bluuebunny/crossref_metadata_2025 huggingface dataset:
RMBase v3.0: decode the landscape, mechanisms and functions of RNA modifications
Authors: Xuan Jiajia , Chen Lifan , Chen Zhirong , Pang Junjie , Huang Junhong , Lin Jinran , Zheng Lingling , Li Bin , Qu Lianghu , Yang Jianhua
Published: November 2023

Although over 170 chemical modifications have been identified, their prevalence, mechanism and function remain largely unknown. To enable integrated analysis of diverse RNA modification profiles, we have developed RMBase v3.0 (http://bioinformaticsscience.cn/rmbase/), a comprehensive platform consisting of eight modules. These modules facilitate the exploration of transcriptome-wide landscape, biogenesis, interactome and functions of RNA modifications. By mining thousands of epitranscriptome datasets with novel pipelines, the ‘RNA Modifications’ module reveals the map of 73 RNA modifications of 62 species. the ‘Genes’ module allows to retrieve RNA modification profiles and clusters by gene and transcript. The ‘Mechanisms’ module explores 23 382 enzyme-catalyzed or snoRNA-guided modified sites to elucidate their biogenesis mechanisms. The ‘Co-localization’ module systematically formulates potential correlations between 14 histone modifications and 6 RNA modifications in various cell-lines. The ‘RMP’ module investigates the differential expression profiles of 146 RNA-modifying proteins (RMPs) in 18 types of cancers. The ‘Interactome’ integrates the interactional relationships between 73 RNA modifications with RBP binding events, miRNA targets and SNPs. The ‘Motif’ illuminates the enriched motifs for 11 types of RNA modifications identified from epitranscriptome datasets. The ‘Tools’ introduces a novel web-based ‘modGeneTool’ for annotating modifications. Overall, RMBase v3.0 provides various resources and tools for studying RNA modifications.
TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells
Authors: Jaiswal Aruna S , Dutta Arijit , Srinivasan Gayathri , Yuan Yaxia , Zhou Daohong , Shaheen Montaser , Sadideen Doraid T , Kirby Austin , Williamson Elizabeth A , Gupta Yogesh K , Olsen Shaun K , Xu Mingjiang , Loranc Eva , Mukhopadhyay Pramiti , Pertsemlidis Alexander , Bishop Alexander J R , Sung Patrick , Nickoloff Jac A , Hromas Robert
Published: November 2023

BRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638–5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3′ exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loops and degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers.
Splicing factor Prp18p promotes genome-wide fidelity of consensus 3′-splice sites
Authors: Roy Kevin R , Gabunilas Jason , Neutel Dean , Ai Michelle , Yeh Zoe , Samson Joyce , Lyu Guochang , Chanfreau Guillaume F
Published: November 2023

The fidelity of splice site selection is critical for proper gene expression. In particular, proper recognition of 3′-splice site (3′SS) sequences by the spliceosome is challenging considering the low complexity of the 3′SS consensus sequence YAG. Here, we show that absence of the Prp18p splicing factor results in genome-wide activation of alternative 3′SS in S. cerevisiae, including highly unusual non-YAG sequences. Usage of these non-canonical 3′SS in the absence of Prp18p is enhanced by upstream poly(U) tracts and by their potential to interact with the first intronic nucleoside, allowing them to dock in the spliceosome active site instead of the normal 3′SS. The role of Prp18p in 3′SS fidelity is facilitated by interactions with Slu7p and Prp8p, but cannot be fulfilled by Slu7p, identifying a unique role for Prp18p in 3′SS fidelity. This fidelity function is synergized by the downstream proofreading activity of the Prp22p helicase, but is independent from another late splicing helicase, Prp43p. Our results show that spliceosomes exhibit remarkably relaxed 3′SS sequence usage in the absence of Prp18p and identify a network of spliceosomal interactions centered on Prp18p which are required to promote the fidelity of the recognition of consensus 3′SS sequences.
Music in the Metaverse: an alternative solution for immune-boosting and mental health maintenance in the post-COVID-19 age
Authors: Situmorang Dominikus David Biondi
Published: November 2023

In this article, the author explains more about the other benefits that people can enjoy when listening to music in the Metaverse, significantly boosting immunity and maintaining mental health.
Genome-Enabled Analysis of Population Dynamics and Virulence-Associated Loci in the Oat Crown Rust Fungus Puccinia coronata f. sp. avenae
Authors: Hewitt Tim C. , Henningsen Eva C. , Pereira Danilo , McElroy Kerensa , Nazareno Eric S. , Dugyala Sheshanka , Nguyen-Phuc Hoa , Li Feng , Miller Marisa E. , Visser Botma , Pretorius Zacharias A. , Boshoff Willem H. P. , Sperschneider Jana , Stukenbrock Eva H. , Kianian Shahryar F. , Dodds Peter N. , Figueroa Melania
Published: November 2023

