bluuebunny/crossref_metadata_2025 huggingface dataset:
Physicochemical and Functional Characterization of Potato Starch (Solanum Tuberosum ssp. Andigenum) from the Quebrada De Humahuaca, Argentina
Authors: Calliope Sonia , Wagner Jorge , Samman Norma
Published: September 2019

The physicochemical properties of starches of 16 Andean potato genotypes from the Quebrada de Humahuaca, Jujuy, are studied and possible applications are evaluated. Moisture, protein, ash, phosphorus, amylose/amylopectin ratio, particle size, swelling power, water absorption index, solubility index, syneresis, turbidity, thermal properties, gelatinization, retrogradation, and their corresponding enthalpies are determined. The analysis of principal components allowed obtaining groups of varieties with similar properties. Four groups of genotypes are obtained: one group is characterized by high gelatinization temperatures, so it can be used for products that require high processing temperatures; the second, with greater swelling power, can be applied in products that require water retention; other can be used in the production of edible film because it has higher amylose content which improves its mechanical properties; the latter is characterized by having a high stability and lower syneresis which indicates it is possible to use in processes that require refrigeration and freezing. The information obtained in this study can be useful for the production of potatoes with differentiated characteristics of their starches and with the possibility to be applied both in food and in non‐food products.
The top 5 sections of the FERPA regulations: Annual FERPA notification — The checklist, Part 2
Authors: Rainsberger Richard
Published: September 2019

The Family Educational Rights and Privacy Act requires us to notify students annually of their FERPA rights. Furthermore, the Family Policy Compliance Office wants us to print this notification in a publication the student is most likely to read: the college catalog, student handbook, or schedule of classes.
Does Smoking Impair Bone Regeneration in the Dental Alveolar Socket?
Authors: Shah Furqan A. , Sayardoust Shariel , Omar Omar , Thomsen Peter , Palmquist Anders
Published: September 2019

Smoking is a major risk factor for dental implant failure. In addition to higher marginal bone loss around implants, the cellular and molecular responses to injury and implant physicochemical properties are also differentially affected in smokers. The purpose of this work is to determine if smoking impairs bone microstructure and extracellular matrix composition within the dental alveolar socket after tooth extraction. Alveolar bone biopsies obtained from Smokers (> 10 cigarettes per day for at least 10 years) and Ctrl (never-smokers), 7–146 months after tooth extraction, were investigated using X-ray micro-computed tomography, backscattered electron scanning electron microscopy, and Raman spectroscopy. Both Smokers and Ctrl exhibited high inter- and intra-individual heterogeneity in bone microstructure, which varied between dense cortical and porous trabecular architecture. Regions of disorganised/woven bone were more prevalent during early healing. Remodelled lamellar bone was predominant at longer healing periods. Bone mineral density, bone surface-to-volume ratio, mineral crystallinity, the carbonate-to-phosphate ratio, the mineral-to-matrix ratio, the collagen crosslink ratio, and the amounts of amino acids phenylalanine and proline/hydroxyproline were also comparable between Smokers and Ctrl. Bone microstructure and composition within the healing dental alveolar socket are not significantly affected by moderate-to-heavy smoking.
Rare variants in FANCA induce premature ovarian insufficiency
Authors: Yang Xi , Zhang Xiaojin , Jiao Jiao , Zhang Feng , Pan Yuncheng , Wang Qiqi , Chen Qing , Cai Baozhu , Tang Shuyan , Zhou Zixue , Chen Siyuan , Yin Hao , Fu Wei , Luo Yang , Li Da , Li Guoqing , Shang Lingyue , Yang Jialing , Jin Li , Shi Qinghua , Wu Yanhua
Published: September 2019

Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome sequencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified in FANCA (Fanconi anemia complementation group A): c.1772G > A (p.R591Q) and c.3887A > G (p.E1296G). Both variants are heterozygous in the patients and very rare in the human population. In vitro functional studies further demonstrated that these two missense variants of FANCA exhibited reduced protein expression levels compared with the wild type, suggesting the partial loss of function. Moreover, mono-ubiquitination levels of FANCD2 upon mitomycin C stimulation were significantly reduced in cells overexpressing FANCA variants. Furthermore, a loss-of-function mutation of Fanca was generated in C57BL/6 mice for in vivo functional assay. Consistently, heterozygous mutated female mice (Fanca+/−) showed reduced fertility and declined numbers of follicles with aging when compared with the wild-type female mice. Collectively, our results suggest that heterozygous pathogenic variants in FANCA are implicated in non-syndromic POI in Han Chinese women, provide new insights into the molecular mechanisms of POI and highlight the contribution of FANCA variants in female subfertility.
End-stage liver failure: filling the treatment gap at the intensive care unit
Authors: Chamuleau Robert A. F. M. , Hoekstra Ruurdtje
Published: September 2019

End-stage liver failure is a condition of collapsing liver function with mortality rates up to 80. Liver transplantation is the only lifesaving therapy. There is an unmet need for therapy to extend the waiting time for liver transplantation or regeneration of the native liver. Here we review the state-of-the-art of non-cell based and cell-based artificial liver support systems, cell transplantation and plasma exchange, with the first therapy relying on detoxification, while the others aim to correct also other failing liver functions and/or modulate the immune response. Meta-analyses on the effect of non-cell based systems show contradictory outcomes for different types of albumin purification devices. For bioartificial livers proof of concept has been shown in animals with liver failure. However, large clinical trials with two different systems did not show a survival benefit. Two clinical trials with plasma exchange and one with transplantation of mesenchymal stem cells showed positive outcomes on survival. Detoxification therapies lack adequacy for most patients. Correction of additional liver functions, and also modulation of the immune system hold promise for future therapy of liver failure.
On the dynamics of stock price bubbles: comments on a model by Miao and Wang
Authors: Sorger Gerhard
Published: September 2019

We consider the model by Miao and Wang (Am Econ Rev 108:2590–2628, 2018), in which endogenous collateral constraints may generate stock price bubbles. Whereas Miao and Wang (2018) characterize the local dynamics around stationary equilibria only under the assumption of risk neutral households, we extend this characterization to the case of risk aversion.
Second variation of Selberg zeta functions and curvature asymptotics
Authors: Fedosova Ksenia , Rowlett Julie , Zhang Genkai
Published: September 2019

We give an explicit formula for the second variation of the logarithm of the Selberg zeta function,Z(s), on Teichmüller space. We then use this formula to determine the asymptotic behavior as$$\mathfrak {R}s \rightarrow \infty $$Rs→∞of the second variation. As a consequence, for$$m \in {\mathbb {N}}$$m∈N, we obtain the complete expansion inmof the curvature of the vector bundle$$H^0(X_t, {\mathcal {K}}_t)\rightarrow t\in {\mathcal {T}}$$H0(Xt,Kt)→t∈Tof holomorphic m-differentials over the Teichmüller space$${\mathcal {T}}$$T, formlarge. Moreover, we show that this curvature agrees with the Quillen curvature up to a term of exponential decay,$$O(m^2 \mathrm{e}^{-l_0 m}),$$O(m2e-l0m),where$$l_0$$l0is the length of the shortest closed hyperbolic geodesic.
Large-scale habitat model reveals a key role of large trees and protected areas in the metapopulation survival of the saproxylic specialist Cucujus cinnaberinus
Authors: Bełcik Michał , Goczał Jakub , Ciach Michał
Published: September 2019

