bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relevance of Pyrogenic Carbon for Carbon Budgets From Fires: Insights From the FIREX Experiment
Authors: Santin Cristina , Doerr Stefan H. , Jones Matthew W. , Merino Agustin , Warneke Carsten , Roberts James M.
Published: August 2020

Vegetation fires play an important role in global and regional carbon cycles. Due to climate warming and land use shifts, fire patterns are changing and fire impacts increasing in many of the world's regions. Reducing uncertainties in carbon budgeting calculations from fires is therefore fundamental to advance our current understanding and forecasting capabilities. Here we study 20 chamber burns from the FIREX FireLab experiment, which burnt a representative set of North American wildland fuels, to assess the following: (i) differences in carbon emission estimations between the commonly used “consumed biomass” approach and the “burnt carbon” approach; (ii) pyrogenic carbon (PyC) production rates; and (iii) thermal and chemical recalcitrance of the PyC produced, as proxies of its biogeochemical stability. We find that the “consumed biomass” approach leads to overestimation of carbon emissions by 2–27% (most values between 2% and 10%). This accounting error arises largely from not considering PyC production and, even if relatively small, can therefore have important implications for medium‐ and long‐term carbon budgeting. A large fraction (34–100%) of this PyC was contained in the charred fine residue, a postfire material frequently overlooked in fire carbon research. However, the most recalcitrant PyC was in the form of woody charcoal, with estimated half‐lives for most samples exceeding 1,000 years. Combustion efficiency was relatively high in these laboratory burns compared to actual wildland fire conditions, likely leading to lower PyC production rates. We therefore argue that the PyC production values obtained here, and associated overestimation of carbon emissions, should be taken as low‐end estimates for wildland fire conditions.
Tearing Instability in Alfvén and Kinetic‐Alfvén Turbulence
Authors: Boldyrev Stanislav , Loureiro Nuno F.
Published: August 2020

Recently, it has been realized that magnetic plasma turbulence and magnetic field reconnection are inherently related phenomena. Turbulent fluctuations generate regions of sheared magnetic field that become unstable to the tearing instability and reconnection, thus modifying turbulence at the corresponding scales. In this contribution, we give a brief review of some recent results on tearing‐mediated magnetic turbulence. We illustrate the main ideas of this rapidly developing field of study by concentrating on two important examples—magnetohydrodynamic Alfvén turbulence and small‐scale kinetic‐Alfvén turbulence. Due to various potential applications of these phenomena in space physics and astrophysics, we specifically try not to overload the text by heavy analytical derivations but rather present a qualitative discussion accessible to a non‐expert in the theories of turbulence and reconnection.
Atomic‐Scale Simulations of Meteor Ablation
Authors: Guttormsen Gabrielle , Fletcher Alex C. , Oppenheim Meers M.
Published: August 2020

Meteoroids smaller than a microgram constantly bombard the Earth, depositing material in the mesosphere and lower thermosphere. Meteoroid ablation, the explosive evaporation of meteoroids due to erosive impacts of atmospheric particles, consists of sputtering and thermal ablation. This paper presents the first atomic‐scale modeling of sputtering, the initial stage of ablation where hypersonic collisions between the meteoroid and atmospheric particles cause the direct ejection of atoms from the meteoroid surface. Because meteoroids gain thermal energy from these particle impacts, these interactions are important for thermal ablation as well. In this study, a molecular dynamics simulator calculates the energy distribution of the sputtered particles as a function of the species, velocity, and angle of the incoming atmospheric particles. The sputtering yield generally agrees with semi‐empirical equations at normal incidence but disagrees with the generally accepted angular dependence. Λ, the fraction of energy from a single atmospheric particle impact incorporated into the meteoroid, was found to be less than 1 and dependent on the velocity, angle, atmospheric species, and meteoroid material. Applying this new Λ to an ablation model results in a slower meteoroid temperature increase and mass loss rate as a function of altitude. This alteration results in changes in the expected electron line densities and visual magnitudes of meteoroids. Notably, this analysis leads to the prediction that meteoroids will generally ablate 1–4 km lower than previously predicted. This affects analysis of radar and visual measurements, as well as determination of meteoroid mass.
Origin and Distribution of Daytime Electron Density Irregularities in the Low‐Latitude F Region
Authors: Kil Hyosub , Lee Woo Kyoung , Paxton Larry J.
Published: August 2020

Electron density irregularities on the dayside in the low‐latitude F region are understood as remnants (or fossils) of nighttime plasma bubbles. We provide observational evidence of the connection of daytime irregularities to nighttime bubbles and the transport of the daytime irregularities by the vertical motion of the background ionosphere. The distributions of irregularities are derived using the measurements of the ion density by the first Republic of China satellite from March 1999 to June 2004. The seasonal and longitudinal distributions of daytime and nighttime irregularities in low latitudes show a close similarity. The high occurrence rate of daytime irregularities at the longitudes where strong irregularities occur frequently at night provides strong evidence of the association of daytime irregularities with nighttime bubbles. Nighttime irregularities are concentrated in the equatorial region, whereas daytime irregularities spread over broader latitudes. The seasonal and longitudinal variation of the latitudinal spread of daytime irregularities is consistent with the morphologies of plasma density and vertical plasma velocity. The zonal wave number 4 pattern, which corresponds to that in plasma density, is identified in the distribution of daytime irregularities. These observations lead to the conclusion that the morphology of daytime irregularities in the low‐latitude F region is dominated by the morphology of bubbles at night and the ionospheric fountain process on the dayside.
Modeling the Evolution of Aquatic Organisms in Dynamic River Basins
Authors: Stokes Maya F. , Perron J. Taylor
Published: August 2020

