bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Validity of Combining History Elements and Physical Examination Tests for Traumatic and Degenerative Symptomatic Meniscal Tears
Authors: Décary Simon , Fallaha Michel , Frémont Pierre , Martel‐Pelletier Johanne , Pelletier Jean‐Pierre , Feldman Debbie E. , Sylvestre Marie‐Pierre , Vendittoli Pascal‐André , Desmeules François
Published: October 2017

Background

The current approach to the clinical diagnosis of traumatic and degenerative symptomatic meniscal tears (SMTs) proposes combining history elements and physical examination tests without systematic prescription of imaging investigations, yet the evidence to support this diagnostic approach is scarce.

Objective

To assess the validity of diagnostic clusters combining history elements and physical examination tests to diagnose or exclude traumatic and degenerative SMT compared with other knee disorders.

Design

Prospective diagnostic accuracy study.

Settings

Patients were recruited from 2 orthopedic clinics, 2 family medicine clinics, and from a university community.

Patients

A total of 279 consecutive patients who underwent consultation for a new knee complaint.

Methods

Each patient was assessed independently by 2 evaluators. History elements and standardized physical examination tests performed by a physiotherapist were compared with the reference standard: an expert physicians' composite diagnosis including a clinical examination and confirmatory magnetic resonance imaging. Participating expert physicians were orthopedic surgeons (n = 3) or sport medicine physicians (n = 2). Penalized logistic regression (least absolute shrinkage and selection operator) was used to identify history elements and physical examination tests associated with the diagnosis of SMT and recursive partitioning was used to develop diagnostic clusters.

Main Outcome Measures

Diagnostic accuracy measures were calculated including sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LR+/–) with associated 95% confidence intervals (CIs).

Results

Eighty patients had a diagnosis of SMT (28.7%), including 35 traumatic tears and 45 degenerative tears. The combination a history of trauma during a pivot, medial knee pain location, and a positive medial joint line tenderness test was able to diagnose (LR+ = 8.9; 95% CI 6.1‐13.1) or exclude (LR– = 0.10; 95% CI 0.03‐0.28) a traumatic SMT. Combining a history of progressive onset of pain, medial knee pain location, pain while pivoting, absence of valgus or varus knee misalignment, or full passive knee flexion was able to moderately diagnose (LR+ = 6.4; 95% CI 4.0‐10.4) or exclude (LR– = 0.10; 95% CI 0.03‐0.31) a degenerative SMT. Internal validation estimates were slightly lower for all clusters but demonstrated positive LR superior to 5 and negative LR inferior to 0.2 indicating moderate shift in posttest probability.

Conclusion

Diagnostic clusters combining history elements and physical examination tests can support the differential diagnosis of SMT. These results represent the initial derivation of the clusters and external validation is mandatory.

Level of Evidence

I
The Fifth-Century Crisis
Authors: Smith Christopher
Published: October 2017

This essay seeks to establish the parameters of our uncertainty concerning one of the most difficult periods of Roman history, the period between the traditional end of the Roman monarchy and the passing of the Licinio-Sextian legislation. In addition to some methodological observations, the essay attempts to offer a model for understanding Roman choices and decisions in a period of change and transformation.
Plebeian Tribunes and the Government of Early Rome
Authors: Drogula Fred K.
Published: October 2017

Many modern scholars have argued that the consulship was not created at the foundation of the Republic as Roman tradition maintained, and that the government of the early Republic went through several stages of development before it reached the familiar ‘classical constitution.’ Building on this work, this article considers what the early civilian government of Rome may have looked like. It is argued that the Romans did not create an entirely new government (based on consuls) following the removal of the monarchy, but instead made use of existing sources of power and authority: rich land-owning clans dominated military activity outside the city, while priests, thecuriae, and minor officials exercised responsibilities of civilian governance in Rome. The plebeian tribunate was probably the first significant office to be created in the Republic, and the unusual nature of its power (sacrosanctity) and the absence of any other chief magistracy enabled the tribunes to acquire a broad range of prerogatives. A series of reforms eventually led to the development of the familiar ‘classical constitution’, and the consulship and praetorship became the most prestigious and desired magistracies (and—outside the city—the most powerful), but the tribunes long retained the broadest prerogatives for civilian governance inside the city.
Reynolds number scaling in cryogenic turbulent Rayleigh–Bénard convection in a cylindrical aspect ratio one cell
Authors: Musilová Věra , Králík Tomáš , La Mantia Marco , Macek Michal , Urban Pavel , Skrbek Ladislav
Published: October 2017