Deforestation for agricultural purposes and logging over centuries has resulted in a significant loss of forest cover and the deep structural and functional simplification of persistent European woodlands, which has led to a large-scale decline in biodiversity. Despite recent reforestation efforts in many regions of Europe, populations of numerous forest species remain unrecovered. Due to the loss of ecological continuity and the simplification of the ecosystem structure and functionality, the value of secondary forests in sustaining habitat specialists is being questioned. Here, we build a large-scale habitat suitability model to predict the current potential of forests to host populations of the flagship European saproxylic beetleCucujus cinnaberinus. Our maximum entropy model revealed that the distribution of suitable habitats strongly corresponds to the occurrence of large and well-preserved forest complexes that are characterized by an ecological continuity of the stands. Among the analysed environmental variables, the mean tree diameter and distance to protected areas were the most important suitable habitat contributors. The optimum habitats were identified almost exclusively within some parts of the Carpathians and the northeastern part of the country, particularly in the Białowieża Forest, which include the best preserved European forests. Although a large number of small habitat patches was revealed across the country, these patches were highly scattered and had low predicted suitability. This study demonstrates that most woodlands are unsuitable forC. cinnaberinus, which points to the limited value of secondary forests for habitat specialists. Our findings emphasize the importance of large and intact forests with undisrupted ecological continuity as key areas for the persistence of the rare saproxylic beetle, which provokes questions about the effectiveness of reforestation as a tool for the conservation of forest habitat specialists.
The Implicit Association Test in health professions education: A meta-narrative review
Authors: Sukhera Javeed , Wodzinski Michael , Rehman Maham , Gonzalez Cristina M.
Published: September 2019

Introduction Implicit bias is a growing area of interest among educators. Educational strategies used to elicit awareness of implicit biases commonly include the Implicit Association Test (IAT). Although the topic of implicit bias is gaining increased attention, emerging critique of the IAT suggests the need to subject its use to greater theoretical and empirical scrutiny.

Methods The authors employed a meta-narrative synthesis to review existing research on the use of the IAT in health professions education. Four databases were searched using key terms yielding 1151 titles. After title, abstract and full-text screening, 38 articles were chosen for inclusion. Coding and analysis of articles sought a meaningful synthesis of educational approaches relating to the IAT, and the assumptions and theoretical positions that informed these approaches.

Results Distinct, yet complementary, meta-narratives were found in the literature. The dominant perspective utilizes the IAT as a metric of implicit bias to evaluate the success of an educational activity. A contrasting narrative describes the IAT as a tool to promote awareness while triggering discussion and reflection.

Discussion Whether used as a tool to measure bias, raise awareness or trigger reflection, the use of the IAT provokes tension between distinct meta-narratives, posing a challenge to educators. Curriculum designers should consider the premise behind the IAT before using it, and be prepared to address potential reactions from learners such as defensiveness or criticism. Overall, findings suggest that educational approaches regarding implicit bias require critical reflexivity regarding assumptions, values and theoretical positioning related to the IAT.
From corpus usages to cognitively informed dictionary senses
Authors: Dalpanagioti Thomai
Published: September 2019

This paper ofers a step-by-step guide to compiling a dictionary entry by applying cognitive semantic theories to corpus data. In this way, the paper aims to make a contribution to the feld of cognitive lexicography. The focus of attention is on the lexicographic tasks of identifying lexical units, capturing usage patterns and providing defnitions. In an attempt to systematize these demanding and highly subjective tasks, we combine the principles of corpus linguistics (corpus pattern analysis) and cognitive semantics (frame semantics, conceptual metaphor and metonymy theory, principled polysemy approach). The proposed integrated (corpus-based and cognitively oriented) lexicographic approach is demonstrated in the analysis of a polysemous lexical item from the semantic feld of motion, the verb float. The independent semantic and phraseological analysis of foat is compared with the corresponding entries of monolingual learners’ dictionaries to specify in what respects the described approach can improve EFL lexicography. The paper is not restricted to a theoretical discussion of lexicographic issues or a critical review of existing entries; rather, a new version of the float entry is ofered. The proposed entry is claimed to be more transparent and streamlined than existing ones and can serve learners better in both decoding and encoding tasks.
THE CHERN–SCHWARTZ–MACPHERSON CLASS OF AN EMBEDDABLE SCHEME
Authors: ALUFFI PAOLO
Published: September 2019

The Chern–Schwartz–MacPherson class of a hypersurface in a nonsingular variety may be computed directly from the Segre class of the Jacobian subscheme of the hypersurface; this has been known for a number of years. We generalize this fact to arbitrary embeddable schemes: for every subscheme$X$of a nonsingular variety $V$, we define an associated subscheme$\mathscr{Y}$of a projective bundle$\mathscr{V}$over$V$and provide an explicit formula for the Chern–Schwartz–MacPherson class of$X$in terms of the Segre class of $\mathscr{Y}$in $\mathscr{V}$. If$X$is a local complete intersection, a version of the result yields a direct expression for the Milnor class of$X$.

