bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondria transported by Kinesin 3 prevent localized calcium spiking to inhibit caspase-dependent specialized cell death
Authors: Sharmin Rashna , Elkhalil Aladin , Pena Sara , Gaddipati Pranya , Clark Ginger , Shah Pavak K. , Pellegrino Mark W. , Shaham Shai , Ghose Piya
Published: January 2025

Polarized cells (such as neurons), defined by distinct compartments are, like many cell types, subject to developmental elimination, as in neurite pruning. The molecular mechanism behind specialized elimination remains a largely open question. We previously introduced the “tri-partite” embryonic cell death program Compartmentalized Cell Elimination (CCE) in the scaffolding tail-spike epithelial cell and sex-specific CEM neurons ofC. elegans. CCE is stereotyped and ordered, with three distinct programs eliminating three cell compartments, and bearing morphological hallmarks reminiscent of neurite pruning. Here we report first, that, prior to CCE onset, mitochondria undergo UNC-116/Kinesin 1-dependent irreversible retrograde transport; and second, that the caspase protease CED-3 promotes the completion of the proximal nicking event of CCE by helping inhibit the kinesin 3 homolog UNC-104. While known canonically to carry only synaptic vesicles, UNC-104/Kinesin 3, in the CCE context, and in the absence of CED-3/Caspase, can transport mitochondria anterogradely to the severing site. We observe both caspase activity and Ca2+spiking at this site prior to nicking. Mitochondria appear to protect against nicking in the absence of CED-3 via their MCU-1 uniporter-dependent Ca2+uptake capacity. Our study sheds light on the molecular machinery of specialized cell elimination and pruning, highlighting involvement of region-specific Ca2+signaling, an anti-death function of mitochondria via local Ca2+uptake, mitochondrial transport as a regulatory strategy, with UNC-116/kinesin 1-mediated retrograde transport important for cell elimination priming and UNC-104/kinesin 3 in a previously undescribed role as a non-canonical anterograde mitochondrial motor.
PRPS activity tunes redox homeostasis in Myc-driven lymphoma
Authors: MacMillan Austin C , Karki Bibek , Yang Juechen , Gertz Karmela R , Zumwalde Samantha , Patel Jay G , Czyzyk-Krzeska Maria F , Meller Jarek , Cunningham John T
Published: January 2025

Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.
Pillar arrays as tunable interfacial barriers for microphysiological systems
Authors: Goswami Ishan , Kim Yongdeok , Neiman Gabriel , Siemons Brian , Velazquez Jazmin I. , Yazgan Kerem , Ng Tammy , Healy Kevin E.
Published: January 2025

We report on the design and fabrication of a novel circular pillar array as an interfacial barrier for microfluidic microphysiological systems (MPS). Traditional barrier interfaces, such as porous membranes and microchannel arrays, present limitations due to inconsistent pore size, complex fabrication and device assembly, and lack of tunability using a scalable design. Our pillar array overcomes these limitations by providing precise control over pore size, porosity, and hydraulic resistance through simple modifications of pillar dimensions. Serving as an interface between microfluidic compartments, it facilitates cell aggregation for tissue formation and acts as a tunable diffusion barrier that mimics diffusion in vivo. We demonstrate the utility of barrier design to engineer physiologically relevant cardiac microtissues and a heterotypic model with vasculature within the device. Its tunable properties offer significant potential for drug screening/testing and disease modeling, enabling comparisons of drug permeability and cell migration in MPS tissue with or without vasculature.
The Existence and Uniqueness of Solutions in the Leaf Photosynthesis-Transpiration-Stomatal Conductance Model
Authors: Masutomi Yuji , Kobayashi Kazuhiko
Published: January 2025

TheAn-E-gsmodel, which consistently describes leaf photosynthesis (An), transpiration (E), and stomatal conductance (gs), is widely recognized and utilized as a “standard model” for quantifying these processes in terrestrial plants. However, since its proposal over 30 years ago, the model has faced a longstanding challenge: the “solution selection” problem, arising from the existence of multiple solutions with no guarantee that the obtained solution is correct.

In this study, we mathematically proved that theAn-E-gsmodel always has a unique solution satisfying the criteriags>0andCi>0, whereCirepresents the CO2concentration inside the leaf. This result establishes a rigorous mathematical theorem on the existence and uniqueness of solutions in the model. The theorem resolves the longstanding “solution selection” problem by enabling the unambiguous identification of the correct solution through selecting the unique solution that satisfies these criteria. Furthermore, the theorem ensures the validity of past estimations that satisfy these criteria and guarantees that future studies applying these criteria will yield correct estimations. These findings provide a robust mathematical foundation for theAn-E-gsmodel, reinforcing its role as the standard model for estimating leaf photosynthesis, transpiration, and stomatal conductance across diverse disciplines, from plant biology to climate science and beyond.
A pilot study on the biological applications of indole alkaloids derived from Nagaland biodiversity
Authors: Ovung Aben , Mavani A. , Roymahapatra Gourisankar , Bhattacharyya Jhimli
Published: January 2025

