distinct circuit abnormalities but share deficits in the piriform cortex and olfactory discrimination. Using advanced artificial intelligence, we developed a whole-brain mapping platform to analyze the distribution of the Thy1-YFP projection neurons in three ASD mouse models (Tbr1+/–,Nf1+/–,Vcp+/R95G). Our analysis revealed changes in axonal patterns and neuronal distribution, indicating deficits in projection neuron differentiation and maintenance. Notably, the piriform cortex consistently exhibited reduced YFP+cells and signals and impaired functionality across all models. Visual and somatosensory cortices were also affected, but the patterns varied. These findings highlight that the sensory regions, especially the piriform cortex, are susceptible to ASD-related mutations, strengthening the notion that different sensory experiences are common in ASD.

Highlights

AI-powered whole-mouse brain quantification accelerates neural connectivity study.

Autism-linked mutations lead to various circuit abnormalities of Thy1-YFP neurons.

Multiple sensory regions all exhibit circuit deficits among the three autism models.

Abnormalities of olfaction and piriform cortex circuits are common in autism models.
Causal relationships between gut microbiome and age-related traits
Authors: Grosso Federica , Zanetti Daniela , Sanna Serena
Published: February 2025

In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive investigation of 4,033 potential causal relationships between 37 traits representing gut microbiome composition and function and 109 age-related phenotypes, using two-samples Mendelian randomization. Five causal relationships remained significant after multiple testing correction and sensitivity analyses, specifically between two taxa ofCoriobacterialesand the risk of developing age-related macular degeneration, speciesBifidobacterium adolescentisand levels of TNFSF12 protein in plasma, and the lactose-galactose degradation microbial I pathway and levels of IL-15Rα and TRAIL proteins in plasma. The causal relationship between the lactose-galactose degradation I pathway and TRAIL protein levels was further confirmed using independent data. These results support the role of gut microbiome in regulating the inflammatory circuit, albeit future studies are needed to investigate the underlying biological mechanisms.
The additional diagnostic yield of long-read sequencing in undiagnosed rare diseases
Authors: Del Gobbo Giulia F. , Boycott Kym M.
Published: February 2025

Long-read sequencing (LRS) is a promising technology positioned to study the significant proportion of rare diseases (RDs) that remain undiagnosed as it addresses many of the limitations of short-read sequencing, detecting and clarifying additional disease-associated variants that may be missed by the current standard diagnostic workflow for RDs. Some key areas where additional diagnostic yields may be realized include: (1) detection and resolution of structural variants (SVs); (2) detection and characterization of tandem repeat expansions; (3) coverage of regions of high sequence similarity; (4) variant phasing; (5) the use of de novo genome assemblies for reference-based or graph genome variant detection; and (6) epigenetic and transcriptomic evaluations. Examples from over 50 studies support that the main areas of added diagnostic yield currently lie in SV detection and characterization, repeat expansion assessment, and phasing (with or without DNA methylation information). Several emerging studies applying LRS in cohorts of undiagnosed RDs also demonstrate that LRS can boost diagnostic yields following negative standard-of-care clinical testing and provide an added yield of 7%–17% following negative short-read genome sequencing. With this evidence of improved diagnostic yield, we discuss the incorporation of LRS into the diagnostic care pathway for undiagnosed RDs, including current challenges and considerations, with the ultimate goal of ending the diagnostic odyssey for countless individuals with RDs.
Effective time-dependent temperature for fermionic master equations beyond the Markov and the secular approximations
Authors: Litzba Lukas , Kleinherbers Eric , König Jürgen , Schützhold Ralf , Szpak Nikodem
Published: February 2025

We consider a fermionic quantum system exchanging particles with an environment at a fixed temperature and study its reduced evolution by means of a Redfield-I equation with time-dependent (non-Markovian) coefficients. We find that the description can be efficiently reduced to a standard-form Redfield-II equation, however, with a obeying a universal law. At early times, after the system and environment start in a product state, the appears to be very high, yet eventually it settles down towards the true environment value. In this way, we obtain a time-local master equation, offering high accuracy at all times and preserving the crucial properties of the density matrix. It includes non-Markovian relaxation processes beyond the secular approximation and time-averaging methods and can be further applied to various types of Gorini-Kossakowski-Sudarshan-Lindblad equations. We derive the theory from first principles and discuss its application using a simple example of a single quantum dot.