Puccinia coronata f. sp. avenae ( Pca) is an important fungal pathogen causing crown rust that impacts oat production worldwide. Genetic resistance for crop protection against Pca is often overcome by the rapid virulence evolution of the pathogen. This study investigated the factors shaping adaptive evolution of Pca using pathogen populations from distinct geographic regions within the United States and South Africa. Phenotypic and genome-wide sequencing data of these diverse Pca collections, including 217 isolates, uncovered phylogenetic relationships and established distinct genetic composition between populations from northern and southern regions from the United States and South Africa. The population dynamics of Pca involve a bidirectional movement of inoculum between northern and southern regions of the United States and contributions from clonality and sexuality. The population from South Africa is solely clonal. A genome-wide association study (GWAS) employing a haplotype-resolved Pca reference genome was used to define 11 virulence-associated loci corresponding to 25 oat differential lines. These regions were screened to determine candidate Avr effector genes. Overall, the GWAS results allowed us to identify the underlying genetic factors controlling pathogen recognition in an oat differential set used in the United States to assign pathogen races (pathotypes). Key GWAS findings support complex genetic interactions in several oat lines, suggesting allelism among resistance genes or redundancy of genes included in the differential set, multiple resistance genes recognizing genetically linked Avr effector genes, or potentially epistatic relationships. A careful evaluation of the composition of the oat differential set accompanied by the development or implementation of molecular markers is recommended.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Development of a Large-Scale Soil DNA Extraction Method for Molecular Quantification of Fusarium oxysporum f. sp. fragariae in Soil
Authors: Matson Michael E. H. , Kane Saben M. , Crouch Uma T. , Zepada Sascha K. , Martin Frank N.
Published: November 2023

The most common soilborne diseases affecting the strawberry industry in California include Verticillium wilt due to Verticillium dahliae, charcoal root rot due to Macrophomina phaseolina, and Fusarium wilt due to Fusarium oxysporum f. sp. fragariae. Detection of these pathogens in soil is an important facet of disease management and fumigation recommendations. Whereas the soil populations of both M. phaseolina and V. dahliae can be readily quantified with quantitative PCR (qPCR) assays using DNA extractions with 500 mg of soil, the single-cell nature of the F. oxysporum chlamydospore does not provide enough pathogen DNA from 500-mg extractions to be reliably quantified. Here, we describe an improved DNA extraction protocol from 10 to 15 g of soil that allows for the quantification of F. oxysporum f. sp. fragariae populations below 10 CFU/g. The relationship between results from the TaqMan qPCR assay and pathogen population density in soil was determined by using this extraction method in pathogen-free soils artificially infested with a hygromycin-resistant strain of F. oxysporum f. sp. fragariae to facilitate accurate colony counts when plated on a selective medium. Although the protocol was developed for F. oxysporum f. sp. fragariae, it is applicable for detection and quantification of other soilborne pathogens.
Autotransplantation for Restoration of Dentition Defects After Excision of Jaw Cysts
Authors: Liu Zhuying , Zhou Nian-gou , Li Yongqi , Zhou Libin
Published: November 2023

Bone defect caused by jaw cystectomy has always been the main factor affecting postoperative wound healing and is also the common cause of maxillofacial bone defect, which brings challenges to the subsequent restoration of missing teeth. In this paper, the authors report a 22-year-old young woman who had a mandibular cyst in the left lower posterior tooth area. She underwent mandibular bone cyst excision and simultaneous extraction of teeth 36 and 37. One and two months after the removal of the mandibular bone cyst, autologous tooth transplantation was performed in stages from tooth 28 to tooth 36 and from tooth 18 to tooth 37. The case shows that tooth autotransplantation is a viable option for the restoration of dentition defects after the excision of jaw cysts, which can promote the healing of the bone defect after the operation.
Infantile Scalp Hemangiomas: Surgical Management and Lessons Learned
Authors: DiDonna Nicole , Khan Kamran , Wood Jeyhan
Published: November 2023

Infantile hemangiomas (IH) are common benign vascular tumors in pediatric patients, often found on the scalp. While most IH naturally regress without intervention, surgical excision becomes necessary when severe anatomic or physiological complications arise. This review examines previously published case studies on pediatric scalp IH excisions, focusing on surgical outcomes and complications. A comprehensive search of the US National Library of Medicine National Institutes of Health (PubMed) database identified 19 relevant case studies. Most patients were female, with a wide age range at the time of excision. Various anatomic locations and sizes of the hemangiomas were observed. The reviewed literature demonstrates that surgical excision of scalp IH can be performed with minimal complications, even for sizable tumors. Successful outcomes and low complication rates highlight the effectiveness of surgical intervention in cases of life-threatening IH sequelae. Further research is warranted to explore optimal timing, techniques, and adjunct therapies for surgical management of scalp IH.
Which Skeletal Factors Can Affect Lip Canting in Facial Asymmetry?: Statistical Analysis
Authors: Jo Hyunmi , Lee Hwaseon , Park Jin Hoo , Kim Jun-Young , Jung Young-Soo , Jung Hwi-Dong
Published: November 2023

