bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Clinical Response of Upadacitinib and Risankizumab is Associated with Reduced Inflammatory Bowel Disease Anti-TNFα Inadequate Response Mechanisms
Authors: Wang Jing , Macoritto Michael , Guay Heath , Davis Justin W. , Levesque Marc C. , Cao Xiaohong 
Published: May 2022

AbstractBackground and AimsJAK1 inhibitor upadacitinib and IL23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are anti-TNFα inadequate responders (TNF-IR). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.MethodsEight tissue transcriptomic datasets from IBD patients treated with anti-TNFα therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. RNAseq colon tissue data from clinical studies of TNF-IR Crohn’s disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab.ResultsWe found seven TNF-IR up-regulated modules (M1-M7) related to innate/adaptive immune responses, interferon signaling and tissue remodeling, and five TNF-IR down-regulated modules (M8-M12) primarily related to metabolism. TNF-IR up-regulated cell types were inflammatory fibroblasts, post-capillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells while subtypes of immature enterocytes, WNT5B+ cells and myofibroblasts were TNF-IR down-regulated cell types. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR up-regulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, four of the six TNF-IR up-regulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab.ConclusionsCollectively, these data suggest that upadacitinib and risankizumab affect TNF-IR up-regulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.
Chromosome-level Reference Genome Provides Insights into Divergence and Stress Adaptation of the African Oil Palm
Authors: Wang Le , Lee May , Wan Zi Yi , Bai Bin , Ye Baoqing , Alfiko Yuzer , Ramadsyah Ramadsyah , Purwantomo Sigit , Song Zhuojun , Suwanto Antonius , Yue Gen Hua 
Published: May 2022

AbstractThe palm family (Arecaceae), consisting of ∼ 2600 species, is the third most economically important family of plants. The African oil palm (Elaeis guineensis) is one of the most important palms. However, the genome sequences of palms available are still limited and fragmented. Here, we report a high-quality chromosome-level reference genome of an oil palm Dura. The genome of 1.7 Gb was assembled by integrating long reads with ∼ 150 × genome coverage. The assembled genome covered 94.5% of the estimated genome size, within which 91.6% were assigned into 16 pseudochromosomes and 73.7% were repetitive sequences. Relying on the conserved synteny with oil palm, the existing draft genome sequences of both date palm and coconut were further assembled into chromosomal level. Transposon burst, particularly long terminal repeat retrotransposons (LTRs) retrotransposons, following the last whole-genome duplication (WGD), likely explains genome size variation across palms. Convergent evolution of fruit colors tends to eliminate the roles of the virescens gene in controlling accumulation of anthocyanins in exocarp of ripe fruit of palms. Recent duplications of high tandemly repeated pathogenesis-related proteins (PRs) from the same tandem arrays played an important role in defense responses to Ganoderma. Whole genome re-sequencing of both ancestral African and introduced oil palms in Southeast Asia revealed that genes under putative selection were notably associated with stress responses, suggesting adaptation to stresses in the new habitat. The genomic resources and insights gained in this study could be exploited for accelerating genetic improvement and understanding the evolution of palms.
Evolution and Diversification Dynamics of Butterflies
Authors: Kawahara Akito Y. , Storer Caroline , Carvalho Ana Paula S. , Plotkin David M. , Condamine Fabien , Braga Mariana P. , Ellis Emily A. , St Laurent Ryan A. , Li Xuankun , Barve Vijay , Cai Liming , Earl Chandra , Frandsen Paul B. , Owens Hannah L. , Valencia-Montoya Wendy A. , Aduse-Poku Kwaku , Toussaint Emmanuel F. A. , Dexter Kelly M. , Doleck Tenzing , Markee Amanda , Messcher Rebeccah , Nguyen Y-Lan , Badon Jade Aster T. , Benítez Hugo A. , Braby Michael F. , Buenavente Perry A. C. , Chan Wei-Ping , Collins Steve C. , Childers Richard A. Rabideau , Dankowicz Even , Eastwood Rod , Fric Zdenek F. , Gott Riley J. , Hall Jason P. W. , Hallwachs Winnie , Hardy Nate B. , Sipe Rachel L. Hawkins , Heath Alan , Hinolan Jomar D. , Homziak Nicholas T. , Hsu Yu-Feng , Inayoshi Yutaka , Itliong Micael G.A. , Janzen Daniel H. , Kitching Ian J. , Kunte Krushnamegh , Lamas Gerardo , Landis Michael J. , Larsen Elise A. , Larsen Torben B. , Leong Jing V. , Lukhtanov Vladimir , Maier Crystal A. , Martinez Jose I. , Martins Dino J. , Maruyama Kiyoshi , Maunsell Sarah C. , Mega Nicolás Oliveira , Monastyrskii Alexander , Morais Ana B. B. , Müller Chris J. , Naive Mark Arcebal K. , Nielsen Gregory , Padrón Pablo Sebastián , Peggie Djunijanti , Romanowski Helena Piccoli , Sáfián Szabolcs , Saito Motoki , Schröder Stefan , Shirey Vaughn , Soltis Doug , Soltis Pamela , Sourakov Andrei , Talavera Gerard , Vila Roger , Vlasanek Petr , Wang Houshuai , Warren Andrew D. , Willmott Keith R. , Yago Masaya , Jetz Walter , Jarzyna Marta A. , Breinholt Jesse W. , Espeland Marianne , Ries Leslie , Guralnick Robert P. , Pierce Naomi E. , Lohman David J. 
Published: May 2022

