bluuebunny/crossref_metadata_2025 huggingface dataset:
Can hierarchy hold back the dynamics of self-reinforcing processes? A simulation study on path dependence in hierarchies
Authors: Petermann Arne , Schreyögg Georg , Fürstenau Daniel
Published: October 2019

Theories of path dependence and incumbent inertia assume that self-reinforcing mechanisms lead to highly persistent and eventually inefficient institutional solutions. The resulting lock-in is likely to threaten the viability of an organization. While path dependence theory was initially developed as a market-based approach, it has more recently been transferred to institutional settings and in particular to hierarchies. Some critics doubt, however, its applicability to hierarchical organizations. The major argument states that asymmetric power structures in organizations differ significantly from symmetric coordination modes and autonomous evolutionary dynamics. Hierarchical authority is assumed to be stronger and to rule out emergent autonomous dynamics. This reasoning raises the question whether hierarchical structures are actually strong enough to suppress (deliberately) the power of evolutionary self-reinforcing organizational dynamics, or vice versa. To our knowledge, there are no studies to date examining in detail these reverse dynamics. In this paper, we build on simulations to study these competing dynamics and possible conditions that favor one view or the other. We suggest using agent-based simulation and modeling, conceiving of institutional change as an interdependent multi-level process that can be analyzed numerically. The results indicate that in most situations self-reinforcing organizational dynamics can actually overrule hierarchical authority, whilst in some other situations formal authority proves to be stronger.
Generators and number fields for torsion points of a special elliptic curve
Authors: Sankari Hasan , Bojakli Mustafa
Published: October 2019

Let E be an elliptic curve with Weierstrass form y2=x3−px, where p is a prime number and let E[m] be its m-torsion subgroup. Let p1=(x1,y1) and p2=(x2,y2) be a basis for E[m], then we prove that ℚ(E[m])=ℚ(x1,x2,ξm,y1) in general. We also find all the generators and degrees of the extensions ℚ(E[m])/ℚ for m=3 and m=4.
Tansanal total mesorectal excision (TaTME): systematization and mediated results in 10 patients
Authors: de Melo e Patriarca da Silva Neiva Guilherme Inácio Bertoldo , Soares Fábio Alves , Silva Silvana Marques e , Viana Pedro Wilson Diniz , Neto Mário Nóbrega de Araújo , Oliveira Olane Marquez de , Nascimento Mauricio Cotrim
Published: October 2019

Background Transanal total mesorectal excision is a surgical technique for minimally invasive resection of the rectum and perirectal tissues. It is indicated for patients with medial and distal rectum cancer confined to the mesorectal envelope. This study describes a series of patients undergoing transanal total mesorectal excision.

Methods Ten patients were selected to undergo transanal total mesorectal excision using the SILS-Port® platform. All patients included here had middle or low rectal cancer. Abdominal access for proximal colon mobilization was performed by laparoscopy in all cases. As a rule, in 9 of the 10 cases, the surgical specimen was removed transanally.

Results During a 41-month period, 10 patients underwent transanal total mesorectal excision based on curative intent. The first indication for transanal total mesorectum excision was medial and distal rectal cancer, locally invasive and confined to the mesortal envelope. The median age of patients with rectal cancer at the time of surgery was 61 years (mean 59.4 years, range 22–78 years), with 80% (8) female and 20% (2) male. The median surgical time was 305′ (mean 314′, range 260‒420′). The median postoperative length of stay was five days (average of 7.3 days, interval of 3–23 days). There was no postoperative mortality. Surgical complications included postoperative ileus (n = 1), bladder paresis (n = 1), and ileostomy stenosis (n = 1). All patients had negative surgical margins for neoplasia and more than 12 resected lymph nodes. The tumors were between 1 and 9 cm from the anal margin.

Conclusion Total transanal mesorectal excision has been shown to be a viable method for oncologic resection of locally advanced rectal cancer with curative intent.
Control of a purely elastic symmetry-breaking flow instability in cross-slot geometries
Authors: Davoodi Mahdi , Domingues Allysson F. , Poole Robert J.
Published: October 2019