Rivers are conduits for aquatic organisms and host an exceptional number of species. Over geologic time, rivers and the aquatic organisms that live in them are subject to changes in topography that can alter where rivers flow. Differences in erosion rates across drainage divides cause some river basins to grow and others to shrink. Occasionally, rivers are abruptly rerouted by river captures that create both new dispersal corridors and barriers for aquatic organisms. These changes in habitat connectivity can lead to the evolution of new species, which has prompted suggestions that river captures may be a mechanism to produce high freshwater biodiversity. We test this hypothesis by building a model, Bio‐SLANT (Biodiversity on Simulated LAndscapes using Neutral Theory). Bio‐SLANT couples a computational landscape model that simulates river basin reorganization to a macroevolutionary model that simulates the dispersal, speciation, and extinction of organisms. We first show that modeled basin area exerts a primary control on within‐basin species richness due to the species‐area relationship. We then describe the effects of drainage area exchange between river basins. River capture increases species richness, but only temporarily, whereas elevated rates of speciation and extinction provide a persistent biological record of river network reorganization. When river captures are frequent, speciation rates increase more than extinction rates, resulting in a positive diversification rate under most of the biological parameters tested. We explore the implications of our results for species richness in landscapes with basins of different relative sizes and for diversification in tectonically active and inactive settings.
Retreating Glacier and Advancing Forest Over the Past 200 Years in the Central Himalayas
Authors: Sigdel Shalik Ram , Zhang Hui , Zhu Haifeng , Muhammad Sher , Liang Eryuan
Published: August 2020

The Himalayan glaciers, as unique reservoirs of freshwater for densely populated Asian countries, have been receiving considerable attention in public and scientific research. However, little is known about their long‐term fluctuations as related to climate variability. Herein, we reconstructed glacier fluctuation events by tree ring‐based moraine dating and repeated photographs. We assessed these fluctuations over the past 200 years in the Gangapurna and Annapurna III glaciers, located in the central Himalayas. We detected five major glacier fluctuation events in the 1790s, 1920s, 1930s, 1960s, and 1970s. A higher rate of glacier recession was observed from the 1980s onward, coinciding with climate warming. As shown by repeated photographs, the retreating rate of the Gangapurna glacier from 1979 to 2016 (up to 24.4 m yr−1) is much higher than the Annapurna III glacier (7.54 m yr−1) from 1950 to 2016. Their different frontal retreat rates were likely related to microtopography and glacier sizes. Older moraines developed during and after the Little Ice Age (LIA) were already covered by dense forest, presenting the evidence for retreating glaciers and advancing forests in the central Himalayas. Ongoing warming tends to speed up such ecological processes by resetting biophysical environment of the deglaciated forefields. In general, glaciers have shown retreating trends over the last 200 years, presenting a risk for preserving water resources in the Himalayas and nearby regions. Alternatively, advancing forest tends to amplify warming rate by reducing albedo, which is a new issue for investigating ecohydrological feedbacks between mountain forests, climate, and water resources.
Loss of symbiont infectivity following thermal stress can be a factor limiting recovery from bleaching in cnidarians
Authors: Kishimoto Mariko , Baird Andrew H , Maruyama Shinichiro , Minagawa Jun , Takahashi Shunichi
Published: August 2020

Increases in seawater temperature can cause coral bleaching through loss of symbiotic algae (dinoflagellates of the family Symbiodiniaceae). Corals can recover from bleaching by recruiting algae into host cells from the residual symbiont population or from the external environment. However, the high coral mortality that often follows mass-bleaching events suggests that recovery is often limited in the wild. Here, we examine the effect of pre-exposure to heat stress on the capacity of symbiotic algae to infect cnidarian hosts using the Aiptasia (sea-anemone)-Symbiodiniaceae model system. We found that the symbiont strain Breviolum sp. CS-164 (ITS2 type B1), both free-living and in symbiosis, loses the capacity to infect the host following exposure to heat stress. This loss of infectivity is reversible, however, a longer exposure to heat stress increases the time taken for reversal. Under the same experimental conditions, the loss of infectivity was not observed in another strain Breviolum psygmophilum CCMP2459 (ITS2 type B2). Our results suggest that recovery from bleaching can be limited by the loss of symbiont infectivity following exposure to heat stress.
Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873-5p/XIAP axis
Authors: Sun Ling , Zhu Wenwu , Zhao Pengcheng , Wang Qingjie , Fan Baohan , Zhu Yeqian , Lu Yao , Chen Qiushi , Zhang Jian , Zhang Fengxiang
Published: August 2020