We perform an experimental study of turbulent Rayleigh–Bénard convection up to very high Rayleigh number, $10^{8}<Ra<10^{14}$, in a cylindrical aspect ratio one cell, 30 cm in height, filled with cryogenic helium gas. We monitor temperature fluctuations in the convective flow with four small (0.2 mm) sensors positioned in pairs 1.5 cm from the sidewalls and 2.5 cm vertically apart and symmetrically around the mid-height of the cell. Based on one-point and two-point correlations of the temperature fluctuations, we determine different types of Reynolds numbers, $\mathit{Re}$, associated with the large-scale circulation (LSC). We observe a transition between two types of $\mathit{Re}(\mathit{Ra})$ scaling around $\mathit{Ra}=10^{10}{-}10^{11}$, which is accompanied by a scaling change of the skewness of the probability distribution functions (PDFs) of the temperature fluctuations. The $\mathit{Re}(\mathit{Ra})$ dependencies measured near the sidewall at Prandtl number $\mathit{Pr}\sim 1$ are consistent with the $\mathit{Ra}^{4/9}\mathit{Pr}^{-2/3}$ scaling above the transition, while for $\mathit{Ra}<10^{10}$, the $\mathit{Re}(\mathit{Ra})$ dependencies are steeper. It seems likely that this change in $\mathit{Re}(\mathit{Ra})$ scaling is linked to the previously reported change in the Nusselt number $\mathit{Nu}(\mathit{Ra})$ scaling. This behaviour is in agreement with independent cryogenic laboratory experiments with $\mathit{Pr}\sim 1$, but markedly different from the $\mathit{Re}$ scaling obtained in water experiments ($\mathit{Pr}\sim 3.3{-}5.6$). We discuss the results in comparison with different versions of the Grossmann–Lohse theory.
On the critical free-surface flow over localised topography
Authors: Keeler J. S. , Binder B. J. , Blyth M. G.
Published: October 2017

Flow over bottom topography at critical Froude number is examined with a focus on steady, forced solitary wave solutions with algebraic decay in the far field, and their stability. Using the forced Korteweg–de Vries (fKdV) equation the weakly nonlinear steady solution space is examined in detail for the particular case of a Gaussian dip using a combination of asymptotic analysis and numerical computations. Non-uniqueness is established and a seemingly infinite set of steady solutions is uncovered. Non-uniqueness is also demonstrated for the fully nonlinear problem via boundary-integral calculations. It is shown analytically that critical flow solutions have algebraic decay in the far field both for the fKdV equation and for the fully nonlinear problem and, moreover, that the leading-order form of the decay is the same in both cases. The linear stability of the steady fKdV solutions is examined via eigenvalue computations and by a numerical study of the initial value fKdV problem. It is shown that there exists a linearly stable steady solution in which the deflection from the otherwise uniform surface level is everywhere negative.
Modes of synchronisation in the wake of a streamwise oscillatory cylinder
Authors: Tang Guoqiang , Cheng Liang , Tong Feifei , Lu Lin , Zhao Ming
Published: October 2017

A numerical analysis of flow around a circular cylinder oscillating in-line with a steady flow is carried out over a range of driving frequencies $(f_{d})$ at relatively low amplitudes $(A)$ and a constant Reynolds number of 175 (based on the free-stream velocity). The vortex shedding is investigated, especially when the shedding frequency $(f_{s})$ synchronises with the driving frequency. A series of modes of synchronisation are presented, which are referred to as the $p/q$ modes, where $p$ and $q$ are natural numbers. When a $p/q$ mode occurs, $f_{s}$ is detuned to $(p/q)f_{d}$, representing the shedding of $p$ pairs of vortices over $q$ cycles of cylinder oscillation. The $p/q$ modes are further characterised by the periodicity of the transverse force over every $q$ cycles of oscillation and a spatial–temporal symmetry possessed by the global wake. The synchronisation modes $(p/q)$ with relatively small natural numbers are less sensitive to the change of external control parameters than those with large natural numbers, while the latter is featured with a narrow space of occurrence. Although the mode of synchronisation can be almost any rational ratio (as shown for $p$ and $q$ smaller than 10), the probability of occurrence of synchronisation modes with $q$ being an even number is much higher than $q$ being an odd number, which is believed to be influenced by the natural even distribution of vortices in the wake of a stationary cylinder.
Global instability analysis and experiments on buoyant plumes
Authors: Bharadwaj Kuchimanchi K. , Das Debopam
Published: October 2017

