tbuckley/cabot-search huggingface dataset:
Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease
Authors: Emma C. Walker, Sarah Javati, Elizabeth M. Todd, John-Paul Matlam, Xue Lin, Michelle Bryant, Emily Krone, Rashmi Ramani, Pallavi Chandra, Taylor P. Green, Edgar P. Anaya, Julie Y. Zhou, Katherine A. Alexander, R. Spencer Tong, Lapule Yuasi, Sebastian Boluarte, Fan Yang, Lina Greenberg, Jeanne M. Nerbonne, Michael J. Greenberg, Regina A. Clemens, Jennifer A. Philips, Leslie D. Wilson, Carmen M. Halabi, Brian J. DeBosch, Christopher C. Blyth, Todd E. Druley, James W. Kazura, William S. Pomat, Sharon Celeste Morley
Journal: Nature Immunology (2024)

Acute lower respiratory tract infection (ALRI) remains a major worldwide cause of childhood mortality, compelling innovation in prevention and treatment. Children in Papua New Guinea (PNG) experience profound morbidity from ALRI caused by Streptococcus pneumoniae. As a result of evolutionary divergence, the human PNG population exhibits profound genetic variation and diversity. To address unmet health needs of children in PNG, we tested whether genetic variants increased ALRI morbidity. Whole-exome sequencing of a pilot child cohort identified homozygosity for a novel single-nucleotide variant (SNV) in coenzyme Q6 (COQ6) in cases with ALRI. COQ6 encodes a mitochondrial enzyme essential for biosynthesis of ubiquinone, an electron acceptor in the electron transport chain. A significant association of SNV homozygosity with ALRI was replicated in an independent ALRI cohort (P = 0.036). Mice homozygous for homologous mouse variant Coq6 exhibited increased mortality after pneumococcal lung infection, confirming causality. Bone marrow chimeric mice further revealed that expression of variant Coq6 in recipient (that is, nonhematopoietic) tissues conferred increased mortality. Variant Coq6 maintained ubiquinone biosynthesis, while accelerating metabolic remodeling after pneumococcal challenge. Identification of this COQ6 variant provides a genetic basis for increased pneumonia susceptibility in PNG and establishes a previously unrecognized role for the enzyme COQ6 in regulating inflammatory-mediated metabolic remodeling. Morley, Pomat and colleagues identify a homozygous mutation in COQ6 in an indigenous population of Papua New Guinea. This allele predisposes children to increased risk of acute lower respiratory infections in response to Streptococcus pneumoniae. This sensitivity is recapitulated in Coq6DY mice in the nonhematopoietic compartment.
A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes
Authors: Sorabh Sharma, Manjinder Cheema, Patrick L. Reeson, Kamal Narayana, Roobina Boghozian, Ana Paula Cota, Tara P. Brosschot, Rachael D. FitzPatrick, Jakob Körbelin, Lisa A. Reynolds, Craig E. Brown
Journal: Nature Metabolism (2024)

Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with type 1 diabetes. Interleukin-10 promotes the formation of microcirculatory defects in the brain associated with cognitive impairment in a mouse model of type 1 diabetes.
Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation
Authors: Huasheng Yu, Saad S. Nagi, Dmitry Usoskin, Yizhou Hu, Jussi Kupari, Otmane Bouchatta, Hanying Yan, Suna Li Cranfill, Mayank Gautam, Yijing Su, You Lu, James Wymer, Max Glanz, Phillip Albrecht, Hongjun Song, Guo-Li Ming, Stephen Prouty, John Seykora, Hao Wu, Minghong Ma, Andrew Marshall, Frank L. Rice, Mingyao Li, Håkan Olausson, Patrik Ernfors, Wenqin Luo
Journal: Nature Neuroscience (2024)