The cross-slot stagnation point flow is one of the benchmark problems in non-Newtonian fluid mechanics as it allows large strains to develop and can therefore be used for extensional rheometry measurements or, once instability arises, as a mixing device. In such a flow, beyond a critical value for which the ratio of elastic force to viscous force is high enough, elasticity can break symmetry even in the absence of significant inertial forces (i.e. creeping flow), which is an unwanted phenomenon if the device is to be used as a rheometer but beneficial from a mixing perspective. In this work, a passive control mechanism is introduced to the cross-slot by adding a cylinder at the geometric centre to replace the ‘free’ stagnation point with ‘pinned’ stagnation points at the surface of the cylinder. In the current modified geometry, effects of the blockage ratio (the ratio of the diameter of the cylinder to the width of the channel), the Weissenberg number (the ratio of elastic forces to viscous forces) and extensibility parameters ($\unicode[STIX]{x1D6FC}$ and $L^{2}$) are investigated in two-dimensional numerical simulations using both the simplified Phan-Thien and Tanner and finitely extensible nonlinear elastic models. It is shown that the blockage ratio for fixed solvent-to-total-viscosity ratio has a stabilizing effect on the associated symmetry-breaking instability. The resulting data show that the suggested modification, although significantly changing the flow distribution in the region near the stagnation point, does not change the nature of the symmetry-breaking instability or, for low blockage ratio, the critical condition for onset. Using both numerical and physical experiments coupled with a supporting theoretical analysis, we conclude that this instability cannot therefore be solely related to the extensional flow near the stagnation point but it is more likely related to streamline curvature and the high deformation rates towards the corners, i.e. a classic ‘curved streamlines’ purely elastic instability. Our work also suggests that the proposed geometric modification can be an effective approach for enabling higher flow rates to be achieved whilst retaining steady symmetric flow.
Direct numerical simulations of Rayleigh–Bénard convection in water with non-Oberbeck–Boussinesq effects
Authors: Demou Andreas D. , Grigoriadis Dimokratis G. E.
Published: October 2019

Rayleigh–Bénard convection in water is studied by means of direct numerical simulations, taking into account the variation of properties. The simulations considered a three-dimensional (3-D) cavity with a square cross-section and its two-dimensional (2-D) equivalent, covering a Rayleigh number range of $10^{6}\leqslant Ra\leqslant 10^{9}$ and using temperature differences up to 60 K. The main objectives of this study are (i) to investigate and report differences obtained by 2-D and 3-D simulations and (ii) to provide a first appreciation of the non-Oberbeck–Boussinesq (NOB) effects on the near-wall time-averaged and root-mean-squared (r.m.s.) temperature fields. The Nusselt number and the thermal boundary layer thickness exhibit the most pronounced differences when calculated in two dimensions and three dimensions, even though the $Ra$ scaling exponents are similar. These differences are closely related to the modification of the large-scale circulation pattern and become less pronounced when the NOB values are normalised with the respective Oberbeck–Boussinesq (OB) values. It is also demonstrated that NOB effects modify the near-wall temperature statistics, promoting the breaking of the top–bottom symmetry which characterises the OB approximation. The most prominent NOB effect in the near-wall region is the modification of the maximum r.m.s. values of temperature, which are found to increase at the top and decrease at the bottom of the cavity.
Long-term impacts of mid-Holocene drier climatic conditions on Bolivian tropical dry forests
Authors: Plumpton Heather J. , Mayle Francis E. , Whitney Bronwen S.
Published: October 2019

The Bolivian Chiquitano dry forest is the largest block of intact seasonally dry tropical forest in South America and is a priority ecoregion for conservation due to its high threat status. However, the long-term impacts of drier climatic conditions on tropical dry forests are not well understood, despite climate models predicting increased droughts over Bolivia in the coming century. In this paper, we assess the impacts of drier climatic conditions during the mid-Holocene on the Bolivian Chiquitano tropical dry forest using fossilised pollen, phytoliths, macro-charcoal, and geochemical proxies from a sediment core from a large lake (Laguna Mandioré) on the Bolivia–Brazil border. Our results show that drier climatic conditions during the mid-Holocene caused a local-scale, ecotonal expansion of upland savannah at the expense of dry forest. Interaction between drier climatic conditions and fire regime likely exerted a stronger control over the position of the dry forest–savannah ecotone than edaphic factors. However, the majority of the dry forest within the lake catchment maintained a closed canopy throughout the drier conditions of the mid-Holocene, despite floristic turnover towards more drought-tolerant taxa. These findings imply overall resilience of the Chiquitano dry forest biome to future drought, albeit with floristic changes and upland savannah encroachment at ecotones.
Late Miocene changes in C3, C4 and aquatic plant vegetation in the Indus River basin: evidence from leaf wax δ13C from Indus Fan sediments
Authors: Suzuki Kenta , Yamamoto Masanobu , Seki Osamu
Published: October 2019

