bluuebunny/crossref_metadata_2025_split huggingface dataset:
Into the Void: Cavities and Tunnels are Essential for Functional Protein Design
Authors: Zhang Jiahui , Peng Zhengxing 
Published: May 2024

AbstractThe design of functional proteins is crucial as it enables the creation of tailored proteins with specific capabilities, unlocking the potential solutions to various biomedical and industrial challenges. The exact relationship between structure, sequence, and function in protein design is intricate, however, a consensus has been reached that the function of a protein is mostly decided by its structure, which further decides its sequence. While the integration of biology with artificial intelligence has propelled significant advancements in protein design and engineering, structure-based functional protein design, especiallyde novodesign, the quest for satisfactory outcomes remains elusive. In this work, we use backbone geometry to represent the cavities and tunnels of functional proteins and show that they are essential for functional protein design. Correct cavity enables specific biophysical processes or biochemical reactions, while appropriate tunnels facilitate the transport of biomolecules or ions. We also provide a package called CAvity Investigation Navigator (CAIN) to help to do the analysis, which is available athttps://github.com/JiahuiZhangNCSU/CAIN.
Propiconazole and Tianfengsu Regulated the Growth, Flavor, and Nutritionof Brassica rapaby Brassinosteroid Pathway
Authors: Guo Dekang , Gao Qing , Song Yunxue , Liu Zhicheng , Wang Daorui , Xu Hanhong , Lin Fei 
Published: May 2024

ABSTRACTPropiconazole (PCZ) and Tianfengsu (TFS) are widely used plant growth regulators in vegetable production for improving crop growth, quality, and flavor. This study investigated the effects of PCZ and TFS, applied individually or in combination, on the growth, development, flavor quality, and nutritional components of choy sum (Brassica rapa) andArabidopsis thaliana, as well as the underlying molecular mechanisms. The results showed that PCZ inhibited the growth of choy sum andArabidopsisbut enhanced the accumulation of flavor compounds such as soluble sugars, proteins, and vitamin C. In contrast, TFS promoted plant growth and increased the content of nutritional components, including chlorophyll and unsaturated fatty acids. Notably, the combined application of PCZ and TFS significantly improved overall plant quality, achieving the optimal balance of flavor and nutritional value while maintaining high yield. Transcriptomic analysis revealed the molecular mechanisms of PCZ and TFS in differentially regulating the expression of brassinosteroid (BR) signaling and downstream metabolism-related genes. Weighted gene co-expression network analysis (WGCNA) further identified key gene modules and hub genes controlling flavor metabolism in choy sum. This study elucidates the synergistic mechanisms of PCZ and TFS in regulating vegetable growth and quality formation, providing valuable insights for the safe production of high-quality choy sum and the development of novel plant growth regulators or elite varieties.HIGHLIGHTSPCZ and TFS treatments differentially modulate choy sum growth and development by regulating the BR pathway, with PCZ inhibiting while TFS promoting growth.PCZ enhances the accumulation of soluble sugars, soluble proteins, and vitamin C, while TFS increases photosynthetic pigments and unsaturated fatty acids, synergistically improving the flavor and nutritional quality of choy sum.Transcriptomic analysis and WGCNA uncover key genes and modules controlling flavor metabolism in choy sum, providing potential targets for developing novel plant growth regulators or breeding elite varieties
Changes in TP53 gene, telomere length, mitochondrial DNA, and its amount in benign prostatic hyperplasia patients
Authors: Zole Egija , Baumanis Edgars , Freimane Lauma , Dāle Rolands , Leiše Andrejs , Lietuvietis Vilnis , Ranka Renāte 
Published: May 2024