The north-eastern Indian state, Nagaland with its rich biodiversity, is well known for traditional, natural medicines. However, the scientific basis of the working principle(s) of such drugs are yet to be explored. Plant alkaloids, the nitrogen-containing organic molecules, are traditionally been used for various medicinal purposes from ages. There is a need for drug discovery from natural sources to create a broader drug portfolio for human use. And, Nagaland medicinal plant based bioactive molecules have huge potential for the same. As a pilot study, this work aims to study thein silicoabsorption, distribution, metabolism and excretion (ADME) properties, toxicity prediction and structural properties of the indole alkaloid molecules, Ajmalicine (AJM) and Serpentine (SER) and its docking interaction pattern with various forms of DNA. ADME analysis confirms that the alkaloids meet the criteria of a standard drug. The ProTox II prediction showed the probability of the toxicity profile of the input compounds. Density functional theory (DFT) revealed the HOMO-LUMO energy gap of the drug molecules along with the quantum chemical parameters from the optimized geometry of the ligands. Molecular docking (MD) analysis showed successful binding of the molecules into the groove region of the various forms of DNA structure for both the cases. The results of this theoretical pilot study provides information that will be helpful in the development of effective and modified drugs for medicinal and pharmaceutical purposes as well as in the planning of practical laboratory experiments.
Elucidating Protein Dynamics through the Optimal Annealing of Variational Autoencoders
Authors: Adhikari Subinoy , Mondal Jagannath
Published: January 2025

Proteins traverse intricate conformational landscapes, with transitions and long-lived states that hold the key to their biological function. Yet, unraveling these dynamics remains a formidable challenge. An emerging approach has been to train the conformational ensemble via deep Variational autoencoders (VAEs) in a bid to machine learn the underlying reduced dimensional representation. However, training VAEs typically involves a fixedβvalue of 1, whereβacts as the crucial weighing factor between the reconstruction and regularization terms. This static setup can often lead to poste-rior collapse, which significantly hinders the model’s ability to capture complex protein dynamics accurately. To mitigate this issue, annealing theβparameter offers a potential alternative. However, this approach frequently falls short in fully addressing the problem, majorly due to arbitrary choice of upper bound ofβand annealing schedule. In this work, we introduce an innovative approach for selecting theβparameter by utilizing the Fraction of Variance Explained (FVE) score to identify its optimal value. We demonstrate that training annealed VAEs at their optimumβin a single cycle consistently outperformed their non-annealed counterparts, as evident from their higher Variational Approach for Markov Processes-2 and Generalized Matrix Rayleigh Quotient scores and distinct free energy surface minima on both folded and intrinsically disordered proteins. The improved latent space representations significantly improve state space discretization, thereby refining Markov State Models and providing more accurate insights into conformational landscapes as reflected in distinct contact maps. These findings not only underscore the potential of annealed VAEs in resolving complex conformational spaces but also highlight the critical interplay between annealing schedules and latent space structures.
Constructing structural and functional brain networks from regional brain profiles
Authors: Song Donghui
Published: January 2025

Brain network analysis has become an important approach to understanding brain function. Given the human brain's complexity and dynamic nature, traditional brain networks based on temporal synchronization may not capture all the nuances of brain activity. The emerging trend is to construct brain networks from regional information, creating pathways that connect regional profiles to network-level insights to better understand brain function. In this study, we constructed structural networks based on regional brain structural information, specifically gray matter volume (GMV), and functional networks based on regional brain activity, measured by brain entropy (BEN). We compared these newly constructed networks with traditional networks: functional connectivity networks (FCN) based on temporal synchronization, structural connectivity networks (SCN) derived from fiber tracking, and MEG-derived functional networks. Our results reveal that GMV network (GMVN) and BEN network (BENN) show correlations with these networks but also exhibit distinct differences. Furthermore, we conducted connectome gradient analyses, uncovering meaningful brain function distribution patterns in both GMVN and BENN. Finally, we used GMVN, BENN, and traditional FCN to predict cognitive and emotional scores. The results showed that BENN, in the resting state, provided the best prediction of both cognitive and emotional scores. This study systematically evaluates the relationship between brain networks constructed from regional brain information and existing networks, as well as their ability to predict behavioral phenotypes. It demonstrates that networks built from regional information capture aspects of brain activity that traditional networks cannot represent and may even provide superior predictive power for behavioral phenotypes. This opens a new path for understanding brain function from regional to network-level information and lays the foundation for future applications in brain development, individual differences, and clinical research.
Identification of INOSITOL PHOSPHORYLCERAMIDE SYNTHASE 2 (IPCS2) as a new rate-limiting component in Arabidopsis pathogen entry control
Authors: Mittendorf Josephine , Haslam Tegan M. , Herrfurth Cornelia , Esnay Nicolas , BOUTTE Yohann , Feussner Ivo , Lipka Volker
Published: January 2025