Lip canting, which is a noticeable factor in patients with facial asymmetry, can be influenced by the dentofacial skeleton. During orthognathic surgery, postoperative changes in facial soft tissue occur along the newly positioned hard tissue. Therefore, the evaluation of soft tissue before surgery is important. The purpose of this study was to investigate the skeletal factors that can affect lip canting by statistically comparing 2 facial horizontal planes using a three-dimensional reconstruction model. The findings of the present study showed a statistical correlation between lip canting and 3 skeletal factors: menton deviation, maxillary canting, and ramal length differences. Furthermore, a statistical correlation was identified between the Frankfort Horizontal plane and the intercanthal plane compared with the lip canting line. This result suggests that the intercanthal plane could be a standard horizontal plane in three-dimensional reconstruction model analysis.
How Does Social Media Correlate With Clinical Appointments: A Quantitative Analysis
Authors: Zhong Yehong , Li Binghang , Ma Hengyuan , Yang Bin
Published: November 2023

Social media has become an important part of plastic surgeons’ practices. Is it true that the more followers, the more efficient it is to the plastic surgeon’s branding? This study is to verify the quantitative correlation between social media and clinical appointments and to optimize its utilization. One hundred and five plastic surgeons were divided into 3 groups according to titles. WEIBO served as a targeted platform and descriptive data, including numbers of followers and clinic appointments were collected for analysis. The promotive effect was quantified as

and correlation analysis was conducted to quantify the relationship between followers and outpatient appointments. From this research, it was found that 62% of participants were social media users, while 38% were not. No statistical significance was found between them by comparing the number of clinic appointments. For surgeons with social media, a positive correlation was proven between followers and clinic appointments, whose Pearson’s correlation was 0.266 (attending: 0.557, associate consultant: 0.315, consultant: 0.060). Meanwhile, the conversion rates in this study were 22.49±44.67% (attending), 13.10±24.57% (associate consultant), and 18.88±36.05% (consultant). Outpatient consultations of senior surgeons without social media (2652±14492) were significantly higher than young surgeons with social media (1800±1718, P<0.05). The regression equation was Clinical Appointments=ln (Followers)×316.906−992.588 (R
2=0.270, P=0.023). In conclusion, this study proved that social media positively influenced clinic appointments but the traditional personal brandings like reputations, academic pedigree, and word of mouth still played an indispensable role in career development. Young surgeons benefited most from social media. The promotive effect of social media would reach its saturation when the followers were up to ∼50,000.
Effect of Cellular Senescence in Disease Progression and Transplantation: Immune Cells and Solid Organs
Authors: Kirchner Varvara A. , Badshah Joshua S. , Hong Suk Kyun , Martinez Olivia , Pruett Timothy L. , Niedernhofer Laura J.
Published: November 2023

Aging of the world population significantly impacts healthcare globally and specifically, the field of transplantation. Together with end-organ dysfunction and prolonged immunosuppression, age increases the frequency of comorbid chronic diseases in transplant candidates and recipients, contributing to inferior outcomes. Although the frequency of death increases with age, limited use of organs from older deceased donors reflects the concerns about organ durability and inadequate function. Cellular senescence (CS) is a hallmark of aging, which occurs in response to a myriad of cellular stressors, leading to activation of signaling cascades that stably arrest cell cycle progression to prevent tumorigenesis. In aging and chronic conditions, senescent cells accumulate as the immune system’s ability to clear them wanes, which is causally implicated in the progression of chronic diseases, immune dysfunction, organ damage, decreased regenerative capacity, and aging itself. The intimate interplay between senescent cells, their proinflammatory secretome, and immune cells results in a positive feedback loop, propagating chronic sterile inflammation and the spread of CS. Hence, senescent cells in organs from older donors trigger the recipient’s alloimmune response, resulting in the increased risk of graft loss. Eliminating senescent cells or attenuating their inflammatory phenotype is a novel, potential therapeutic target to improve transplant outcomes and expand utilization of organs from older donors. This review focuses on the current knowledge about the impact of CS on circulating immune cells in the context of organ damage and disease progression, discusses the impact of CS on abdominal solid organs that are commonly transplanted, and reviews emerging therapies that target CS.
Autophagy: A Silent Protagonist in Kidney Transplantation
Authors: Ponticelli Claudio , Reggiani Francesco , Moroni Gabriella
Published: November 2023

Autophagy is a lysosome-dependent regulated mechanism that recycles unnecessary cytoplasmic components. It is now known that autophagy dysfunction may have a pathogenic role in several human diseases and conditions, including kidney transplantation. Both defective and excessive autophagy may induce or aggravate several complications of kidney transplantation, such as ischemia–reperfusion injury, alloimmune response, and immunosuppressive treatment and side effects. Although it is still complicated to measure autophagy levels in clinical practice, more attention should be paid to the factors that may influence autophagy. In kidney transplantation, the association of low doses of a mammalian target of rapamycin inhibitor with low doses of a calcineurin inhibitor may be of benefit for autophagy modulation. However, further studies are needed to explore the role of other autophagy regulators.
Evolution and sustainability: gathering the strands for an Anthropocene synthesis
Authors: Søgaard Jørgensen Peter , Weinberger Vanessa P. , Waring Timothy M.
Published: November 2023

How did human societies evolve to become a major force of global change? What dynamics can lead societies on a trajectory of global sustainability? The astonishing growth in human population, economic activity and environmental impact has brought these questions to the fore. This theme issue pulls together a variety of traditions that seek to address these questions using different theories and methods. In this Introduction, we review and organize the major strands of work on how the Anthropocene evolved, how evolutionary dynamics are influencing sustainability efforts today, and what principles, strategies and capacities will be important to guide us towards global sustainability in the future. We present a set of synthetic insights and highlight frontiers for future research efforts which could contribute to a consolidated synthesis.