For$V=\mathbb{P}^{n}$, we also obtain expressions for the Chern–Schwartz–MacPherson class of $X$in terms of the ‘Segre zeta function’ of$\mathscr{Y}$.
A China Carved and Collected: Ningbo Whitewood Figurines in the Long Twentieth Century
Authors: Shi Yuanxie
Published: September 2019

How is the craft history of ordinary woodcarvers different from the political and economic history of elites and literati? This article tells a transnational history of Ningbo miniature whitewood figurines that were first collected by Western travelers as souvenirs from the 1870s to 1940s and then shipped to the West as export craft from the 1950s to 1980s. The examination of the makers, buyers, and collectors of these figurines reveals a dialectic process between carving and collecting. Focusing on both the making and circulation of these figurines, the article uncovers a new layer in modern Chinese history: with the political regime changing from the imperial state to socialist state, the carving and business practices of local artisans continued at its own rhythm. Less than three and a half inches tall, Ningbo whitewood figurines represent a miniature China carved and consumed on a global scale during the long twentieth century.
Streaming-enhanced flow-mediated transport
Authors: Parthasarathy Tejaswin , Chan Fan Kiat , Gazzola Mattia
Published: September 2019

We investigate the ability of an active body (master) to manipulate a passive object (slave) purely via contactless flow-mediated mechanisms, motivated by potential applications in microfluidic devices and medicine (drug delivery purposes). We extend prior works on active–passive cylinder pairs by superimposing periodic oscillations to the master’s linear motion. In a viscous fluid, such oscillations produce an additional viscous streaming field, which is leveraged for enhancing slave transport. We see that superimposing oscillations robustly improves transport across a range of Reynolds numbers. Comparison with results without oscillations highlights the flow mechanisms at work, which we capitalize on to design (master) geometries for augmented transport. These principles are found to extend to three-dimensional active–passive shapes as well.
Thomas Wolf c. Richard de Abingdon,1293–1295: A Case Study of Legal Argument
Authors: WHITE SARAH B.
Published: September 2019

This essay examines the legal arguments in Wolf c. Abingdon, a tithes dispute from 1293–5 between the rector and the vicar of Aldington, Kent. The case records contain explicit citations to written law, a surprising find in a seemingly minor case. The presence of explicit citations in particular suggests first that the litigants had access to legal assistance in the provincial court, and second that advocates and possibly judges were turning to written legal sources to resolve disputed points. This essay shows how the litigants' arguments were constructed and determines whether or not these arguments were effective in court.
Surgical management of acquired anterior glottic web: a systematic review
Authors: Fussey J M , Borsetto D , Pelucchi S , Ciorba A
Published: September 2019

Background

Acquired anterior glottic web poses a significant challenge to laryngologists given its propensity to recur following treatment, and there are a wide variety of described techniques.

Methods

A systematic review of the medical literature was undertaken in order to identify all articles pertaining to the management of acquired anterior glottic web.

Results

Thirteen studies meeting the inclusion criteria were identified and analysed. All were retrospective series, with varying surgical techniques and outcome measures. Only two studies reported on the use of topical mitomycin C.

Conclusion

Mucosal graft techniques and keel placement appear to improve success rates, but both carry risks and disadvantages. Based on the available evidence, the use of topical agents such as mitomycin C cannot be recommended in the management of acquired anterior glottic web.
An Actualist Explanation of the Procreation Asymmetry
Authors: Cohen Daniel
Published: September 2019