INOSITOL PHOSPHORYLCERAMIDE SYNTHASE 2 (IPCS2) is involved in the biosynthesis of complex sphingolipids at the trans-Golgi network (TGN). Here, we demonstrate a role of IPCS2 in penetration resistance against non-adapted powdery mildew fungi. A novel ipcs2W205* mutant was recovered from a forward genetic screen for Arabidopsis plants with enhanced epidermal cell entry success of the non-adapted barley fungus Blumeria graminis f. sp. hordei (Bgh). A yeast complementation assay and a sphingolipidomic approach revealed that the ipcs2W205* mutant represents a knock-out and lacks IPCS2-specific enzymatic activity. Further mutant analyses suggested that IPCS2-derived glycosyl inositol phosphorylceramides (GIPCs) are required for cell entry control of non-adapted fungal intruders. Confocal laser scanning microscopy (CLSM) studies indicated that upon pathogen attack, IPCS2 remains at the TGN to produce GIPCs, while focal accumulation of the defense cargo PENETRATION 3 (PEN3) at Bgh penetration sites was reduced in the ipcs2W205* mutant background. Thus, we propose a model in which sorting events at the TGN are facilitated by complex sphingolipids, regulating polar secretion of PEN3 to host-pathogen contact sites to terminate fungal ingress.
Threat reduction must be coupled with targeted recovery programmes to conserve global bird diversity
Authors: Stewart Kerry , Venditti Chris , Carmona Carlos P. , Baker Joanna , Clements Chris , Tobias Joseph A. , González-Suárez Manuela
Published: January 2025

Biodiversity is undergoing severe declines while threats to natural populations continue to escalate worldwide. Ambitious international commitments have been made to preserve biodiversity, with the goal of preventing extinctions and maintaining ecosystem resilience, yet the efficacy of large-scale protection remains unclear. Here we use a trait-based approach to show that global actions – such as the immediate abatement of all threats across at least half of species ranges for ∼10,000 bird species - will only prevent half of projected species extinctions and functional diversity loss attributable to current and future threats in the next 100 years. Nonetheless, targeted recovery programmes prioritizing protection of the 100 most functionally unique threatened birds could avoid 68% of projected functional diversity loss. Actions targeting ‘habitat loss and degradation’ will prevent the greatest number of species extinctions and proportion of functional diversity loss relative to other drivers of extinction, whereas control of ‘hunting and collection’ and ‘disturbance and accidental mortality’ would save fewer species but disproportionately boost functional richness. These findings show that conservation of avian diversity requires action partitioned across all drivers of decline, and highlights the importance of understanding and mitigating the ecological impacts of species extinctions predicted to occur even under optimistic levels of conservation action.
LncRNA-BERT: An RNA Language Model for Classifying Coding and Long Non-Coding RNA
Authors: Romeijn Luuk , Cats Davy , Wolstencroft Katherine , Mei Hailiang
Published: January 2025

Understanding (novel) RNA transcripts generated in next generation sequencing experiments requires accurate classification, given the increasing evidence that long non-coding RNAs (lncRNAs) play crucial regulatory roles. Recent developments in Large Language Models present opportunities for classifying RNA coding potential with sequence-based algorithms that can overcome the limitations of classical approaches that assess coding potential based on a set of predefined features. We present lncRNA-BERT, an RNA language model pre-trained and fine-tuned on human RNAs collected from the GENCODE, RefSeq, and NONCODE databases to classify lncRNAs. LncRNA-BERT matches and outperforms state-of-the-art classifiers on three test datasets, including the cross-species RNAChallenge benchmark. The pre-trained lncRNA-BERT model distinguishes coding from long non-coding RNA without supervised learning which confirms that coding potential is a sequenceintrinsic characteristic. LncRNA-BERT has been shown to benefit from pre-training on human data from GENCODE, RefSeq, and NONCODE, improving upon configurations pre-trained on the commonly used RNAcentral dataset. In addition, we propose a novel Convolutional Sequence Encoding method that is shown to be more effective and efficient than K-mer Tokenization and Byte Pair Encoding for training with long RNA sequences that are otherwise above the common context window size. lncRNA-BERT is available athttps://github.com/luukromeijn/lncRNA-Py.
C-reactive protein and the menstrual cycle in females with sickle cell disease
Authors: Wu Jessica , Bochenek Veronica , Gollomp Kandace , Roe Andrea H.
Published: January 2025