This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
Towards understanding human–environment feedback loops: the Atacama Desert case
Authors: Gayo Eugenia M. , Lima Mauricio , Gurruchaga Andone , Estay Sergio A. , Santoro Calogero M. , Latorre Claudio , McRostie Virginia
Published: November 2023

The overall trajectory for the human–environment interaction has been punctuated by demographic boom-and-bust cycles, phases of growth/overshooting as well as of expansion/contraction in productivity. Although this pattern has been explained in terms of an interplay between population growth, social upscaling, ecosystem engineering and climate variability, the evoked demographic–resource-complexity mechanisms have not been empirically tested. By integrating proxy data for population sizes, palaeoclimate and internal societal factors into empirical modelling approaches from the population dynamic theory, we evaluated how endogenous (population sizes, warfare and social upscaling) and exogenous (climate) variables module the dynamic in past agrarian societies. We focused on the inland Atacama Desert, where populations developed agriculture activities by engineering arid and semi-arid landscapes during the last 2000 years. Our modelling approach indicates that these populations experienced a boom-and-bust dynamic over the last millennia, which was coupled to structure feedback between population sizes, hydroclimate, social upscaling, warfare and ecosystem engineering. Thus, the human–environment loop appears closely linked with cooperation, competition, limiting resources and the ability of problem-solving.

This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
Long-distance social relationships can both undercut and promote local natural resource management
Authors: Pisor Anne C. , Borgerhoff Mulder Monique , Smith Kristopher M.
Published: November 2023

The management of large common-pool resources, like fisheries and forests, is more difficult when more people and more communities can access them—a particular problem given increased population sizes, higher mobility and globalized trade in the Anthropocene. Social relationships spanning communities, such as kin relationships, business or trade relationships and friendships, can make management even more challenging by facilitating and transmitting norms of overharvesting. However, these long-distance relationships can also bolster management by transmitting norms for sustainability, promoting interdependence and laying the groundwork for nested management systems. Here, we review the negative and positive impacts of long-distance relationships on local natural resource management (NRM), providing illustrative examples from our field research on forest and fisheries management in Tanzania. Drawing on the evolutionary literature, the development literature and our field data, we offer suggestions for how development partners can avoid the pitfalls of long-distance relationships and how they can use or even deliberately foster long-distance relationships to promote successful local NRM.

This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
EVALUATION OF MYCOTOXINS IN GRAINS SOLD IN IDAH, AJAKA AND OGBOGBO AREAS OF NIGERIA
Authors: Ukwuru Michael Ukwuru , Muritala Abdullahi
Published: November 2023

Mycotoxin contamination in grains is a significant concern due to its adverse effects on human and animal health. Understanding the levels and patterns of mycotoxin contamination in different regions and storage conditions is crucial for developing effective control strategies. This study aimed to assess mycotoxin levels in stored and recently harvested grains in three regions (Idah, Ajaka, and Ogbogbo) and investigate the implications for food safety. The study involved the analysis of mycotoxin levels in maize, rice, sorghum, and millet using appropriate mycotoxin extraction method based on the mycotoxins of interest and a suitable HPLC system.  The findings revealed the presence of mycotoxins such as aflatoxins (1±0.2-5±0.4 µg/Kg), deoxynivalenol (520±0.8-700±1.2 µg/Kg)  zearalenone (200±0.4-370±0.6 µg/Kg) , ochratoxins (2±0.2-4±0.3 µg/Kg) and fumonisin (0±0.0-4±0.3 µg/Kg) in both recently harvested and stored grains.Patulin was absent in most of the samples. Variations in mycotoxin levels were observed among different grains and regions, highlighting the need for targeted interventions. The European Commission mycotoxin standards in grains for human consumption are: Aflatoxins 4 µg/Kg in maize, millet and sorghum while rice is 8 µg/Kg, Deoxynivalenal 1750 µg/Kg, Zearalenone 100 µg/Kg, for all the grains under study, Ochratoxin A 5 µg/Kg for maize, rice and millet, then 10 µg/Kg for sorghum.Fumonisin is 4000 µg/Kg but no level for rice and patulin is 50 µg/Kg for rice and non for the other grains.  This study demonstrates the persistence of mycotoxin contamination in stored grains and the importance of considering specific crop types and geographical locations when addressing mycotoxin contamination. The findings underscore the significance of implementing effective control measures to mitigate mycotoxin contamination and enhance food safety. The study provides valuable insights into mycotoxin contamination and emphasizes the need for comprehensive risk assessment studies and appropriate regulatory measures.
Identification of NpdA as the protein forming the surface layer in Paracidovorax citrulii and evidence of its occurrence as a surface layer protein in diverse genera of the Betaproteobacteria and Gammaproteobacteria
Authors: Gajbhiye Shabda , Gonzales Erin D. , Toso Daniel B. , Kirk Natalie A. , Hickey William James
Published: November 2023