While morality prohibits us from creating miserable children, it does not require us to create happy children. I offer an actualist explanation of this apparent asymmetry. Assume that for every possible world W, there is a distinct set of permissibility facts determined by the welfare of those who exist in W. Moral actualism says that actual-world permissibility facts should determine one's choice between worlds. But if one doesn't know which world is actual, one must aim for subjective rightness and maximize expected actual-world permissibility. So, because one should expect actual people to be worse off than they could have been if one creates a miserable child, creating a miserable child is subjectively impermissible. And because one should expect actual people to be at least as well off as they could have been if one fails to create a happy child, failing to create a happy child is subjectively permissible.
Logical Expressivism and Carroll's Regress
Authors: Besson Corine
Published: September 2019

In this paper, I address a key argument in favour of logical expressivism, the view that knowing a logical principle such as Modus Ponens is not a cognitive state but a pro-attitude towards drawing certain types of conclusions from certain types of premises. The argument is that logical expressivism is the only view that can take us out of Lewis Carroll's Regress – which suggests that elementary deductive reasoning is impossible. I show that the argument does not hold scrutiny and that logical cognitivism can be vindicated. In the course of the discussion, I draw substantially on a comparison with a similar argument in meta-ethics, for moral expressivism.
On Linguistic Evidence for Expressivism
Authors: Ruiz Andrés Soria , Stojanovic Isidora
Published: September 2019

This paper argues that there is a class of terms, orusesof terms, that are best accounted for by an expressivist account. We put forward two sets of criteria to distinguish between expressive and factual (uses of) terms. The first set relies on the action-guiding nature of expressive language. The second set relies on the difference between one's evidence for making an expressive vs. factual statement. We then put those criteria to work to show, first, that the basic evaluative adjectives such as ‘good’ have expressive as well as factual uses and, second, that many adjectives whose primary meanings are factual, such as ‘powerful’, also have expressive uses.
Keynes Goes Nuclear: Thomas Schelling and the Macroeconomic Origins of Strategic Stability
Authors: Wilson Benjamin
Published: September 2019

Among the most important ideas in Cold War nuclear strategy and arms control was that of “stability”—the notion that by protecting weapons for use in retaliation, the superpowers would be less likely to fight a thermonuclear war. Conventional wisdom among strategists and historians of strategy has long held that stability was inherent to the logic of rational nuclear deterrence. This essay shows the conventional wisdom to be mistaken. It examines the technical practice of Thomas Schelling, who introduced the stability idea in a classic 1958 paper. Celebrated as a game theorist, Schelling was actually trained as a Keynesian macroeconomic modeler during the second half of the 1940s. In 1958, he used Keynesian techniques to frame deterrence as a stable system of dynamic adjustment, akin to the stable macroeconomic system he had modeled as a young economist. Among Schelling's fellow strategists, stability quickly became popular as a rationalization for their preferred nuclear deployment policies.
The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review
Authors: Tiribelli Mario , Palandri Francesca , Sant’Antonio Emanuela , Breccia Massimo , Bonifacio Massimiliano
Published: September 2019

Allogeneic hematopoietic stem-cell transplantation (HSCT) is, at present, the only potentially curative therapy for myelofibrosis (MF). Despite many improvements, outcomes of HSCT are still burdened by substantial morbidity and high transplant-related mortality. Allogeneic transplant is generally considered in intermediate-2 and high-risk patients aged <70 years, but the optimal selection of patients and timing of the procedure remains under debate, as does as the role of JAK inhibitors in candidates for HSCT. Starting from a real-life clinical case scenario, herein we examine some of the crucial issues of HSCT for MF in light of recent refinements on MF risk stratification, data on the use of ruxolitinib before and after transplant and findings on the impact of different conditioning regimens and donor selection.
Exosomes derived from cardiac progenitor cells attenuate CVB3-induced apoptosis via abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways
Authors: Li Xin , Yang Zuocheng , Nie Wenyuan , Jiang Jie , Li Shentang , Li Zhuoying , Tian Lang , Ma Xing
Published: September 2019

