bluuebunny/crossref_metadata_2025_split huggingface dataset:
The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism
Authors: Zhu Ke-Gan , Yang Jiayu , Zhu Yuehong , Zhu Qihang , Pan Wen , Deng Siyu , He Yi , Zuo Duo , Wang Peiyun , Han Yueting , Zhang Hai-Yang 
Published: October 2023

AbstractLymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.
AMPK-induced novel phosphorylation of RUNX1 inhibits STAT3 activation and overcome imatinib resistance in chronic myelogenous leukemia (CML) subjects
Authors: Gayatri Meher Bolisetti , Kancha Rama Krishna , Behera Abhayananda , Patchva Dorababu , Velugonda Nagaraj , Gundeti Sadasivudu , Reddy Aramati Bindu Madhava 
Published: October 2023

AbstractImatinib resistance remains an unresolved problem in CML disease. Activation of JAK2/STAT3 pathway and increased expression of RUNX1 have become one reason for development of imatinib resistance in CML subjects. Metformin has gained attention as an antileukemic drug in recent times. However, the molecular mechanism remains elusive. The present study shows that RUNX1 is a novel substrate of AMP-activated kinase (AMPK), where AMPK phosphorylates RUNX1 at Ser 94 position. Activation of AMPK by metformin could lead to increased cytoplasmic retention of RUNX1 due to Ser 94 phosphorylation. RUNX1 Ser 94 phosphorylation resulted in increased interaction with STAT3, which was reflected in reduced transcriptional activity of both RUNX1 and STAT3 due to their cytoplasmic retention. The reduced transcriptional activity of STAT3 and RUNX1 resulted in the down-regulation of their signaling targets involved in proliferation and anti-apoptosis. Our cell proliferation assays using in vitro resistant cell line models and PBMCs isolated from CML clinical patients and normal subjects demonstrate that metformin treatment resulted in reduced growth and improved imatinib sensitivity of resistant subjects.
GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal
Authors: Senftleber Ninna Karsbæk , Andersen Mette K. , Jørsboe Emil , Stæger Frederik Filip , Nøhr Anne Krogh , Garcia-Erill Genis , Meisner Jonas , Santander Cindy G. , Balboa Renzo F. , Gilly Arthur , Bjerregaard Peter , Larsen Christina Viskum Lytken , Grarup Niels , Jørgensen Marit Eika , Zeggini Eleftheria , Moltke Ida , Hansen Torben , Albrechtsen Anders 
Published: October 2023

AbstractPerturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (βSD(SE) = −0.22 (0.03), p = 6.5 × 10−12) and total cholesterol (−0.17 (0.03), p = 1.1 × 10−8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance.
An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1
Authors: Zhou Yandong , Jennette Michelle R. , Ma Guolin , Kazzaz Sarah A. , Baraniak James H. , Nwokonko Robert M. , Groff Mallary L. , Velasquez-Reynel Marcela , Huang Yun , Wang Youjun , Gill Donald L. 
Published: October 2023

AbstractCa2+ signal-generation through inter-membrane junctional coupling between endoplasmic reticulum (ER) STIM proteins and plasma membrane (PM) Orai channels, remains a vital but undefined mechanism. We identify two unusual overlapping Phe-His aromatic pairs within the STIM1 apical helix, one of which (F394-H398) mediates important control over Orai1-STIM1 coupling. In resting STIM1, this locus is deeply clamped within the folded STIM1-CC1 helices, likely near to the ER surface. The clamped environment in holo-STIM1 is critical—positive charge replacing Phe-394 constitutively unclamps STIM1, mimicking store-depletion, negative charge irreversibly locks the clamped-state. In store-activated, unclamped STIM1, Phe-394 mediates binding to the Orai1 channel, but His-398 is indispensable for transducing STIM1-binding into Orai1 channel-gating, and is spatially aligned with Phe-394 in the exposed Sα2 helical apex. Thus, the Phe-His locus traverses between ER and PM surfaces and is decisive in the two critical STIM1 functions—unclamping to activate STIM1, and conformational-coupling to gate the Orai1 channel.
A tautomerized ligand enabled meta selective C–H borylation of phenol
Authors: Guria Saikat , Hassan Mirja Md Mahamudul , Ma Jiawei , Dey Sayan , Liang Yong , Chattopadhyay Buddhadeb 
Published: October 2023