There are notable sex disparities in the frequency and severity of vaso-occlusive pain episodes (VOEs) in sickle cell disease (SCD), with females experiencing more frequent and severe episodes during the reproductive years. Many individuals report a temporal link between VOEs and the menstrual cycle, suggesting that sex hormones may play a role in modulating inflammation and pain. This study explores the relationship between inflammatory markers and the menstrual cycle in females with SCD. Plasma samples from 13 female and 18 male individuals with confirmed SCD were analyzed for C-reactive protein (CRP) and other inflammatory biomarkers. In female patients, sex hormones were measured to determine the menstrual cycle phase. While no overall difference in CRP levels was observed between males and females, CRP levels fluctuated significantly across the menstrual cycle in females, with higher levels in the follicular phase compared to the luteal phase. Additionally, platelet counts were significantly elevated in females during the follicular phase compared to males. These findings suggest that cyclic inflammation may contribute to the increased frequency and severity of VOEs in females, particularly during the perimenstrual period. Further research is needed to explore whether hormonal interventions can reduce perimenstrual VOEs in SCD.
Regulation of protein abundance in normal human tissues
Authors: Fang Huaying , Jiang Lihua , da Veiga Leprevost Felipe , Jian Ruiqi , Chan Joanne , Glinos Dafni , Lappalainen Tuuli , Nesvizhskii Alexey I. , Reiner Alexander P. , Consortium GTEx , Snyder Michael P. , Tang Hua
Published: January 2025

We report a systematic quantification of 10,841 unique proteins from over 700 GTEx samples, representing five human tissues. Sex, age and genetic factors are associated with variation in protein abundance. In total, 1981 cis-protein quantitative trait loci (cis-pQTL) are identified, of which a majority of protein targets have not been assayed in the recent plasma-based proteogenomic studies. Integrating transcriptomic information from matching tissues delineates concordant as well as discordant expression patterns at RNA and protein levels. Juxtaposition of data from different tissues indicates both shared and tissue-specific genetic architecture that underlie protein abundance. Complementing genomic annotation, RNA-based eQTL studies, as well as the recent establishment of plasma-based proteogenomic characterization, tissue-pQTLs shed light on biology underlying genotype-phenotype association of complex traits and diseases.
12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice
Authors: Kaylan Kerim B. , Nargis Titli , Figatner Kayla , Wang Jiayi E. , Pratuangtham Sarida , Chakraborty Advaita , Casimiro Isabel , Nadler Jerry L. , Boxer Matthew B. , Maloney David J. , Anderson Ryan M. , Mirmira Raghavendra G. , Tersey Sarah A.
Published: January 2025

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes (T2D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we utilized a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the humanALOX12gene. As a model of obesity and dysglycemia, we administered these mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in whichAlox15was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D.
Inhibitory effect of Dolosigranulum pigrum and Corynebacterium pseudodiphtheriticum on pneumococcal in vitro growth
Authors: Cisneros M , Blanco-Fuertes M , Lluansí A , Brotons P , Henares D , Pérez-Argüello A , González-Comino G , Ciruela P , Mira A , Muñoz-Almagro C
Published: January 2025

Background

Streptococcus pneumoniaeis a nasopharynx coloniser that can invade sterile tissues, causing Invasive Pneumococcal Disease (IPD).Dolosigranulum pigrumandCorynebacterium pseudodiphtheriticumare commensal bacteria commonly isolated from the nasopharynx of healthy children, potentially playing a protective role. This study aims to analyse the effects ofD. pigrumandC. pseudodiphtheriticumonS. pneumoniaein vitro growth.

Methods

Pneumococcal strains were collected from IPD patients and healthy carriers in Catalonia (2016-2023).D. pigrumandC. pseudodiphtheriticumstrains were isolated from a healthy child’s nasopharynx.S. pneumoniaewas co-cultured with each commensal bacterium in triplicate experiments. Pneumococcal growth was quantified using a real-time PCR assay targeting thelytAgene. The effect of commensal bacteria on pneumococcal growth was evaluated using a linear mixed-effect regression model.

Results

Twenty-eight pneumococcal strains expressing 24 different serotypes and 26 clonal types were analysed (18 isolated in blood and 10 in nasopharyngeal aspirate). Pneumococcal growth was decreased byD. pigrum(β = −0.763, 95% CI: −0.94 to −0.59, p < 0.0001) andC. pseudodiphtheriticum(β = −0.583, 95% CI: −0.76 to −0.41, p < 0.0001). The combined presence of both had a stronger inhibitory effect (β = −0.971, 95% CI: −1.15 to −0.79, p < 0.0001). No association was found between isolation site or serotype with pneumococcal growth.

Conclusion

D. pigrumandC. pseudodiphtheriticumsignificantly reduced pneumococcal growth, with a synergic effect when combined. This antagonistic effect supports the potential protective factor of healthy nasopharyngeal microbiota against IPD and the development of these microorganisms as probiotics.
Medicare Payment for Calcium Modification Technologies Among Patients Undergoing Percutaneous Coronary Intervention, 2021-2022
Authors: Schlacter Jamie , Yu Huihui , Tsuruo Sarah , Herrin Jeph , Ross Joseph S. , Horwitz Leora I. , Dhruva Sanket S.
Published: January 2025

Background

The Centers for Medicare and Medicaid Services (CMS) New Technology Add-on Payment (NTAP) program supports adoption of new, costly medical technologies demonstrating substantial clinical improvement. In 2021, CMS waived the “substantial clinical improvement” criterion for devices designated under the FDA Breakthrough Devices Program (BDP). This study characterized risk-standardized payments associated with hospitalizations in which Medicare beneficiaries received calcium modification during PCI for acute myocardial infarction (AMI) following the adoption of the Shockwave C2Coronary Intravascular Lithotripsy (IVL) Catheter (Shockwave Medical) with BDP designation.