Viral myocarditis is potentially fatal and lacking a specific treatment. Exosomes secreted by cardiac progenitor cells (CPCs) have emerged as a promising tool for cardioprotection and repair. In this study, we investigated whether CPCs-derived exosomes (CPCs-Ex) could utilize the mTOR signal pathway to reduce the apoptosis in viral myocarditis. In vitro, exosomes were, respectively, added to H9C2 cells after CVB3 infection to detect the anti-apoptosis effect of CPCs-Ex. Compared with the controls, the apoptosis rate was reduced, accompanied with the depressed expression of viral capsid protein 1 (VP1) and pro-apoptosis factors of Bim/caspase families. Meanwhile, the phosphorylation of Akt, mTOR, and p70S6K were promoted, but that of 4EBP1 was suppressed. In vivo, the results of apoptosis, expression of CVB3 and pro-apoptosis factors, and phosphorylation of Akt/mTOR factors of CVB3-infected cardiomyocytes were consistent with that of vitro. Following that, we use Rapamycin and MK-2206 to inhibit the Akt/mTOR signaling pathway, meanwhile, Rattus 4EBP1, p70S6K, Akt1 and Akt2 were transfected to H9C2 cells to establish the stably transfected cell lines. In the group with Rapamycin or MK-2206 pretreatment, CPCs-Ex also could decrease the apoptosis of H9C2 cells and expression of CVB3 mRNA, followed by decreased expression of apoptosis factors. In Akt2, p70S6K and 4EBP1 overexpression groups, CPCs-Ex promoted CVB3-induced apoptosis, VP1 expression and cleavage of caspase-3. Our results therefore identify CPCs-Ex exerts an anti-apoptosis effect in CVB3-infected cells by abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways as well as the expression of Bcl-2 and caspase families. Viral myocarditis, mainly caused by CVB3 infection, is lacking a specific treatment. Our study identified an anti-apoptosis role of CPCs-Ex in CVB3-infected cells and rats, which shown that CPCs-Ex may be an effective tool to treat viral myocarditis. We believe that with more in-depth research on the functionality of CPCs-Ex, there will be a breakthrough in the treatment of viral myocarditis.
Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma
Authors: Zhong Binlong , Shi Deyao , Wu Fashuai , Wang Shangyu , Hu Hongzhi , Cheng Cheng , Qing Xiangcheng , Huang Xin , Luo Xueying , Zhang Zhicai , Shao Zengwu
Published: September 2019

Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients’ health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.
ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation
Authors: Peñaranda-Fajardo Natalia M. , Meijer Coby , Liang Yuanke , Dijkstra Bianca M. , Aguirre-Gamboa Raul , den Dunnen Wilfred F. A. , Kruyt Frank A. E.
Published: September 2019

Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.
A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms
Authors: Priem Dario , Devos Michael , Druwé Sarah , Martens Arne , Slowicka Karolina , Ting Adrian T. , Pasparakis Manolis , Declercq Wim , Vandenabeele Peter , van Loo Geert , Bertrand Mathieu J. M.
Published: September 2019

The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-κB signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-κB-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-κB activation. Apart from acting as an NF-κB inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.
Long non-coding RNA SNHG3 promotes progression of gastric cancer by regulating neighboring MED18 gene methylation
Authors: Xuan Yi , Wang Yanong
Published: September 2019

To understand the mechanistic involvement of long non-coding RNA (lncRNA) SNHG3 in gastric cancer (GC), the relative abundance of SNHG3 was determined by real-time PCR. Overall and metastasis-free survival was analyzed by Kaplan–Meier’s plot. The potential impact of SNHG3 on tumor progression was evaluated both in vitro and in vivo. The in vivo metastasis was monitored in the tail vein-injected mice. Our data suggested that high SNHG3 associated with unfavorable prognosis in respect to overall and metastasis-free survival. SNHG3-deficiency significantly suppressed cell proliferation and cell viability in vitro and xenograft progression in vivo. In addition, ectopic overexpression of SNHG3 promoted cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, we uncovered SNHG3 associated with EZH2 and negatively regulated MED18 expression through methylation modulation. Transient knockdown of MED18 in SNHG3-deficient cells completely rescued the tumor suppressive phenotypes in GC cells. Our data unraveled the oncogenic properties of high SNHG3 in GC, which predominantly depended on epigenetically regulated MED18.
Reduced sleep efficiency, measured using an objective device, was related to an increased prevalence of home hypertension in Japanese adults
Authors: Hirata Takumi , Nakamura Tomohiro , Kogure Mana , Tsuchiya Naho , Narita Akira , Miyagawa Ken , Nochioka Kotaro , Uruno Akira , Obara Taku , Nakaya Naoki , Metoki Hirohito , Kikuya Masahiro , Sugawara Junichi , Kuriyama Shinichi , Tsuji Ichiro , Kure Shigeo , Hozawa Atsushi
Published: September 2019

