bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of p38 activation in T cells increases IL-35 production and protects against obesity by promoting thermogenesis
Authors: Nikolic Ivana , Ruiz-Garrido Irene , Crespo María , Romero-Becerra Rafael , Leiva-Vega Luis , Mora Alfonso , León Marta , Rodríguez Elena , Leiva Magdalena , Plata-Gómez Ana Belén , Alvarez Maria Beatriz , Torres Jorge L. , Hernández-Cosido Lourdes , López Juan Antonio , Vázquez Jesús , Efeyan Alejo , Martin Pilar , Marcos Miguel , Sabio Guadalupe 
Published: August 2023

AbstractObesity is characterized with low grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis has not been well established. We discovered that p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specific deletion of the p38 activators, MKK3/6, were protected against diet-induced obesity and AT inflammation improving their metabolic profile, higher browning and thermogenesis. We identified IL-35 as a driver of adipocyte thermogenic program through ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+T cell infiltration and inflammation in AT. Interestingly, we found that IL35 was reduced in visceral fat from obese patients. Mechanistically we showed that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function and identify p38 and IL-35 as promising targets for metabolic diseases.
Tumor cell-derived lactic acid inhibits the interaction of PD-L1 protein and PD-L1 antibody in the PD-L1/PD-1 blockade therapy-resistant tumor
Authors: Oh Wonkyung , Kim Alyssa Min Jung , Dhawan Deepika , Knapp Deborah W , Lim Seung-Oe 
Published: August 2023

ABSTRACTImmune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.
Allergic inflammation triggers dyslipidemia via IgG signalling
Authors: Fernández-Gallego Nieves , Castillo-González Raquel , Moreno-Serna Lucía , García-Cívico Antonio J. , Sánchez-Martínez Elisa , López-Sanz Celia , Fontes Ana Luiza , Pimentel Lígia L. , Gradillas Ana , Obeso David , Neuhaus René , Ramírez-Huesca Marta , Ruiz-Fernández Ignacio , Nuñez-Borque Emilio , Carrasco Yolanda R. , Ibáñez Borja , Martín Pilar , Blanco Carlos , Barbas Coral , Barber Domingo , Rodríguez-Alcalá Luis M. , Villaseñor Alma , Esteban Vanesa , Sánchez-Madrid Francisco , Jiménez-Saiz Rodrigo 
Published: August 2023

ABSTRACTBackgroundAllergic diseases begin early in life and are often chronic, thus creating an inflammatory environment that may precede or exacerbate other pathologies. In this regard, allergy has been associated to metabolic disorders and with a higher risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood.MethodsWe used a murine model of allergy and atherosclerosis, different diets and sensitization methods, and cell-depleting strategies to ascertain the contribution of acute and late phase inflammation to dyslipidemia. Untargeted lipidomic analyses were applied to define the lipid fingerprint of allergic inflammation at different phases of allergic pathology. Expression of genes related to lipid metabolism was assessed in liver and adipose tissue at different times post-allergen challenge. Also, changes in serum triglycerides (TG) were evaluated in a group of 59 patients ≥14 days after the onset of an allergic reaction.ResultsWe found that allergic inflammation induces a unique lipid signature that is characterized by increased serum TG and changes in the expression of genes related to lipid metabolism in liver and adipose tissue. Alterations in blood TGs following an allergic reaction are independent of T-cell-driven late phase inflammation. On the contrary, the IgG-mediated alternative pathway of anaphylaxis is sufficient to induce a TG increase and a unique lipid profile. Lastly, we demonstrated an increase in serum TG in 59 patients after undergoing an allergic reaction.ConclusionOverall, this study reveals that IgG-mediated allergic inflammation regulates lipid metabolism.
Engineering the highly productive cyanobacteriumSynechococcussp. PCC 11901
Authors: Victoria Angelo J. , Selão Tiago Toscano , Moreno-Cabezuelo José Ángel , Mills Lauren A. , Gale Grant A. R. , Lea-Smith David J. , McCormick Alistair J. 
Published: August 2023