Vegetation changes in the Indus River basin within the past 10.8 million years were investigated based on the analysis of n-fatty acids and their carbon isotopes in sediments from IODP Site U1457 in the Laxmi Basin of the Arabian Sea. The δ13C of long-chain n-C32 fatty acid shifted from −34 to −22 ‰ from 10 to 6.3 Ma, while the δ13C of mid-chain n-C24 fatty acid was nearly constant at around −23 to −22 ‰ over the same period. This large difference in the δ13C values suggests that the mid-chain fatty acids reflect the contribution of aquatic vascular C3 plants. Before 6.3 Ma, the average chain length of n-fatty acids and the δ13C values of long-chain fatty acids were negatively correlated, suggesting that the δ13C values reflected the relative abundance of terrestrial C3 versus aquatic C3 plants in the Indus River basin and western India. After 5.8 Ma, the average chain length was variable, but the δ13C values remained nearly the same, suggesting that the δ13C values reflected heavier δ13C values of both aquatic C3 and C4 plants. A three-end-member model calculation suggests that terrestrial C3 plants were replaced by C4 plants in the Indus River basin and western India from 9.7 or 8.2 to 6.3 Ma. Aridification in those areas during the late Miocene period may have driven the replacement of terrestrial C3 plants by C4 plants. An episodic increase in the abundance of terrestrial plants around 8 Ma is attributed to elevated precipitation by regionally enhanced moisture transport.
First Crusade Letters and Medieval Monastic Scribal Cultures
Authors: SMITH THOMAS W.
Published: October 2019

The letters of the First Crusade have traditionally been read as authentic and trustworthy eyewitness accounts of the expedition and they contribute greatly to scholarly understanding of the campaign. But new research on them demonstrates that many of the documents are in fact twelfth-century confections produced in the monastic communities of the West as a means of supporting, participating in and engaging with the crusading movement. This article develops new approaches to the letters and new research questions which account for and accept the problematic authenticity of the corpus, pivoting away from traditional methodologies to explore the monastic scribal cultures that produced and consumed First Crusade letters.
Social inclusion of people with dementia – an integrative review of theoretical frameworks, methods and findings in empirical studies
Authors: Pinkert Christiane , Köhler Kerstin , von Kutzleben Milena , Hochgräber Iris , Cavazzini Christoph , Völz Silke , Palm Rebecca , Holle Bernhard
Published: October 2019

The social inclusion of people with dementia (PwD) is recognised as a global goal of legislation, societal initiatives and service provision. Ensuring the social inclusion of PwD in these areas implies that its dimensions and domains are clear and unambiguous. However, the concept of social inclusion as it is currently used by researchers and practitioners is often vague or acts as a container concept for a variety of different approaches. This paper reports on an integrative review that analysed qualitative and quantitative studies on social inclusion and exclusion of PwD. It focused not only on the empirical results of the included studies but also on the theoretical embedding and methodological approaches to the concept of social inclusion and exclusion. We find that empirical studies on the social inclusion of PwD are scarce and largely characterised by a lack of or inconsistent conceptualisation. Against this background, the operationalisation of the concept and the assessment of the individual aspects of social inclusion with standardised instruments seem to be premature. Substantial theoretical and methodological work is needed to guide research on the social inclusion of PwD. The empirical results show that relationships with other people and being integrated into social networks are essential aspects of social inclusion. Likewise, the strategies and attitudes of caring persons can help to create or reinforce exclusion.
What contributes to successful whole-class Ensemble Tuition?
Authors: Hallam Susan
Published: October 2019

In 2001, the government in England pledged in the white paper Schools Achieving Success that all primary school pupils who wanted to should have the opportunity to learn to play a musical instrument. The research reported here aimed to establish what contributed to the success of the implementation of this policy. The findings showed that success depended on all school staff being committed to the programme; children having experience of high-quality provision; opportunities to participate in performance; and accessible progression routes.
A Simple and Rapid Staining Technique for Sex Determination of Trichinella Larvae Parasites by Confocal Laser Scanning Microscopy
Authors: Gavarane Inese , Kirilova Elena , Rubeniņa Ilze , Mežaraupe Ligita , Osipovs Sergejs , Deksne Gunita , Pučkins Aleksandrs , Kokina Inese , Bulanovs Andrejs , Kirjušina Muza
Published: October 2019