Exosomes (Exo) secreted from mesenchymal stem cells (hMSCs) are protective against myocardial injury. The purpose of the study was to investigate the role and mechanisms by which exosomes promote cardiomyocyte survival and function following myocardial infarction (MI). hMSCs were cultured under hypoxic and normoxic conditions. Hypoxia-conditioned hMSC-derived exosomes (Hypo-Exo) and normoxic-conditioned hMSC-derived exosomes (Nor-Exo) were collected and intramyocardially injected into rats with MI. The therapeutic effects of Hypo-Exo and Nor-Exo were evaluated after 4 weeks. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of candidate long noncoding RNA urothelial carcinoma associated 1 (lncRNA-UCA1) in Nor-Exo and Hypo-Exo. Intramyocardial injection of lncRNA-UCA1-knockdown-Hypo-Exo in a rat model of MI was then performed and the cardiac function was characterized. The target and downstream of the molecular mechanism lncRNA-UCA1 was disclosed by luciferase reporter assays and western blot. Circulating exosomal lncRNA-UCA1 level in AMI patients and healthy volunteers was assessed. We found that (1) hMSC exosomal (from hypoxic and normoxic conditions) cardioprotection in vitro and in vivo correlated with the presence of encapsulated lncRNA-UCA1 in exosomes; (2) lncRNA-UCA1 targeted miR-873 via sponging, reducing the latter’s suppressive effects on its target XIAP, and this translated into AMPK phosphorylation and increased level of the antiapoptotic protein BCL2; and (3) plasma derived from patients with AMI contained exosomes enriched with the lncRNA-UCA1, unlike that from normal subjects. This study demonstrates that Hypo-Exo lncRNA-UCA1 plays a cardioprotective role via the miR-873-5p/XIAP axis and circulating exosomal lncRNA-UCA1 may be a promising novel biomarker for the diagnosis of AMI.
Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells
Authors: Wiese Maria , Hamdan Feda H. , Kubiak Klaudia , Diederichs Christopher , Gielen Gerrit H. , Nussbaumer Gunther , Carcaboso Angel M. , Hulleman Esther , Johnsen Steven A. , Kramm Christof M.
Published: August 2020

Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.
The critical role of PPARα in the binary switch between life and death induced by endoplasmic reticulum stress
Authors: Xu Ling , Zhang Xiangying , Tian Yuan , Fan Zihao , Li Weihua , Liu Mei , Hu Jianhua , Duan Zhongping , Jin Ronghua , Ren Feng
Published: August 2020

Endoplasmic reticulum stress (ER stress) just like a double-edged sword depending on different conditions in the development of multiple hepatic diseases. But the molecular mechanisms of functional conversion during ER stress have not been fully elucidated. In this study, we aim to illustrate the role of PPARα and the subtle mechanism in the functional conversion of ER stress. Tunicamycin (TM) and thapsigargin (TG), as ER stress inducers, were used to induce ER stress in AML12 cells. During the ER stress, qRT-PCR and immunoblotting was used to measure the expression levels of GRP78 and CHOP which show a gradually increasing trend, while PPARα and autophagy was significantly activated in the early stage but was inhibited in the late stage. Moreover, PPARα inhibition by siRNA promoted cell injury in the mild-ER stress and PPARα activation by WY-14643 reduced cell apoptosis in the serious ER stress. In the mild-ER stress with PPARα knocked down, activation of autophagy by rapamycin significantly improved cell survival, in the serious ER stress with PPARα activation, inhibition of autophagy by 3-MA aggravate cell injury. In addition, in the mild-ER stress with PPARα knocked down, CHOP knocked down by siRNA reduced cell apoptosis, in the serious ER stress activated PPARα, CHOP over-expression mediated by lentiviral vector contributed to serious cell injury. Furthermore, C57BL/6 mice was used to induce ER stress with TM intraperitoneal injection, PPARα and autophagy was upregulated in the mild-ER stress while downregulated in the serious ER stress, measured by qRT-PCR and immunoblotting, further confirmed the finding in vitro. Our results firstly demonstrated that PPARα is a key molecule in the functional conversion of ER stress: protective effects in the mild ER stress was mediated by PPARα-autophagy pathway and destructive effects in the serious ER stress was mediated by PPARα-CHOP pathway.
Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling
Authors: Hong Lei , Li Fengchan , Tang Chaojun , Li Ling , Sun Lili , Li Xiaoqiang , Zhu Li
Published: August 2020

Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism. Sema7A-overexpressed human umbilical vein endothelial cells (Sema7A-HUVECs) were generated and showed lower levels of endothelial cell markers and higher levels of mesenchymal cell markers indicating the occurrence of EndMT. RNA-sequencing analysis showed a total of 1168 upregulated genes and 886 downregulated genes. Among them, most of the molecules associated with EndMT were upregulated in Sema7A-HUVECs. Mechanistically, Sema7A-HUVECs showed a higher TGF-β2 expression and activated TGF-β/Smad Signaling. Importantly, Sema7A overexpression upregulated activating transcription factor 3 (ATF3) that was found to selectively bind the promotor region of TGF-β2, but not TGF-β1, promoting TGF-β2 transcription, which was further confirmed by ATF3-siRNA knockdown approach. Blocking β1 integrin, a known Sema7A receptor, alleviated the expression of ATF3, TGF-β2, and EndMT in Sema7A-overexpressed HUVECs, implying a role of β1 integrin/ATF3/TGF-β2 axis in mediating Sema7A-induced EndMT. Using Sema7A-deficient mice and the partial carotid artery ligation (PCL) model, we showed that Sema7A deletion attenuated EndMT induced by blood flow disturbance in vivo. In conclusion, Sema7A promotes TGF-β2 secretion by upregulating transcription factor ATF3 in a β1 integrin-dependent manner, and thus facilitates EndMT through TGF/Smad signaling, implying Sema7A as a potential therapeutic target for EndMT-related vascular diseases.
TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury
Authors: Xu Shun , Wang Jin , Jiang Jianyuan , Song Jian , Zhu Wei , Zhang Fan , Shao Minghao , Xu Haocheng , Ma Xiaosheng , Lyu Feizhou
Published: August 2020

Neuroinflammation plays a crucial role in the secondary phase of spinal cord injury (SCI), and is initiated following the activation of toll-like receptor 4 (TLR4). However, the downstream mechanism remains unknown. Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research. In addition, several studies have shown that long non-coding RNAs (lncRNAs) based mechanisms were related to signal transduction downstream of TLR4 in the regulation of inflammation. Thus, in this study, we want to determine whether TLR4 can regulate pyroptosis after SCI via lncRNAs. Our results showed that TLR4 was activated following SCI and promoted the expression of lncRNA-F630028O10Rik. This lncRNA functioned as a ceRNA for miR-1231-5p/Col1a1 axis and enhanced microglial pyroptosis after SCI by activating the PI3K/AKT pathway. Furthermore, we determined STAT1 was the upstream transcriptional factor of IncRNA-F630028O10Rik and was induced by the damage-responsive TLR4/MyD88 signal. Our findings provide new insights and a novel therapeutic strategy for treating SCI.
High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer
Authors: Liu Pan , Zhang Chunyu , Liao Yuandong , Liu Junxiu , Huang Jiaming , Xia Meng , Chen Ming , Tan Hao , He Weipeng , Xu Manman , Liu Tianyu , Ooi Shiyin , Du Qiqiao , Qin Shuhang , Zhu Yuan , Zou Qiaojian , Wang Wei , Yao Shuzhong
Published: August 2020

The prognosis for cervical cancer (CCa) patients with lymph node metastasis (LNM) is dismal. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa patients with LNM. However, the precise mechanism of LNM in CCa remains unclear. Herein, we demonstrated that protein tyrosine phosphatase receptor type M (PTPRM), identified from TCGA dataset, was markedly upregulated in CCa with LNM and correlated with LNM. Moreover, PTPRM was an independent prognostic factor of CCa patients in multivariate Cox′s proportional hazards model analysis and associated with poor prognosis. Furthermore, through gain-of-function and loss-of-function approaches, we found that PTPRM promoted CCa cells proliferation, migration, invasion, lymphangiogenesis, and LNM. Mechanistically, PTPRM promoted epithelial–mesenchymal transition (EMT) via Src-AKT signaling pathway and induced lymphangiogenesis in a VEGF-C dependent manner, resulting in LNM of CCa. Importantly, knockdown of PTPRM dramatically reduced LNM in vivo, suggesting that PTPRM plays an important role in the LNM of CCa. Taken together, our findings uncover a novel molecular mechanism in the LNM of CCa and identify PTPRM as a novel prognostic factor and potential therapeutic target for LNM in CCa.
Correction: Therapeutic effects of rapamycin and surgical decompression in a rabbit spinal cord injury model
Authors: Zhang Xin , Qin Chuan , Jing Yingli , Yang Degang , Liu Changbin , Gao Feng , Zhang Chao , Talifu Zuliyaer , Yang Mingliang , Du Liangjie , Li Jianjun
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ARNTL2 promotes pancreatic ductal adenocarcinoma progression through TGF/BETA pathway and is regulated by miR-26a-5p
Authors: Wang Zhifang , Liu Tingting , Xue Wenhua , Fang Yuanyuan , Chen Xiaolong , Xu Lijun , Zhang Lixia , Guan Kelei , Pan Juntao , Zheng Lili , Qin Guijun , Wang Tingting
Published: August 2020

