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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through mYC degradation

Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.mello metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm morrsey Sanjoy mehta Jesse Barnes michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia molina-Pinelo Sohrab Salehi Helena A.Yu Joseph m.Chan charles m.rudin Department of medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility memorial Sloan Kettering Cancer Center New YorkNYUSA Department of Laboratory medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell medical College New York NYUSA Present address:Swiss Institute for Experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the mYC Proto-Oncogen(mYC),implicated in stemness and histological *** overexpression of a degradation-resistant mYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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Integrated Single-cell multiomic Analysis of HIV Latency Reversal Reveals Novel Regulators of Viral Reactivation

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Genomics, Proteomics & Bioinformatics 2024年第1期22卷 67-88页

作者： manickam Ashokkumar Wenwen mei Jackson J.Peterson Yuriko Harigaya David m.murdoch David m.margolis Caleb Kornfein Alex Oesterling Zhicheng Guo Cynthia D.rudin Yuchao Jiang Edward P.Browne Department of medicine University of North Carolina at Chapel HillChapel HillNC 27599USA HIV Cure Center University of North Carolina at Chapel HillChapel HillNC 27599USA Department of Biostatistics University of North Carolina at Chapel HillChapel HillNC 27599USA Department of microbiology and Immunology University of North Carolina at Chapel HillChapel HillNC 27599USA Department of Genetics University of North Carolina at Chapel HillChapel HillNC 27599USA Department of medicine Duke UniversityDurhamNC 27708USA Department of Computer Science Duke UniversityDurhamNC 27708USA Department of Statistics Texas A&M UniversityCollege StationTX 77843USA Department of Biology Texas A&M UniversityCollege StationTX 77843USA Department of Biomedical Engineering Texas A&M UniversityCollege StationTX 77843USA

Despite the success of antiretroviral therapy,human immunodeficiency virus(HIV)cannot be cured because of a reservoir of latently infected cells that evades *** understand the mechanisms of HIV latency,we employed an integrated single-cell RNA sequencing(scRNA-seq)and single-cell assay for transposase-accessible chromatin with sequencing(scATAC-seq)approach to simultaneously profile the transcriptomic and epigenomic characteristics of~125,000 latently infected primary CD4^(+)T cells after reactivation using three different latency reversing *** expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor(TF)activities across the cell *** identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%-79%accurate at predicting viral ***,we validated the role of two candidate HIV-regulating factors,FOXP1 and GATA3,in viral *** data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.

关键词： HIV latency reversal Primary CD4þT cell Single-cell multiomics HIV-regulating factor machine learning

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Three-year field study on grass growth and soil hydrological properties in biochar-amended soil

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Journal of Rock mechanics and Geotechnical Engineering 2024年第7期16卷 2764-2774页

作者： Haowen Guo charles Wang Wai Ng Junjun Ni Qi Zhang Yuchen Wang Department of Civil and Environmental Engineering The Hong Kong University of Science and TechnologyHong KongChina School of Transportation Southeast UniversityNanjingChina

Field monitoring was conducted to investigate and quantify the long-term effects of peanut shell biochar on soil-grass interaction over three *** 10 m5 m grassed plots were constructed in completely decomposed granitic *** of them were amended,respectively,with 5%and 10%biochar contents(m^(3)/m^(3))for grass growth,while the third was without biochar *** the threeyear monitoring,plant characteristics,saturated water permeability(k_(s))of grassed soil and soil suction were *** monitored results show that the grass leaf area index(LAI)and root length density(RLD)with biochar amendment were improved by 38%and 200%,*** the grassed plot without biochar,a threshold RLD existed with a value of 1.7 cm/cm^(3),beyond which k_(s) raised *** threshold RLD increased by 52%when biochar content increased from 0%to 10%.This implies that biochar may restrict the increase in k_(s) of grassed soil due to the rise in the threshold *** presence of biochar and grass can retain over 100%higher suction after heavy rainfalls,while 54%lower peak suction under evapotranspiration(ET)compared with the non-amended *** can alleviate the negative effects on hydraulic properties caused by plant growth and reduce ET-induced excessive water loss.A 5%peanut shell biochar content is recommended for the long-term management of vegetated earthen infrastructures.