The present work investigates the puffing instability of circular buoyant plumes by performing global linear stability analysis and experiments. In the non-dimensional parameter space investigated, plumes exhibit global instability only for axisymmetric perturbations with two unstable modes, which are of oscillatory type. The frequencies of these two unstable global modes agree well with the experiments which suggest that puffing occurs in buoyant plumes as a result of linear global instability. A comprehensive investigation on the effect of various non-dimensional parameters and inlet velocity profiles on frequency and growth rates of the global modes is carried out. The results are used to delineate the stability boundaries for these global modes and to obtain scaling laws for the associated oscillation frequencies. The analysis demonstrates that the two buoyancy parameters, Froude number and source-to-ambient density ratio, play dominant roles in impacting plume transition and oscillation frequencies. Results from global linear stability analysis and earlier experiments have majorly differed in two aspects. The earlier experiments reported a switch in puffing frequency scaling in Richardson number range 100–500, while the instability analysis predicts this switch at around 6000. Also, the instability analysis predicts the occurrence of puffing at density ratios higher than the critical value 0.5–0.6 reported in earlier experiments. To address these differences and validate the results obtained from global linear stability analysis, experiments are performed in a set-up that has been carefully designed to minimize the settling chamber disturbances. The present experiments corroborate the findings of global linear stability analysis. The mechanisms responsible for global instability in plumes have been identified using perturbation vorticity transport equation.
Separation control and drag reduction for boat-tailed axisymmetric bodies through contoured transverse grooves
Authors: Mariotti A. , Buresti G. , Gaggini G. , Salvetti M. V.
Published: October 2017

We describe the results of a numerical and experimental investigation aimed at assessing the performance of a control method to delay boundary layer separation consisting of the introduction on the surface of contoured transverse grooves, i.e. of small cavities with an appropriate shape orientated transverse to the incoming flow. The shape of the grooves and their depth – which must be significantly smaller than the thickness of the incoming boundary layer – are chosen so that the flow recirculations present within the grooves are steady and stable. This passive control strategy is applied to an axisymmetric bluff body with various rear boat tails, which are characterized by different degrees of flow separation. Variational multiscale large eddy simulations and wind tunnel tests are carried out. The Reynolds number, for both experiments and simulations, is $Re=u_{\infty }D/\unicode[STIX]{x1D708}=9.6\times 10^{4}$; due to the different incoming flow turbulence level, the boundary layer conditions before the boat tails are fully developed turbulent in the experiments and transitional in the simulations. In all cases, the introduction of one single axisymmetric groove in the lateral surface of the boat tails produces significant delay of the boundary layer separation, with consequent reduction of the pressure drag. Nonetheless, the wake dynamical structure remains qualitatively similar to the one typical of a blunt-based axisymmetric body, with quantitative variations that are consistent with the reduction in wake width caused by boat tailing and by the grooves. A few supplementary simulations show that the effect of the grooves is also robust to the variation of the geometrical parameters defining their shape. All the obtained data support the interpretation that the relaxation of the no-slip boundary condition for the flow surrounding the recirculation regions, with an appreciable velocity along their borders, is the physical mechanism responsible for the effectiveness of the present separation-control method.
Water waves with moving boundaries
Authors: Fokas Athanasios S. , Kalimeris Konstantinos
Published: October 2017

The unified transform, also known as the Fokas method, provides a powerful methodology for studying boundary value problems. Employing this methodology, we analyse inviscid, irrotational, two-dimensional water waves in a bounded domain, and in particular we study the generation of waves by a moving piecewise horizontal bottom, as it occurs in tsunamis. We show that this problem is characterised by two equations which involve only first-order derivatives. It is argued that under the assumptions of ‘small amplitude waves’ but not of ‘long waves’, the above two equations can be treated numerically via a recently introduced numerical technique for elliptic partial differential equations in a polygonal domain. In the particular case that the moving bottom is horizontal and under the assumption of ‘small amplitude waves’, but not of ‘long waves’, these equations yield a non-local generalisation of the Boussinesq system. Furthermore, under the additional assumption of ‘long waves’ the above system yields a Boussinesq-type system, which however includes the effect of the moving boundary.
Irreversible mixing by unstable periodic orbits in buoyancy dominated stratified turbulence
Authors: Lucas Dan , Caulfield C. P.
Published: October 2017