Methods

We analyzed Medicare beneficiaries hospitalized for AMI who underwent PCI between January 2021 and December 2022, stratifying them into four groups: no calcium modification, rotational atherectomy (RA), orbital atherectomy (OA), and coronary IVL. Risk-standardized Medicare payments at 30 days, including index facility, physician, and post-acute care costs, were assessed using non-parametric median and chi-square tests.

Results

Among 87,238 patients, 76,462 (87.6%) received no calcium modification, 8,316 (9.5%) underwent RA, 793 (0.9%) underwent OA, and 1,668 (1.9%) underwent IVL. IVL use increased from 1.6% in October 2021 to 4.4% in December 2022. Median total risk-standardized Medicare payments were significantly higher for patients receiving calcium modification technologies ($27,579 for IVL, $27,353 for OA, $23,240 for RA) compared to those without ($19,115; p<0.001). Payment differences were largest for index facility payments.

Conclusion

Coronary IVL during PCI for Medicare patients hospitalized for AMI was associated with significantly increased Medicare payments. Further studies must determine whether IVL, and calcium modification technologies in general, improve outcomes for patients hospitalized for AMI undergoing PCI and thus warrant higher payments via NTAP.
Genetic mapping in Collaborative Cross mouse strains identifies loci that affect initial sensitivity to cocaine
Authors: Schoenrock SA , Gaines CH , Kumar P , Khan S , Farrington J , Ferris MT , Pardo-Manuel de Villena F , Valdar W , Bubier JA , Tarantino LM
Published: January 2025

We identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response and self-administration of cocaine. In the current study, we crossed each of these strains to C57BL/6NJ (B6N) mice to produce two F2 populations and identify genetic loci that influence locomotor response to cocaine. We identified three significant loci on chromosomes 7, 11 and 14 in the CC041 F2 mapping cross that collectively explain 14% of the phenotypic variance for locomotor response to cocaine. We used a bioinformatic approach to identify high quality candidate genes that are genetically plausible, have functional relevance and are suitable for further exploration. Our study is the first to use CC strains to perform QTL mapping for addiction-related phenotypes and proposes several candidate genes for follow-up analyses.
Deep Tissue Second-Harmonics of Collagen Fibers in a Transparent Rat Heart from a Myocardial Infarction Model
Authors: Matsuyama Makoto
Published: January 2025

The combination of tissue-clearing techniques with light-sheet microscopy has enabled detailed visualization of histological changes from the micrometer to millimeter scale, deepening understanding of various disease processes. However, these protocols are not fully optimized for animal species beyond mice or for organs outside the brain. Additionally, the lack of suitable fluorescent probes for target molecules limits their broader application.

In this study, we present a protocol for whole-organ clearing of rat hearts in a myocardial infarction model, achieving complete transparency and enabling label-free imaging of collagen fibers in the myocardial wall up to a depth of ∼5 mm using Second Harmonic Generation (SHG) microscopy. For the first time, we successfully compared collagen fiber orientations between infarcted and healthy myocardial regions. Our approach facilitates high-resolution tissue remodeling analysis in cardiovascular research without the need for antibody staining, demonstrating that tissue-clearing techniques are feasible even in animal species with limited available antibodies.

Summary statement

We present a novel method for visualizing collagen fibers deep within the heart using a combination of tissue clearing and advanced microscopy, providing valuable data for cardiac research.
Catalytic degradation of circulating targets with FcRn-mediated cycling LYTACs
Authors: Kougentakis Christos , Shurtleff Matthew J. , Lieser Rachel M. , Chen Tao , Collins Christina L. , Johnson Isabel E. , Gu Siyi , Akama Keith T. , Doran Kyle H. , Fung Cyra K. , Hildebrandt Darin J. , Khaleghi Rozhan , Li Diana , Rank Steve , Tran Thomas-Toan , Yau Richard , Holly Ryan W. , Langsdorf Christopher , Lindhout Darrin A. , McWhirter Sarah M. , Iwig Jeffrey S. , Lewis Jason G. , Staben Steven T. , Turtle Eric D. , Lind Nicholas A.
Published: January 2025