The roundworms of Trichinella genus are worldwide distributed and their prevalence in nature is high. Trichinella genus parasites are the causative agents of foodborne zoonosis trichinellosis. The main prevention and control of the infection are meat inspection by the magnetic stirrer method for the detection of Trichinella larvae in muscle samples. The treatment can be effective if the parasite is discovered early in the intestinal phase. Once the Trichinella larva has reached the muscle tissue, the parasite remains therein and there is no treatment for this life cycle stage. The Trichinella species is dioecious with separate male and female individuals. The developed staining technique that uses confocal laser scanning microscopy (CLSM) displays sufficient results for Trichinella larvae examination and this protocol is applicable to study the internal and external structures and for the sex determination of T. britovi and T. spiralis larvae samples. In the present study, a luminescent derivative was synthesized and used for staining of T. spiralis and T. britovi larvae samples for the examination by CLSM. Various fixatives, such as AFA, 70% ethanol, and Bouin's and Carnoy's solutions were tested for sample preparation. The synthesized luminescent compound demonstrates best visualization results for samples fixed in Bouin's fixative.
In VivoMultivesicular Body and Exosome Secretion in the Intestinal Epithelial Cells of Turtles During Hibernation
Authors: Vistro Waseem Ali , Huang Yufei , Bai Xuebing , Yang Ping , Haseeb Abdul , Chen Hong , Liu Yifei , Yue Zhang , Tarique Imran , Chen Qiusheng
Published: October 2019

The present study was designed to investigate thein vivobiological processes of multivesicular bodies (MVBs) and exosomes in mitochondria-rich cells (MRCs), goblet cells (GCs), and absorptive cells (ACs) in turtle intestines during hibernation. The exosome markers, cluster of differentiation 63 (CD63) and tumor susceptibility gene 101 (TSG101), were positively expressed in intestinal villi during turtle hibernation. The distribution and formation processes of MVBs and exosomes in turtle MRCs, GCs, and ACs were further confirmed by transmission electron microscopy. During hibernation, abundantly secreted early endosomes (ees) were localized in the luminal and basal cytoplasm of the MRCs and ACs, and late endosomes (les) were dispersed with the supranuclear parts of the MRCs and ACs. Many “heterogeneous” MVBs were identified throughout the cytoplasm of the MRCs and ACs. Interestingly, the ees, les, and MVBs were detected in the cytoplasm of the GCs during hibernation; however, they were absent during nonhibernation. Furthermore, the exocytosis pathways of exosomes and autophagic vacuoles were observed in the MRCs, GCs, and ACs during hibernation. In addition, the number of different MVBs with intraluminal vesicles (ILVs) and heterogeneous endosome–MVB–exosome complexes was significantly increased in the MRCs, GCs, and ACs during hibernation. All these findings indicate that intestinal epithelial cells potentially perform a role in the secretion of MVBs and exosomes, which are essential for mucosal immunity, during hibernation.
News Media Coverage of Stakeholder Views on Suicide and Its Reporting in New Zealand
Authors: Jenkin Gabrielle L. S. , Slim Ben E. , Collings Sunny
Published: October 2019

Abstract. Background: Periodically, a debate around suicide reporting becomes prominent in the media. At one point, the Chief Coroner of New Zealand made a public call to the media to open up discussions around suicide and its reporting. Following this action, a high-profile debate emerged in the media. Aims: Our aim was to identify the key players in this debate and examine their perspectives. Method: From a Factiva search of news items from high-circulation newspapers, we identified key stakeholders and documented their perspectives using a framing matrix. Results: Seven stakeholder groups were identified with coroners and health service providers dominant in the news. Framing around the issues varied. There was consensus among the majority of stakeholders supporting continued public health type coverage of the issue of suicide, but a number of differences in levels of support for the reporting individual suicides. Limitations: Although specific to New Zealand, the findings will be of interest to countries considering reporting restrictions. Conclusion: The debate around suicide and its reporting appears to have been obfuscated by the conflating of two different types of media reporting on suicide: news media coverage of suicide as a public health issue and the reporting of individual suicide cases.
Spatial Accessibility and Social Inclusion: The Impact of Portugal's Last Health Reform
Authors: Lopes H. S. , Ribeiro V. , Remoaldo P. C.
Published: October 2019