关键词： Soil-grass interaction Biochar Long-term Water infiltration Soil drying

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The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

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Neural Regeneration Research 2024年第6期19卷 1308-1317页

作者： Daniel J.Hellenbrand charles m.Quinn Zachariah J.Piper Ryan T.Elder Raveena R.mishra Taylor L.marti Phoebe m.Omuro Rylie m.Roddick Jae Sung Lee William L.murphy Amgad S.Hanna Department of Neurosurgery University of Wisconsin-Madison School of Medicine and Public HealthMadisonWIUSA Department of Biomedical Engineering University of Wisconsin-MadisonMadisonWIUSA Department of Orthopedics and Rehabilitation University of Wisconsin-MadisonMadisonWIUSA Department of materials Science and Engineering University of Wisconsin-MadisonMadisonWIUSA Forward BIO Institute University of Wisconsin-MadisonMadisonWIUSA

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural ***,a major aim of current research involves targeting the immune response as a treatment for spinal cord *** much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine *** objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord *** were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex *** demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days *** contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days *** spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured *** a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male *** conclusion,pro-inflammatory cytokines in

关键词： astrocytes chemokines cytokines inflammation macrophages microglia secondary damage spinal cord injury

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COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history

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Journal of Sport and Health Science 2024年第1期13卷 99-107页

作者： Kyle A.Smith Tiffany m.Zúñiga Forrest L.Baker Helena Batatinha charles R.Pedlar Shane C.Burgess michael P.Gustafson Emmanuel Katsanis Richard J.Simpson School of Nutritional Sciences and Wellness The University of ArizonaTucsonAZ 85721USA Department of Pediatrics The University of ArizonaTucsonAZ 85724USA Faculty of Sport Allied Health and Performance ScienceSt.Mary's UniversityTwickenham TW14SXUK Institute of Sport Exercise and Health University College LondonLondon WC1E 7HUUK Department of Animal and Comparative Biomedical Sciences The University of ArizonaTucsonAZ 85721USA The University of Arizona Cancer Center The University of ArizonaTucsonAZ 85719USA Laboratory medicine and Pathology Mayo Clinic ArizonaPhoenixAZ 85054USA Department of Immunobiology The University of ArizonaTucsonAZ 85724USA Department of medicine The University of ArizonaTucsonAZ 85724USA Department of Pathology The University of ArizonaTucsonAZ 85724USA

Background:The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)specific T-cells and neutralizing antibodies(nAbs)during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019(COVID-19).We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb ***:Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 *** major leukocyte subtypes were enumerated before,during,and after exercise by flow cytometry,and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays,T-cell receptor(TCR)-βsequencing,and SARS-CoV-2 nAb ***:COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded ***,non-infected participants had a significantly reduced mobilization of CD4+and CD8+naive T-cells,as well as CD4+central memory T-cells,after vaccination(synthetic immunity group);this was not seen after vaccination in those with prior SARS-CoV-2 infection(hybrid immunity group).Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent *** groups mobilized T-cells that reacted to spike protein;however,only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid *** increased significantly during exercise only in the hybrid immunity ***:These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.

关键词： Anti-viral COVID-19 Exercise immunology SARS-CoV-2 T-Cells Vaccine

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Asbestos Exposure during Gasket Removal from Aircraft Engine

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Occupational Diseases and Environmental medicine 2024年第2期12卷 59-67页

作者： charles L. Blake Kevin m. Guth Raymond D. Harbison Apex Companies Marietta USA Center for Environmental and Occupational Risk Analysis and management College of Public Health University of South Florida Tampa USA

We have previously evaluated asbestos exposure associated with various maintenance procedures on light aircraft. The purpose of this study was to evaluate asbestos exposure during engine maintenance on light aircraft. This test was designed to evaluate the potential for asbestos exposure to mechanics and others who remove asbestos-containing engine gaskets from reciprocating style aircraft engines. Utilized in this test was an air cooled, horizontally opposed, aviation gasoline burning engine, assembled during 1986 and operated intermittently up into 2015, having accumulated 1680 hours run time. Nearly 75% of the asbestos-containing gaskets installed during 1986 were still in place at the time of testing. Chrysotile asbestos contents of such gaskets ranged from 55% to 60% by area, for those of sheet style and 5% by area, for the spiral wound metal/asbestos style. Despite the levels of effort required to effect gasket removals, the professional aircraft mechanic was not exposed to airborne asbestos fibers at the lower limits of sampling and analytical detection achieved;all of which were substantially less than the current Occupational Safety and Health Administration Permissible Exposure Limits for asbestos. The results of this testing indicate an absence of gasket related asbestos exposure risk to mechanics who work with light aircraft engines, including those having asbestos-containing gaskets. These results are consistent with the findings of mlyarek and Van Orden who studied the asbestos exposure risk occasioned during overhaul of larger radial style reciprocating aircraft engines [1].