AbstractRemote meta selective C–H functionalization of aromatic compounds remains a challenging problem in chemical synthesis. Here, we report an iridium catalyst bearing a bidentate pyridine-pyridone (PY-PYRI) ligand framework that efficiently catalyzes this meta selective borylation reaction. We demonstrate that the developed concept can be employed to introduce a boron functionality at the remote meta position of phenols, phenol containing bioactive and drug molecules, which was an extraordinary challenge. Moreover, we have demonstrated that the method can also be applied for the remote C6 borylation of indole derivatives including tryptophan that was the key synthetic precursor for the total synthesis of Verruculogen and Fumitremorgin A alkaloids. The inspiration of this catalytic concept was started from the O–Si secondary interaction, which by means of several more detailed control experiments and detailed computational investigations revealed that an unprecedented Bpin shift occurs during the transformation of iridium bis(boryl) complex to iridium tris(boryl) complex, which eventually control the remote meta selectivity by means of the dispersion between the designed ligand and steering silane group.
Nanobody-based VSR7 tracing shows clathrin-dependent TGN to Golgi recycling
Authors: Shao Xiaoyu , Xu Hao , Pimpl Peter 
Published: October 2023

AbstractReceptor-mediated transport of soluble proteins is nature’s key to empowering eukaryotic cells to access a plethora of macromolecules, either by direct accumulation or as products from resulting biochemical pathways. The transport efficiency of these mechanisms results from the receptor’s capability to capture, transport, and release ligands on the one hand and the cycling ability that allows for performing multiple rounds of ligand transport on the other. However, the plant VACUOLAR SORTING RECEPTOR (VSR) protein family is diverse, and their ligand-specificity and bidirectional trafficking routes and transport mechanisms remain highly controversial. Here we employ nanobody-epitope interaction-based molecular tools to assess the function of the VSR 7 in vivo. We demonstrate the specificity of the VSR7 for sequence-specific vacuolar sorting signals, and we trace its anterograde transport and retrograde recycling route. VSR7 localizes at the cis-Golgi apparatus at steady state conditions and transports ligands downstream to release them in the trans-Golgi network/early endosome (TGN/EE) before undergoing clathrin-dependent recycling from the TGN/EE back to the cis-Golgi.
Large interlayer Dzyaloshinskii-Moriya interactions across Ag-layers
Authors: Arregi Jon Ander , Riego Patricia , Berger Andreas , Vedmedenko Elena Y. 
Published: October 2023

AbstractSeeking to enhance the strength of the interlayer Dzyaloshinskii-Moriya interaction (IL-DMI) through a combination of atomic and Rashba type spin-orbit coupling (SOC) we studied the strength and the thickness evolution of effective interlayer coupling in Co/Ag/Co trilayers by means of surface sensitive magneto-optical measurements that take advantage of the light penetration depth. Here, we report the observation of oscillatory, thickness-dependent chiral interaction between ferromagnetic layers. Despite the weakness of the Ag atomic SOC, the IL-DMI in our trilayers is orders of magnitude larger than that of known systems using heavy metals as a spacer except of recently reported −0.15 mJ/m2 in Co/Pt/Ru(t)/Pt/Co and varies between ≈ ±0.2 mJ/m2. In contrast to known multilayers Co/Ag/Co promotes in-plane chirality between magnetic layers. The strength of IL-DMI opens up new routes for design of three-dimensional chiral spin structures combining intra- and interlayer DMI and paves the way for enhancements of the DMI strength.
Increasing atmospheric dryness reduces boreal forest tree growth
Authors: Mirabel Ariane , Girardin Martin P. , Metsaranta Juha , Way Danielle , Reich Peter B. 
Published: October 2023