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and the therapeutic outcomes remain undesirable. Increasing evidence shows that aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) plays crucial roles in tumorigenesis of multiple tumors. However, the expression status and functions of ARNTL2 in PDAC remain elusive. Here we showed that ARNTL2 expression was markedly upregulated in PDAC tissues and cell lines. elevated expression of ARNTL2 was positively related to unfavorable prognosis. Knockdown of ARNTL2 could suppress motility and invasive ability of PDAC cells in vitro, as well as tumor development in vivo. In addition, microRNA-26a-5p (miR-26a-5p) was identified as the crucial specific arbitrator for ARNTL2 expression and the expression of miR-26a-5p was inversely correlated with ARNTL2 expression in PDAC tissues. Functionally, elevated expression of miR-26a-5p was found to inhibit the proliferation, migration, and invasion of PDAC cells in vitro, while ARNTL2 increased expression could partially abolish the suppressive effect of miR-26a-5p. Mechanism study indicated that elevated expression of miR-26a-5p suppressed TGF/BETA signaling pathway by targeting ARNTL2 in PDAC cells. In conclusion, our data suggested that ARNTL2 acted as an oncogene to regulate PDAC growth. MiR-26a-5p/ARNTL2 axis may be a novel therapeutic candidate target in PDAC treatment.
ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy
Authors: Liao Zhihong , Zhang Xinheng , Song Cailiang , Lin Wencheng , Cheng Yuzhen , Xie Zi , Chen Sheng , Nie Yu , Li Aijun , Zhang Huanmin , Li Hongxin , Li Haiyun , Xie Qingmei
Published: August 2020

Autophagy and apoptosis, which are important processes for host immunity, are commonly exploited by viruses to facilitate their survival. However, to the best of our knowledge, very few studies have researched the mechanisms of action of the autophagic and apoptotic signaling pathways following viral infection. Thus, the present study aimed to investigate the mechanisms of action of growth arrest and DNA-damage-inducible β (GADD45β), an important resistance gene involved in the host resistance to ALV-J. Both ALV-J infection and the overexpression of GADD45β inhibited autophagy during the early stages, which prevented the autophagosomes from binding to the lysosomes and resulted in an incomplete autophagic flux. Notably, GADD45β was discovered to interact with MEKK4 in DF-1 cells. The genetic knockdown of GADD45β and MEKK4 using small interfering RNA-affected ALV-J infection, which suggested that ALV-J may promote the binding of GADD45β to MEKK4 to activate the p38MAPK signaling pathway, which subsequently inhibits autophagy. Furthermore, ALV-J was revealed to affect the autophagic pathway prior to affecting the apoptotic pathway. In conclusion, to the best of our knowledge, the present study was the first to investigate the combined effects of ALV-J infection on autophagy and apoptosis, and to suggest that ALV-J inhibits autophagy via the GADD45β/MEKK4/p38MAPK signaling pathway.
Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused
Authors: Liao Hengqing , Cai Jing , Liu Chen , Shen Longyan , Pu Xiaohong , Yao Yixing , Han Bo’ang , Yu Tingting , Cheng Steven Y. , Yue Shen
Published: August 2020

Reversible phosphorylation of Suppressor of fused (Sufu) is essential for Sonic Hedgehog (Shh) signal transduction. Sufu is stabilized under dual phosphorylation of protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Its phosphorylation is reduced with the activation of Shh signaling. However, the phosphatase in this reversible phosphorylation has not been found. Taking advantage of a proteomic approach, we identified Protein phosphatase 4 regulatory subunit 2 (Ppp4r2), an interacting protein of Sufu. Shh signaling promotes the interaction of these two proteins in the nucleus, and Ppp4 also promotes dephosphorylation of Sufu, leading to its degradation and enhancing the Gli1 transcriptional activity. Finally, Ppp4-mediated dephosphorylation of Sufu promotes proliferation of medulloblastoma tumor cells, and expression of Ppp4 is positively correlated with up-regulation of Shh pathway target genes in the Shh-subtype medulloblastoma, underscoring the important role of this regulation in Shh signaling.
The circEPSTI1/mir-942-5p/LTBP2 axis regulates the progression of OSCC in the background of OSF via EMT and the PI3K/Akt/mTOR pathway
Authors: Wang Jie , Jiang Canhua , Li Ning , Wang Fei , Xu Ying , Shen Zhengzhong , Yang Lina , Li Zaiye , He Caiyun
Published: August 2020

Oral squamous cell carcinoma (OSCC) in the background of oral submucous fibrosis (OSF) caused by areca nut chewing has a high incidence in Asia-Pacific countries. However, the molecular mechanism remains unclear. Here, we performed circRNA microarray analysis to screen the circRNA expression profiles in OSCC and OSF. We identified circEPSTI1 as a circRNA with consistent, sequential upregulation from normal buccal mucosa (NBM) to OSF to OSCC. Functionally, circEPSTI1 significantly promoted OSCC cell proliferation and invasion, as evidenced by the CCK8, colony formation, wound healing, and transwell assays with circEPSTI1 overexpression and silencing. OSCC patients with circEPSTI1high status exhibited poor prognoses. CircEPSTI1 sponged miR-942-5p and accelerated epithelial-mesenchymal transition (EMT) to increase LTBP2 expression in OSCC through phosphorylation of PI3K/Akt/mTOR signaling pathway components. Blocking the PI3K/Akt/mTOR signaling pathway with the dual PI3k/mTOR inhibitor BEZ235 reversed OSCC progression induced by overexpression of circEPSTI1 and LTBP2. Collectively, these results indicate that the circEPSTI1/miR-942-5p/LTBP2 axis affects OSCC cell proliferation and invasion via the acceleration of EMT and the phosphorylation of PI3K/Akt/mTOR signaling pathway components. CircEPSTI1 may be an independent diagnostic and prognostic marker and a potential therapeutic target for OSCC patients with OSF.
Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing
Authors: Gidlöf Olof , Bader Kerstin , Celik Selvi , Grossi Mario , Nakagawa Shinichi , Hirose Tetsuro , Metzler Bernhard , Olde Björn , Erlinge David
Published: August 2020