Few studies have reported the relationship between reduced sleep efficiency and the prevalence of hypertension independent of sleep duration in Japan. This study aimed to evaluate whether reduced sleep efficiency, measured using an objective device for >1 week, was related to an increased prevalence of hypertension independent of sleep duration in the general Japanese population. We conducted a cross-sectional study of 904 participants aged ≥20 years who lived in Miyagi Prefecture, Japan. Sleep efficiency was measured using a contactless biomotion sleep sensor for 10 continuous days. The participants were classified into two groups according to their sleep efficiency: reduced (<90%) or not reduced (≥90%). Hypertension was defined as morning home blood pressure ≥135/85 mmHg or self-reported treatment for hypertension. Multivariable logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between sleep efficiency and hypertension adjusted for potential confounders. The results showed that two hundred and ninety-four individuals (32.5%) had reduced sleep efficiency, and 331 (36.6%) had hypertension. Individuals with reduced sleep efficiency had a higher body mass index and shorter sleep duration. In the multivariable analysis, reduced sleep efficiency was significantly related to an increased prevalence of hypertension (OR, 1.62; 95% CI, 1.15–2.28). In conclusion, reduced sleep efficiency was significantly related to an increased prevalence of hypertension in Japanese adults. Improvements in sleep efficiency may be important to reduce blood pressure in Japanese adults.
Developmental cell death regulates lineage-related interneuron-oligodendroglia functional clusters and oligodendrocyte homeostasis
Authors: Orduz David , Benamer Najate , Ortolani Domiziana , Coppola Eva , Vigier Lisa , Pierani Alessandra , Angulo María Cecilia
Published: September 2019

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.
Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury
Authors: Claser Carla , Nguee Samantha Yee Teng , Balachander Akhila , Wu Howland Shanshan , Becht Etienne , Gunasegaran Bavani , Hartimath Siddesh V. , Lee Audrey W. Q. , Theng Theng Ho Jacqueline , Bing Ong Chee , Newell Evan W. , Goggi Julian , Guan Ng Lai , Renia Laurent
Published: September 2019

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8β antibodies in C57BL/6 mice infected withP. bergheiANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRβ−/−mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.
A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1
Authors: Zheng Xiao-Feng , Acharya Sanket S. , Choe Katherine N. , Nikhil Kumar , Adelmant Guillaume , Satapathy Shakti Ranjan , Sharma Samanta , Viccaro Keith , Rana Sandeep , Natarajan Amarnath , Sicinski Peter , Marto Jarrod A. , Shah Kavita , Chowdhury Dipanjan
Published: September 2019

Mitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3β, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3β phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.
MLL1 is required for PAX7 expression and satellite cell self-renewal in mice
Authors: Addicks Gregory C. , Brun Caroline E. , Sincennes Marie-Claude , Saber John , Porter Christopher J. , Francis Stewart A. , Ernst Patricia , Rudnicki Michael A.
Published: September 2019

PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.
Epigenome editing strategies for the functional annotation of CTCF insulators
Authors: Tarjan Daniel R. , Flavahan William A. , Bernstein Bradley E.
Published: September 2019

The human genome is folded into regulatory units termed ‘topologically-associated domains’ (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.
Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis
Authors: Kumari Rajni , Deshmukh Ruhi S. , Das Sanjeev
Published: September 2019