Published by the American Physical Society
2025
Consistent electroweak phenomenology of a nearly degenerate
Z′
boson
Authors: Lo Chiatto Prisco , Yu Felix
Published: February 2025

Extracting constraints on the kinetic mixing of a new U(1)′ gauge boson hiding under the Standard Model Z boson resonance requires the formalism of non-Hermitian two-point correlation functions at 1-loop order. We derive self-consistent collider constraints on Z′ bosons with kinetic mixing in a narrow mass window around the Z boson, considering both model-independent and model-dependent bounds. Our treatment elucidates the importance of both avoided level crossing and the dispersive seesaw effect in interpreting the existing constraints. We also discuss the implications for future measurements on the Z-pole.

Published by the American Physical Society
2025
Constraints on neutrino nonstandard interactions from COHERENT, PandaX-4T and XENONnT
Authors: Li Gang , Song Chuan-Qiang , Tang Feng-Jie , Yu Jiang-Hao
Published: February 2025

We investigate constraints on neutrino nonstandard interactions (NSIs) in the effective field theory framework, using data from the first measurement of solar B8 neutrinos via coherent elastic neutrino-nucleus scattering (CEνNS) in the PandaX-4T and XENONnT experiments and data from the COHERENT experiment. The impacts of neutrino NSIs on the CEνNS cross section and the matter effect in the propagation of solar neutrinos are included, while we obtain that the expected number of CEνNS events is more sensitive to neutrino NSIs appearing in the cross section. Due to relatively large statistical uncertainties, the sensitivities of the PandaX-4T and XENONnT experiments to the neutrino NSIs are currently limited, compared to the COHERENT experiment. Besides, we find that since the central value of the measured CEνNS counts significantly differs from the Standard Model prediction, the sensitivity of PandaX-4T experiment is even more restricted compared to XENONnT. However, the measurements of PandaX-4T and XENONnT are uniquely sensitive to the neutrino NSIs for the τ flavor due to oscillation feature of the solar B8 neutrinos. We also assess how the experimental central value, exposure, and systematic uncertainties will affect the constraints on neutrino NSIs from various CEνNS measurements in the future.

Published by the American Physical Society
2025
Holographic foliations: Self-similar quasicrystals from hyperbolic honeycombs
Authors: Boyle Latham , Kulp Justin
Published: February 2025

Discrete geometries in hyperbolic space are of longstanding interest in pure mathematics and have come to recent attention in holography, quantum information, and condensed matter physics. Working at a purely geometric level, we describe how any regular tessellation of (d+1)-dimensional hyperbolic space naturally admits a d-dimensional boundary geometry with self-similar “quasicrystalline” properties. In particular, the boundary geometry is described by a local, invertible, self-similar substitution tiling, that discretizes conformal geometry. We greatly refine an earlier description of these local substitution rules that appear in the 1D/2D example and use the refinement to give the first extension to higher dimensional bulks; including a detailed account for all regular 3D hyperbolic tessellations. We comment on global issues, including the reconstruction of bulk geometries from boundary data, and introduce the notion of a “holographic foliation”: a foliation by a stack of self-similar quasicrystals, where the full geometry of the bulk (and of the foliation itself) is encoded in any single leaf in a local, invertible way. In the {3,5,3} tessellation of 3D hyperbolic space by regular icosahedra, we find a 2D boundary quasicrystal admitting points of 5-fold symmetry which is not the Penrose tiling, and record and comment on a related conjecture of William Thurston. We end with a large list of open questions for future analytic and numerical studies.

Published by the American Physical Society
2025
Electronic structure and energy landscape of
BSiSii
related defects
Authors: Flötotto Aaron , Beenken Wichard J. D. , Lauer Kevin , Krischok Stefan , Runge Erich
Published: February 2025

Boron is an important dopant for silicon. Together with an adjacent interstitial Si atom, it forms the so-called BSiSii defect, which has been proposed as a source of light-induced degradation (LID) in solar cells made from boron-doped Czochralski-grown silicon. Furthermore, the BSiSii defect is an intermediate configuration in many models for boron diffusion in silicon. In the present comprehensive density-functional-theory-based study, we have calculated the energy landscape around the BSiSii defect and related defects involving one B atom and one interstitial Si atom for different chemical potentials of electrons corresponding to neutral, positively, and negatively charged supercells. Among the found metastable defect configurations, we identify possible recombination centers based on the defect-dependent electronic density of states and the minimal energy paths between them. The resulting potential energy landscape is checked against empirical models for boron diffusion and LID.

Published by the American Physical Society
2025