We consider turbulence driven by a large-scale horizontal shear in Kolmogorov flow (i.e. with sinusoidal body forcing) and a background linear stable stratification with buoyancy frequency $N_{B}^{2}$ imposed in the third, vertical direction in a fluid with kinematic viscosity $\unicode[STIX]{x1D708}$. This flow is known to be organised into layers by nonlinear unstable steady states, which incline the background shear in the vertical and can be demonstrated to be the finite-amplitude saturation of a sequence of instabilities, originally from the laminar state. Here, we investigate the next order of motions in this system, i.e. the time-dependent mechanisms by which the density field is irreversibly mixed. This investigation is achieved using ‘recurrent flow analysis’. We identify (unstable) periodic orbits, which are embedded in the turbulent attractor, and use these orbits as proxies for the chaotic flow. We find that the time average of an appropriate measure of the ‘mixing efficiency’ of the flow $\mathscr{E}=\unicode[STIX]{x1D712}/(\unicode[STIX]{x1D712}+{\mathcal{D}})$ (where ${\mathcal{D}}$ is the volume-averaged kinetic energy dissipation rate and $\unicode[STIX]{x1D712}$ is the volume-averaged density variance dissipation rate) varies non-monotonically with the time-averaged buoyancy Reynolds numbers $\overline{Re}_{B}=\overline{{\mathcal{D}}}/(\unicode[STIX]{x1D708}N_{B}^{2})$, and is bounded above by $1/6$, consistently with the classical model of Osborn (J. Phys. Oceanogr., vol. 10 (1), 1980, pp. 83–89). There are qualitatively different physical properties between the unstable orbits that have lower irreversible mixing efficiency at low $\overline{Re}_{B}\sim O(1)$ and those with nearly optimal $\mathscr{E}\lesssim 1/6$ at intermediate $\overline{Re}_{B}\sim 10$. The weaker orbits, inevitably embedded in more strongly stratified flow, are characterised by straining or ‘scouring’ motions, while the more efficient orbits have clear overturning dynamics in more weakly stratified, and apparently shear-unstable flow.
Flows of liquid4He due to oscillating grids
Authors: Švančara P. , La Mantia M.
Published: October 2017

We investigate cryogenic flows of liquid4He between two grids oscillating in phase, at temperatures ranging from approximately 1.3 to 2.5 K, resulting in suitably defined Reynolds numbers up to$10^{5}$. We specifically study the flow-induced motions of small particles suspended in the fluid by using the particle tracking velocimetry technique. We focus on turbulent flows of superfluid4He that occur below approximately 2.2 K and are known to display, in certain conditions, features different from those observed in flows of classical viscous fluids, such as water. We find that, at large enough length scales, larger than the mean distance between quantized vortices, representing the quantum length scale of the flow, the shapes of the velocity and velocity increment statistical distributions are very similar to those obtained in turbulent flows of viscous fluids. The experimental outcome strongly supports the view that, in the range of investigated parameters, particles probing flows of superfluid4He behave as if they were tracking classical flows.
Land, belonging and structural oblivion among contemporary white Kenyans
Authors: McIntosh Janet
Published: October 2017

In recent years, settler descendants in Kenya have found their rights to hold land in Laikipia challenged by Maasai activists. Many have defended themselves by drawing on colonial-era discourses about pastoralist ecology and what constitutes good use of the land. These discourses have side-stepped ecological history and the moral problematics of colonial land seizure, while treating Maasai anger and nostalgia as manipulative and inauthentic. At the same time, new ‘community-based’ conservation movements, in conjunction with Afro-Kenyan activism, have prodded some white Kenyans into loosening their epistemology and making preliminary, partial concessions to Afro-Kenyan points of view. Yet, I suggest, these concessions themselves are part of a new, shifting model of whiteness: one that responds to new political imperatives, yet retains certain ways of justifying white advantages in landholding. I draw on these shifts to explore similarities with and disjunctures from colonial whiteness among these contemporary white Kenyans feeling the pressure to move from one historical era to another.
Mobilizing the past:creuseurs, precarity and the colonizing structure in the Congo Copperbelt
Authors: Makori Timothy
Published: October 2017

