bluuebunny/crossref_metadata_2025_split huggingface dataset:
Top-DTI: Integrating Topological Deep Learning and Large Language Models for Drug Target Interaction Prediction
Authors: Talo Muhammed , Bozdag Serdar 
Published: February 2025

MotivationThe accurate prediction of drug–target interactions (DTI) is a crucial step in drug discovery, providing a foundation for identifying novel therapeutics. Traditional drug development is both costly and time-consuming, often spanning over a decade. Computational approaches help narrow the pool of compound candidates, offering significant starting points for experimental validation. In this study, we propose Top-DTI framework for predicting DTI by integrating topological data analysis (TDA) with large language models (LLMs). Top-DTI leverages persistent homology to extract topological features from protein contact maps and drug molecular images. Simultaneously, protein and drug LLMs generate semantically rich embeddings that capture sequential and contextual information from protein sequences and drug SMILES strings. By combining these complementary features, Top-DTI enhances predictive performance and robustness.ResultsExperimental results on the public BioSNAP and Human DTI benchmark datasets demonstrate that the proposed Top-DTI model outperforms state-of-the-art approaches across multiple evaluation metrics, including AUROC, AUPRC, sensitivity, and specificity. Furthermore, the Top-DTI model achieves superior performance in the challenging cold-split scenario, where the test and validation sets contain drugs or targets absent from the training set. This setting simulates real-world scenarios and highlights the robustness of the model. Notably, incorporating topological features alongside LLM embeddings significantly improves predictive performance, underscoring the value of integrating structural and sequence-based representations.AvailabilityThe data and source code of Top-DTI is available athttps://github.com/bozdaglab/Top_DTIunder Creative Commons Attribution Non Commercial 4.0 International Public License.
Differences Among Fungal Microbiomes Associated with Tar Spot of Corn in Ecuador, Guatemala, and Indiana, USA
Authors: Sic-Hernandez Wily R. , Gribskov Michael , Acosta Alex G. , Cruz Andres , Zambrano Jose L. , Racancoj Coyoy Astrid J. , Cruz C. D. , Goodwin Stephen B. 
Published: February 2025

ABSTRACTTar spot of corn, caused by the obligate fungal pathogenPhyllachora maydis, was previously found to be associated withMonographella maydis(syn.Microdochium maydis) andConiothyrium phyllachoraein Mexico. WhileM. maydiswas once believed to cause fisheye lesions andC. phyllachoraewas described as a mycoparasite ofP. maydis, their presence and roles in tar spot remain uncertain. This study hypothesizes that the tar spot-associated fungal microbiome varies geographically and includes fungal species with inconsistent associations with the disease. To test this, tar spot-infected leaves were collected in Guatemala, Ecuador, and the USA. This study shows that the distribution and abundance of these fungi exhibit a geographical pattern and are not consistently associated with tar spot lesions in all locations. We confirmed the presence ofMicrodochiumin some parts of Ecuador and Guatemala but not in the USA. The role ofMicrodochiumremains unclear and whether it can be a primary pathogen needs to be tested by additional research, as its occurrence and abundance depend more on geographical locations rather than the presence of fisheye lesions.Coniothyriumwas detected at low abundance in samples from Ecuador and Guatemala but was absent in the USA. Additionally, we identified the likely mycoparasiteParaphaeosphaeriaas highly prevalent across samples from all three countries. Microbiome diversity analysis grouped tar spot samples into four distinct clusters: two dominated byP. maydis, one primarily associated withMicrodochium, and a fourth characterized by a combination ofP. maydisandParaphaeosphaeria.
The effect of feeding on microbiome and biogas composition in anaerobic CSTR
Authors: Samiotis Georgios , Panou Manthos , Tsioni Vassiliki , Sfetsas Themistoklis 
Published: February 2025