While restoration of coronary blood flow to the ischemic heart is the most effective strategy for reducing infarct size, reperfusion injury represents a significant limiting factor on clinical outcomes in myocardial infarction patients. Ischemic preconditioning (IPC) has been shown to inhibit reperfusion injury and represents an attractive model for studying cardioprotective signal transduction pathways. Long non-coding RNAs (lncRNAs) are a structurally and functionally heterogenous class of RNA transcripts with unknown roles in IPC-induced cardioprotection. Through microarray-based expression profiling of 31,423 lncRNAs in cardiac tissue from IPC mice, we identified the nuclear transcript Neat1 to be rapidly and robustly decreased in response to IPC. siRNA-mediated knock down of Neat1 reduced apoptosis and necrosis in murine cardiomyocytes (CM) and human iPS-derived CMs in response to prolonged hypoxia and hypoxia-reoxygenation, assessed with Annexin V/propidium iodide-staining, a Caspase 3/7 activity assay, LDH release, and western blot for cleaved Caspase 3. Mechanistically, Neat1 was shown to regulate processing of pro-apoptotic microRNA-22 (miR-22) in murine and human CM nuclei using a luciferase reporter assay. Hypoxia-induced downregulation of Neat1 was shown to result in accumulation of unprocessed pri-miRNA and decreased availability of biologically active miRNA, including miR-22. Addition of exogenous synthetic miR-22 reversed the protective effect of Neat1 knock down in human iPS-CM. In conclusion, we have identified the nuclear lncRNA Neat1 as part of a conserved oxygen-sensitive feedback mechanism by regulation of miRNA processing and a potential target in cardioprotection.
In vitro analysis reveals necroptotic signaling does not provoke DNA damage or HPRT mutations
Authors: Miles Mark A. , Hawkins Christine J.
Published: August 2020

Most anticancer drugs provoke apoptotic signaling by damaging DNA or other means. Genotoxic therapies may enhance a patient’s risk of developing “therapy-related cancers” due to the accumulation of oncogenic mutations that may occur in noncancerous cells. Mutations can also form upon apoptotic signaling due to sublethal caspase activity, implying that apoptosis activating drugs may also be oncogenic. Necroptosis is a different way of killing cancer cells: this version of caspase-independent cell death is characterized by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase-like domain protein (MLKL) activation, leading to cell membrane rupture and controlled cell lysis. The mutagenic potential of sublethal necroptotic signaling has not yet been directly investigated. Smac mimetics drugs, which activate apoptotic or necroptotic cell death, do not induce mutations but the mechanistic basis for this lack of mutagenic activity has not been determined. In this study, we compared the mutagenic potential of these two cell death pathways by engineering cells to activate either apoptotic or necroptotic signaling by exposing them to Smac mimetics with or without TNFα, and/or enforcing or preventing expression of apoptotic or necroptotic regulators. We discovered that sublethal concentrations of Smac mimetics in contexts that activated apoptotic signaling provoked DNA damage and mutations in surviving cells. Mutagenesis was dependent on executioner caspase activation of the nuclease CAD. In contrast, RIPK3- and MLKL-dependent necroptotic signaling following Smac mimetic treatment was not mutagenic. Likewise, DNA damage was not provoked in cells expressing a lethal constitutively active MLKL mutant. These data reveal that cells surviving sublethal necroptotic signaling do not sustain genomic damage and provide hope for a reduced risk of therapy-related malignancies in patients treated with necroptosis-inducing drugs.
H. pylori infection confers resistance to apoptosis via Brd4-dependent BIRC3 eRNA synthesis
Authors: Chen Yanheng , Sheppard Donald , Dong Xingchen , Hu Xiangming , Chen Meihua , Chen Ruichuan , Chakrabarti Jayati , Zavros Yana , Peek Richard M. , Chen Lin-Feng
Published: August 2020