ABSTRACTSynechococcussp. PCC 11901 (PCC 11901) is a fast-growing marine cyanobacterial strain that has a capacity for sustained biomass accumulation to very high cell densities, comparable to that achieved by commercially relevant heterotrophic organisms. However, genetic tools to engineer PCC 11901 for biotechnology applications are limited. Here we describe a suite of tools based on the CyanoGate MoClo system to unlock the engineering potential of PCC 11901. First, we characterised neutral sites suitable for stable genomic integration that do not affect growth even at high cell densities. Second, we tested a suite of constitutive promoters, terminators, and inducible promoters including a 2,4-diacetylphloroglucinol (DAPG)-inducible PhlF repressor system, which has not previously been demonstrated in cyanobacteria and showed tight regulation and a 228-fold dynamic range of induction. Lastly, we developed a DAPG-inducible dCas9-based CRISPR interference (CRISPRi) system and a modular method to generate markerless mutants using CRISPR-Cas12a. Based on our findings, PCC 11901 is highly responsive to CRISPRi-based repression and showed high efficiencies for single insertion (31-81%) and multiplex double insertion (25%) genome editing with Cas12a. We envision that these tools will lay the foundations for the adoption of PCC 11901 as a robust model strain for engineering biology and green biotechnology.On sentence summaryGenetic parts were characterised inSynechococcussp. PCC 11901, including a tightly regulated inducible promoter system, efficient CRISPRi and a novel markerless Cas12a genome editing approach.
Loss of Polycomb Repressive Complex 2 function causes asparaginase resistance in T-acute lymphoblastic leukemia through decreased WNT pathway activity
Authors: Lefeivre Thomas , Tudose Cosmin , Grosu Theodora-Ioana , Jones Luke , León Theresa E. , Wynne Kieran , Oliviero Giorgio , Smith Owen P. , Trinquand Amélie , Mansour Marc R. , Ryan Colm J. , Bond Jonathan 
Published: August 2023

AbstractLoss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor prognosis and treatment resistance in T-acute lymphoblastic leukemia (T-ALL). We leveraged clinical mutational and transcriptional data to identify a functional link between PRC2 alterations and changes in WNT signaling pathway activity in leukemia cells. Computational integration of transcriptomic, proteomic and phosphoproteomic data from an isogenic T-ALL cellular model revealed reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in cells lacking core PRC2 factor EZH2. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels that bolstered leukemia cell asparagine reserves. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a novel and clinically tractable means to tackle induction treatment failure in high-risk T-ALL.
A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma
Authors: Achom Mingkee , Sadagopan Ananthan , Bao Chunyang , McBride Fiona , Xu Qingru , Konda Prathyusha , Tourdot Richard W. , Li Jiao , Nakhoul Maria , Gallant Daniel S. , Ahmed Usman Ali , O’Toole Jillian , Freeman Dory , Lee Gwo-Shu Mary , Hecht Jonathan L. , Kauffman Eric C. , Einstein David J , Choueiri Toni K. , Zhang Cheng-Zhong , Viswanathan Srinivas R. 
Published: August 2023

AbstractXp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between theTFE3gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlieTFE3fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenicTFE3fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show thatTFE3fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio inTFE3fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.
FLN-2 functions in parallel to LINC complexes and Cdc42/actin pathways during P-cell nuclear migration through constricted spaces inCaenorhabditis elegans
Authors: Ma Linda , Kuhn Jonathan , Chang Yu-Tai , Elnatan Daniel , Luxton G.W. Gant , Starr Daniel A. 
Published: August 2023