Abstracthis study investigates the performance of two Continuous Stirred Tank Reactors (CSTRs) with a focus on biogas yield, physicochemical parameters, and microbial dynamics. By integrating experimental observations with insights from recent literature, the research aims to elucidate the intricate relationships between reactor conditions, microbiome composition, and biogas production efficiency. Two substrates were used: a control substrate (SB1) and a protein-rich test substrate (SB2). The study monitored key parameters such as pH, Total Alkalinity of Carbonates (TAC), and volatile fatty acids (FOS), and analyzed the microbial communities using high-throughput sequencing. Results indicated significant temporal variations in pH, TAC, and nitrogen levels, with a declining FOS/TAC ratio. The introduction of SB2 led to increased biogas production and methane content, particularly at higher Hydraulic Retention Times (HRT). The study also high-lighted the role of specific microbial taxa in enhancing biogas quality. These findings contribute to the development of optimized strategies for sustainable biogas production and process control.
Optogenetic restoration of neuron subtype-specific cortical activity ameliorates motor deficits in Huntington’s Disease mice
Authors: Blumenstock Sonja , Arakelyan David , del Grosso Nicholas , Schneider Sonja , Shao Yufeng , Gjoni Enida , Klein Rüdiger , Dudanova Irina , Komiyama Takaki 
Published: February 2025

AbstractHuntington’s disease (HD) is a devastating movement disorder without a current cure. Although the monogenic basis of HD is well-defined, the complex downstream effects that underlie behavioral symptoms are poorly understood. These effects include cortical dysfunctions, yet the role of specific cortical neuronal subtypes in HD symptoms remain largely unexplored. Here, we used longitudinalin vivotwo-photon calcium imaging to examine the activity of two cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal projection neurons (CSPNs) in the motor cortex of R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron type-specific abnormalities in movement-related activity, including hypoactivity of vasoactive intestinal peptide (VIP)-INs and CSPNs. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CSPNs and ameliorated motor deficits in R6/2 mice. Our findings highlight cortical INs as a potential therapeutic target for HD and possibly other neurological diseases.
Next-Generation Protein Sequencing and individual ion mass spectrometry enable complementary analysis of interleukin-6
Authors: Skinner Kenneth A. , Fisher Troy D. , Lee Andrew , Su Taojunfeng , Forte Eleonora , Sanchez Aniel , Caldwell Michael A. , Kelleher Neil L. 
Published: February 2025

AbstractThe vast complexity of the proteome currently overwhelms any single analytical technology in capturing the full spectrum of proteoform diversity. In this study, we evaluated the complementarity of two cutting-edge proteomic technologies—single-molecule protein sequencing and individual ion mass spectrometry—for analyzing recombinant human IL-6 (rhIL-6) at the amino acid, peptide, and intact proteoform levels. For single-molecule protein sequencing, we employ the recently released Platinum®instrument. Next-Generation Protein Sequencing™(NGPS™) on Platinum utilizes cycles of N-terminal amino acid recognizer binding and aminopeptidase cleavage to enable parallelized sequencing of single peptide molecules. We found that NGPS produces single amino acid coverage of multiple key regions of IL-6, including two peptides within helices A and C which harbor residues that reportedly impact IL-6 function. For top-down proteoform evaluation, we use individual ion mass spectrometry (I2MS), a highly parallelized orbitrap-based charge detection MS platform. Single ion detection of gas-phase fragmentation products (I2MS2) gives significant sequence coverage in key regions in IL-6, including two regions within helices B and D that are involved in IL-6 signaling. Together, these complementary technologies deliver a combined 52% sequence coverage, offering a more complete view of IL-6 structural and functional diversity than either technology alone. This study highlights the synergy of complementary protein detection methods to more comprehensively cover protein segments relevant to biological interactions.Abstract Figure
Early life infection withCryptosporidium parvuminduces inflammatory responses to dietary antigens
Authors: Saraav Iti , Huang Wanyi , Jung Jisun , Xu Rui , Fu Yong , McDonald Keely , Schriefer Lawrence A. , Rodgers Rachel , Baldridge Megan T. , Newberry Rodney D , Hsieh Chyi , Sibley L. David 
Published: February 2025