Caspase-10 belongs to the class of initiator caspases and is a close homolog of caspase-8. However, the lack of caspase-10 in mice and limited substrate repertoire restricts the understanding of its physiological functions. Here, we report that ATP-citrate lyase (ACLY) is a caspase-10 substrate. Caspase-10 cleaves ACLY at the conserved Asp1026 site under conditions of altered metabolic homeostasis. Cleavage of ACLY abrogates its enzymatic activity and suppresses the generation of acetyl-CoA, which is critical for lipogenesis and histone acetylation. Thus, caspase-10-mediated ACLY cleavage results in reduced intracellular lipid levels and represses GCN5-mediated histone H3 and H4 acetylation. Furthermore, decline in GCN5 activity alters the epigenetic profile, resulting in downregulation of proliferative and metastatic genes. Thus caspase-10 suppresses ACLY-promoted malignant phenotype. These findings expand the substrate repertoire of caspase-10 and highlight its pivotal role in inhibiting tumorigenesis through metabolic and epigenetic mechanisms.
An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy
Authors: Bernkopf Dominic B. , Brückner Martina , Hadjihannas Michel V. , Behrens Jürgen
Published: September 2019

The paralogous scaffold proteins axin and conductin/axin2 are key factors in the negative regulation of the Wnt pathway transcription factor β-catenin, thereby representing interesting targets for signaling regulation. Polymerization of axin proteins is essential for their activity in suppressing Wnt/β-catenin signaling. Notably, conductin shows less polymerization and lower activity than axin. By domain swapping between axin and conductin we here identify an aggregation site in the conductin RGS domain which prevents conductin polymerization. Induction of conductin polymerization by point mutations of this aggregon results in enhanced inhibition of Wnt/β-catenin signaling. Importantly, we identify a short peptide which induces conductin polymerization via masking the aggregon, thereby enhancing β-catenin degradation, inhibiting β-catenin-dependent transcription and repressing growth of colorectal cancer cells. Our study reveals a mechanism for regulating signaling pathways via the polymerization status of scaffold proteins and suggests a strategy for targeted colorectal cancer therapy.
Vegetation structural change since 1981 significantly enhanced the terrestrial carbon sink
Authors: Chen Jing M. , Ju Weimin , Ciais Philippe , Viovy Nicolas , Liu Ronggao , Liu Yang , Lu Xuehe
Published: September 2019

Satellite observations show that leaf area index (LAI) has increased globally since 1981, but the impact of this vegetation structural change on the global terrestrial carbon cycle has not been systematically evaluated. Through process-based diagnostic ecosystem modeling, we find that the increase in LAI alone was responsible for 12.4% of the accumulated terrestrial carbon sink (95 ± 5 Pg C) from 1981 to 2016, whereas other drivers of CO2 fertilization, nitrogen deposition, and climate change (temperature, radiation, and precipitation) contributed to 47.0%, 1.1%, and −28.6% of the sink, respectively. The legacy effects of past changes in these drivers prior to 1981 are responsible for the remaining 65.5% of the accumulated sink from 1981 to 2016. These results refine the attribution of the land sink to the various drivers and would help constrain prognostic models that often have large uncertainties in simulating changes in vegetation and their impacts on the global carbon cycle.
Martensitic phase transformation in TiNi
Authors: Sewak R. , Dey C. C.
Published: September 2019

From temperature dependent perturbed angular correlation (PAC) measurements (77–873 K) in equiatomic TiNi intermetallic alloy, martensitic phase transformations have been observed. Three frequency components corresponding to three different phases of TiNi have been found in the temperature range 298–873 K. The results of quadrupole frequency and asymmetry parameters at room temperature are found to be: ωQ = 14(1) Mrad/s, η = 0 (33%), ωQ = 40.0(5) Mrad/s, η = 0.66(3) (52%) and ωQ = 56.7(3)Mrad/s, η = 0.39(2) (15%). The frequency component with η = 0 and which enhances to ~52% at 373 K can be attributed to the cubic austenite phase. The predominant component (~52%) found at room temperature has been attributed to monoclinic martensitic phase of TiNi and the third component with values of ωQ and η similar to those for the martensitic phase is attributed to the intermediate orthorhombic phase. At 77 K, no intermediate and austenite phases have been found but only the martensite phase is observed at this temperature. From XRD measurements at room temperature also, three phases of TiNi have been observed.