Circulating proteins are common targets for the discovery of occupancy-based inhibitors including monoclonal antibodies. Effective inhibition of target pathogenicity with blocking approaches, however, is often challenged by target parameters that lead to insufficient occupancy and/or incomplete pharmacology limited by only single site binding. Extracellular targeted protein degradation approaches, such as lysosomal targeting chimeras (LYTACs), offer an opportunity to minimize these challenges by an event-driven mechanism that selectively, thoroughly and irreversibly eliminates drivers of disease. First generation LYTACs, designed to traffic to the lysosome, show limited durability since the therapeutic is degraded along with the target protein of interest. Here we describe cataLYTACs, which overcome this limitation by combining stabilized asialoglycoprotein (ASGPR) ligands, pH-sensitive target binding and recycling via the neonatal Fc receptor (FcRn). These cataLYTACs degraded superstoichiometric levels of a target protein, IgE, in vitro and demonstrated deep and sustained clearance of human IgE in mouse models. In non-human primates, cataLYTACs resulted in >98% clearance of circulating endogenous IgE for 2 weeks and outperformed the standard of care blocking antibody, omalizumab (Xolair®), in both free IgE elimination and duration of action. CataLYTACs represent a new therapeutic modality for a wide range of disease states driven by circulating factors, with the potential for superior efficacy and duration of action compared to traditional inhibitors.
Peptidic tryptophan halogenation by a promiscuous flavin-dependent enzyme
Authors: Rice Andrew J. , Gadgil Mayuresh G. , Mitchell Douglas A.
Published: January 2025

Amino acids undergo numerous enzymatic modifications, including free amino acids and those incorporated into polypeptides. The extensive structural modifications observed in ribosomally synthesized and post-translationally modified peptides (RiPPs) provide compelling examples of natural modifications to amino acids. However, the broad applicability of amino acid-modifying enzymes for synthetic purposes is limited by narrow substrate scope and often unknown regulatory or accessory factor requirements. Here, we characterize ChlH, a flavin-dependent halogenase (FDH) from the chlorolassin biosynthetic gene cluster. Reconstitution of ChlH and the associated flavin reductase ChlRin vitrounexpectedly showed that ChlH acts on the linear precursor peptide ChlA rather than the threaded lasso peptide product. Unlike characterized peptide-modifying FDHs, which are limited to either heavily altered peptidic scaffolds or the terminus of a linear peptide, ChlH halogenates internal Trp residues of linear peptides, as well as N- and C-terminal Trp. Ala and Trp scanning mutagenesis of ChlA revealed a broad substrate tolerance and the capacity to modify Trp at nearly every position of the core region. Halogenation of disparate RiPP precursor peptides, pharmacologically relevant peptides, and an internal Trp of a protein was achieved using wild-type ChlH. A rapid cell-free biosynthetic assay was also used to assess a mutagenic panel of ChlA, which provided insight into ChlH’s preferences. In contrast to characterized FDHs, ChlH halogenates diverse peptide sequences, and we predict this promiscuity may find utility in the modification of additional peptide and protein substrates of biotechnological value.
Cis-regulatory chromatin contacts form de novo in the absence of loop extrusion
Authors: Aboreden Nicholas G. , Zhao Han , Shan Fengnian , Liu Fuhai , Zhang Haoyue , Blobel Gerd A.
Published: January 2025

NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, leading to the formation of structural loops. However, to what extent loop extrusion contributes to the establishment vs maintenance ofcis-regulatory element (CRE) connectivity is poorly understood. Here, we explored the de novo establishment of chromatin folding patterns at the mitosis-to-G1-phase transition upon acute NIPBL loss. NIPBL depletion primarily impaired the formation of cohesin-mediated structural loops with NIPBL dependence being proportional to loop length. In contrast, the majority of CRE loops were established independently of loop extrusion regardless of length. However, NIPBL depletion slowed the re-formation of CRE loops with weak enhancers. Transcription of genes at NIPBL-independent loop anchors was activated normally in the absence of NIPBL. In sum, establishment of most regulatory contacts and gene transcription following mitotic exit is independent of loop extrusion.
A novel citizen science-based wildlife monitoring and management tool for oil palm plantations
Authors: Maharani Nunik , Nardiyono  , Munthe Claudia Retina , Swayanuar Priya , Ni’Matullah Safwanah , Sueif Syafiie , Zaini Syahmi , Supriatna Jatna , Kusrini Mirza , Dennis Rona , van Balen Bas , van Strien Arco , Meijaard Erik
Published: January 2025