Abstract The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human (h)DRG neurons—critical information to decipher their functions—are lacking due to technical difficulties. In this study, we isolated somata from individual hDRG neurons and conducted deep RNA sequencing (RNA-seq) to detect, on average, over 9,000 unique genes per neuron, and we identified 16 neuronal types. These results were corroborated and validated by spatial transcriptomics and RNAscope in situ hybridization. Cross-species analyses revealed divergence among potential pain-sensing neurons and the likely existence of human-specific neuronal types. Molecular-profile-informed microneurography recordings revealed temperature-sensing properties across human sensory afferent types. In summary, by employing single-soma deep RNA-seq and spatial transcriptomics, we generated an hDRG neuron atlas, which provides insights into human somatosensory physiology and serves as a foundation for translational work.
Grapevine pangenome facilitates trait genetics and genomic breeding
Authors: Zhongjie Liu, Nan Wang, Ying Su, Qiming Long, Yanling Peng, Lingfei Shangguan, Fan Zhang, Shuo Cao, Xu Wang, Mengqing Ge, Hui Xue, Zhiyao Ma, Wenwen Liu, Xiaodong Xu, Chaochao Li, Xuejing Cao, Bilal Ahmad, Xiangnian Su, Yuting Liu, Guizhou Huang, Mengrui Du, Zhenya Liu, Yu Gan, Lei Sun, Xiucai Fan, Chuan Zhang, Haixia Zhong, Xiangpeng Leng, Yanhua Ren, Tianyu Dong, Dan Pei, Xinyu Wu, Zhongxin Jin, Yiwen Wang, Chonghuai Liu, Jinfeng Chen, Brandon Gaut, Sanwen Huang, Jinggui Fang, Hua Xiao, Yongfeng Zhou
Journal: Nature Genetics (2024)

Grapevine breeding is hindered by a limited understanding of the genetic basis of complex agronomic traits. This study constructs a graph-based pangenome reference (Grapepan v.1.0) from 18 newly generated phased telomere-to-telomere assemblies and 11 published assemblies. Using Grapepan v.1.0, we build a variation map with 9,105,787 short variations and 236,449 structural variations (SVs) from the resequencing data of 466 grapevine cultivars. Integrating SVs into a genome-wide association study, we map 148 quantitative trait loci for 29 agronomic traits (50.7% newly identified), with 12 traits significantly contributed by SVs. The estimated heritability improves by 22.78% on average when including SVs. We discovered quantitative trait locus regions under divergent artificial selection in metabolism and berry development between wine and table grapes, respectively. Moreover, significant genetic correlations were detected among the 29 traits. Under a polygenic model, we conducted genomic predictions for each trait. In general, our study facilitates the breeding of superior cultivars via the genomic selection of multiple traits. By constructing a graph-based grapevine pangenome reference (Grapepan v.1.0) and incorporating structural variations and phenotypic maps, the study investigates the genetic basis of agronomic traits, empowering grapevine genomic breeding.
The ZmCPK39–ZmDi19–ZmPR10 immune module regulates quantitative resistance to multiple foliar diseases in maize
Authors: Mang Zhu, Tao Zhong, Ling Xu, Chenyu Guo, Xiaohui Zhang, Yulin Liu, Yan Zhang, Yancong Li, Zhijian Xie, Tingting Liu, Fuyan Jiang, Xingming Fan, Peter Balint-Kurti, Mingliang Xu
Journal: Nature Genetics (2024)

Gray leaf spot, northern leaf blight and southern leaf blight are three of the most destructive foliar diseases affecting maize (Zea mays L.). Here we identified a gene, ZmCPK39, that encodes a calcium-dependent protein kinase and negatively regulates quantitative resistance to these three diseases. The ZmCPK39 allele in the resistant line displayed significantly lower pathogen-induced gene expression than that in the susceptible line. A marked decrease in ZmCPK39 abundance mitigated the phosphorylation and degradation of the transcription factor ZmDi19. This led to elevated expression of ZmPR10, a gene known to encode an antimicrobial protein, thereby enhancing maize resistance to foliar diseases. Moreover, the F
Large DNA deletions occur during DNA repair at 20-fold lower frequency for base editors and prime editors than for Cas9 nucleases
Authors: Gue-Ho Hwang, Seok-Hoon Lee, Minsik Oh, Segi Kim, Omer Habib, Hyeon-Ki Jang, Heon Seok Kim, Youngkuk Kim, Chan Hyuk Kim, Sun Kim, Sangsu Bae
Journal: Nature Biomedical Engineering (2024)