H. pylori infection is one of the leading causes of gastric cancer and the pathogenicity of H. pylori infection is associated with its ability to induce chronic inflammation and apoptosis resistance. While H. pylori infection-induced expression of pro-inflammatory cytokines for chronic inflammation is well studied, the molecular mechanism underlying the apoptosis resistance in infected cells is not well understood. In this study, we demonstrated that H. pylori infection-induced apoptosis resistance in gastric epithelial cells triggered by Raptinal, a drug that directly activates caspase-3. This resistance resulted from the induction of cIAP2 (encoded by BIRC3) since depletion of BIRC3 by siRNA or inhibition of cIAP2 via BV6 reversed H. pylori-suppressed caspase-3 activation. The induction of cIAP2 was regulated by H. pylori-induced BIRC3 eRNA synthesis. Depletion of BIRC3 eRNA decreased H. pylori-induced cIAP2 and reversed H. pylori-suppressed caspase-3 activation. Mechanistically, H. pylori stimulated the recruitment of bromodomain-containing factor Brd4 to the enhancer of BIRC3 and promoted BIRC3 eRNA and mRNA synthesis. Inhibition of Brd4 diminished the expression of BIRC3 eRNA and the anti-apoptotic response to H. pylori infection. Importantly, H. pylori isogenic cagA-deficient mutant failed to activate the synthesis of BIRC3 eRNA and the associated apoptosis resistance. Finally, in primary human gastric epithelial cells, H. pylori also induced resistance to Raptinal-triggered caspase-3 activation by activating the Brd4-dependent BIRC3 eRNA synthesis in a CagA-dependent manner. These results identify a novel function of Brd4 in H. pylori-mediated apoptosis resistance via activating BIRC3 eRNA synthesis, suggesting that Brd4 could be a potential therapeutic target for H. pylori-induced gastric cancer.
Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer
Authors: Lim Shen Kiat , Tabatabaeian Hossein , Lu Ssu Yi , Kang Shin-Ae , Sundaram Gopinath Meenakshi , Sampath Prabha , Chan Siew Wee , Hong Wan Jin , Lim Yoon Pin
Published: August 2020

WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein–protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATS-independent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS- and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3′UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.
The different role of YKL-40 in glioblastoma is a function of MGMT promoter methylation status
Authors: Chen Wei-jun , Zhang Xiang , Han Hua , Lv Jian-nan , Kang En-ming , Zhang Yu-lian , Liu Wei-ping , He Xiao-sheng , Wang James , Wang Gui-huai , Yu Yan-bing , Zhang Wei
Published: August 2020

Inter- and intratumoral heterogeneity is a hallmark of glioblastoma (GBM) that facilitates recurrence, treatment resistance, and worse prognosis. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a significant prognostic marker for Temozolomide (TMZ) resistance in GBM patients.YKL-40is a molecular marker for the mesenchymal subtype of GBMs and is responsible for TMZ resistance. However, underlying mechanisms by which MGMT epigenetics impacts patient outcomes and the function of YKL-40 are not fully determined. Herein, we performed in vitro and in vivo experiments, six humanIDH1/2wild-type glioblastoma stem-like cells (GSCs) were established and studied to further determine a potential interaction of YKL-40 and MGMT promoter methylation. We demonstrated thatYKL-40functioned differently in humanIDH1/2wild-type GSCs. InMGMTpromoter-methylated (MGMT-m) GSCs, it acted as a tumor suppressor gene. On the other hand, inMGMTpromoter-unmethylated (MGMT-um) GSCs, it promoted tumorigenesis. Notably, the reason thatYKL-40played different roles in GSCs could not be interpreted by the molecular classification of each GSCs, but is a function ofMGMTpromoter methylation status and involves theRAS–MEK–ERKpathway.YKL-40mediated TMZ sensitivity by activating DNA damage responses (DDRs) inMGMT-mGSCs, and it mediated resistance to TMZ by inhibiting DDRs inMGMT-umGSCs. Our report demonstrated thatMGMTpromoter methylation status might influence a gene’s function in human cancer. Moreover, our data also highlight the point that gene function should be investigated not only according to the molecular tumor classification, but also the epigenetic signature.
Microscopic origins of performance losses in highly efficient Cu(In,Ga)Se2 thin-film solar cells
Authors: Krause Maximilian , Nikolaeva Aleksandra , Maiberg Matthias , Jackson Philip , Hariskos Dimitrios , Witte Wolfram , Márquez José A. , Levcenko Sergej , Unold Thomas , Scheer Roland , Abou-Ras Daniel
Published: August 2020

Thin-film solar cells based on polycrystalline absorbers have reached very high conversion efficiencies of up to 23-25%. In order to elucidate the limiting factors that need to be overcome for even higher efficiency levels, it is essential to investigate microscopic origins of loss mechanisms in these devices. In the present work, a high efficiency (21% without anti-reflection coating) copper indium gallium diselenide (CIGSe) solar cell is characterized by means of a correlative microscopy approach and corroborated by means of photoluminescence spectroscopy. The values obtained by the experimental characterization are used as input parameters for two-dimensional device simulations, for which a real microstructure was used. It can be shown that electrostatic potential and lifetime fluctuations exhibit no substantial impact on the device performance. In contrast, nonradiative recombination at random grain boundaries can be identified as a significant loss mechanism for CIGSe solar cells, even for devices at a very high performance level.
Real-space recipes for general topological crystalline states
Authors: Song Zhida , Fang Chen , Qi Yang
Published: August 2020

