bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Organized Convection Parameterization on the MJO and Precipitation in E3SMv1. Part I: Mesoscale Heating
Authors: Chen C.‐C. , Richter J. H. , Liu C. , Moncrieff M. W. , Tang Q. , Lin W. , Xie S. , Rasch P. J. 
Published: June 2021

AbstractMesoscale organization of convection is typically not represented in global circulation models, and hence its influence on the global circulation is not accounted for. The heating component of a parameterization that represents the dynamical and physical effects of circulations associated with organized convection, referred to as the multiscale coherent structure parameterization (MCSP), is implemented in the Energy Exascale Earth System Model version 1 (E3SMv1). Numerical simulations are conducted to assess its impact on the simulated climate. Besides E3SMv1 simulations, we performed high‐resolution (2 km) simulations using the Weather Research and Forecasting (WRF) Model to determine the temperature tendencies induced by mesoscale convective systems embedded in deep convection. We tuned the free parameters of the MCSP based on the WRF simulations. MCSP heating enhances Kevin wave spectra in E3SMv1, improves the representation of the Madden‐Julian Oscillation, and reduces precipitation biases over the tropical Pacific.
Long‐Term Trends Show Improvements in Water Quality in the Chicago Metropolitan Region With Investment in Wastewater Infrastructure, Deep Tunnels, and Reservoirs
Authors: Pluth T. B. , Brose D. A. , Gallagher D. W. , Wasik J. 
Published: June 2021

AbstractThe ecological degradation of streams draining urban land, known as the urban stream syndrome, is characterized by elevated nutrients and contaminants, increased hydrologic flashiness, and altered biotic assemblages. This study demonstrated an improvement in chemical characteristics by evaluating water quality trends from 1975 to 2012 and from 2013 to 2018 in the Chicago, Calumet, and Des Plaines River Systems in Cook County, Illinois. Data from 41 monitoring locations were compiled and 11 water quality parameters were analyzed for long‐term monotonic trends and differences in water quality parameters between select time periods to investigate the outcomes from improvements in water reclamation plant (WRP) and tunnel and reservoir infrastructure carried out by the Metropolitan Water Reclamation District of Greater Chicago. From 1975 to 2012, significant decreasing trends in concentrations were demonstrated at most sampling locations for total organic carbon (TOC), total Kjeldahl nitrogen (TKN), ammonium nitrogen (), total suspended solids (TSS), fecal coliform (FC), and sulfate. Significant increasing trends were demonstrated for dissolved oxygen (DO) and chloride concentrations and temperature. Total phosphorus (TP) concentrations increased downstream of the Stickney, Kirie, and Calumet WRPs from 1975 to 2012, but decreased downstream of the Kirie WRP and had no trends downstream of the Stickney and Calumet WRPs from 2013 to 2018. Improvements in TKN, , TOC, TSS, FC, TP, and DO concentrations over four decades demonstrated the benefits of expanding secondary wastewater treatment and implementing the Tunnel and Reservoir Plan System, instream and side‐stream elevated pool aeration stations, and effluent disinfection.
Dependence of Penetration Electric Field Efficiency on the Interplanetary Electric Field
Authors: Ross Jack R. , Huang Chao‐Song 
Published: June 2021

AbstractSouthward interplanetary magnetic field (IMF) causes the generation of penetration electric fields in the ionosphere at middle and low latitudes. Penetration efficiency, which is defined to be the ratio of the change of the equatorial ionospheric zonal electric field to the change of the dawn‐dusk (Ey) component of the interplanetary electric field, is used to represent the quantitative relationship between interplanetary and ionospheric electric fields. We have searched equatorial vertical ion drift data measured by the Jicamarca Unattended Long‐term Investigations of the Ionosphere and Atmosphere (JULIA) radar over 19 years (2001–2019) for penetration electric fields when the correlation between interplanetary and ionospheric electric fields is greater than 0.8. In total, 450 penetration electric field events are identified. It is found that the penetration efficiency peaks near noon and decreases afterward. The penetration efficiency depends on the rate of change of Ey with time, the initial Ey when the IMF starts to turn southward, and the change in Ey between the beginning of the IMF southward turning and the subsequent northward turning. The initial Ey is well‐correlated with the change in Ey. A positive initial Ey or a smaller change in Ey results in a higher penetration efficiency. The quantitative dependence of penetration efficiency on the structures of Ey is derived for the first time. The results of this study are expected to improve the accuracy of prediction of penetration electric fields.
High‐Pressure Phase Stability and Thermoelastic Properties of Iron Carbonitrides and Nitrogen in the Deep Earth
Authors: Huang Shengxuan , Wu Xiang , Zhu Feng , Lai Xiaojing , Li Jie , Neill Owen K. , Qin Shan , Rapp Robert , Zhang Dongzhou , Dera Przemyslaw , Chariton Stella , Prakapenka Vitali B. , Chen Bin 
Published: June 2021