When used to edit genomes, Cas9 nucleases produce targeted double-strand breaks in DNA. Subsequent DNA-repair pathways can induce large genomic deletions (larger than 100 bp), which constrains the applicability of genome editing. Here we show that Cas9-mediated double-strand breaks induce large deletions at varying frequencies in cancer cell lines, human embryonic stem cells and human primary T cells, and that most deletions are produced by two repair pathways: end resection and DNA-polymerase theta-mediated end joining. These findings required the optimization of long-range amplicon sequencing, the development of a k-mer alignment algorithm for the simultaneous analysis of large DNA deletions and small DNA alterations, and the use of CRISPR-interference screening. Despite leveraging mutated Cas9 nickases that produce single-strand breaks, base editors and prime editors also generated large deletions, yet at approximately 20-fold lower frequency than Cas9. We provide strategies for the mitigation of such deletions. DNA repair after Cas9-mediated double-strand breaks induces large DNA deletions at frequencies 20-fold higher than elicited by base editors and prime editors leveraging Cas9 nickases producing single-strand breaks.
Clinical validation of an AI-based pathology tool for scoring of metabolic dysfunction-associated steatohepatitis
Authors: Hanna Pulaski, Stephen A. Harrison, Shraddha S. Mehta, Arun J. Sanyal, Marlena C. Vitali, Laryssa C. Manigat, Hypatia Hou, Susan P. Madasu Christudoss, Sara M. Hoffman, Adam Stanford-Moore, Robert Egger, Jonathan Glickman, Murray Resnick, Neel Patel, Cristin E. Taylor, Robert P. Myers, Chuhan Chung, Scott D. Patterson, Anne-Sophie Sejling, Anne Minnich, Vipul Baxi, G. Mani Subramaniam, Quentin M. Anstee, Rohit Loomba, Vlad Ratziu, Michael C. Montalto, Nick P. Anderson, Andrew H. Beck, Katy E. Wack
Journal: Nature Medicine (2024)

Metabolic dysfunction-associated steatohepatitis (MASH) is a major cause of liver-related morbidity and mortality, yet treatment options are limited. Manual scoring of liver biopsies, currently the gold standard for clinical trial enrollment and endpoint assessment, suffers from high reader variability. This study represents the most comprehensive multisite analytical and clinical validation of an artificial intelligence (AI)-based pathology system, AI-based measurement of metabolic dysfunction-associated steatohepatitis (AIM-MASH), to assist pathologists in MASH trial histology scoring. AIM-MASH demonstrated high repeatability and reproducibility compared to manual scoring. AIM-MASH-assisted reads by expert MASH pathologists were superior to unassisted reads in accurately assessing inflammation, ballooning, MAS ≥ 4 with ≥1 in each score category and MASH resolution, while maintaining non-inferiority in steatosis and fibrosis assessment. These findings suggest that AIM-MASH could mitigate reader variability, providing a more reliable assessment of therapeutics in MASH clinical trials. In a prospective, regulatory-grade study of assistance to pathologists in MASH histology scoring, AIM-MASH-assisted reads by expert MASH pathologists were superior to unassisted reads and decreased inter-reader variability.
Rewiring of uric acid metabolism in the intestine promotes high-altitude hypoxia adaptation in humans
Authors: Qian Su, Yu-Chun Li, Dao-Hua Zhuang, Xin-Yuan Liu, Han Gao, Dong Li, Yu Chen, Ming-Xia Ge, Yi-Ming Han, Zong-Liang Gao, Fan-Qian Yin, Long Zhao, Yun-Xia Zhang, Li-Qin Yang, Qin Zhao, Yong-Jun Luo, Zhigang Zhang, Qing-Peng Kong
Journal: Molecular Biology and Evolution (2024)