AbstractRising atmospheric vapour pressure deficit (VPD) associated with climate change affects boreal forest growth via stomatal closure and soil dryness. However, the relationship between VPD and forest growth depends on the climatic context. Here we assess Canadian boreal forest responses to VPD changes from 1951-2018 using a well-replicated tree-growth increment network with approximately 5,000 species-site combinations. Of the 3,559 successful growth models, we observed a relationship between growth and concurrent summer VPD in one-third of the species-site combinations, and between growth and prior summer VPD in almost half of those combinations. The relationship between previous year VPD and current year growth was almost exclusively negative, while current year VPD also tended to reduce growth. Tree species, age, annual temperature, and soil moisture primarily determined tree VPD responses. Younger trees and species like white spruce and Douglas fir exhibited higher VPD sensitivity, as did areas with high annual temperature and low soil moisture. Since 1951, summer VPD increases in Canada have paralleled tree growth decreases, particularly in spruce species. Accelerating atmospheric dryness in the decades ahead will impair carbon storage and societal-economic services.
DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Authors: Yepuri Gautham , Ramirez Lisa M. , Theophall Gregory G. , Reverdatto Sergei V. , Quadri Nosirudeen , Hasan Syed Nurul , Bu Lei , Thiagarajan Devi , Wilson Robin , Díez Raquel López , Gugger Paul F. , Mangar Kaamashri , Narula Navneet , Katz Stuart D. , Zhou Boyan , Li Huilin , Stotland Aleksandr B. , Gottlieb Roberta A. , Schmidt Ann Marie , Shekhtman Alexander , Ramasamy Ravichandran 
Published: October 2023

AbstractInter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits ofDIAPH1silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
A canonical trajectory of executive function maturation from adolescence to adulthood
Authors: Tervo-Clemmens Brenden , Calabro Finnegan J. , Parr Ashley C. , Fedor Jennifer , Foran William , Luna Beatriz 
Published: October 2023

AbstractTheories of human neurobehavioral development suggest executive functions mature from childhood through adolescence, underlying adolescent risk-taking and the emergence of psychopathology. Investigations with relatively small datasets or narrow subsets of measures have identified general executive function development, but the specific maturational timing and independence of potential executive function subcomponents remain unknown. Integrating four independent datasets (N = 10,766; 8–35 years old) with twenty-three measures from seventeen tasks, we provide a precise charting, multi-assessment investigation, and replication of executive function development from adolescence to adulthood. Across assessments and datasets, executive functions follow a canonical non-linear trajectory, with rapid and statistically significant development in late childhood to mid-adolescence (10–15 years old), before stabilizing to adult-levels in late adolescence (18–20 years old). Age effects are well captured by domain-general processes that generate reproducible developmental templates across assessments and datasets. Results provide a canonical trajectory of executive function maturation that demarcates the boundaries of adolescence and can be integrated into future studies.
Isoform-resolved transcriptome of the human preimplantation embryo
Authors: Torre Denis , Francoeur Nancy J. , Kalma Yael , Gross Carmel Ilana , Melo Betsaida S. , Deikus Gintaras , Allette Kimaada , Flohr Ron , Fridrikh Maya , Vlachos Konstantinos , Madrid Kent , Shah Hardik , Wang Ying-Chih , Sridhar Shwetha H. , Smith Melissa L. , Eliyahu Efrat , Azem Foad , Amir Hadar , Mayshar Yoav , Marazzi Ivan , Guccione Ernesto , Schadt Eric , Ben-Yosef Dalit , Sebra Robert 
Published: October 2023