Agricultural expansion is one of the greatest threats to global biodiversity. At the same time, many wildlife species survive or even thrive in agricultural landscapes that retain patches of natural ecosystems. This is especially true for tropical oil palm (Elaeis guineensis, Jacq.) plantations that have both replaced tropical forest and other species-rich ecosystems, but as perennial crops can also function as wildlife habitat, especially if fragments of natural ecosystems are retained. There is an urgent need to understand how to manage and monitor wildlife in these fragmented oil palm landscapes. Still, the lack of large, quantitative datasets on species abundance impedes learning. We piloted a novel citizen science-based biodiversity monitoring system in Austindo Nusantara Jaya’s seven Indonesian oil palm estates, across different biogeographical regions, over a 5-year period. The company-wide monitoring system called PENDAKI, the Indonesian acronym for Care for Biodiversity, is the first of its kind in the palm oil industry. Here we demonstrate that such unstructured and opportunistic data collected mainly by lay people can result in valuable information on temporal and spatial changes in species occupancy. Between September 2019 and June 2024, PENDAKI has resulted in 148,286 wildlife observations, that included 699 reliably identified faunal and 186 floral species, with contributions from 3,950 employee contributors. We estimate species-specific occupancy rates using Bayesian occupancy modeling, ideally suited for opportunistic data where survey effort is unknown. We show that these occupancy data can reliably show temporal and spatial changes in the distribution of iconic wildlife such as orangutans (Pongo pygmaeus). We combined data from reliably identified species with at least 50 records to create the “Living Plantation Index”, an estate-specific annual index of wildlife diversity based on occupancy estimates. We conclude that citizen science-based biodiversity monitoring works remarkably well in oil palm plantations because of the large number of people typically working there. In the process we discovered the emergence of co-benefits such as increasing environmental stewardship awareness across the workforce, raising the profile of the conservation department within the company. We also noted the benefits in terms of suitable data to meet regulatory and voluntary disclosure requirements.
Salt warning labels in the out-of-home food sector: online and real-world randomised controlled trials
Authors: Evans Rebecca , Brealey Jane , Clarke Natasha , Falbe Jennifer , Finlay Amy , Jones Andrew , Thorp Paula , Witham Beth , Witkam Rozemarijn , Robinson Eric
Published: January 2025

Background

High salt intake is a significant cause of diet-related disease. The salt content of much of the food provided in the out-of-home food sector (OOHFS; e.g., restaurants) can be excessive, but policy options to address this are lacking. An emerging policy approach with limited evidence from randomised controlled trials (RCTs) is the use of ‘high in salt’ warning labels on restaurant menus.

Methods

UK adults participated in an RCT to test the perceived message effectiveness (PME) and impact on hypothetical food choice of salt warning labels in packaged food and restaurant scenarios (Study 1). Next, the same outcomes were examined in a real-world RCT. Customers selected, consumed and purchased meals in a restaurant from menus with vs. without salt warning labels (Study 2).

Findings

Study 1 (N = 2391) demonstrated that salt warning labels were perceived by consumers as being effective in discouraging high salt intake and reduced hypothetical salt selection vs. control across both packaged food (on average −0.08g [95% CI −0.12 to −0.04] per item) and restaurant (on average − 0.26g [95% CI −0.43 to −0.10] per meal) scenarios. Study 2 (N = 454) replicated findings from Study 1, for perceived effectiveness and reduced salt selection vs. control (−0.54g [95% CI −0.83 to −0.25] per meal) in a real-world restaurant setting.

Interpretation

Salt warning labels on restaurant menus are a promising policy option to address excessive salt intake in the OOHFS.

Funding

National Institute for Health and Care Research Oxford Health Biomedical Research Centre (NIHR203316); European Research Council (8031940).
Berry curvature and shift vector effects at high-order wave mixing in biased bilayer graphene
Authors: Avetissian H. K. , Matevosyan H. H. , Mkrtchian G. F.
Published: January 2025

In this paper, we present a microscopic quantum theory that elucidates the nonlinear and nonperturbative optical response of biased bilayer graphene subjected to bichromatic strong laser fields. This response is analyzed using a four-band Hamiltonian derived from calculations. For the laser-stimulated dynamics, we employ structure gauge-invariant evolutionary equations to accurately describe the evolution of the single-particle density matrix across the entire Brillouin zone. The resonant generation of electron-hole pairs by the high-frequency component of the field, combined with the induction of high-order harmonic generation and high-order wave mixing by the strong low-frequency field component, leads to significant alterations in the resulting spectra. These changes are driven by the effects of Berry curvature and the shift vector, which modify the relative contributions of interband and intraband channels, thereby fundamentally reshaping the radiation spectra at high-order frequency multiplication. The numerical results are further supported by approximate analytical calculations, demonstrating that high-order wave mixing can be modeled using the classical trajectory analysis of electron-hole pairs, with Berry curvature and the shift vector significantly influencing the saddle-point equations.

Published by the American Physical Society
2025
Molecular
Pψ
pentaquarks from light-meson exchange saturation
Authors: Yang Zi-Ying , Peng Fang-Zheng , Yan Mao-Jun , Sánchez Mario Sánchez , Pavon Valderrama Manuel
Published: January 2025

Theoretical predictions of the spectrum of heavy meson-baryon bound states are a fundamental tool for disentangling the nature of the different pentaquark states that have been observed in experimental facilities. Here we explore this spectrum in a phenomenological model that describes the heavy meson-baryon interaction in terms of a contact-range interaction, where the coupling strength is saturated by the exchange of light scalar and vector mesons, i.e., σ, ρ, and ω exchanges. Saturation determines the couplings modulo an unknown proportionality constant that can be calibrated from a molecular candidate. If we use the PψN(4312) as input, we predict a series of molecular pentaquarks including the PψN(4440) and PψN(4457), the recent PψsΛ(4338) and the PψsΛ(4459).