The phytopathogen Paracidovorax citrulli possesses an ortholog of a newly identified surface layer protein (SLP) termed NpdA but has not been reported to produce a surface layer (S-layer). This study had two objectives. First, to determine if P. citrulli formed a NpdA-based S-layer and, if so, assess the effects of S-layer formation on virulence, production of nanostructures termed nanopods, and other phenotypes. Second, to establish the distribution of npdA orthologs throughout the Pseudomonadota and examine selected candidate cultures for physical evidence of S-layer formation. Formation of a NpdA-based S-layer by P. citrulli AAC-001 was confirmed by gene deletion mutagenesis (ΔnpdA), proteomics, and cryo-electron microscopy. There were no significant differences between the wild type and mutant in virulence assays with detached watermelon fruit. Nanopods contiguous with S-layers of multiple biofilm cells were visualized by transmission electron microscopy. Orthologs of npdA were identified in 62 Betaproteobacteria species and 49 Gammaproteobacteria species.  In phylogenetic analyses, NpdA orthologs largely segregated into distinct groups. Cryo-electron microscopy imaging revealed a NpdA-like S-layer in all but one of the 16 additional cultures examined. We conclude that NpdA represents a new family of SLP, forming an S-layer in P. citrulli and other Pseudomonadota. While the S-layer didn’t contribute to virulence in watermelon fruit, a potential role of the P. citrulli S-layer in another dimension of pathogenesis cannot be ruled out. Lastly, formation of cell-bridging nanopods in biofilms is a new property of S-layers; it remains to be determined if nanopods can mediate intercellular movement of materials.
The development of a new type of functional fresh apple juice using
prebiotic fibers, ginger extract, and cardamom essential oil: Antioxidant
capacity and chemical analysis
Authors: Hassanzadeh Hamed , Hosseini Mohammadyar , Galali Yaseen , Ghanbarzadeh Babak
Published: November 2023

The formulation of a novel functional fresh apple juice enriched with dietary
prebiotic fiber (inulin or polydextrose), ginger extract (GE), and cardamom
essential oil (CEO) was carried out based on a combined D-optimal design. In the
first stage, sensory evaluation was performed to screen and select the optimum
sample for further experiments. The sensory evaluation showed that the sample
containing inulin 0.25 g/100 g GE and 0.03 g/100 g CEO had the highest
organoleptic score. In the second stage, various chemical experiments, including
pH, acidity, formalin index, total phenol, flavonoids, antioxidant capacity, and
vitamin C content, were evaluated on the selected enriched apple juices. The
addition of GE and CEO caused changes in nutritional characteristics, including
antioxidant capacity, total phenol, flavonoids, vitamin C, and IC50,
from 35 g/100 g, 350 mg GAE/g, 17 mg/L, 370 mg/kg, and 1,800 mg/kg to 45 g/100
g, 460 mg GAE/g, 21 mg/L, 420 mg/kg, and 1,200 mg/kg respectively. The steady
shear flow and dynamic oscillatory shear rheological tests were also performed
on the screened samples, and results showed that the addition of dietary fiber
in apple juices increased the apparent viscosity, storage modulus, loss modulus,
and complex viscosity. In general, adding plant extracts and processed essential
oil to apple juice increased the nutritional-nutraceutical value and sensory
attributes of apple juice.
Physicochemical characteristics and volatile profile of novel lemon
varieties, Minimon and Jeramon
Authors: Kang Heejin , Lee Sunmee , Kim Jaecheol , Park Hyosun , Kim Suna
Published: November 2023

Although most lemons are imported into Korea, their consumption is increasing.
Development of domestic varieties of Jeramon and
Minimon is currently underway in an effort to meet the
increasing demand for fresh lemons. In this study, an analysis of the
physicochemical characteristics of Jeramon and
Minimon, including their flavor components and antioxidant
properties, was conducted. The results revealed that these new varieties of
Korean lemon can be regarded as good sources of antioxidants and phytochemicals.
Compared to Sunkist, the most consumed lemon variety in Korea,
Minimon contained more than twice as much
β-cryptoxanthin, and the content of L-ascorbic acid
was more than three-four-fold higher in both Minimon and
Jeramon. In addition, results from measurement of DPPH and
ABTS radical scavenging activities indicated that Jeramon
extract exhibited the highest antioxidant activity. In the volatile profile
analysis, the profiles of volatile components showed high similarity among the
three lemon samples, and the composition ratio was largely dominated by
terpenoids. A markedly higher ratio of d-limonene and thymol was detected in the
Minimon variety compared with that in the other two
varieties. Collectively, the findings from this study on Korean lemon varieties
provide a basis as well as valuable guidance for breeding domestic lemon
varieties.
TNFα hinders FGF4 efficacy to mitigate ALS astrocyte dysfunction and cGAS-STING pathway-induced innate immune reactivity
Authors: Velasquez Erika , Savchenko Ekaterina , Marmolejo-Martínez-Artesero Sara , Challuau Désiré , Aebi Aline , Pomeshchik Yuriy , Lamas Nuno Jorge , Vihinen Mauno , Rezeli Melinda , Schneider Bernard , Raoul Cedric , Roybon Laurent
Published: November 2023