The Copperbelt of Congo was once the bastion of industrial development and no individual embodied its modernity as fully as the salaried industrial miner. Today, with the near collapse of the state-run mining company, Gécamines, and the liberalization of the mining industry starting in 2002, the majority of miners are no longer trained and salaried industrial workers but rather children and youth eking out a precarious living as artisanal miners orcreuseurs. In Congo, artisanal mining is paradoxical, for, although it indexes a future of unskilled, untrained, flexible work in rural and peri-urban enclaves, its organization of labour and rudimentary techniques of copper extraction allude to and borrow from the colonial and precolonial past.Creuseursmobilize the past as a strategic response to the threat of dispossession of ‘their’ land by the state and foreign investors, and they do so by laying claim to an anterior ‘sovereign’ – the ancestors – whose existence predates colonialism. This paradoxical emplacement of artisanal mining, its entanglement in time, invites interrogation of some of the ways in which scholars have understood precarity not only as a politically induced condition resulting from neoliberalism but also as an outcome of the enduring nature of the colonizing structure in Africa.
Surviving in a “Society”-centric World: Comments on Engseng Ho's “Inter-Asian Concepts for Mobile Societies”
Authors: Thum Rian
Published: October 2017

While this essay will speak primarily from a historian's perspective, I want first to acknowledge that the idea of “societies” has had a peculiarly interdisciplinary hold on scholarship, bridging the humanities and social sciences. For sociologists it is a disciplinary foundation, for anthropologists it is often an escape hatch from the problematic notion of “cultures,” and for historians it is an organizational scheme that has stealthily metamorphosed into an unconsidered worldview. While some disciplines, especially sociology, have invested more effort than others in critically examining the idea of societies, each has produced critiques that perhaps should have killed off “societies” altogether. And yet enormous numbers of new works continue to take “societies” as their objects of study (e.g., Thum 2014), with even transnational and global studies framed as the interaction of supposedly distinct societies.
Individual differences predict ERP signatures of second language learning of novel grammatical rules
Authors: NICHOLS EMILY S. , JOANISSE MARC F.
Published: October 2017

We investigated the extent to which second-language (L2) learning is influenced by the similarity of grammatical features in one's first language (L1). We used event-related potentials to identify neural signatures of a novel grammatical rule – grammatical gender – in L1 English speakers. Of interest was whether individual differences in L2 proficiency and age of acquisition (AoA) influenced these effects. L2 and native speakers of French read French sentences that were grammatically correct, or contained either a grammatical gender or word order violation. Proficiency and AoA predicted Left Anterior Negativity amplitude, with structure violations driving the proficiency effect and gender violations driving the AoA effect. Proficiency, group, and AoA predicted P600 amplitude for gender violations but not structure violations. Different effects of grammatical gender and structure violations indicate that L2 speakers engage novel grammatical processes differently from L1 speakers and that this varies appreciably based on both AoA and proficiency.
Examining Facets of Depression and Social Anxiety: The Relation among Lack of Positive Affect, Negative Cognitions, and Emotion Dysregulation
Authors: Blanco Ivan , Joormann Jutta
Published: October 2017

Depression and Social Anxiety Disorder are commonly conceptualized by the presence of negative affect. However, these disorders are also characterized by lack of positive affect, presence of negative cognitions, and emotion dysregulation which may play an important role in the onset and maintenance of these disorders. The present study explored differences among these variables in 189 clinical patients diagnosed with Major Depression, Social Anxiety Disorder, or both. Results showed differences in lack of positivity F(2, 185) = 18.92, p = .0001, η2 = .17, presence of negative cognitions F(2, 185) = 13.97, p = .0001, η2 = .13, and the use of rumination F(2, 185) = 14.63, p = .0001, η2 = .14 and punishment F(2, 181) = 7.64, p = .001, η2 = .08 among groups. Overall, lack of positivity, negative cognitions, and emotion dysregulation were elevated in the comorbid group, whereas lack of positivity and negative cognitions were specifically found for patients diagnosed with depression compared to socially anxious patients. In addition, the study examined the relation of both, lack of positivity and negative cognitions, to emotion regulation processes among groups. Overall, lack of positivity was associated with fear and avoidance in the social anxiety group (all r > .417, p < .01), whereas lack of positivity and negative cognitions were associated with rumination across the three groups (all r > .370, p < .01). Limitations of the present study and future directions are discussed.
Domain-Specificity of Need for Cognition Among High School	Students
Authors: Keller Ulrich , Strobel Anja , Martin Romain , Preckel Franzis
Published: October 2017