Health policies seek to promote access to health care and should provide appropriate geographical accessibility to each demographical functional group. The dispersal demand of health‐care services and the provision for such services at fixed locations contribute to the growth of inequality in their access. Therefore, the optimal distribution of health facilities over the space/area can lead to accessibility improvements and to the mitigation of the social exclusion of the groups considered most vulnerable. Requiring for such, the use of planning practices joined with accessibility measures. However, the capacities of Geographic Information Systems in determining and evaluating spatial accessibility in health system planning have not yet been fully exploited. This paper focuses on health‐care services planning based on accessibility measures grounded on the network analysis. The case study hinges on mainland Portugal. Different scenarios were developed to measure and compare impact on the population's accessibility. It distinguishes itself from other studies of accessibility measures by integrating network data in a spatial accessibility measure: the enhanced two‐step floating catchment area. The convenient location for health‐care facilities can increase the accessibility standards of the population and consequently reduce the economic and social costs incurred. Recently, the Portuguese government implemented a reform that aimed to improve, namely, the access and equity in meeting with the most urgent patients. It envisaged, in terms of equity, the allocation of 89 emergency network points that ensured more than 90% of the population be within 30 min from any one point in the network. Consequently, several emergency services were closed, namely, in rural areas. This reform highlighted the need to improve the quality of the emergency care, accessibility to each care facility, and equity in their access. Hence, accessibility measures become an efficient decision‐making tool, despite its absence in effective practice planning. According to an application of this type of measure, it was possible to verify which levels of accessibility were decreased, including the most disadvantaged people, with a larger time of dislocation of 12 min between 2001 and 2011.
Maximum Sprite Streamer Luminosity Near the Stratopause
Authors: Füllekrug Martin , Nnadih Stanislaus , Soula Serge , Mlynarczyk Janusz , Stock Micheal , Lapierre Jeff , Kosch Michael
Published: October 2019

Sprites are composed of numerous streamers which exhibit transient luminosities in the upper middle atmosphere above thunderclouds after initiation by an intense positive lightning discharge, often followed by lightning continuing current. Here we report the discovery of a sprite which exhibits its main luminosity near the stratopause. This novel phenomenon is attributed to a sudden surge of intracloud lightning leader activity, based on a rigorous analysis of our observed electromagnetic waveforms. Each lightning leader discharge causes an additional electric field that generates a small amount of electromagnetic energy near the stratopause and thereby contributes to the overall sprite luminosity morphology. The observation of sprite streamers near the stratopause is important because it is relevant for the ongoing assessment of the lightning impact on N2 and CO2 with emissions from the near to far infrared part of the spectrum.
Provenance of Block Fields Along Lunar Wrinkle Ridges
Authors: French Renee A. , Watters Thomas R. , Robinson Mark S.
Published: October 2019

Block fields and associated relatively high reflectance material along wrinkle ridge summits are revealed in meter‐scale Lunar Reconnaissance Orbiter Camera images. Wrinkle ridges with block fields in Mare Australe, Crisium, Fecunditatis, Frigoris, Nubium, the northern half of Oceanus Procellarum, Serenitatis, and Tranquillitatis are evenly distributed, and block density generally increases with wrinkle ridge slope. The median cross‐sectional area (proxy for diameter) of the 1,368 blocks measured in this study is ~7 m2, and 75% of these blocks are ≤~14 m2. We propose that the largest variation in cross‐sectional area of the blocks is related to substrate physical properties of the mare basalt and not a function of the slope on which they occur, suggesting that physical properties rather than slope are a stronger control on block size. The maximum length of blocks may constrain the minimum basalt flow thickness or joint width; our block measurements suggest basalt flows ~2–14 m thick, agreeing with previous estimates. The data suggest that blocks originate from mare basalt layers that buckle and break as a result of movement along ridge‐forming thrust faults. High reflectance material associated with wrinkle ridge blocks likely represents freshly exposed rock and soil. Meter‐scale blocks may erode relatively quickly due to collisional disruption, indicating recent downslope movement of regolith exposing preexisting blocks or blocks formed and exposed by recent activity on ridge‐forming faults.
Further evidence of involvement of TMEM132E in autosomal recessive nonsyndromic hearing impairment
Authors: Liaqat Khurram , Hussain Shabir , Bilal Muhammad , Nasir Abdul , Acharya Anushree , Ali Raja Hussain , Nawaz Shoaib , Umair Muhammad , Schrauwen Isabelle , Ahmad Wasim , Leal Suzanne M.
Published: October 2019