SummaryTo examine the effect of early-life infection withCryptosporidium parvumon the development of oral tolerance, we developed a low-dose infection model in neonatal mice.C. parvuminfection in neonatal mice results in immunopathology in the colon. IL-1β released duringC. parvuminfection blocked the formation of colonic goblet cell associated antigen passages, which normally serve as a conduit for antigen uptake and development of peripheral regulatory T cells (pTregs), responsible for long-term oral tolerance. Following infection withC. parvum, adoptively transferred OT-II cells, which respond to ovalbumin (ova), developed reduced frequency of Foxp3+Rorγt+cells in mesenteric lymph nodes with an expansion of TH1-like Tregs in the colon. The altered pTreg profile was accompanied by a strong TH1 immune response and robust IgG2c antibody responses to orally administered ova. Our findings suggest that intestinal inflammation and altered pTreg development leads to loss of oral tolerance during early life infection withC. parvum.
Enabling the Study of Gene Function in Gymnosperms: VIGS inEphedra tweedieana
Authors: Garcia Anthony , Bùi Jo Trang , Michael Todd P. , Ickert-Bond Stefanie M. , Di Stilio Verónica S. 
Published: February 2025

ABSTRACTPremiseAs the sister clade to angiosperms, gymnosperms are key to enabling the reconstruction of ancestral gene regulatory networks for seed plants. However, tools to rapidly and efficiently investigate gene function in gymnosperms remain limited due to the challenges of long life cycles and large genome sizes. Species within the xerophytic genusEphedra(Gnetales) have comparatively smaller genomes and shrubby growth habits with shorter life spans, making them better suited for greenhouse cultivation and laboratory experiments.Methods and ResultsHere, we implement Virus-Induced Gene Silencing (VIGS) to manipulate gene expression inEphedra tweedieana. Agrobacterium-mediated vacuum infiltration of Tobacco Rattle Virus (TRV2 and TRV1) in seedlings resulted in highly efficient silencing of theE. tweedieana PHYTOENE DESATURASEorthologEtwPDS. The expected photobleaching phenotype was observed as early as two weeks. It lasted at least three months, in stems, shoot tips, leaves, axillary meristems, and lateral branches of treated plants.ConclusionsThis first report of transient transformation and targeted gene silencing in a gymnosperm will further enable functional studies of the genetic mechanisms underpinning adaptations in this important and underrepresented lineage of seed plants.
Construction of a low-temperature degrading synthetic bacterial community of corn straw
Authors: Fang Yi , Li Jiaqi , Zhang Wanyi , Ye xuhong , Zhu Xiaolin Zhu , Xie Yang , Feng Youzhi , Yu Yongjie , Yu Susu , Zhang Li , Zou Hongtao 
Published: February 2025

AbstractThe stability of the cellulose structure in straw creates a challenge for short-term degradation in the natural environment, especially in the cold regions of north China. Therefore, to secure strains that can degrade straw at low temperatures, we selected soil samples from straw-returning land and used cellulose as the only carbon source. After conducting preliminary screening and further re-screening, we ultimately selected three strains that exhibited efficient degradation of corn straw at a temperature of 4 ℃. Subsequently, the synthetic bacterial community C was constructed using these strains:Stenotrophomonas maltophilia,Flavobacterium johnsoniaeandPantoea rodasii.We conducted a 45-day solid-state and liquid-state fermentation experiment at low-temperature (12 ℃). The activity of lignocellulase was determined, and the enzyme production conditions were optimized. The results show that the liquid fermentation degradation rate of straw increased by 40 % compared with the control group in the natural state (without adding C). Similarly, the solid-state fermentation degradation rate of straw increased by 30 %, which was significantly faster than that of the control group. Finally, the enzyme production conditions of strain C were optimized as follows: culture time 96 h, inoculation amount 4 %, temperature 12 ℃, pH 6.0, and Alkaline Carboxymethyl Cellulase (CMCase) activity 24.34 U/mL. The microbial system C efficiently degrades straw at low temperature, which is valuable for improving the comprehensive utilization rate of straw and has a broad application prospect in improving soil fertility.
DMT-induced shifts in criticality correlate with ego-dissolution
Authors: Irrmischer Mona , Aqil Marco , Luan Lisa , Wang Tongyu , Engelbregt Hessel , Carhart-Harris Robin , Linkenkaer-Hansen Klaus , Timmermann Christopher 
Published: February 2025