Astrocytes play an important role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the relentless degeneration of motor neurons (MNs) in the central nervous system. Despite evidence showing that ALS astrocytes are toxic to MNs, little is understood about the earliest pathological changes that lead to their neurotoxic phenotype. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) harboring the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1), to examine cellular pathways and network changes similar to early stages of the disease. By using proteomics as a molecular indicator, we observed significant alterations in the levels of proteins linked to ALS pathology and the cGAS-STING pathway-induced innate immunity. Interestingly, we found that the protein profile of reactive ALS astrocytes differed from that of wildtype astrocytes treated with the pro-inflammatory cytokine TNFα. Notably, we showed that fibroblast growth factor 4 (FGF4) reversed ALS astrocyte dysfunction and reactivity, but failed to provide protection to MNs when expressed in the spinal cord of the SOD1G93Amouse model of ALS. Further analysis showed that ALS astrocyte reactivity which was rescued by FGF4 was abrogated by TNFα. The latter is capable of exacerbating the dysfunction and reactivity of ALS astrocytes compared to control. Our data show that iPSC-derived ALS astrocytes are dysfunctional and spontaneously exhibit a reactive phenotype when generated from iPSCs. This suggests that this phenotype may resemble the early stages of the disease. Our data also demonstrate that reducing mutant astrocyte reactivity in vivo using FGF4 is not sufficient to prevent MN death in a mouse model of ALS. To mitigate ALS, future studies should investigate whether dual therapies that both lower astrocyte reactivity and reverse disease-associated cellular dysfunction could prevent MN death.

Graphic abstract

Highlights

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ALS astrocytes are dysfunctional and reactive compared to wildtype astrocytes

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FGF4 reverses ALS astrocyte dysfunction and reactivity

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FGF4 lowers ALS astrocyte reactivity in vivo but fails to protect ALS motor neurons from death

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ALS astrocyte reactivity rescued by FGF4 is attenuated by TNFα
Prioritizing genomic variants through neuro-symbolic, knowledge-enhanced learning
Authors: Althagafi Azza , Zhapa-Camacho Fernando , Hoehndorf Robert
Published: November 2023

Motivation

Whole-exome and genome sequencing have become common tools in diagnosing patients with rare diseases. Despite their success, this approach leaves many patients undiagnosed. A common argument is that more disease variants still await discovery, or the novelty of disease phenotypes results from a combination of variants in multiple disease-related genes. Interpreting the phenotypic consequences of genomic variants relies on information about gene functions, gene expression, physiology, and other genomic features. Phenotype-based methods to identify variants involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been successfully applied to prioritizing variants, such methods are based on known gene–disease or gene–phenotype associations as training data and are applicable to genes that have phenotypes associated, thereby limiting their scope. In addition, phenotypes are not assigned uniformly by different clinicians, and phenotype-based methods need to account for this variability.

Results

We developed an Embedding-based Phenotype Variant Predictor (EmbedPVP), a computational method to prioritize variants involved in genetic diseases by combining genomic information and clinical phenotypes. EmbedPVP leverages a large amount of background knowledge from human and model organisms about molecular mechanisms through which abnormal phenotypes may arise. Specifically, EmbedPVP incorporates phenotypes linked to genes, functions of gene products, and the anatomical site of gene expression, and systematically relates them to their phenotypic effects through neuro-symbolic, knowledge-enhanced machine learning. We demonstrate EmbedPVP’s efficacy on a large set of synthetic genomes and genomes matched with clinical information.

Availability

EmbedPVP and all evaluation experiments are freely available athttps://github.com/bio-ontology-research-group/EmbedPVP.

Contact

robert.hoehndorf@kaust.edu.sa

Supplementary information

Supplementary data are available atBioinformatics.
Behavioral adaptation to changing energy constraints via altered frequency of movement selection
Authors: Darveniza Thomas , Zhu Shuyu I. , Pujic Zac , Sun Biao , Levendosky Matthew , Wong Robert , Agarwal Ramesh , McCullough Michael H. , Goodhill Geoffrey J.
Published: November 2023

Animal behavior is strongly constrained by energy consumption. A natural manipulation which provides insight into this constraint is development, where an animal must adapt its movement to a changing energy landscape as its body grows. Unlike many other animals, for fish it is relatively easy to estimate the energy consumed by their movements via fluid mechanics. Here we simulated the fluid mechanics of>100,000 experimentally-recorded movement bouts from larval zebrafish across different ages and fluid conditions as they huntedParamecia. We find that these fish adapt to their changing relationship with the fluid environment as they grow by adjusting the frequency with which they select different types of movements, so that more expensive movements are chosen less often. This strategy was preserved when fish were raised in an unnaturally viscous environment. This work suggests a general principle by which animals could minimize energy consumption in the face of changing energy costs over development.
Microglial NF-κB Signaling Deficiency Protects Against Metabolic Disruptions Caused by Volatile Organic Compound via Modulating the Hypothalamic Transcriptome
Authors: Debarba L.K. , Jayarathne H.S.M. , Stilgenbauer L. , Terra dos Santos A.L. , Koshko L. , Scofield S. , Sullivan R. , Mandal A. , Klueh U. , Sadagurski M.
Published: November 2023