AbstractNuclear migration through narrow constrictions is important for development, metastasis, and pro-inflammatory responses. Studies performed in tissue culture cells have implicated LINC (linker of nucleoskeleton and cytoskeleton) complexes, microtubule motors, the actin cytoskeleton, and nuclear envelope repair machinery as important mediators of nuclear movements through constricted spaces. However, little is understood about how these mechanisms operate to move nucleiin vivo. InC. eleganslarvae, 6 pairs of hypodermal P cells migrate from lateral to ventral positions through a constricted space between the body wall muscles and the cuticle. P-cell nuclear migration is mediated in part by LINC complexes using a microtubule-based pathway and by an independent CDC-42/actin-based pathway. However, when both LINC complex and actin-based pathways are knocked out, many nuclei still migrate, suggesting the existence of additional pathways. Here we show that FLN-2 functions in a third pathway to mediate P-cell nuclear migration. The predicted N-terminal actin binding domain in FLN-2 that is found in canonical filamins is dispensable for FLN-2 function, this and structural predictions suggest that FLN-2 is not a divergent filamin. The immunoglobulin (Ig)-like repeats 4-8 of FLN-2 were necessary for P-cell nuclear migration. Furthermore, in the absence of the LINC complex componentunc-84,fln-2mutants had an increase in P-cell nuclear rupture. We conclude that FLN-2 functions to maintain the integrity of the nuclear envelope in parallel with the LINC complex and CDC-42/actin-based pathways to move P-cell nuclei through constricted spaces.
Monarch butterflyCryptochrome 1loss-of-function mutants reveal differences in light entrainment of 24-hour behavioral rhythms in insects
Authors: Iiams Samantha E. , Wan Guijun , Zhang Jiwei , Lugena Aldrin B. , Zhang Ying , Hayden Ashley N. , Merlin Christine 
Published: August 2023

SUMMARYLight is one of the strongest cues for entrainment of circadian clocks in most organisms. Previous work inDrosophila melanogaster(dm) has shown that entrainment relies on both the visual system and the circadian, blue-light photoreceptor Cryptochrome (dmCRY). Here, we used the monarch butterflyDanaus plexippus(dp) to test conservation of this mechanism among insects and the relative importance of monarchCryptochrome 1(dpCry1) in the entrainment of its clockin vivo. We showed that loss of functionaldpCry1abolishes adult circadian eclosion behavior and molecular circadian rhythms in the monarch brain. These rhythms can be restored by entrainment to temperature cycles, demonstrating that the core circadian clock is intact indpCry1mutants. Importantly, we showed that rhythmic flight activity is also disrupted indpCry1mutants but not in the visually impaireddpNinaB1mutants, suggesting that unlikeDrosophilalight-entrainment of the monarch circadian clock relies solely on dpCRY1 photoreception.
Characterization and contribution of RPE senescence to Age-related macular degeneration inTnfrsf10knock out mice
Authors: Wada Iori , Mori Kenichiro , Sreekumar Parameswaran G , Ji Rui , Spee Christine , Hong Elise , Ishikawa Keijiro , Sonoda Koh-Hei , Kannan Ram 
Published: August 2023