Abstract. Need for Cognition (NFC) is increasingly investigated in educational research. In contrast to other noncognitive constructs in this area, such as academic self-concept and interest, NFC has consistently been conceptualized as domain-general. We employed structural equation modeling to address the question of whether NFC can be meaningfully and gainfully conceptualized as domain-specific. To this end, we developed a domain-specific 20-item NFC scale with parallel items for Science, Mathematics, German, and French. Additionally, domain-general NFC was assessed with five domain-general items. Using a cross-sectional sample of more than 4,500 Luxembourgish 9th graders, we found that a nested-factor model incorporating both a general factor and domain-specific factors better accounted for the data than a single-factor or a correlated-factor model. However, the influence of the general factor was markedly stronger than in corresponding models for academic self-concept and interest. When controlling for the domain-specific factors, only Mathematics achievement was significantly predicted by the domain-general factor, while all achievement measures (Mathematics, French, and German) were predicted by the corresponding domain-specific factor. The nested domain-specific NFC factors were clearly empirically distinguishable from first-order domain-specific interest factors.
Ocean Showers Power the Global Electric Circuit
Authors: Underwood Emily
Published: October 2017

Satellite measurements confirm hundred-year-old observations collected by boat.
When Does HARKing Hurt? Identifying When Different Types of Undisclosed Post Hoc Hypothesizing Harm Scientific Progress
Authors: Rubin Mark
Published: October 2017

Hypothesizing after the results are known, or HARKing, occurs when researchers check their research results and then add or remove hypotheses on the basis of those results without acknowledging this process in their research report ( Kerr, 1998 ). In the present article, I discuss 3 forms of HARKing: (a) using current results to construct post hoc hypotheses that are then reported as if they were a priori hypotheses; (b) retrieving hypotheses from a post hoc literature search and reporting them as a priori hypotheses; and (c) failing to report a priori hypotheses that are unsupported by the current results. These 3 types of HARKing are often characterized as being bad for science and a potential cause of the current replication crisis. In the present article, I use insights from the philosophy of science to present a more nuanced view. Specifically, I identify the conditions under which each of these 3 types of HARKing is most and least likely to be bad for science. I conclude with a brief discussion about the ethics of each type of HARKing.
A novel lnc-PCF promotes the proliferation of TGF-β1-activated epithelial cells by targeting miR-344a-5p to regulate map3k11 in pulmonary fibrosis
Authors: Liu Huizhu , Wang Bingsi , Zhang Jinjin , Zhang Songzi , Wang Youlei , Zhang Jie , Lv Changjun , Song Xiaodong
Published: October 2017

Emerging evidence suggests that microRNA (miRNA) and long noncoding RNA (lncRNA) play important roles in disease development. However, the mechanism underlying mRNA interaction with miRNA and lncRNA in idiopathic pulmonary fibrosis (IPF) remains unknown. This study presents a novel lnc-PCF that promotes the proliferation of TGF-β1-activated epithelial cells through the regulation of map3k11 by directly targeting miR-344a-5p during pulmonary fibrogenesis. Bioinformatics and in vitro translation assay were performed to confirm whether or not lnc-PCF is an actual lncRNA. RNA fluorescent in situ hybridization (FISH) and nucleocytoplasmic separation showed that lnc-PCF is mainly expressed in the cytoplasm. Knockdown and knockin of lnc-PCF indicated that lnc-PCF could promote fibrogenesis by regulating the proliferation of epithelial cells activated by TGF-β1 according to the results of xCELLigence real-time cell analysis system, flow cytometry, and western blot analysis. Computational analysis and a dual-luciferase reporter system were used to identify the target gene of miR-344a-5p, whereas RNA pull down, anti-AGO2 RNA immunoprecipitation, and rescue experiments were conducted to confirm the identity of this direct target. Further experiments verified that lnc-PCF promotes the proliferation of activated epithelial cells that were dependent on miR-344a-5p, which exerted its regulatory functions through its target gene map3k11. Finally, adenovirus packaging sh-lnc-PCF was sprayed into rat lung tissues to evaluate the therapeutic effect of lnc-PCF. These findings revealed that lnc-PCF can accelerate pulmonary fibrogenesis by directly targeting miR-344a-5p to regulate map3k11, which may be a potential therapeutic target in IPF.
Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib
Authors: Quintavalle Cristina , Hindupur Sravanth Kumar , Quagliata Luca , Pallante Pierlorenzo , Nigro Cecilia , Condorelli Gerolama , Andersen Jesper Bøje , Tagscherer Katrin Elisabeth , Roth Wilfried , Beguinot Francesco , Heim Markus Hermann , Ng Charlotte Kiu Yan , Piscuoglio Salvatore , Matter Matthias Sebastian
Published: October 2017