Abstract Adaptation to high-altitude hypoxia is characterized by systemic and organ-specific metabolic changes. This study investigates whether intestinal metabolic rewiring is a contributing factor to hypoxia adaptation. We conducted a longitudinal analysis over 108 days, with seven time points, examining fecal metabolomic data from a cohort of 46 healthy male adults traveling from Chongqing (a.s.l. 243 m) to Lhasa (a.s.l. 3,658 m) and back. Our findings reveal that short-term hypoxia exposure significantly alters intestinal metabolic pathways, particularly those involving purines, pyrimidines, and amino acids. A notable observation was the significantly reduced level of intestinal uric acid, the end product of purine metabolism, during acclimatization (also called acclimation) and additional two long-term exposed cohorts (Han Chinese and Tibetans) residing in Shigatse, Xizang (a.s.l. 4,700 m), suggesting that low intestinal uric acid levels facilitate adaptation to high-altitude hypoxia. Integrative analyses with gut metagenomic data showed consistent trends in intestinal uric acid levels and the abundance of key uric acid-degrading bacteria, predominantly from the Lachnospiraceae family. The sustained high abundance of these bacteria in the long-term resident cohorts underscores their essential role in maintaining low intestinal uric acid levels. Collectively, these findings suggest that the rewiring of intestinal uric acid metabolism, potentially orchestrated by gut bacteria, is crucial for enhancing human resilience and adaptability in extreme environments.
Environmental risk factors should not be overlooked: comment on the article by Brooks et al entitled "The risk of lung cancer in rheumatoid arthritis and rheumatoid arthritis–associated interstitial lung disease”
Authors: Andreea Lazarut‐Nistor, David G. Hutchinson
Journal: Arthritis & Rheumatology (2024)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The characterization of ancient <i>Methanococcales</i> malate dehydrogenases reveals that strong thermal stability prevents unfolding under intense γ-irradiation
Authors: Dominique Madern, Frédéric Halgand, Chantal Houée-Levin, Anne-Béatrice Dufour, Sandrine Coquille, Salomé Ansanay-Alex, Sophie Sacquin-Mora, Céline Brochier-Armanet
Journal: Molecular Biology and Evolution (2024)

Malate dehydrogenases (MalDHs) (EC.1.1.1.37), which are involved in the conversion of oxaloacetate to pyruvate in the tricarboxylic acid cycle, are a relevant model for the study of enzyme evolution and adaptation. Likewise, a recent study showed that Methanococcales, a major lineage of Archaea, is a good model to study the molecular processes of proteome thermoadaptation in prokaryotes. Here, we use ancestral sequence reconstruction and paleoenzymology to characterize both ancient and extant MalDHs. We observe a good correlation between inferred optimal growth temperatures and experimental optimal temperatures for activity (A-Topt). In particular, we show that the MalDH present in the ancestor of Methanococcales was hyperthermostable and had an A-Topt of 80 °C, consistent with a hyperthermophilic lifestyle. This ancestor gave rise to two lineages with different thermal constraints: one remained hyperthermophilic, while the other underwent several independent adaptations to colder environments. Surprisingly, the enzymes of the first lineage have retained a thermoresistant behavior (i.e. strong thermostability and high A-Topt), whereas the ancestor of the second lineage shows a strong thermostability, but a reduced A-Topt. Using mutants, we mimic the adaptation trajectory toward mesophily and show that it is possible to significantly reduce the A-Topt without altering the thermostability of the enzyme by introducing a few mutations. Finally, we reveal an unexpected link between thermostability and the ability to resist γ-irradiation-induced unfolding.
Periodontal disease: A systemic condition
Authors: German E. M. Villoria, Ricardo G. Fischer, Eduardo M. B. Tinoco, Joerg Meyle, Bruno G. Loos
Journal: Periodontology 2000 (2024)