AbstractIron‐dominant metallic phases are likely the primary hosts for nitrogen in the reduced deep Earth, hence the storage of nitrogen in the lower mantle and the core is governed by the behavior of the Fe‐N‐C system at high temperatures and pressures. In this study, phase transitions and thermoelastic properties of iron carbonitrides were investigated at high pressure‐temperature conditions by diamond anvil cell experiments and first‐principles calculations. Experimental data revealed no phase transition in ε‐type Fe4 (N0.6C0.4) or Fe7 (N0.75C0.25)3 up to 60 GPa at room temperature. At high temperature, Fe7 (N0.75C0.25)3 transforms into the Fe3C‐type phase at ∼27 GPa, and then into the Fe7C3‐type phase at ∼45 GPa, which is also corroborated by our theoretical calculations. We found that the phase stability of iron carbonitrides mainly depends on the N/C ratio, and the elastic properties of iron carbonitrides are dominantly affected by the Fe/(N+C) ratio. Iron carbonitrides with diverse structures may be the main host for nitrogen in the deep mantle. Some iron carbonitride inclusions in lower mantle diamonds could be the residue of the primordial mantle or originate from subducted nitrogen‐bearing materials, rather than iron‐enriched phases of the outer core. In addition, our experiments confirmed the existence of Fe7C3‐type Fe7C3‐Fe7N3 solid solutions above 40 GPa. Fe7C3‐type Fe7(C, N)3 has comparable density and thermoelastic properties to its isostructural endmembers and may be a promising candidate constituent of the Earth's inner core.
CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice
Authors: Gan Lu , Liu Demin , Liu Jing , Chen Erya , Chen Chan , Liu Lian , Hu Hang , Guan Xiaohui , Ma Wen , Zhang Yanzi , He Yarong , Liu Bofu , Tang Songling , Jiang Wei , Xue Jianxin , Xin Hongbo 
Published: June 2021

AbstractCD38 is the main enzyme for nicotinamide adenine dinucleotide (NAD) degradation in mammalian cells. Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases. Our study showed that CD38 deficiency significantly alleviated angiotensin II (Ang II)-induced vascular remodeling in mice, as shown by decreased blood pressures; reduced vascular media thickness, media-to-lumen ratio, and collagen deposition; and restored elastin expression. However, our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang II-induced vascular remodeling, suggesting that the effects of CD38 on Ang II-induced vascular remodeling might rely primarily on vascular smooth muscle cells (VSMCs), not lymphocytes. In addition, we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang II-induced vascular senescence by suppressing the biogenesis, secretion, and internalization of senescence-associated small extracellular vesicles (SA-sEVs), which facilitated the senescence of neighboring non-damaged VSMCs. Furthermore, we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction, particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria–lysosomal axis in VSMCs. In conclusion, our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang II-induced VSMC senescence and vascular remodeling.
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer
Authors: Ramesh Prashanthi , Lannagan Tamsin R. M. , Jackstadt Rene , Atencia Taboada Lidia , Lansu Nico , Wirapati Pratyaksha , van Hooff Sander R. , Dekker Danielle , Pritchard Jessica , Kirov Aleksandar B. , van Neerven Sanne M. , Tejpar Sabine , Kops Geert J. P. L. , Sansom Owen J. , Medema Jan Paul 
Published: June 2021

AbstractEvasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice
Authors: Chi Xiaochun , Luo Weiwei , Song Jiagui , Li Bing , Su Tiantian , Yu Miao , Wang Tianzhuo , Wang Zhenbin , Liu Cheng , Li Zhen , He Huiying , Zhan Jun , Zhang Hongquan 
Published: June 2021