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. However, its function in HCC has not been addressed yet. Our study revealed that both transcript and protein levels of PED were significantly high in HCC compared with non-tumoral tissue. Clinico-pathological correlation revealed that PEDhigh HCCs showed an enrichment of gene signatures associated with metastasis and poor prognosis. Further, we observed that PED overexpression elevated the migration potential and PED silencing the decreased migration potential in liver cancer cell lines without effecting cell proliferation. Interestingly, we found that PED expression was regulated by a hepatocyte specific nuclear factor, HNF4α. A reduction of HNF4α induced an increase in PED expression and consequently, promoted cell migration in vitro. Finally, PED reduced the antitumoral effect of sorafenib by inhibiting caspase-3/7 activity. In conclusion, our data suggest that PED has a prominent role in HCC biology. It acts particularly on promoting cell migration and confers resistance to sorafenib treatment. PED may be a novel target for HCC therapy and serve as a predictive marker for treatment response against sorafenib.
MiR-629 promotes human pancreatic cancer progression by targeting FOXO3
Authors: Yan Haijiao , Li Qing , Wu Jun , Hu Wenwei , Jiang Jingting , Shi Liangrong , Yang Xin , Zhu Danxia , Ji Mei , Wu Changping
Published: October 2017

The FOXO signaling pathway has been reported to have an important role in human cancer. Expression of miR-629 was markedly upregulated in pancreatic cancer and negatively correlated with FOXO3. Therefore, exploring the regulatory mechanism of miR-629 and FOXO3 signaling may provide valuable clinical targets for pancreatic cancer therapy. In the current study, we found that overexpressing and inhibiting miR-629, respectively, enhanced and reduced the cell proliferation and metastasis of pancreatic cancer cells in vitro and in vivo compared with parental cells or cells transfected with a control vector. Furthermore, we found that miR-629 negatively regulated FOXO3 protein expression and decreased the activity of a luciferase reporter construct containing the FOXO3 3′-untranslated region. These results show that miR-629 regulates FOXO3 at the posttranscriptional level, resulting in enhanced cell proliferation and invasion of pancreatic carcinoma. Furthermore, we found that overexpressing miR-629 enhanced, while inhibiting miR-629 reduced, the stem cell-like phenotype of pancreatic cancer cells in vitro. A functional polymorphism at miR-629-binding site in the 3′-UTR of FOXO3 gene confers a decreased risk of progression in pancreatic carcinoma. Furthermore, these findings suggest that miR-629 has a vital role in promoting the development of pancreatic cancer and may represent a novel prognostic biomarker and therapeutic target.
Circular RNA profiling reveals an abundant circLMO7 that regulates myoblasts differentiation and survival by sponging miR-378a-3p
Authors: Wei Xuefeng , Li Hui , Yang Jiameng , Hao Dan , Dong Dong , Huang Yongzhen , Lan Xianyong , Plath Martin , Lei Chuzhao , Lin Fengpeng , Bai Yueyu , Chen Hong
Published: October 2017