Autosomal-recessive (AR) nonsyndromic hearing impairment (NSHI) displays a high degree of genetic heterogeneity with >100 genes identified. Recently, TMEM132E, which is highly expressed in inner hair cells, was suggested as a novel ARNSHI gene for DFNB99. A missense variant c.1259G>A: p.(Arg420Gln) in TMEM132E was identified that segregated with ARNSHI in a single Chinese family with two affected members. In the present study, a family of Pakistani origin with prelingual profound sensorineural hearing impairment displaying AR mode of inheritance was investigated via exome and Sanger sequencing. Compound heterozygous variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu) in TMEM132E were observed in affected but not in unaffected family members. TMEM132E variants identified in this and the previously reported ARNSHI family are located in the extracellular domain. In conclusion, we present a second ARNSHI family with TMEM132E variants which strengthens the evidence of the involvement of this gene in the etiology of ARNSHI.
No more helper adenovirus: production of gutless adenovirus (GLAd) free of adenovirus and replication-competent adenovirus (RCA) contaminants
Authors: Lee Dongwoo , Liu Jida , Junn Hyun Jung , Lee Eun-Joo , Jeong Kyu-Shik , Seol Dai-Wu
Published: October 2019

Gene therapy is emerging as an effective treatment option for various inherited genetic diseases. Gutless adenovirus (GLAd), also known as helper-dependent adenovirus (HDAd), has many notable characteristics as a gene delivery vector for this particular type of gene therapy, including broad tropism, high infectivity, a large transgene cargo capacity, and an absence of integration into the host genome. Additionally, GLAd ensures long-term transgene expression in host organisms owing to its minimal immunogenicity, since it was constructed following the deletion of all the genes from an adenovirus. However, the clinical use of GLAd for the treatment of inherited genetic diseases has been hampered by unavoidable contamination of the highly immunogenic adenovirus used as a helper for GLAd production. Here, we report the production of GLAd in the absence of a helper adenovirus, which was achieved with a helper plasmid instead. Utilizing this helper plasmid, we successfully produced large quantities of recombinant GLAd. Importantly, our helper plasmid-based system exclusively produced recombinant GLAd with no generation of helper plasmid-originating adenovirus and replication-competent adenovirus (RCA). The recombinant GLAd that was produced efficiently delivered transgenes regardless of their size and exhibited therapeutic potential for Huntington’s disease (HD) and Duchenne muscular dystrophy (DMD). Our data indicate that our helper plasmid-based GLAd production system could become a new platform for GLAd-based gene therapy.
PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells
Authors: Hein Ashley L. , Brandquist Nichole D. , Ouellette Caroline Y. , Seshacharyulu Parthasarathy , Enke Charles A. , Ouellette Michel M. , Batra Surinder K. , Yan Ying
Published: October 2019

PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or biological inhibitors for the highly conserved A or C subunit of PP2A. Recent studies of specific pathways indicate that some PP2A complexes also possess tumor-promoting functions. We have previously reported an essential role of PR55α, a PP2A regulatory subunit, in the support of oncogenic phenotypes, including in vivo tumorigenicity/metastasis of pancreatic cancer cells. In this report, we have elucidated a novel role of PR55α-regulated PP2A in the activation of YAP oncoprotein, whose function is required for anchorage-independent growth during oncogenesis of solid tumors. Our data show two lines of YAP regulation by PR55α: (1) PR55α inhibits the MOB1-triggered autoactivation of LATS1/2 kinases, the core member of the Hippo pathway that inhibits YAP by inducing its proteasomal degradation and cytoplasmic retention and (2) PR55α directly interacts with and regulates YAP itself. Accordingly, PR55α is essential for YAP-promoted gene transcriptions, as well as for anchorage-independent growth, in which YAP plays a key role. In summary, current findings demonstrate a novel YAP activation mechanism based on the PR55α-regulated PP2A phosphatase.
Drivers of the composition of active rhizosphere bacterial communities in temperate grasslands
Authors: Vieira Selma , Sikorski Johannes , Dietz Sophie , Herz Katharina , Schrumpf Marion , Bruelheide Helge , Scheel Dierk , Friedrich Michael W , Overmann Jörg
Published: October 2019

The active bacterial rhizobiomes and root exudate profiles of phytometers of six plant species growing in central European temperate grassland communities were investigated in three regions located up to 700 km apart, across diverse edaphic conditions and along a strong land use gradient. The recruitment process from bulk soil communities was identified as the major direct driver of the composition of active rhizosphere bacterial communities. Unexpectedly, the effect of soil properties, particularly soil texture, water content, and soil type, strongly dominated over plant properties and the composition of polar root exudates of the primary metabolism. While plant species-specific selection of bacteria was minor, the RNA-based composition of active rhizosphere bacteria substantially differed between rhizosphere and bulk soil. Although other variables could additionally be responsible for the consistent enrichment of particular bacteria in the rhizosphere, distinct bacterial OTUs were linked to the presence of specific polar root exudates independent of individual plant species. Our study also identified numerous previously unknown taxa that are correlated with rhizosphere dynamics and hence represent suitable targets for future manipulations of the plant rhizobiome.
Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis
Authors: Someda Masataka , Kuroki Shunsuke , Miyachi Hitoshi , Tachibana Makoto , Yonehara Shin
Published: October 2019