关键词： Asbestos Exposure Gaskets Aircraft Engine Friction materials

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Three-dimensional analysis of age and sex differences in femoral head asphericity in asymptomatic hips in the United States

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World Journal of Orthopedics 2024年第8期15卷 754-763页

作者： mahad m Hassan Aliya G Feroe Brenton W Douglass Andrew E Jimenez Benjamin Kuhns charles F mitchell Robert L Parisien Daniel A maranho Eduardo N Novais Young-Jo Kim Ata m Kiapour Department of Orthopedic Surgery University of MinnesotaMinneapolisMN 55454United States Department of Orthopedic Surgery TRIA Orthopaedic CenterBloomingtonMN 55122United States Department of Orthopedic Surgery Boston Children’s HospitalBostonMA 02115United States Department of Orthopedic Surgery Mayo ClinicRochesterMN 55901United States Department of Orthopaedics and Rehabilitation Yale School of MedicineNew HavenCT 06510United States Department of Orthopedic Surgery American Hip Institute Research FoundationDes PlainesIL 60018United States Department of Orthopedic Surgery Mount SinaiNew YorkNY 10029United States Department of Biomechanics Medicineand Rehabilitation of the Locomotor SystemRibeirao Preto Medical SchoolUniversity of São PauloRibeirao Preto 14048-900São PauloBrazil

BACKGROUND The sphericity of the femoral head is a metric used to evaluate hip pathologies and is associated with the development of osteoarthritis and femoral-acetabular *** To analyze the three-dimensional asphericity of the femoral head of asymptomatic pediatric *** hypothesized that femoral head asphericity will vary significantly between male and female pediatric hips and increase with age in both *** Computed tomography scans were obtained on 158 children and adolescents from a single institution in the United States(8-18 years;50%male)without hip *** femoral measurements including the femoral head diameter,femoral head volume,residual volume,asphericity index,and local diameter difference were used to evaluate femoral head *** In both sexes,the residual volume increased by age(Pmaller femoral head size in older ages(>13 years)in females,there were no sex-differences in residual volume and aspherity *** were no age-related changes in mean diameter difference in both sexes(P=0.07)with no significant sex-differences across different age groups(P=0.06).In contrast,there were significant increases in local aspherity(maximum diameter difference)across whole surface of the femoral head and all quadrants except the inferior regions in males(P=0.03).There were no sex-differences in maximum diameter difference at any regions and age group(P>0.05).Increased alpha angle was only correlated to increased mean diameter difference across overall surface of the femoral head(P=0.024).CONCLUSION There is a substantial localized asphericity in asymptomatic hips which increases with age *** 2D measured alpha angle can capture overall asphericity of the femoral head,it may not be sensitive enough to represent regional asphericity patterns.

关键词： Hip Femoral head Sphericity Skeletal growth Sex differences

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Aging impairs the osteocytic regulation of collagen integrity and bone quality

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Bone Research 2024年第1期12卷 78-94页

作者： charles A.Schurman Serra Kaya Neha Dole Nadja m.maldonado Luna Natalia Castillo Ryan Potter Jacob P.Rose Joanna Bons Christina D.King Jordan B.Burton Birgit Schilling Simon melov Simon Tang Eric Schaible Tamara Alliston Department of Orthopaedic Surgery University of CaliforniaSan FranciscoCA 94143USA UC Berkeley/UCSF Graduate Program in Bioengineering San FranciscoCA 94143USA Buck Institute for Research on Aging NovatoCA 94945USA Washington University in St Louis Department of OrthopedicsSt.LouisMO 63130USA Advanced Light Source Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA

Poor bone quality is a major factor in skeletal fragility in elderly *** molecular mechanisms that establish and maintain bone quality,independent of bone mass,are unknown but are thought to be primarily determined by *** hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling(PLR),which maintains bone material *** examined bones from young and aged mice with osteocyte-intrinsic repression of TGFβsignaling(TβRII^(ocy−/−))that suppresses *** control aged bone displayed decreased TGFβsignaling and PLR,but aging did not worsen the existing PLR suppression in male TβRII^(ocy−/−)*** relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical *** effects of age on bone mass,density,and mineral material behavior were independent of osteocytic TGFβ.We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of TGFβ-dependent maintenance of collagen integrity.