AbstractButterflies are a diverse and charismatic insect group that are thought to have diversified via coevolution with plants and in response to dispersals following key geological events. These hypotheses have been poorly tested at the macroevolutionary scale because a comprehensive phylogenetic framework and datasets on global distributions and larval hosts of butterflies are lacking. We sequenced 391 genes from nearly 2,000 butterfly species to construct a new, phylogenomic tree of butterflies representing 92% of all genera and aggregated global distribution records and larval host datasets. We found that butterflies likely originated in what is now the Americas, ∼100 Ma, shortly before the Cretaceous Thermal Maximum, then crossed Beringia and diversified in the Paleotropics. The ancestor of modern butterflies likely fed on Fabaceae, and most extant families were present before the K/Pg extinction. The majority of butterfly dispersals occurred from the tropics (especially the Neotropics) to temperate zones, largely supporting a “cradle” pattern of diversification. Surprisingly, host breadth changes and shifts to novel host plants had only modest impacts.
Global and tissue-specific aging effects on murine proteomes
Authors: Keele Gregory R. , Zhang Ji-Gang , Szpyt John , Korstanje Ron , Gygi Steven P. , Churchill Gary A. , Schweppe Devin K. 
Published: May 2022

ABSTRACTMaintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional changes with age. To define the effects of age directly at the protein level, we performed discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes at adult and late midlife ages (8 and 18 months). Consistent with previous studies, age-related changes in protein abundance often have no corresponding transcriptional change. Aging resulted in increases in immune protein abundance across all tissues, consistent with a global pattern of immune infiltration with age. Our protein-centric data revealed tissue-specific aging changes with potential functional consequences, including altered endoplasmic reticulum and protein trafficking in the spleen. We further observed changes in the stoichiometry of protein complexes with important roles in protein homeostasis such as the CCT/TriC complex and large ribosomal subunit. These data provide a foundation for understanding how proteins contribute to systemic aging across tissues.
USP11 promotes endothelial apoptosis-resistance in pulmonary hypertension by deubiquitinating HINT3
Authors: Jang Andrew J. , Tseng Victor , Kim Jae Sun , Stearman Robert S. , Zhao Yutong , Zhao Jing , Choi Jiwoong , Lister John , Passineau Michael J. , Lam Wilbur A. , Park Changwon , Benza Raymond J. , Kang Bum-Yong 
Published: May 2022

ABSTRACTIntroductionPulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. Evolving evidence indicates that the ubiquitin-specific proteases (USPs), play an important role in the pathogenesis of PAH by deubiquitinating key proteins involved in cell proliferation, migration, and apoptosis. Our genome-wide association study (GWAS) analysis-paired with transcriptomic profiling indicated that deubiquitinase USP11 and histidine triad nucleotide binding protein 3 (HINT3) are positively correlated and that their expression increased in lungs of PAH patients compared to control (fail donor) group, and inversely correlated with survival. However, mechanisms and function of the USP11/HNT3 axis have not been explored in PAH. Therefore, we aimed to investigate that HINT3 stabilized by USP11 activation links to endothelial apoptosis-resistance in PAH.Methods and ResultsExpression of USP11 and HINT3 was increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice using qRT-PCR and Western blot analyses. USP11 and HINT3 interacted physically as shown by co-immunoprecipitation (co-IP) assay in human pulmonary artery endothelial cells (HPAECs). HINT3 levels were decreased upon transfection of HA-tagged Ubi plasmid into HPAECs. Pretreatment with the potent proteasome inhibitor MG132 prolonged the half-life of HINT3 protein, indicating that HINT3 is degraded by polyubiquitination. HINT3 was stabilized and destabilized by forced overexpression or siRNA knockdown of USP11 respectively. Similarly, treatment with mitoxantrone, a USP11 antagonist, reduced HPAEC HINT3 expression. HINT3 interacted with the antiapoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, knockdown of HINT3 function led to depletion of BCL2.ConclusionsThe HINT3-USP11 axis contributes to apoptosis-resistance in pulmonary artery endothelial cells, as is potentially a novel and attractive therapeutic target for ubiquitination modulators.
Selenocysteine metabolism is a targetable vulnerability inMYCN-amplified cancers
Authors: Alborzinia Hamed , Chen Zhiyi , Yildiz Umut , Freitas Florencio Porto , Vogel Felix C.E. , Varga Julianna , Batani Jasmin , Bartenhagen Christoph , Schmitz Werner , Büchel Gabriele , Michalke Bernhard , Zheng Jashuo , Meierjohann Svenja , Girardi Enrico , Espinet Elisa , Florez Andres , dos Santos Ancely Ferreira , Aroua Nesrine , Schlicker Lisa , Xavier da Silva Thamara N. , Przybylla Adriana , Zeisberger Petra , Superti-Furga Giulio , Eilers Martin , Conrad Marcus , Fischer Matthias , Schulze Almut , Trumpp Andreas , Friedmann Angeli José Pedro 
Published: May 2022

AbstractUnderstanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma.Statement of significanceGiven the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.
Machine Learning Reveals The Effect of Maternal Age on The Mouse Pre-Implantation Embryo Developmental Timing
Authors: Daniel Nati , Wasserman Tanya , Adler Zohar , Czyzewski Tomer , Savir Yonatan 
Published: May 2022

SummaryIn recent years, many women have delayed childbearing, thus increasing the necessity for assisted reproductive technology (ART) for older women1–3. Despite advances in ART4, its success rate in advanced-age women is still very low3,4. As time-lapse imaging became available, morphological features of the developing pre-implantation embryo, in-vitro, are heavily used to assess its potency5–9. Timing of embryo cleavage is also an important factor that correlates with blastocyst formation and pregnancy rates8,10–14. Yet, our understanding of the interplay between embryos’ morphology, viability, and maternal age is limited, as manual approaches to infer embryo morphokinetics are time-consuming, subjective, and prone to errors. Machine learning15–18 was recently harnessed to predict embryo developmental potential19,20, however, with limited success.Here, we develop an artificial intelligence (AI) platform that infers the embryos’ developmental stage and captures tens of morphological properties and developmental dynamics. We show that developmental timing is the most informative and predictive morphokinetic property, particularly for embryos from maternally aged females. Analyzing the timing distributions reveals that viable embryos are confined into an age-independent temporal corridor while non-viable embryos deviate from it towards slower transition times. Yet, the deviation of non-viable embryos from the temporal corridor is age-dependent. Furthermore, there is a significant correlation between consecutive developmental stages transition times that diminishes in maternally old embryos. Overall, our results suggest that maternally old embryos’ most apparent morphokinetic property is the loss of temporal regulation. Our results and platform pave the way for a more accurate, maternally-age-dependent, assisted reproductive technology.
Menin-MLL Inhibitor MI-503 Blocks Menin Nuclear Export and Suppresses Hypergastrinemia
Authors: Merchant Juanita L. , Wang Zhen , Sundaresan Sinju 
Published: May 2022

AbstractMenin is the protein product of the Multiple Endocrine Neoplasia 1 (MEN1) gene locus at 11q13 and is a known tumor suppressor of neuroendocrine neoplasms (NENs). Gastrin-expressing NENs (gastrinomas) comprise the most frequent and malignant of the MEN1-dependent endocrine tumors. When gastrinomas are part of the MEN1 syndrome, they exhibit a greater propensity to develop within the submucosal Brunner’s glands of the duodenum. Therefore, models to analyze the biology of these intestinal gastrin-expressing NENs should consider their submucosal location.AimThe goal of this study was to determine whether the Menin-MLL inhibitor MI-503 suppressed hypergastrinemia.MethodsA murine model of hypergastrinemia generated by omeprazole treatment of mice carrying a conditional deletion of Men1 bred onto a somatostatin null genetic background (OMS) was treated intraperitoneally with MI-503 for 1 month. Primary enteric glial cells were prepared from these OMS mice and were treated with increasing doses of MI-503. Similarly human AGS and mouse STC-1 gastrin producing cell lines were treated with EGF without or with MI-503.>ResultsWe found that the treatment reduced serum and gastro-duodenal tissue expression of gastrin. Ex vivo MI-503 treatment of glial fibrillary acidic protein (GFAP)+ enteric cells isolated from the OMS mice or gastrin-expressing cell lines revealed that MI-503 blocked the nuclear export of Menin and suppressed gastrin gene expression. RNA-Seq analysis of gastrin-treated GFAP+ enteric cells revealed that they express EGF receptor ligands and that EGF treatment of GFAP+ cells also induced Menin translocation and concurrent induction of gastrin gene expression.ConclusionWe concluded that MI-503 inhibits gastrin gene expression by blocking Menin translocation.
A structural basis for prion strain diversity
Authors: Manka Szymon W. , Wenborn Adam , Betts Jemma , Joiner Susan , Saibil Helen R. , Collinge John , Wadsworth Jonathan D.F. 
Published: May 2022