AbstractKindlin-2 is known to play important roles in the development of mesoderm-derived tissues including myocardium, smooth muscle, cartilage and blood vessels. However, nothing is known for the role of Kindlin-2 in mesoderm-derived reproductive organs. Here, we report that loss of Kindlin-2 in Sertoli cells caused severe testis hypoplasia, abnormal germ cell development and complete infertility in male mice. Functionally, loss of Kindlin-2 inhibits proliferation, increases apoptosis, impairs phagocytosis in Sertoli cells and destroyed the integration of blood-testis barrier structure in testes. Mechanistically, Kindlin-2 interacts with LATS1 and YAP, the key components of Hippo pathway. Kindlin-2 impedes LATS1 interaction with YAP, and depletion of Kindlin-2 enhances LATS1 interaction with YAP, increases YAP phosphorylation and decreases its nuclear translocation. For clinical relevance, lower Kindlin-2 expression and decreased nucleus localization of YAP was found in SCOS patients. Collectively, we demonstrated that Kindlin-2 in Sertoli cells is essential for sperm development and male reproduction.
K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR
Authors: Zhang Pengshan , Zhang Zhe , Fu Yinkun , Zhang Ying , Washburn Michael P. , Florens Laurence , Wu Min , Huang Chen , Hou Zhaoyuan , Mohan Man 
Published: June 2021

AbstractDual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2–DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.
PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53
Authors: Wang Wuyi , Wei Jinlai , Zhang Hairong , Zheng Xiangru , Zhou He , Luo Yajun , Yang Jianguo , Deng Qican , Huang Siqi , Fu Zhongxue 
Published: June 2021

AbstractColorectal cancer is the most common gastrointestinal cancer and causes severe damage to human health. PRDX2 is a member of the peroxiredoxin family reported to have a high level of expression in colorectal cancer. However, the mechanisms by which PRDX2 promotes the proliferation of colorectal cancer are still unclear. Here, the results indicated that PRDX2 expression was upregulated in colorectal cancer and closely correlated with poor prognosis. Functionally, PRDX2 promoted the proliferation of colorectal cancer cells. Mechanistically, PRDX2 could bind RPL4, reducing the interaction between RPL4 and MDM2. These findings demonstrate that the oncogenic property of PRDX2 may be attributed to its regulation of the RPL4-MDM2-p53 pathway, leading to p53 ubiquitinated degradation.
A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors
Authors: Moirangthem Ranjita Devi , Ma Kuiying , Lizot Sabrina , Cordesse Anne , Olivré Juliette , de Chappedelaine Corinne , Joshi Akshay , Cieslak Agata , Tchen John , Cagnard Nicolas , Asnafi Vahid , Rausell Antonio , Simons Laura , Zuber Julien , Taghon Tom , Staal Frank J. T. , Pflumio Françoise , Six Emmanuelle , Cavazzana Marina , Lagresle-Peyrou Chantal , Soheili Tayebeh , André Isabelle 
Published: June 2021

AbstractSeveral obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).
Non-invasive electrophysiology in glaucoma, structure and function—a review
Authors: Al-Nosairy Khaldoon O. , Hoffmann Michael B. , Bach Michael 
Published: June 2021

AbstractGlaucoma, its early diagnosis, and monitoring of interventions remain an ongoing challenge. We here review developments in functional assessment and its relation to morphology, evaluating recent insights in electrophysiology in glaucoma and highlighting how glaucoma research and diagnostics benefit from combined approaches of OCT and electrophysiological investigations. After concise overviews of OCT and non-invasive electrophysiology in glaucoma, we evaluate commonalities and complementarities of OCT and electrophysiology for our understanding of glaucoma. As a specific topic, the dynamic range (floor effects) of the various techniques is discussed.
Non-infectious uveitis affecting the posterior segment treated with fluocinolone acetonide intravitreal implant: 3-year fellow eye analysis
Authors: Pavesio Carlos , Heinz Carsten 
Published: June 2021

Abstract
Background
Prevention of non-infectious uveitis of the posterior segment (NIU-PS) recurrence using 0.2 μg/day fluocinolone acetonide implant (FAi) was assessed over 3 years (NCT01694186). Outcomes for FAi-treated and fellow eyes with NIU-PS were compared, to evaluate FAi versus conventional treatment strategies.