AbstractBenign prostatic hyperplasia (BPH) is a growing issue due to an ageing population; however, there are not enough studies connecting it with ageing hallmarks. Some of the ageing hallmarks are changes in telomere length (TL) and genetic changes like possible mutations in theTP53gene or mitochondrial genome (mtDNA). Our study investigated these factors to see if they could be linked with BPH.Prostate tissue samples were obtained from 32 patients with BPH (and 30 blood samples). As a healthy control group, age-matching blood DNA samples were used. For mtDNA sequence data comparison, 50 samples of a general Latvian population were used. The full mtDNA genome was sequenced using Next Generation Sequencing (NGS), forTP53gene – Sanger sequencing, and for mtDNA amount and telomere length – qPCR assay.BPH patients in prostate tissue had much higher TL than in blood cells, and the healthy controls had the shortest telomeres. Also, the mtDNA amount in BPH prostate tissue was the highest compared with blood, and controls had the smallest amount. In theTP53gene, we did not find any mutations that could be linked to BPH. In the mtDNA genome, we found several unique mutations and heteroplasmic changes, as well as changes that have been linked before with prostate cancer (PC).In conclusion, prolonged telomeres and changes in mtDNA amount might be involved in the development of BPH. Concerning mtDNA genome changes, some of the heteroplasmic or homoplasmic variants might contribute to the development of BPH. More studies should be conducted to prove or disapprove of these connections.
Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration
Authors: Cui Xuehao , Zhao Qiuchen , Mahata Bidesh , Wen Dejia , Yu-Wai-Man Patrick , Li Xiaorong 
Published: May 2024

AbstractAge-related macular degeneration (AMD) is a significant cause of visual impairment in the aging population, with the pathophysiology driven by a complex interplay of genetics, environmental influences and immunometabolic factors. These immunometabolic mechanisms, in particular, those distinguishing between the dry and wet forms of AMD, remain incompletely understood. Utilizing an integrated multiomic approach, incorporating Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq), we have effectively delineated distinct immunometabolic pathways implicated in the development of AMD. Our comprehensive analysis indicates that the androgen-IL10RA-CD16+ monocyte axis could protect against wet AMD. We have also identified several immune and metabolic signatures unique to each AMD subtype, with TNFα and Notch signaling pathways being central to disease progression. Furthermore, our analysis, leveraging expression Quantitative Trait Loci (eQTLs) from the Genotype-Tissue Expression (GTEx) project coupled with MR, have highlighted genes such asMTOR,PLA2G7,MAPKAPK3,ANGPTL1, andARNTas prospective therapeutic targets. The therapeutic potential of these candidate genes was validated with observations from existing drug trial databases. Our robust genetic and transcriptomic approach has identified promising directions for novel AMD interventions, emphasizing the significance of an integrated multiomic approach in tackling this important cause of visual impairment.
Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization
Authors: Xu Zhan , Liu Fengshuo , Ding Yunfeng , Pan Tianhong , Wu Yi-Hsuan , Liu Jun , Bado Igor L. , Zhang Weijie , Wu Ling , Gao Yang , Hao Xiaoxin , Yu Liqun , Edwards David G. , Chan Hilda L. , Aguirre Sergio , Dieffenbach Michael Warren , Chen Elina , Shen Yichao , Hoffman Dane , Dominguez Luis Becerra , Rivas Charlotte Helena , Chen Xiang , Wang Hai , Gugala Zbigniew , Satcher Robert L. , Zhang Xiang H.-F. 
Published: May 2024

SUMMARYMicroenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout ofEsr1in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization.HIGHLIGHTSSAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages.Knockout ofEsr1in macrophages allows T cell infiltration and retards bone colonization.
Controllable multi-halogenation of a non-native substrate by SyrB2 iron halogenase
Authors: Wilson R. Hunter , Chatterjee Sourav , Smithwick Elizabeth R. , Damodaran Anoop R. , Bhagi-Damodaran Ambika 
Published: May 2024