AbstractBackgroundRetinal pigment epithelial cells (RPE) play vital role in the pathogenesis of age-related macular degeneration (AMD). Our laboratory has shown that RPE cellular senescence contributed to the pathophysiology of experimental AMD, and SASP members are involved in this process. Recently, we presented confirmatory evidence to earlier GWAS studies that dysregulation of tumor necrosis factor receptor superfamily 10A (TNFRSF10A) dysregulation leads to AMD development and is linked to RPE dysfunction. This study aims to investigate the contribution of RPE senescence to AMD pathophysiology usingTNFRSF10Asilenced human RPE (hRPE) cells and Tnfrsf10 KO mice.MethodsSub-confluent primary hRPE cells andTNFRSF10Asilenced hRPE were exposed to stress-induced premature senescence with H2O2 (500 μM, 48h), and senescence-associated markers (βgal, p16, and p21) were analyzed by RT-PCR and WB analysis. The effect of H2O2-induced senescence in non-silenced and silenced hRPE on OXPHOS and glycolysis was determined using Seahorse XF96 analyzer. Male C57BL/6J Tnfrsf10 KO (Tnfrsf10-/-) mice were used to study the regulation of senescence by TNFRSF10Ain vivo. Expression of p16 and p21 in control and KO mice of varying ages were determined by RT-PCR, WB, and immunostaining analysis.ResultsThe senescence-associated p16 and p21 showed a significant (p< 0.01) upregulation with H2O2 induction at the gene (1.8- and 3-fold) and protein (3.2- and 4-fold) levels in hRPE cells. The protein expression of p16 and p21 was further significantly increased by co-treatment with siRNA (p< 0.05 vs. H2O2). Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) (pmol/min/total DNA) increased with senescence induction by H2O2 for 48h in control RPE, and knockdown ofTNFRSF10Acaused a further increase in OCR and ECAR. In addition, co-treatment with PKC activator significantly improved all parameters. Similarly,in vivostudies showed upregulation of p16 and p21 by RT-PCR, WB, and immunostaining analysis in RPE/choroid of Tnfrsf10 KO mice. When subjected to examination across distinct age groups, namely young (1-3 months), middle (6-9 months), and old (12-15 months) mice, a discernible age-related elevation in the expression of p16 and p21 was observed.ConclusionsOur findings suggest that TNRSF10A is a regulator of regulates in RPE senescence. Further work on elucidating pathways of senescence will facilitate the development of new therapeutic targets for AMD.
A genome-wide cytotoxicity screen of Cluster F1 mycobacteriophage Girr reveals novel inhibitors ofMycobacterium smegmatisgrowth
Authors: Pollenz Richard S , Barnhill Kaylee , Biggs Abbigail , Bland Jackson , Carter Victoria , Chase Michael , Clark Hayley , Coleman Caitlyn , Daffner Marshall , Deam Caitlyn , Finocchiaro Alyssa , Franco Vanessa , Fuller Thomas , Pinera Juan Gallardo , Horne Mae , Howard Zoe , Kanahan Olivia , Miklaszewski Christopher , Miller Sydney , Morgan Ryan , Onalaja Oluwatobi , Otero Louis , Padhye Shivani , Rainey Emily , Rasul Fareed , Rodier Alexandra , Schlosser Sydni , Sciacchitano Ava , Stewart Emma , Thakkar Rajvi , Heller Danielle 
Published: August 2023

AbstractOver the past decade, thousands of bacteriophage genomes have been sequenced and annotated. A striking observation from this work is that known structural features and functions cannot be assigned for >65% of the encoded proteins. One approach to begin experimentally elucidating the function of these uncharacterized gene products is genome-wide screening to identify phage genes that confer phenotypes of interest like inhibition of host growth. This study describes the results of a screen evaluating the effects of overexpressing each gene encoded by the temperate Cluster F1 mycobacteriophage Girr on the growth of the host bacteriumMycobacterium smegmatis. Overexpression of 29 of the 102 Girr genes (∼28% of the genome) resulted in mild to severe cytotoxicity. Of the 29 toxic genes described, 12 have no known function (NKF) and are predominately small proteins of <125 amino acids. Overexpression of the majority of these 12 cytotoxic NKF proteins resulted in moderate to severe growth reduction and represent novel antimicrobial products. The remaining 17 toxic genes have predicted functions, encoding products involved in phage structure, DNA replication/modification, DNA binding/gene regulation, or other enzymatic activity. Comparison of this dataset with prior genome-wide cytotoxicity screens of mycobacteriophages Waterfoul and Hammy reveals some common functional themes, though several of the predicted Girr functions associated with cytotoxicity in our report, including genes involved in lysogeny, have not been described previously. This study, completed as part of the HHMI-supported SEA-GENES project, highlights the power of parallel, genome-wide overexpression screens to identify novel interactions between phages and their hosts.
MEK inhibition enhances the antitumor effect of radiation therapy inNF1-deficient glioblastoma
Authors: Ioannou Maria , Lalwani Kriti , Ayanlaja Abiola A. , Chinnasamy Viveka , Pratilas Christine A. , Schreck Karisa C. 
Published: August 2023