Among caspase family members, Caspase-8 is unique, with associated critical activities to induce and suppress death receptor-mediated apoptosis and necroptosis, respectively. Caspase-8 inhibits necroptosis by suppressing the function of receptor-interacting protein kinase 1 (RIPK1 or RIP1) and RIPK3 to activate mixed lineage kinase domain-like (MLKL). Disruption ofCaspase-8expression causes embryonic lethality in mice, which is rescued by depletion of eitherRipk3orMlkl, indicating that the embryonic lethality is caused by activation of necroptosis. Here, we show that knockdown ofCaspase-8expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent onRipk1andRipk3; however, the enhancement of RA-induced cell differentiation is independent ofMlkland necrosome formation. RA treatment obviously enhanced the expression of RA-specific target genes having the retinoic acid response element (RARE) in their promoter regions to induce cell differentiation, and induced marked expression of RIPK1, RIPK3, and MLKL to stimulate necroptosis.Caspase-8knockdown induced RIPK1 and RIPK3 to translocate into the nucleus and to form a complex with RA receptor (RAR), and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity toRAREthan RAR without RIPK1 or RIPK3. InCaspase-8-deficient as well asCaspase-8- andMlkl-deficient mouse embryos, the expression of RA-specific target genes was obviously enhanced. Thus, Caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo.
MicroRNA-421 confers paclitaxel resistance by binding to the KEAP1 3′UTR and predicts poor survival in non-small cell lung cancer
Authors: Duan Fu-Gang , Wang Mei-Fang , Cao Ya-Bing , Dan Li  , Li Run-Ze , Fan Xing-Xing , Khan Imran , Lai Huan-Ling , Zhang Yi-Zhong , Hsiao Wendy Wen-Luan , Yao Xiao-Jun , Wu Qi-Biao , Liu Liang , Tang Yi-Jun , Leung Elaine Lai-Han
Published: October 2019

MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated protein 1(KEAP1) expression by targeting its 3′-untranslated region (3′UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, β-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting β-catenin reduced miR-421 levels in A549 cells. In addition, β-catenin upregulation enhanced miR-421 expression, indicating that β-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.
Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
Authors: Burocziova Monika , Burdova Kamila , Martinikova Andra S. , Kasparek Petr , Kleiblova Petra , Danielsen Stine A. , Borecka Marianna , Jenikova Gabriela , Janečková Lucie , Pavel Jozef , Zemankova Petra , Schneiderova Michaela , Schwarzova Lucie , Ticha Ivana , Sun Xiao-Feng , Jiraskova Katerina , Liska Vaclav , Vodickova Ludmila , Vodicka Pavel , Sedlacek Radislav , Kleibl Zdenek , Lothe Ragnhild A. , Korinek Vladimír , Macurek Libor
Published: October 2019

Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.
Correction: TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma
Authors: Giallongo Cesarina , Tibullo Daniele , Camiolo Giuseppina , Parrinello Nunziatina L. , Romano Alessandra , Puglisi Fabrizio , Barbato Alessandro , Conticello Concetta , Lupo Gabriella , Anfuso Carmelina Daniela , Lazzarino Giacomo , Volti Giovanni Li , Palumbo Giuseppe Alberto , Di Raimono Francesco
Published: October 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma
Authors: Mai ShiJuan , Xiao RuoWen , Shi Lu , Zhou XiaoMin , Yang Te , Zhang MeiYin , Weng NuoQing , Zhao XinGe , Wang RuiQi , Liu Ji , Sun Rui , Qin HaiDe , Wang HuiYun
Published: October 2019

miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.
Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
Authors: Dehghan Esmaeil , Goodarzi Mohammad , Saremi Bahar , Lin Rueyling , Mirzaei Hamid
Published: October 2019

Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan inC. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan inC. elegansunder high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.
A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers
Authors: Akerberg Brynn N. , Gu Fei , VanDusen Nathan J. , Zhang Xiaoran , Dong Rui , Li Kai , Zhang Bing , Zhou Bin , Sethi Isha , Ma Qing , Wasson Lauren , Wen Tong , Liu Jinhua , Dong Kunzhe , Conlon Frank L. , Zhou Jiliang , Yuan Guo-Cheng , Zhou Pingzhu , Pu William T.
Published: October 2019

Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.
Modification of boron nitride nanocages by titanium doping results unexpectedly in exohedral complexes
Authors: Li Ruyi , Wang Yang
Published: October 2019

Despite their early experimental production and observation, the unambiguous molecular structures of metal-containing boron nitride (BN) nanocages still remain mysterious. It has been commonly assumed that this family of compounds has the metal atom confined inside the cage, just like their isoelectronic cousins, carbon metallofullerenes do. Here, we demonstrate that Ti(BN)n ($$n$$
n
= 12–24) complexes have, unexpectedly, an exohedral structure instead of an endohedral one, which could be verified by collision-induced dissociation experiments. The predicted global minimum structures exhibit some common bonding features accounting for their high stability, and could be readily synthesized under typical conditions for generating BN nanoclusters. The Ti doping dramatically changes not only the cage topology, but the arrangement of B and N atoms, endowing the resultant compounds with potential for $${\mathrm{CO}}_{2}$$

CO

2

capture and nitrogen fixation. These findings may expand or alter the understanding of BN nanostructures functionalized with other transition metals.
Broad-spectrum resistance to bacterial blight in rice using genome editing
Authors: Oliva Ricardo , Ji Chonghui , Atienza-Grande Genelou , Huguet-Tapia José C. , Perez-Quintero Alvaro , Li Ting , Eom Joon-Seob , Li Chenhao , Nguyen Hanna , Liu Bo , Auguy Florence , Sciallano Coline , Luu Van T. , Dossa Gerbert S. , Cunnac Sébastien , Schmidt Sarah M. , Slamet-Loedin Inez H. , Vera Cruz Casiana , Szurek Boris , Frommer Wolf B. , White Frank F. , Yang Bing
Published: October 2019

Bacterial blight of rice is an important disease in Asia and Africa. The pathogen,Xanthomonas oryzaepv.oryzae(Xoo), secretes one or more of six known transcription-activator-like effectors (TALes) that bind specific promoter sequences and induce, at minimum, one of the three host sucrose transporter genesSWEET11,SWEET13andSWEET14, the expression of which is required for disease susceptibility. We used CRISPR–Cas9-mediated genome editing to introduce mutations in all threeSWEETgene promoters. Editing was further informed by sequence analyses of TALe genes in 63Xoostrains, which revealed multiple TALe variants forSWEET13alleles. Mutations were also created inSWEET14, which is also targeted by two TALes from an AfricanXoolineage. A total of five promoter mutations were simultaneously introduced into the rice line Kitaake and the elite mega varieties IR64 and Ciherang-Sub1. Paddy trials showed that genome-editedSWEETpromoters endow rice lines with robust, broad-spectrum resistance.
CO3+1 network formation in ultra-high pressure carbonate liquids
Authors: Wilding Martin , Bingham Paul A. , Wilson Mark , Kono Yoshio , Drewitt James W. E. , Brooker Richard A. , Parise John B.
Published: October 2019

Carbonate liquids are an important class of molten salts, not just for industrial applications, but also in geological processes. Carbonates are generally expected to be simple liquids, in terms of ionic interactions between the molecular carbonate anions and metal cations, and therefore relatively structureless compared to more “polymerized” silicate melts. But there is increasing evidence from phase relations, metal solubility, glass spectroscopy and simulations to suggest the emergence of carbonate “networks” at length scales longer than the component molecular anions. The stability of these emergent structures are known to be sensitive to temperature, but are also predicted to be favoured by pressure. This is important as a recent study suggests that subducted surface carbonate may melt near the Earth’s transition zone (~44 km), representing a barrier to the deep carbon cycle depending on the buoyancy and viscosity of these liquids. In this study we demonstrate a major advance in our understanding of carbonate liquids by combining simulations and high pressure measurements on a carbonate glass, (K2CO3-MgCO3) to pressures in excess of 40 GPa, far higher than any previous in situ study. We show the clear formation of extended low-dimensional carbonate networks of close CO32− pairs and the emergence of a “three plus one” local coordination environment, producing an unexpected increase in viscosity with pressure. Although carbonate melts may still be buoyant in the lower mantle, an increased viscosity by at least three orders of magnitude will restrict the upward mobility, possibly resulting in entrainment by the down-going slab.