Published by the American Physical Society
2025
Dark photon dark matter radio signal from the Milky Way electron density
Authors: Arza Ariel
Published: January 2025

We consider Thomson-like processes between dark matter dark photons and free electrons in the Milky Way. The result is a radio signal background that can be detectable with current or future radio telescope arrays. In particular, we computed sensitivity prospects for the Atacama Large Millimeter Array radio telescope and for the future Square Kilometer Array, concluding that unconstrained parameter space in a wide range of dark photon masses can be probed.

Published by the American Physical Society
2025
Random sampling of ligand arrangements on a one-dimensional lattice
Authors: Mohanta Dibyajyoti , Dvirnas Albertas , Ambjörnsson Tobias
Published: January 2025

We introduce a transfer-matrix-based sequential sampling scheme for generating random samples of ligand arrangements on one-dimensional templates. The number of ligand types is arbitrary, the binding constants can have positional dependence, and cooperativity parameters are included. From the random arrangements, any (linear or nonlinear) observable can be calculated using sample averaging. As an example case study, we investigate the competitive binding of three ligand types (the sequence-specific binder netropsin, YOYO-1, and ethidium bromide) to a DNA molecule. We also employ our random sampling method of ligands to determine the quality of synthetically generated DNA barcodes as a function of concentration of a ligand (e.g., netropsin) in optical DNA mapping (ODM) experiments. We provide publically available softwares, with a computational time that scales linearly with the lattice size, for generating random ligand arrangements and for generating synthetic barcodes.

Published by the American Physical Society
2025
Superconductivity of electron-doped chalcohydrides under high pressure
Authors: Du Yu , Wang Zefang , Liu Hanyu , Liu Guoji , Zhong Xin
Published: January 2025

As a typical representative of covalent superconductors, SH3 has emerged as a significant milestone in superconductivity history and has greatly sparked interest in compressed hydrogen-rich superconductors. Authors of previous studies on theoretical design of ternary chalcogen-hydrogen compounds (known as chalcohydrides) have mainly focused on intercalating molecular motifs into the interstitial sites of the structural lattice or substituting atoms in the SH3 backbone. Given the low electronegativity and small radius, lithium (Li) is empowered to serve as an excellent electron donor that can effectively turn the crystal structure and modulate the superconducting behavior. Here, we introduce Li into binary chalcohydrides and investigate ternary Li-M-H (M = S, Se, and Te) compounds using the state-of-the-art structure prediction method in conjunction with first-principles calculations. As a result, five stable stoichiometries, including LiSH7, Li2SH6, LiSH, Li2SH, and LiS2H, are identified at 100–200 GPa. Notably, metallic LiSH7 and Li2SH6 exhibit a layered structure where the covalent bond between sulfur and hydrogen breaks up and the hydrogen atoms are released to recombine into molecules confined into the interlayer. Furthermore, our electron-phonon simulations reveal that the estimated superconducting transition temperature (Tc) of Li2SH6 (46 K) is lower than that (77 K) of Li2SeH6 at 200 GPa, which contrasts with the general belief that the light-weight elemental compound (high Debye temperature) has higher superconductivity. Our results offer critical insights into designing high-temperature superconductors with layered structures among multinary hydrides.

Published by the American Physical Society
2025
Media sentiments and firm’s sales growth: the moderating role of offering characteristics
Authors: Misra Shekhar , Pedada Kiran , Ben Lee , Agnihotri Raj , Sinha Ashish
Published: January 2025

Purpose

Although the interest in firm media sentiment has been increasing, the impact of news media sentiments on consumers’ perception of firms’ offerings and, subsequently, their sales remain unknown. This study aims to address this research question in this study. Furthermore, the authors consider the role of two boundary conditions, i.e., offerings’ similarity and offerings’ service ratio, that moderate the main relationship.

Design/methodology/approach

Using a comprehensive and novel data set of over 900 firms between 2009 and 2019 from multiple sources, this study addresses the research questions. The authors use a fixed effects panel regression model to estimate the model.

Findings

A firm’s news media sentiments can influence consumers’ perception of the corporate brand, thereby driving sales growth. This study finds that when a firm’s offerings are not differentiated from its competitors, news media sentiments become more important and so does when a firm offers more services than a product.

Research limitations/implications

To the best of the authors’ knowledge, this study is the first to assess customers’ responses as manifested in the sales growth of a firm’s offerings, using both primary and secondary data and analysis.

Practical implications

The findings provide actionable insights to managers by identifying specific offerings-related attributes – similarity and service ratio – where media sentiments play a critical role in influencing sales growth.

Originality/value

While existing studies in marketing have primarily considered user-generated social media sentiments, this study departs from this literature by investigating earned media sentiments through traditional media outlets such as newspapers and business magazines, which have rarely been studied in marketing.