AbstractIndividuals with neurofibromatosis type 1 (NF-1), an autosomal dominant neurogenetic and tumor predisposition syndrome, are susceptible to developing low-grade glioma (LGG) and, less commonly, high-grade glioma (HGG). These gliomas exhibit loss of the neurofibromin gene (NF1), and 10-15% of sporadic HGG have somaticNF1alterations. Loss of NF1 leads to hyperactive RAS signaling, creating opportunity given the established efficacy of MEK inhibitors (MEKi) in plexiform neurofibromas and some individuals with LGG. We observed thatNF1-deficient glioblastoma neurospheres were sensitive to the combination of a MEKi (mirdametinib) with irradiation, as evidenced by synergistic inhibition of cell growth, colony formation, and increased cell death. In contrast,NF1-intact neurospheres were not sensitive to the combination, despite complete ERK pathway inhibition. No neurosphere lines exhibited enhanced sensitivity to temozolomide combined with mirdametinib. Mirdametinib decreased transcription of homologous recombination genes and RAD51 foci, associated with DNA damage repair, in sensitive models. Heterotopic xenograft models displayed synergistic growth inhibition to mirdametinib combined with irradiation inNF1-deficient glioma xenografts, but not those with intactNF1. In sensitive models, benefits were observed at least three weeks beyond the completion of treatment, including sustained phospho-ERK inhibition on immunoblot and decreased Ki-67 expression. These observations demonstrate synergistic activity between mirdametinib and irradiation inNF1-deficient glioma models and may have clinical implications for patients with gliomas that harbor germline or somaticNF1alterations.
Colchicine inhibited oxidative stress-induced endothelial cell senescence via blocking NF-κB and MAPKs: Implications in vascular diseases
Authors: Zhou Huakang , Khan Dilaware , Hussain Sajid Muhammad , Gerdes Norbert , Hagenbeck Carsten , Rana Majeed , Cornelius Jan Frederick , Muhammad Sajjad 
Published: August 2023

AbstractSmoking, alcohol abuse, and hypertension are – among others the potential risk factors for cardiovascular diseases. These risk factors generate oxidative stress and cause oxidative stress-induced DNA damage, resulting in cellular senescence and senescence-associated secretory phenotype (SASP). The SASP factors in feed-forward response exacerbate inflammation and cause tissue remodeling, resulting in atherosclerotic plaque formation and rupture. Colchicine was used to ameliorate oxidative stress-induced senescence in human umbilical vein endothelial cells. Oxidative stress was quantified by reactive oxygen species (ROS) assay and oxidative stress-induced DNA damage was analyzed by 8-OHDG immunofluorescence staining. Endothelial cell senescence was visualized by β-gal staining. The relative mRNA expression was quantified by qPCR and protein analysis was performed by Western blot. Colchicine inhibited ROS generation and mitigated oxidative stress-induced DNA damage. It dampened oxidative stress-induced endothelial cell senescence and improved the expression of DNA repair protein KU80 and aging marker Lamin B1. The drug attenuated the expression of senescence marker P21 at mRNA and protein levels. The pathway analysis showed that colchicine inhibited NF-κB and MAPKs pathways and subdued mTOR activation. Colchicine also attenuated mRNA expression of interleukin (IL)-1β, IL-6, IL-8 MCP-1, ICAM-1, and E-selectin. Furthermore, colchicine reduced the mRNA and protein expression of matrix metalloproteinase (MMP-2). In summary, colchicine blocked oxidative stress-induced senescence and SASP by inhibiting the activation of NF-κB and MAPKs pathways.