ABSTRACTGeminal, multi-halogenated functional groups are widespread in natural products and pharmaceuticals, yet no synthetic methodologies exist that enable selective multi-halogenation of unactivated C-H bonds. Biocatalysts are powerful tools for late-stage C-H functionalization, as they operate with high degrees of regio-, chemo-, and stereoselectivity. 2-oxoglutarate (2OG)-dependent non-heme iron halogenases chlorinate and brominate aliphatic C-H bonds offering a solution for achieving these challenging transformations. Here, we describe the ability of a non-heme iron halogenase, SyrB2, to controllably halogenate non-native substrate alpha-aminobutyric acid (Aba) to yield mono-chlorinated, di-chlorinated, and tri-chlorinated products. These chemoselective outcomes are achieved by controlling the loading of 2OG cofactor and SyrB2 biocatalyst. By using a ferredoxin-based biological reductant for electron transfer to the catalytic center of SyrB2, we demonstrate order-of-magnitude enhancement in the yield of tri-chlorinated product that were previously inaccessible using any single halogenase enzyme. We also apply these strategies to broaden SyrB2’s reactivity scope to include multi-bromination and demonstrate chemoenzymatic conversion of the ethyl side chain in Aba to an ethylyne functional group. We show how steric hindrance induced by the successive addition of halogen atoms on Aba’s C4carbon dictates the degree of multi-halogenation by hampering C3-C4bond rotation within SyrB2’s catalytic pocket. Overall, our work showcases the synthetic potential of iron halogenases to facilitate multi-C-H functionalization chemistry.
Bottom-up reconstruction of functional Death Domain Signalosomes reveals a requirement for polymer stability and avidity
Authors: Lichtenstein Mauriz A. , Cao Fakun , Lobnow Finn , Dirvanskyte Paulina , Kulesza Anna , Ziska Elke , Taylor Marcus J. 
Published: May 2024

AbstractA key feature of innate immune signaling is the compartmentalization of signaling effectors into cellular structures referred to as signalosomes. Critical to the formation of these compartments are protein polymers composed of Death Domains (DD). However, the biophysical properties these polymeric scaffolds require for signal transduction are not clearly defined. Here, we engineered a single-component signalosome, referred to as Chimeric Higher-order Assemblies for Receptor Mediated Signaling (CHARMS). We found that CHARMS functionality depends on the stability provided by the DD polymer, which could also be achieved with bacterial DDs and synthetic filament-forming domains. This demonstrates the importance of kinetic stability and inducibility, irrespective of the origin of the motif. By varying the multiplicity of TRAF6 interaction motifs, we demonstrate that avidity is a tunable property that can control the amplitude of signaling outputs. This work lays out a reductionist framework to dissect the required properties of signaling through polymeric scaffolds by adjusting their assembly kinetics, stability and avidity.
(p)ppGpp and DksA play crucial role in reducing the efficacy of β-lactam antibiotics by modulating bacterial membrane permeability
Authors: Chawla Meenal , Verma Jyoti , Kumari Shashi , Matta Tushar , Senapati Tarosi , Babele Prabhakar , Kumar Yashwant , Bhadra Rupak K , Das Bhabatosh 
Published: May 2024

AbstractThe key signaling molecules in the bacterial stress sensing pathway, the alarmone (p)ppGpp and transcription factor DksA, help in survival during nutritional deprivation and exposure to xenobiotics by modulating cellular metabolic pathways. InVibrio cholerae, (p)ppGpp metabolism is solely linked with the functions of three proteins: RelA, SpoT, and RelV. At threshold or elevated concentrations of (p)ppGpp, the level of cellular metabolites and proteins in the presence and absence of DksA inV. choleraeand other bacteria has not yet been comprehensively studied. We engineered the genome ofV. choleraeto develop DksA null mutants in the presence and absence of (p)ppGpp biosynthetic enzymes. We observed a higher sensitivity of the (p)ppGpp0ΔdksA V. choleraemutant to different ꞵ-lactam antibiotics compared to the wild-type (WT) strain. Our whole-cell metabolomic and proteome analysis revealed that the cell membrane and peptidoglycan biosynthesis pathways are significantly altered in the (p)ppGpp0, ΔdksA, and (p)ppGpp0ΔdksA V. choleraestrains. Further, the mutant strains displayed enhanced inner and outer membrane permeability in comparison to the WT strains. These results directly correlate with the tolerance and survival ofV. choleraeto ꞵ-lactam antibiotics. These findings may help in the development of adjuvants for ꞵ-lactam antibiotics by inhibiting the functions of stringent response modulators.ImportanceThe (p)ppGpp biosynthetic pathway is widely conserved in bacteria. Intracellular levels of (p)ppGpp and the transcription factor DksA play crucial roles in bacterial multiplication and viability in the presence of antibiotics and/or other xenobiotics. The present findings have shown that (p)ppGpp and DksA significantly reduces the efficacy of ꞵ-lactam and other antibiotics by modulating the availability of peptidoglycan and cell membrane-associated metabolites by reducing membrane permeability. Nevertheless, the whole-cell proteome analysis of (p)ppGpp0, ΔdksA, and (p)ppGpp0ΔdksAstrains identified the biosynthetic pathways and associated enzymes that are directly modulated by the stringent response effector molecules. Thus, the (p)ppGpp metabolic pathways and DksA could be a potential target for increasing the efficacy of antibiotics and developing antibiotic adjuvants.
Simultaneous co-circulation of two genotypes of dengue virus serotype 3 causing a large outbreak in Sri Lanka in year 2023
Authors: Ariyaratne Dinuka , Senadheera Bhagya , Kuruppu Heshan , Jayadas Tibutius Thanesh Pramanayagam , Gomes Laksiri , Ranasinghe Diyanath , Bary Farha , Wijewickrama Ananda , Aguilar Sully Márquez , Bennett Shannon , Jeewandara Chandima , Malavige Gathsaurie Neelika 
Published: May 2024