Methods
Eligible subjects had >1-year recurrent NIU-PS history and either ≥2 separate recurrences requiring treatment, or corticosteroid therapy (systemic or ocular) in the 12 months preceding study entry. Bilateral disease was present and analysed in 59/87 FAi-treated participants. Recurrence rates, best-corrected visual acuity (BCVA) changes, cataract surgery, intraocular pressure (IOP) events and adjunctive medication use were compared for FAi-treated and fellow eyes.

Results
Over 36 months, more FAi-treated than fellow eyes remained recurrence-free (28.8% vs. 5.1%, P = 0.001; mean 1.9 vs. 4.7 recurrences, respectively, P < 0.0001). FAi-treated eyes gained +9.6 letters BCVA, versus a loss of −4.4 in fellow eyes (P < 0.0001). Systemic medications were given to 42.4% of subjects. Intra/periocular adjunctive injections were lower in FAi-treated than fellow eyes (20.3% vs. 66.1%, P < 0.0001); topical corticosteroid use was also lower in FAi-treated than fellow eyes (27.1% vs 52.5%, P = 0.0041). IOP-related events occurred at similar rates in both FAi-treated and fellow eyes, excepting IOP-lowering surgery (5.1% vs. 15.3%, respectively; P = 0.1251). Cataract surgery occurred in 72.0% of FAi-treated and 37.0% of fellow eyes.

Conclusions
In subjects with bilateral NIU-PS, continuous, low-dose corticosteroid with 0.2 μg/day FAi reduced recurrence and adjunctive medication requirements, and improved vision over 36 months, providing greater protection against ocular inflammation than a reactive approach using standard of care.
Optimisation of a TALE nuclease targeting the HIV co-receptor CCR5 for clinical application
Authors: Schwarze Lea Isabell , Głów Dawid , Sonntag Tanja , Uhde Almut , Fehse Boris 
Published: June 2021

AbstractDisruption of theC-C-Chemokine-receptor-5(CCR5) gene induces resistance towards CCR5-tropic HIV. Here we optimised our previously described CCR5-Uco-TALEN and its delivery by mRNA electroporation. The novel variant, CCR5-Uco-hetTALEN features an obligatory heterodimeric Fok1-cleavage domain, which resulted in complete abrogation of off-target activity at previously found homodimeric as well as 7/8 in silico predicted, potential heterodimeric off-target sites, the only exception being highly homologousCCR2. Prevailing 18- and 10-bp deletions at the on-target site revealed microhomology-mediated end-joining as a major repair pathway. Notably, the CCR5Δ55–60protein resulting from the 18-bp deletion was almost completely retained in the cytosol. Simultaneous cutting atCCR5andCCR2induced rearrangements, mainly 15-kb deletions between the cut sites, in up to 2% of T cells underlining the necessity to restrict TALEN expression. We optimised in vitro mRNA production and showed thatCCR5-on- andCCR2off-target activities of CCR5-Uco-hetTALEN were limited to the first 72 and 24–48 h post-mRNA electroporation, respectively. Using single-cell HRMCA, we discovered high rates of TALEN-induced biallelic gene editing ofCCR5, which translated in large numbers of CCR5-negative cells resistant to HIVenv-pseudotyped lentiviral vectors. We conclude that CCR5-Uco-hetTALEN transfected by mRNA electroporation facilitates specific, high-efficiencyCCR5gene-editing (30%–56%) and it is highly suited for clinical translation subject to further characterisation of off-target effects.
E2F6 initiates stable epigenetic silencing of germline genes during embryonic development
Authors: Dahlet Thomas , Truss Matthias , Frede Ute , Al Adhami Hala , Bardet Anaïs F. , Dumas Michael , Vallet Judith , Chicher Johana , Hammann Philippe , Kottnik Sarah , Hansen Peter , Luz Uschi , Alvarez Gonzalo , Auclair Ghislain , Hecht Jochen , Robinson Peter N. , Hagemeier Christian , Weber Michael 
Published: June 2021

AbstractIn mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development.