Abstract For decades, periodontitis has been considered to be a local inflammatory disease of the periodontal tissues in the oral cavity. Initially, associations of periodontitis with a multitude of noncommunicable diseases were each studied separately, and relationships were shown. The associations of periodontitis with morbidities, such as cardiovascular diseases, rheumatoid arthritis, diabetes mellitus, respiratory diseases, have been demonstrated. As most such studies were cross‐sectional in nature, questions about causality cannot be univocally answered. And periodontitis as an independent risk factor for one systemic disease, becomes even more difficult to assess since recently periodontitis has also been associated with multimorbidity. Periodontitis and many systemic diseases share environmental, lifestyle and genetic risk factors, and share immunopathology. Moreover, suffering from one common noncommunicable disease may increase the susceptibility for another such chronic disease; the systemic effects of one condition may be one of various risk factors for another such disease. The overarching effect of any systemic disease is it causing a pro‐inflammatory state in the individual; this has also been shown for periodontitis. Moreover, in periodontitis a prothrombotic state and elevated immunological activity have been shown. As such, when we consider periodontal disease as another systemic disease, it can affect the susceptibility and progression of other systemic diseases, and importantly, vice versa. And with this, it is not surprising that periodontitis is associated with a variety of other noncommunicable diseases. The medical definition of a systemic disease includes diseases that affect different organs and systems. Thus, the aim of this opinion paper is to propose that periodontitis should be considered a systemic disease in its own right and that it affects the individual's systemic condition and wellbeing. The dental and medical profession and researchers alike, should adapt this paradigm shift, advancing periodontal disease out of its isolated anatomical location into the total of chronic noncommunicable diseases, being for some conditions a comorbid disease and, vice versa, comorbidities can affect initiation and progression of periodontal disease.
TDFPS-Designer: an efficient toolkit for barcode design and selection in nanopore sequencing
Authors: Junhai Qi, Zhengyi Li, Yao-zhong Zhang, Guojun Li, Xin Gao, Renmin Han
Journal: Genome biology (2024)

Oxford Nanopore Technologies (ONT) offers ultrahigh-throughput multi-sample sequencing but only provides barcode kits that enable up to 96-sample multiplexing. We present TDFPS-Designer, a new toolkit for nanopore sequencing barcode design, which creates significantly more barcodes: 137 with a length of 20 base pairs, 410 at 24 bp, and 1779 at 30 bp, far surpassing ONT's offerings. It includes GPU-based acceleration for ultra-fast demultiplexing and designs robust barcodes suitable for high-error ONT data. TDFPS-Designer outperforms current methods, improving the demultiplexing recall rate by 20% relative to Guppy, without a reduction in precision.
Specialization restricts the evolutionary paths available to yeast sugar transporters
Authors: Johnathan G Crandall, Xiaofan Zhou, Antonis Rokas, Chris Todd Hittinger
Journal: Molecular Biology and Evolution (2024)

Abstract Functional innovation at the protein level is a key source of evolutionary novelties. The constraints on functional innovations are likely to be highly specific in different proteins, which are shaped by their unique histories and the extent of global epistasis that arises from their structures and biochemistries. These contextual nuances in the sequence–function relationship have implications both for a basic understanding of the evolutionary process and for engineering proteins with desirable properties. Here, we have investigated the molecular basis of novel function in a model member of an ancient, conserved, and biotechnologically relevant protein family. These Major Facilitator Superfamily sugar porters are a functionally diverse group of proteins that are thought to be highly plastic and evolvable. By dissecting a recent evolutionary innovation in an α-glucoside transporter from the yeast Saccharomyces eubayanus, we show that the ability to transport a novel substrate requires high-order interactions between many protein regions and numerous specific residues proximal to the transport channel. To reconcile the functional diversity of this family with the constrained evolution of this model protein, we generated new, state-of-the-art genome annotations for 332 Saccharomycotina yeast species spanning ∼400 My of evolution. By integrating phylogenetic and phenotypic analyses across these species, we show that the model yeast α-glucoside transporters likely evolved from a multifunctional ancestor and became subfunctionalized. The accumulation of additive and epistatic substitutions likely entrenched this subfunction, which made the simultaneous acquisition of multiple interacting substitutions the only reasonably accessible path to novelty.
Correction: Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers
Authors: Haoyang Mi, Shamilene Sivagnanam, Courtney B. Betts, Shannon M. Liudahl, Elizabeth M. Jaffee, Lisa M. Coussens, Aleksander S. Popel
Journal: Cancer Research (2024)