关键词： maintain primarily integrity

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Selective Hydrodeoxygenation of Lignin-Derived Vanillin via Hetero-Structured High-Entropy Alloy/Oxide Catalysts

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Energy & Environmental materials 2024年第3期7卷 202-210页

作者： Yan Sun Kaili Liang Ren Tu Xudong Fan charles Q.Jia Zhiwen Jia Yingnan Li Hui Yang Enchen Jiang Hanwen Liu Yonggang Yao Xiwei Xu Key Laboratory for Biobased materials and Energy of ministry of Education College of Materials and EnergySouth China Agricultural UniversityGuangzhou 510640China Department of Chemical Engineering and Applied Chemistry University of Toronto200 College StreetToronto ON M5S3E5Canada State Key Laboratory of materials Processing and Die&mould Technology School of Materials Science and EngineeringHuazhong University of Science and TechnologyWuhan 430074China

The chemoselective hydrodeoxygenation of natural lignocellulosic materials plays a crucial role in converting biomass into value-added *** their complex molecular structures often require multiple active sites synergy for effective activation and achieving high ***,it is reported that a high-entropy alloy(HEA)on high-entropy oxide(HEO)hetero-structured catalyst for highly active,chemoselective,and robust vanillin *** heterogenous HEA/HEO catalysts were prepared by thermal reduction of senary HEOs(NiZnCuFeAlZrO_(x)),where exsolvable metals(e.g.,Ni,Zn,Cu)in situ emerged and formed randomly dispersed HEA nanoparticles anchoring on the HEO *** catalyst exhibits excellent catalytic performance:100%conversion of vanillin and 95%selectivity toward high-value 2-methyl-4 methoxy phenol at low temperature of 120℃,which were attributed to the synergistic effect among HEO matrix(with abundant oxygen vacancies),anchored HEA nanoparticles(having excellent hydrogenolysis capability),and their intimate hetero-interfaces(showing strong electron transferring effect).Therefore,our work reported the successful construction of HEA/HEO heterogeneous catalysts and their superior multifunctionality in biomass conversion,which could shed light on catalyst design for many important reactions that are complex and require multifunctional active sites.

关键词： biomass conversion heterogeneous catalysts high-entropy oxide high-entropy alloys lignin pyrolysis

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Estimating the Yield Loss of Winter Wheat from Drought in the United States Southern Plains Region as Influenced by El Niño-Southern Oscillation (ENSO)

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Agricultural Sciences 2024年第9期15卷 1018-1034页

作者： Prem Woli Gerald R. Smith charles R. Long Francis m. Rouquette, Jr. Texas A&m AgriLife Research Center Overton USA

Wheat (Triticum aestivum L.) production is a major economic activity in most regional and rural areas in the Southern Plains, a semi-arid region of the United States. This region is vulnerable to drought and is projected to experience a drier climate in the future. Since the interannual variability in climate in this region is linked to an ocean-atmospheric phenomenon, called El Niño-Southern Oscillation (ENSO), droughts in this region may be associated with ENSO. Droughts that occur during the critical growth phases of wheat can be extremely costly. However, the losses due to an impending drought can be minimized through mitigation measures if it is predicted in advance. Predicting the yield loss from an imminent drought is crucial for stakeholders. One of the reliable ways for such prediction is using a plant physiology-based agricultural drought index, such as Agricultural Reference Index for Drought (ARID). This study developed ENSO phase-specific, ARID-based models for predicting the drought-induced yield loss for winter wheat in this region by accounting for its phenological phase-specific sensitivity to drought. The reasonable values of the drought sensitivity coefficients of the yield model for each ENSO phase (El Niño, La Niña, or Neutral) indicated that the yield models reflected reasonably well the phenomena of water stress decreasing the winter wheat yields in this region during different ENSO phases. The values of various goodness-of-fit measures used, including the Nash-Sutcliffe Index (0.54 to 0.67), the Willmott Index (0.82 to 0.89), and the percentage error (20 to 26), indicated that the yield models performed fairly well at predicting the ENSO phase-specific loss of wheat yields from drought. This yield model may be useful for predicting yield loss from drought and scheduling irrigation allocation based on the phenological phase-specific sensitivity to drought as impacted by ENSO.

关键词： ARID Drought Drought Index ENSO El Niño Growth-Stage model Phenological-Phase Prediction Semi-Arid Wheat Yield Loss

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