AbstractAs many other countries, Sri Lanka experienced a marked rise in the number of dengue cases in 2023, with an unusual pattern of disease epidemiology. This rise coincided with the emergence of dengue virus (DENV) serotype 3 in Sri Lanka as the predominant serotype after 2009. Interestingly, a discrepancy between NS1 rapid antigen test positivity and quantitative real time PCR positivity was observed, with 50% of NS1 positive samples being negative by molecular diagnostics. Following sequencing of the DENV-3 strains in 2023, we identified two DENV-3 genotypes (I and III) co-circulating. While DENV-3 genotype III was detected by the modified CDC DENV-3 primers, genotype I evaded detection due to key mutations at forward and reverse primer binding sites. The co-circulation of multiple genotypes associated with an increase in cases highlights the importance of continuous surveillance of DENVs to identify mutations resulting in non-detection by diagnostics and differences in virulence.One-sentence summary lineCo-circulation of two genotypes of the dengue virus serotype-3 (I and III) were responsible for the large dengue outbreak in Sri Lanka in 2023, with genotype I not been detected by certain PCR primers.
Cluster-randomized trial of digital adherence technologies and differentiated care to reduce poor end-of-treatment outcomes and recurrence among adults with drug-sensitive pulmonary TB in Ethiopia
Authors: Tadesse Amare W , Sahile Mamush , Foster Nicola , McQuaid Christopher Finn , Weldemichael Gedion Teferra , Abdurhman Tofik , Mohammed Zemedu , Belachew Mahilet , Shiferaw Amanuel , Assefa Demelash , Gadissa Demekech , Yazew Hiwot , Yakob Nuria , Shewamene Zewdneh , Goscé Lara , van Rest Job , Madden Norma , Charalambous Salome , van Kalmthout Kristian , Bedru Ahmed , Letta Taye , Jerene Degu , Fielding Katherine L 
Published: May 2024