AbstractHuman preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.
eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Authors: Nguyen Jennifer P. , Arthur Timothy D. , Fujita Kyohei , Salgado Bianca M. , Donovan Margaret K. R. ,   iPSCORE Consortium, Aguiar Lana Ribeiro , Arias Angelo D. , Benaglio Paola , Berggren W. Travis , Belmonte Juan Carlos Izpisua , Borja Victor , Cook Megan , DeBoever Christopher , Diffenderfer Kenneth E. , Farnam KathyJean , Garcia Melvin , Harismendy Olivier , Henson Benjamin A. , Jakubosky David , Jepsen Kristen , Li He , Nariai Naoki , O’Connor Daniel T. , Okubo Jonathan , Panopoulos Athanasia D. , Rao Fengwen , Reyna Joaquin , Silva Nayara , Smith Erin N. , Sohmer Josh , Yost Shawn , Young Greenwald William. W. , Matsui Hiroko , Kim Ji Hyun , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A. 
Published: October 2023

AbstractThe impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation
Authors: Chen Hongxia , Zhao Xi , Yang Wei , Zhang Qi , Hao Rongjiao , Jiang Siao , Han Huihui , Yu Zuyin , Xing Shuang , Feng Changjiang , Wang Qianqian , Lu Hao , Li Yuanfeng , Quan Cheng , Lu Yiming , Zhou Gangqiao 
Published: October 2023

AbstractRadiation triage and biological dosimetry are critical for the medical management of massive potentially exposed individuals following radiological accidents. Here, we performed a genome-wide screening of radiation-responding mRNAs, whose N6-methyladenosine (m6A) levels showed significant alteration after acute irradiation. The m6A levels of three genes, Ncoa4, Ate1 and Fgf22, in peripheral blood mononuclear cells (PBMCs) of mice showed excellent dose-response relationships and could serve as biomarkers of radiation exposure. Especially, the RNA m6A of Ncoa4 maintained a high level as long as 28 days after irradiation. We demonstrated its responsive specificity to radiation, conservation across the mice, monkeys and humans, and the dose-response relationship in PBMCs from cancer patients receiving radiation therapy. Finally, NOCA4 m6A-based biodosimetric models were constructed for estimating absorbed radiation doses in mice or humans. Collectively, this study demonstrated the potential feasibility of RNA m6A in radiation accidents management and clinical applications.
Origin of fungal hybrids with pathogenic potential from warm seawater environments
Authors: del Olmo Valentina , Mixão Verónica , Fotedar Rashmi , Saus Ester , Al Malki Amina , Księżopolska Ewa , Nunez-Rodriguez Juan Carlos , Boekhout Teun , Gabaldón Toni 
Published: October 2023

AbstractHybridisation is a common event in yeasts often leading to genomic variability and adaptation. The yeast Candida orthopsilosis is a human-associated opportunistic pathogen belonging to the Candida parapsilosis species complex. Most C. orthopsilosis clinical isolates are hybrids resulting from at least four independent crosses between two parental lineages, of which only one has been identified. The rare presence or total absence of parentals amongst clinical isolates is hypothesised to be a consequence of a reduced pathogenicity with respect to their hybrids. Here, we sequence and analyse the genomes of environmental C. orthopsilosis strains isolated from warm marine ecosystems. We find that a majority of environmental isolates are hybrids, phylogenetically closely related to hybrid clinical isolates. Furthermore, we identify the missing parental lineage, thus providing a more complete overview of the genomic evolution of this species. Additionally, we discover phenotypic differences between the two parental lineages, as well as between parents and hybrids, under conditions relevant for pathogenesis. Our results suggest a marine origin of C. orthopsilosis hybrids, with intrinsic pathogenic potential, and pave the way to identify pre-existing environmental adaptations that rendered hybrids more prone than parental lineages to colonise and infect the mammalian host.
Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Authors: Åkesson Julia , Hojjati Sara , Hellberg Sandra , Raffetseder Johanna , Khademi Mohsen , Rynkowski Robert , Kockum Ingrid , Altafini Claudio , Lubovac-Pilav Zelmina , Mellergård Johan , Jenmalm Maria C. , Piehl Fredrik , Olsson Tomas , Ernerudh Jan , Gustafsson Mika 
Published: October 2023

AbstractSensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.