AbstractRecent cryo-EM studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a comparable, parallel in-register intermolecular β-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N- and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding how divergent prion strains emerge from an identical PrP substrate. Here, we determined the near-atomic resolution cryo-EM structure of infectious,ex vivomouse prion fibrils from the ME7 prion strain and have compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding sub-domains of PrP rungs and the way in which they are interrelated, providing the first structural definition of intra-species prion strain-specific conformations.
Dendritic cell Piezo1 integrating mechanical stiffness and inflammatory signals directs the differentiation of TH1 and Treg cells in cancer
Authors: Wang Yuexin , Yang Hui , Jia Anna , Wang Yufei , Yang Qiuli , Dong Yingjie , Bi Yujing , Liu Guangwei 
Published: May 2022

AbstractDendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the mechanical sensor Piezo1 expressed by DCs integrates innate inflammatory stimuli and stiffness signals and directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.
Rabphilin 3A binds the N-peptide of SNAP-25 to promote SNARE complex assembly in exocytosis
Authors: Li Tianzhi , Cheng Qiqi , Wang Shen , Ma Cong 
Published: May 2022

AbstractExocytosis of secretory vesicles requires the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and small GTPase Rabs. As a Rab3/Rab27 effector protein on secretory vesicles, Rabphilin 3A was implicated to interact with SNAP-25 to regulate vesicle exocytosis in neurons and neuroendocrine cells, yet the underlying mechanism remains unclear. In this study, we have characterized the physiologically relevant binding sites between Rabphilin 3A and SNAP-25. We found that an intramolecular interplay between the N-terminal Rab-binding domain and C-terminal C2AB domain enables Rabphilin 3A to strongly bind the SNAP-25 N-peptide region via its C2B bottom α-helix. Disruption of this interaction significantly impaired docking and fusion of vesicles with the plasma membrane in PC12 cells. In addition, we found that this interaction allows Rabphilin 3A to accelerate SNARE complex assembly. Furthermore, we revealed that this interaction accelerates SNARE complex assembly via inducing a conformational switch from random coils to α-helical structure in the SNAP-25 SNARE motif. Altogether, our data suggest that promotion of SNARE complex assembly by binding of the C2B bottom α-helix of Rabphilin 3A to the N-peptide of SNAP-25 underlies a pre-fusion function of Rabphilin 3A in vesicle exocytosis.
Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage
Authors: Bigelman Einat , Pasmanik-Chor Metsada , Dassa Bareket , Itkin Maxim , Malitsky Sergey , Dorot Orly , Pichinuk Edward , Levin-Zaidman Smadar , Dezorella Nili , Gross Atan , Abashidze Anastasia , Kleinberg Yuval , Keren Gad , Entin-Meer Michal 
Published: May 2022

AbstractBackgroundRenal injury induces major changes in plasma and cardiac metabolites. We sought to identify a key metabolite that may affect cardiac mitochondria following an acute kidney injury (AKI) that may be harnessed to protect the heart following an acute ischemic event.Methods and ResultsMetabolomics profiling of cardiac lysates and plasma samples derived from rats that underwent AKI 1 or 7 days earlier by 5/6 nephrectomy versus sham-operated controls was performed. We detected only 26 differential metabolites in both heart and plasma samples at the two selected time points, relative to sham. Out of which, kynurenic acid (kynurenate, KYNA) seemed most relevant. Interestingly, KYNA given at 10 mM concentration significantly rescued the viability of H9C2 cardiac myoblast cells grown under anoxic conditions and largely improved their mitochondrial structure and function as determined by flow cytometry and cell staining with MitoTracker dyes. Moreover, KYNA diluted in the drinking water of animals induced with an acute myocardial infarction, highly enhanced their cardiac recovery according to echocardiography and histopathology.Conclusion and translational aspectKYNA may represent a key metabolite absorbed by the heart following AKI. This metabolite can enhance cardiac cell viability following an ischemic event in a mechanism that is mediated, at least in part, by the protection of the cardiac mitochondria. A short-term administration of KYNA may be highly beneficial in the treatment of the acute phase of kidney disease in order to attenuate progression to CRS and in ischemic cardiac conditions to reduce ischemic myocardial damage.HighlightsThe levels of the L-Tryptophan-derived metabolite, Kynurenic acid (KYNA), are significantly elevated in the heart and the plasma of animals induced with an acute kidney disease.KYNA rescues the viability of cardiac cells from an ischemic damage both in vitro and in vivo.KYNA can protect the structure & function of cardiac mitochondria in H9C2 cardiomyoblast cells upon exposure to anoxia.Graphical abstract