ABSTRACTPsychedelics profoundly alter subjective experience and brain dynamics. Brain oscillations express signatures of near-critical dynamics, relevant for healthy function. Alterations in the proximity to criticality have been suggested to underlie the experiential and neurological effects of psychedelics. Here, we investigate the effects of a psychedelic substance (DMT) on the criticality of brain oscillations, and in relation to subjective experience. We find that DMT shifts the dynamics of brain oscillations away from criticality in alpha and adjacent frequency bands. In this context, entropy is increased while complexity is reduced. We find that the criticality shifts observed in alpha and theta bands correlate with the intensity ratings of ego-dissolution, a hallmark of psychedelic experience. Finally, using a recently developed metric, the functional excitatory-inhibitory ratio, we find that the DMT-induced criticality shift in brain oscillations is towards subcritical regimes. These findings have major implications for the understanding of psychedelic mechanisms of action in the human brain and for the neurological basis of altered states of consciousness.
Bridge protein-mediated viral targeting of cells expressing endogenous μ-opioid G protein-coupled receptors in the mouse and monkey brain
Authors: Kamaguchi Riki , Amemori Satoko , Amemori Ken-ichi , Osakada Fumitaka 
Published: February 2025

AbstractTargeting specific cell types is essential for understanding their functional roles in the brain. Although genetic approaches enable cell-type-specific targeting in animals, their application to higher mammalian species, such as nonhuman primates, remains challenging. Here, we developed a nontransgenic method using bridge proteins to direct viral vectors to cells endogenously expressing μ-opioid receptors (MORs), a G protein-coupled receptor. The bridge protein comprises the avian viral receptor TVB, the MOR ligand β-endorphin (βed), and an interdomain linker. EnvB-enveloped viruses bind to the TVB component, followed by the interaction of βed with MORs, triggering viral infection in MOR-expressing cells. We optimized the secretion signals, domain configurations, and interdomain linkers of the bridge proteins to maximize viral targeting efficiency and specificity. Alternative configurations incorporating different ligands and viral receptors also induced viral infection in MOR-expressing cells. The optimized βed-f2-TVB bridge protein with EnvB-pseudotyped lentiviruses induced infection in MOR-expressing cells in the striatum of mice and monkeys. An intersectional approach combining βed-f2-TVB with a neuron-specific promoter refined cell-type specificity. This study establishes the foundation for the rational bridge protein design and the feasibility of targeting G protein-coupled receptors beyond tyrosine kinase receptors, thereby expanding targetable cell types in the brain and throughout the body.Graphical abstract
Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles
Authors: Finan Jennifer M. , Guo Yifei , Bartlett Alexandra Q. , Reyer Matthew , Hawthorne Kevin , Haerr Margaret , Halamish Hen , Lamikanra Olayinka , Calvert Valerie , Chen Canping , Xia Zheng , Petricoin Emanuel F. , Sears Rosalie C. , Byrne Katelyn T. , Brody Jonathan R. 
Published: February 2025

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and thus, it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. Herein, we demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. We found that HuR knockout (KO) tumors have impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs can increase tumor growth. Further, we observed that PDAC EVs contain HuR-dependent mRNA and protein cargoes relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function and endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, we showed that HuR increases endothelial cell presence and sprouting, while decreasing ICAM-1 expression. Importantly, we found utilizing a genetic EV reporter, that decreased ICAM-1 within WT tumors occurs in endothelial cells that have imported PDAC EVs, suggesting that this signaling axis is directly modulating endothelial cell behaviorin vivo. Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.
Cortical astrocyte activation triggers meningeal nociception and migraine-like pain
Authors: Bree Dara , Zhao Jun , Stratton Jennifer , Levy Dan 
Published: February 2025