Prolonged exposure to benzene, a prevalent volatile organic compound (VOC), at concentrations found in smoke, triggers hyperglycemia, and inflammation in mice. Corroborating this with existing epidemiological data, we show a strong correlation between environmental benzene exposure and metabolic impairments in humans. To uncover the underlying mechanisms, we employed a controlled exposure system and continuous glucose monitoring (CGM), revealing rapid blood glucose surges and disturbances in energy homeostasis in mice. These effects were attributed to alterations in the hypothalamic transcriptome, specifically impacting insulin and immune response genes, leading to hypothalamic insulin resistance and neuroinflammation. Moreover, benzene exposure activated microglial transcription characterized by heightened expression of IKKβ/NF-κB-related genes. Remarkably, selective removal of IKKβ in immune cells or adult microglia in mice alleviated benzene-induced hypothalamic gliosis, and protected against hyperglycemia. In summary, our study uncovers a crucial pathophysiological mechanism, establishing a clear link between airborne toxicant exposure and the onset of metabolic diseases.
Computational Identification of Potential Inhibitors Targetingcdk1in Colorectal Cancer
Authors: Ogbodo Uchechukwu C. , Enejoh Ojochenemi A. , Okonkwo Chinelo H. , Gnanasekar Pranavathiyani , Gachanja Pauline W. , Osata Shamim , Atanda Halimat C. , Iwuchukwu Emmanuel A. , Achilonu Ikechukwu , Awe Olaitan I.
Published: November 2023

Despite improved treatment options, colorectal cancer (CRC) remains a huge public health concern with a significant impact on affected individuals. Cell cycle dysregulation and overexpression of certain regulators and checkpoint activators are important recurring events in the progression of cancer. Cyclin-dependent kinase 1 (CDK1), a key regulator of the cell cycle component central to the uncontrolled proliferation of malignant cells, has been reportedly implicated in CRC. This study aimed to identify CDK1 inhibitors with potential for clinical drug research in CRC. Ten thousand (10,000) naturally occurring compounds were evaluated for their inhibitory efficacies against CDK1 through molecular docking studies. The stability of the lead compounds in complex with CDK1 was evaluated using molecular dynamics simulation for one thousand (1,000) nanoseconds. The top-scoring candidates’ ADME characteristics and drug-likeness were profiled using SwissADME. Four hit compounds namely spiraeoside, robinetin, 6-hydroxyluteolin, and quercetagetin were identified from molecular docking analysis to possess the least binding scores. Molecular dynamics simulation revealed that robinetin and 6-hydroxyluteolin complexes were stable within the binding pocket of the CDK1 protein. The findings from this study provide insight into novel candidates with specific inhibitory CDK1 activities that can be further investigated through animal testing, clinical trials, and drug development research for CRC treatment.
Machine Learning Approaches Reveal Future Harmful Algae Blooms in Jeju, Korea
Authors: Jang Huey
Published: November 2023

Cyanobacterial algae blooms have proven to suppress diversity and abundance of other organisms while previous research shows the direct correlation between the growth of cyanobacteria and increasing global temperatures. Freshwater temperatures in Jeju island are most prone to climate change within the Korean peninsula, but research on Harmful Algae Blooms (HABs) in these environments has been scarcely conducted. The purpose of this study is to predict the cell numbers of the four HAB species in Jeju island’s four water supply sources in 2050 and 2100. Using the water quality data across the last 24 years, Scikit-learn GBM was developed to predict cell numbers of HAB based on four variables determined through multiple linear regression: temperature, pH, EC, and DO. Meanwhile, XGBoost was designed to predict four different levels of HAB bloom warnings. Future freshwater temperature was obtained through the linear relationship model between air and freshwater temperature. The performances of the Scikit-learn GBM on the cell numbers of each species were as follows (measured by MAE and R2): Microcystis (132.313; 0.857), Anabaena (36.567; 0.035), Oscillatoria (24.213; 0.672), and Apahnizomenon (65.716; 0.506). This model predicted that Oscillatoria would increase by 31.04% until 2100 and the total cell number of the four algeas would increase 376,414/ml until 2050 and reach 393,873/ml in 2100 (247.088; 0.617). The XGboost model predicted a 17% increase in the ‘Warning’ level of the Algae Alert System until 2100. The increase in HABs will ultimately lead to agricultural setbacks throughout Jeju; algae blooms in dams will produce neurotoxins and hapatotoxins, limiting the usage of agricultural water. Immediate solutions are required to suppress the growth rate of algae cells brought by global climate change in Jeju freshwaters.
A Pair of Cadmium-exposed Zebrafish Affect Boldness and Landmark use in the Un-exposed Majority
Authors: Shelton Delia S. , Suriyampola Piyumika S. , Dinges Zoe M. , Glaholt Stephen P. , Shaw Joseph R. , Martins Emília P.
Published: November 2023

Some individuals have a disproportionate effect on group responses. These individuals may possess distinct attributes that differentiate them from others. These characteristics may include susceptibility to contaminant exposure such as cadmium, a potent trace metal present in water and food. Here, we tested whether a pair of cadmium-exposed individuals could exert an impact on the behavior of the unexposed majority. We used behavioral assessments to characterize the extent of the effects of the cadmium-exposed pair on group boldness, cohesion, activity and responses to landmarks. We found that groups with a pair of cadmium-exposed fish approached and remained closer to novel stimuli and landmarks than did groups with pairs of fish treated with uncontaminated water (control). Shoals with cadmium and water treated fish exhibited similar levels of cohesion and activity. The results suggest that fish acutely exposed to environmentally-relevant cadmium concentrations can have profound effects on the un-exposed majority.
Correlative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment
Authors: Daugird Timothy A. , Shi Yu , Holland Katie L. , Rostamian Hosein , Liu Zhe , Lavis Luke D. , Rodriguez Joseph , Strahl Brian D. , Legant Wesley R.
Published: November 2023