AbstractBackgroundThe impact of Digital Adherence Technologies (DATs) on long-term tuberculosis treatment outcomes remains unclear. We aimed to assess the effectiveness of DATs and differentiated care in improving tuberculosis treatment outcomes and recurrence.MethodsWe conducted a pragmatic cluster-randomised trial in Ethiopia. Seventy-eight health facilities (clusters) were randomised to three arms (1:1:1): smart pillbox, medication labels, or standard of care. Adults (≥18 years) with drug-sensitive pulmonary tuberculosis on a fixed-dose combination tuberculosis treatment regimen were enrolled and followed-up for 12 months after treatment initiation. Those in the pillbox arm received a pillbox with customisable audio-visual reminders, while participants in the label arm received their TB medication with a weekly unique code label. Opening the box or texting the code prompted real-time dose logging on the adherence platform, facilitating differentiated response by a healthcare worker. The primary outcome comprised death, loss to follow-up, treatment failure, switch to drug-resistant tuberculosis treatment, or recurrence; secondary outcomes included loss to follow-up. Analysis accounted for clustered design with multiple imputation for the primary outcome. The trial is complete and registered with PACTR202008776694999.FindingsFrom 24/05/2021-08/08/2022, 8477 individuals undergoing tuberculosis treatment were assessed for eligibility, and 3885 participants enrolled, of whom 3858 were included in the intention-to-treat population. The median age was 30 years and 41% were female. At 12 months, using multiple imputation, neither the pillbox (adjusted OR 1.04, 95% CI: 0.74-1.45; adjusted risk difference, 1.0 percentage points, 95% CI -1.2 to 3.1) nor the label (adjusted OR 1.14, 95%CI: 0.83-1.61; adjusted risk difference, 0.4 percentage points, 95% CI -1.8 to 2.6) interventions reduced the risk of the primary composite outcome. Results were similar in complete case and per-protocol analyses.InterpretationThe DAT interventions showed no reduction in unfavourable outcomes. This emphasizes the necessity to optimise DATs to enhance TB management strategies and treatment outcomes.
Discovery and characterization of stereodefined PMO-gapmers targeting tau
Authors: Kanatsu Kunihiko , Takahashi Yoshinori , Sakaguchi Tetsuya , Kim Dae-Shik , Murota Miki , Shan Mingde , Fukami Kazuki , Itano Wataru , Kikuta Kenji , Yoshimura Hikaru , Kurokawa Toshiki , Nagayama Yuko , Ishikawa Rena , Dairiki Ryo , Zhou Zhi , Sanders Kristen , Stupalski Jacob , Yasui So , Liu Diana , Benayoud Farid , Fang Hui , Jing Enxuan , Ogo Makoto , Fang Francis G. , Wang John , Choi Hyeong-wook 
Published: May 2024

ABSTRACTAntisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurogenerative diseases, new chemical modifications improving activity and safety profile are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers. Herein, a stereopure PMO-gapmer was developed as a new construct to improve safety and stability by installing charge-neutral PMOs at the wing region and by fully controlling phosphorus stereochemistries. The developed stereopure PMO-gapmer construct was applied to the discovery of ASO candidates for the reduction of microtubule-associated protein tau (MAPT, tau). Sequence screening targetingMAPTfollowed by screening of optimal phosphorus stereochemistry identified stereopure development candidates. While evaluating the stereopure PMO-gapmers, we observed a dramatic difference in safety profile among stereoisomers in which only one phosphorus stereochemistry differs. These results further highlight the benefits of developing stereopure ASOs as safe and well-characterized candidates for clinical studies.
Hypergraph Cortical Cytoarchitectonic Parcellation with Multimodal Canine Brain Atlas
Authors: Zhai Shiyao , Jiang Chenyao , Chen Zhenglin , Yu Dongmei , Gul Ijaz , Yuan Xi , Song Hengrui , Yangliu  , Zhang Ziheng , Xu Tao , Xu Hu , Wan Jiusheng , Mao Aiguo , Li Jie , Han Yuxing , Qin Peiwu 
Published: May 2024

AbstractBrain atlases are vital tools in exploring the brain structure-function relationship. The burgeoning cross-species atlases have significantly accelerated our understanding of human brain development, evolution, function, and diseases. However, the existing coarse-grained macroscopic canine brain atlases greatly constrain their utility as an animal model for neurocognition research. Finer-grained brain atlas and partitions are crucial for decoding brain spatial heterogeneity and topology at different scales. Therefore, we conduct macroscopic and microscopic brain imaging to construct an interactive online dataset of multimodal canine brain atlas. Additionally, we develop a pioneering method for cortical cytoarchitectonic partitioning based on hypergraph learning. By integrating high-dimensional cytoarchitectonic features and spatial connections between cortical columns, the method leads to fine-grained partitioning patterns. This innovative approach aims to decode the biological heterogeneity of cortical microstructures, contributing to the structural annotation of canine atlas as well as public human brain atlases. The study not only offers valuable resources but also presents a novel zonation approach to investigate the cellular organization pattern and topology of the cortex.