SummaryMigraine attacks are believed to originate in the brain, but the exact mechanisms by which the brain generates peripheral nociceptive signals that drive migraine pain remain unclear. Sensory cortex hyperexcitability has been observed consistently across different migraine subtypes. Astrocytes detect aberrant increases in cortical activity via their Gq-coupled receptors and respond by releasing gliotransmitters and other factors with proinflammatory and nociceptive properties. In the present study, we used a rat model to investigate whether heightened cortical astrocyte Gq-coupled signaling is sufficient to drive peripheral trigeminal meningeal nociceptive responses linked to the generation of migraine headaches. We used an AAV-based chemogenetic approach that allows selective activation of cortical astrocyte Gq-GPCR signaling. We targeted astrocytes in the visual cortex as hyperexcitability in this region has been implicated in migraine. Furthermore, the meninges overlying the visual cortex are densely innervated by nociceptive fibers. We combined this chemogenetic approach with in vivo single-unit recording of meningeal nociceptors to assess changes in their ongoing activity and mechanosensitivity, along with testing of migraine-like behaviors. We further targeted calcitonin gene-related peptide (CGRP), using a monoclonal antibody (anti-CGRP mAb), to assess the relevance of cortical astrocyte activation to migraine. We discovered that heightened activation of Gq-coupled signaling in visual cortex astrocytes drives persistent discharge and increased mechanosensitivity of meningeal nociceptors. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Blocking calcitonin gene-related peptide signaling suppressed astrocyte-mediated increases in meningeal nociceptor discharge and alleviated associated migraine-related behaviors. Our findings reveal a previously unappreciated role for augmented visual cortex astrocyte signaling as a triggering factor sufficient to generate meningeal nociception and migraine pain and greatly expand our understanding of migraine pathophysiology.
Alternatively Folded State of IgG4: Acid-Induced Compaction is Common between IgG1 and IgG4
Authors: Imamura Hiroshi , Honda Shinya 
Published: February 2025

AbstractImmunoglobulin G1 (IgG1) antibodies undergo denaturation in acidic conditions, resulting in an alternatively folded state (AFS). The AFS structure is more compact than the native state. However, the prevalence of AFS in other subclasses remains largely unexplored. This study provides evidence that humanized IgG4 can also adopt AFS structure, as demonstrated through size-exclusion chromatography coupled with small-angle X-ray scattering (SEC-SAXS) analysis. These findings suggest that the anomalous compaction of immunoglobulins G (IgGs) is resilient to variations in sequence and structure among subclasses.
Impact of Soil Salinity on Microbial Community Composition in Coastal Agricultural lands of Bangladesh: A Metagenomic Approach
Authors: Das Sumit , Nayem Maksudur Rahman , Hira Kamrun Nahar , Shermin Romana , Hosen Md. Razib , Hossain Md. Amzad , Tariquzzaman Md. , biswas Razib , Rahman Farazi Abinash , Saha Mithun Kumar , Rabbi Mohammad Fazle Alam 
Published: February 2025

AbstractA significant obstacle to agricultural productivity is soil salinity, especially in coastal areas where the problem is made worse by climate change and rising sea levels. This study investigates the impact of salinity on microbial community structure and function in agricultural soils from Kuakata, Bangladesh, using 16S rRNA metagenomic sequencing technique. Both saline (EC > 4 dS/m) and non-saline (EC < 1.5 dS/m) areas had soil samples taken; saline soils showed symptoms of crop stress, such as yellowing and blackish discoloration. In comparison to their non-saline counterparts, our investigation showed that saline soils had much reduced microbial diversity and different community compositions. Both soil types were dominated by Proteobacteria and Chloroflexi, while saline soils displayed an enrichment of anaerobic texa (e.g., Desulfobacterota, Pseudomonas) and sulfate-reducing bacteria (e.g., Desulfobacterota, Deferrisomatota). Interestingly, saline soils had a much larger percentage of anaerobic microorganisms (36.4%) than non-saline soils (29.3%) which might results in enhanced denitrification, sulphate reduction, and hydrogen sulphide buildup. These processes disrupt nutrient cycling, lower organic matter decomposition and create toxic conditions for plant growth, ultimately contributing to crop failure. This study provides an insight into the distinct microbial composition in saline and non-saline samples, which can assist in understanding the role of microbial populations in agriculture in saline environments.