In the nucleus, biological processes are driven by proteins that diffuse through and bind to a meshwork of nucleic acid polymers. To better understand this interplay, we developed an imaging platform to simultaneously visualize single protein dynamics together with the local chromatin environment in live cells. Together with super-resolution imaging, new fluorescent probes, and biophysical modeling, we demonstrated that nucleosomes display differential diffusion and packing arrangements as chromatin density increases whereas the viscoelastic properties and accessibility of the interchromatin space remain constant. Perturbing nuclear functions impacted nucleosome diffusive properties in a manner that was dependent on local chromatin density and supportive of a model wherein transcription locally stabilizes nucleosomes while simultaneously allowing for the free exchange of nuclear proteins. Our results reveal that nuclear heterogeneity arises from both active and passive process and highlights the need to account for different organizational principals when modeling different chromatin environments.
Analysis of sugar-induced cell death dynamics in S. cerevisiae strains with deleted genes involved in several key metabolic processes
Authors: Valiakhmetov Airat Ya.
Published: November 2023

Background

incubation of exponentially growing yeast S.cerevisiae with glucose in the absence of other nutrients results inSugarInducedCellDeath (SICD). SICD is accompanied by the accumulation of reactive oxygen species (ROS), has the nature of primary necrosis, affects cells in the S-phase of the cell cycle, and is completely suppressed by dissipation of ΔΨ. The specific mechanism linking the ΔΨ status to the induction of SICD remains unclear. This study aimed to attempt to identify the specific molecular mechanism responsible for ROS overproduction and the development of SICD.

Methods

The main method employed was the analysis of SICD development in a set of knockout mutants targeting key participants in metabolic processes.

Results

A statistically significant decrease in the number of cells with ROS overproduction was observed in the ΔAFO1, ΔPOX1, ΔYNO1, ΔTRK1, ΔTRK2, ΔVSB1, and ΔYPR003C strains. A significant decrease in the number of cells with SICD was shown in the ΔTRK1, ΔVSB1, and ΔYPR003C strains. The development of SICD is not due to the presence of a nitrogen reactive species (NRS). Deletion of certain genes expressed during the S-phase of the cell cycle did not alter the dynamics of ROS accumulation and the development of SICD. The presence of exogenous or endogenous glutathione significantly suppresses both processes studied, although not as effectively as ΔΨ dissipation.

Conclusions

The development of SICD is dependent on the presence of ROS, but is not strictly linked to it, as evidenced by the effects of glutathione and mutations related to its biosynthesis. In all strains tested, SICD was critically dependent on ΔΨ, although the nature of its generator remains unclear.
Single-cell spatial proteomics identifies the JAK/STAT pathway as an actionable therapeutic target in lethal cutaneous drug reactions
Authors: Nordmann Thierry M. , Anderton Holly , Hasegawa Akito , Schweizer Lisa , Zhang Peng , Stadler Pia-Charlotte , Sinha Ankit , Metousis Andreas , Rosenberger Florian A. , Zwiebel Maximillian , Satoh Takashi K. , Anzengruber Florian , Tanzer Maria C. , Saito Yuki , Gong Ting , Thielert Marvin , Kimura Haruna , Silke Natasha , Rodriguez Edwin H. , Gaetana Restivo , Nguyen Hong Ha , Gross Annette , Levesque Mitchell P. , Murray Peter J. , Ingen-Housz-Oro Saskia , Mund Andreas , Abe Riichiro , Silke John , Ji Chao , French Lars E. , Mann Matthias
Published: November 2023

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction and an emerging public health issue. Triggered by common medications, TEN patients undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms driving keratinocyte cell death have been proposed, the main drivers remain unknown and no effective therapy exists. To systematically map molecular changes that are associated with TEN and identify potential druggable targets, we employed the single- cell spatial proteomics technique Deep Visual Proteomics. We analyzed formalin-fixed paraffin-embedded archived skin-tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified over 5,000 proteins in keratinocytes and skin-infiltrating immune cells. Most strikingly, this revealed a robust enrichment of Type-I and -II interferon signature in the immune cell and keratinocyte compartment of TEN patients, along with a drastic activation of pSTAT1. Targeted inhibition with pan- JAK inhibitor (JAKi) tofacitinib reduced keratinocyte-directed cytotoxicity in a novel live-cell imaging assay, using patient-derived keratinocytes and peripheral blood mononuclear cells (PBMCs). Furthermore, oral administration of pan-JAKi tofacitinib or baricitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Lastly, JAKi treatment was safe and associated with rapid cutaneous re- epithelialization and recovery in four patients with TEN. This study uncovers the JAK- STAT and interferon signaling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAK inhibition as a curative therapy.