Topological crystalline states (TCSs) are short-range entangled states jointly protected by onsite and crystalline symmetries. Here we present a unified scheme for constructing all TCSs, bosonic and fermionic, free and interacting, from real-space building blocks and connectors. Building blocks are lower-dimensional topological states protected by onsite symmetries alone, and connectors are glues that complete the open edges shared by two or multiple building blocks. The resulted assemblies are selected against two physical criteria we call the no-open-edge condition and the bubble equivalence. The scheme is then applied to obtaining the full classification of bosonic TCSs protected by several onsite symmetry groups and each of the 17 wallpaper groups in two dimensions and 230 space groups in three dimensions. We claim that our construction scheme can give the complete set of TCSs for bosons and fermions, and prove the boson case analytically using a spectral-sequence expansion.
Independent phase modulation for quadruplex polarization channels enabled by chirality-assisted geometric-phase metasurfaces
Authors: Yuan Yueyi , Zhang Kuang , Ratni Badreddine , Song Qinghua , Ding Xumin , Wu Qun , Burokur Shah Nawaz , Genevet Patrice
Published: August 2020

Geometric-phase metasurfaces, recently utilized for controlling wavefronts of circular polarized (CP) electromagnetic waves, are drastically limited to the cross-polarization modality. Combining geometric with propagation phase allows to further control the co-polarized output channel, nevertheless addressing only similar functionality on both co-polarized outputs for the two different CP incident beams. Here we introduce the concept of chirality-assisted phase as a degree of freedom, which could decouple the two co-polarized outputs, and thus be an alternative solution for designing arbitrary modulated-phase metasurfaces with distinct wavefront manipulation in all four CP output channels. Two metasurfaces are demonstrated with four arbitrary refraction wavefronts, and orbital angular momentum modes with four independent topological charge, showcasing complete and independent manipulation of all possible CP channels in transmission. This additional phase addressing mechanism will lead to new components, ranging from broadband achromatic devices to the multiplexing of wavefronts for application in reconfigurable-beam antenna and wireless communication systems.
Direct insights into the role of epoxy groups on cobalt sites for acidic H2O2 production
Authors: Zhang Qingran , Tan Xin , Bedford Nicholas M. , Han Zhaojun , Thomsen Lars , Smith Sean , Amal Rose , Lu Xunyu
Published: August 2020

Hydrogen peroxide produced by electrochemical oxygen reduction reaction provides a potentially cost effective and energy efficient alternative to the industrial anthraquinone process. In this study, we demonstrate that by modulating the oxygen functional groups near the atomically dispersed cobalt sites with proper electrochemical/chemical treatments, a highly active and selective oxygen reduction process for hydrogen peroxide production can be obtained in acidic electrolyte, showing a negligible amount of onset overpotential and nearly 100% selectivity within a wide range of applied potentials. Combined spectroscopic results reveal that the exceptionally enhanced performance of hydrogen peroxide generation originates from the presence of epoxy groups near the Co–N4 centers, which has resulted in the modification of the electronic structure of the cobalt atoms. Computational modeling demonstrates these electronically modified cobalt atoms will enhance the hydrogen peroxide productivity during oxygen reduction reaction in acid, providing insights into the design of electroactive materials for effective peroxide production.
The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members
Authors: Rai Amrita , Bleimling Nathalie , Vetter Ingrid R. , Goody Roger S.
Published: August 2020

EHBP1 is an adaptor protein that regulates vesicular trafficking by recruiting Rab8 family members and Eps15-homology domain-containing proteins 1/2 (EHD1/2). It also links endosomes to the actin cytoskeleton. However, the underlying molecular mechanism of activation of EHBP1 actin-binding activity is unclear. Here, we show that both termini of EHBP1 have membrane targeting potential. EHBP1 associates with PI(3)P, PI(5)P, and phosphatidylserine via its N-terminal C2 domain. We show that in the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular complex with its central calponin homology (CH) domain and auto-inhibits actin binding. Rab8 binding to the bMERB domain relieves this inhibition. We have analyzed the CH:bMERB auto-inhibited complex and the active bMERB:Rab8 complex biochemically and structurally. Together with structure-based mutational studies, this explains how binding of Rab8 frees the CH domain and allows it to interact with the actin cytoskeleton, leading to membrane tubulation.
Behavioral and neuronal underpinnings of safety in numbers in fruit flies
Authors: Ferreira Clara H. , Moita Marta A.
Published: August 2020

Living in a group allows individuals to decrease their defenses, enabling other beneficial behaviors such as foraging. The detection of a threat through social cues is widely reported, however, the safety cues that guide animals to break away from a defensive behavior and resume alternate activities remain elusive. Here we show that fruit flies display a graded decrease in freezing behavior, triggered by an inescapable threat, with increasing group sizes. Furthermore, flies use the cessation of movement of other flies as a cue of threat and its resumption as a cue of safety. Finally, we find that lobula columnar neurons, LC11, mediate the propensity for freezing flies to resume moving in response to the movement of others. By identifying visual motion cues, and the neurons involved in their processing, as the basis of a social safety cue this study brings new insights into the neuronal basis of safety in numbers.