Circular RNAs (circRNAs) have been identified from various tissues and species, but their regulatory functions during developmental processes are not well understood. We examined circRNA expression profiles of two developmental stages of bovine skeletal muscle (embryonic and adult musculus longissimus) to provide first insights into their potential involvement in bovine myogenesis. We identified 12 981 circRNAs and annotated them to the Bos taurus reference genome, including 530 circular intronic RNAs (ciRNAs). One parental gene could generate multiple circRNA isoforms, with only one or two isoforms being expressed at higher expression levels. Also, several host genes produced different isoforms when comparing development stages. Most circRNA candidates contained two to seven exons, and genomic distances to back-splicing sites were usually less than 50 kb. The length of upstream or downstream flanking introns was usually less than 105 nt (mean≈11 000 nt). Several circRNAs differed in abundance between developmental stages, and real-time quantitative PCR (qPCR) analysis largely confirmed differential expression of the 17 circRNAs included in this analysis. The second part of our study characterized the role of circLMO7—one of the most down-regulated circRNAs when comparing adult to embryonic muscle tissue—in bovine muscle development. Overexpression of circLMO7 inhibited the differentiation of primary bovine myoblasts, and it appears to function as a competing endogenous RNA for miR-378a-3p, whose involvement in bovine muscle development has been characterized beforehand. Congruent with our interpretation, circLMO7 increased the number of myoblasts in the S-phase of the cell cycle and decreased the proportion of cells in the G0/G1 phase. Moreover, it promoted the proliferation of myoblasts and protected them from apoptosis. Our study provides novel insights into the regulatory mechanisms underlying skeletal muscle development and identifies a number of circRNAs whose regulatory potential will need to be explored in the future.
miR-99a reveals two novel oncogenic proteins E2F2 and EMR2 and represses stemness in lung cancer
Authors: Feliciano Andrea , Garcia-Mayea Yoelsis , Jubierre Luz , Mir Cristina , Hummel Manuela , Castellvi Josep , Hernández-Losa Javier , Paciucci Rosanna , Sansano Irene , Sun Yilin , Ramón y Cajal Santiago , Kondon Hiroshi , Soriano Aroa , Segura Miguel , Lyakhovich Alex , LLeonart Matilde E
Published: October 2017

Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA expression is found in human tumours because it is involved in tumour growth, progression and metastasis. In this study, we analysed microRNA expression in 47 lung cancer biopsies. Among the most downregulated microRNAs we focussed on the miR-99a characterisation. In vitro experiments showed that miR-99a expression decreases the proliferation of H1650, H1975 and H1299 lung cancer cells causing cell cycle arrest and apoptosis. We identified two novel proteins, E2F2 (E2F transcription factor 2) and EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2), downregulated by miR-99a by its direct binding to their 3′-UTR. Moreover, miR-99a expression prevented cancer cell epithelial-to-mesenchymal transition (EMT) and repressed the tumourigenic potential of the cancer stem cell (CSC) population in both these cell lines and mice tumours originated from H1975 cells. The expression of E2F2 and EMR2 at protein level was studied in 119 lung cancer biopsies. E2F2 and EMR2 are preferentially expressed in adenocarcinomas subtypes versus other tumour types (squamous and others). Interestingly, the expression of E2F2 correlates with the presence of vimentin and both E2F2 and EMR2 correlate with the presence of β-catenin. Moreover, miR-99a expression correlates inversely with E2F2 and directly with β-catenin expression in lung cancer biopsies. In conclusion, miR-99a reveals two novel targets E2F2 and EMR2 that play a key role in lung tumourigenesis. By inhibiting E2F2 and EMR2, miR-99a represses in vivo the transition of epithelial cells through an EMT process concomitantly with the inhibition of stemness features and consequently decreasing the CSC population.
Suppression of BMP-7 by histone deacetylase 2 promoted apoptosis of renal tubular epithelial cells in acute kidney injury
Authors: Ma Taotao , Huang Cheng , Xu Qingqing , Yang Yang , Liu Yaru , Meng Xiaoming , Li Jun , Ye Min , Liang Hong
Published: October 2017

Cisplatin, a highly effective and widely used chemotherapeutic agent, has a major limitation for its nephrotoxicity. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. We recently identified a novel strategy for attenuating its nephrotoxicity in chemotherapy by histone deacetylase (HDAC) inhibitors via epigenetic modification to enhance bone morphogenetic protein 7 (BMP-7) expression. Cisplatin upregulated the activity of HDAC2 in the kidney. Inhibition of HDAC with clinically used trichostatin A (TSA) or valproic acid (VPA) suppressed cisplatin-induced kidney injury and epithelial cell apoptosis. Overexpression of HDAC2 promotes CP-treated tubular epithelium cells apoptosis. Chromatin immunoprecipitation assay clearly detected HDAC2 assosiation with BMP-7 promoter. Western blot and immunofluorescence results demonstrated that the expression of BMP-7 was clearly induced by TSA or VPA in vivo and in vitro. Interestingly, administration of recombinant BMP-7 (rhBMP-7) reduced cisplatin-induced kidney dysfunction. Moreover, BMP-7 treatment suppressed epithelial cell apoptosis and small interfering RNA-based knockdown of BMP-7 expression abolished HDAC inhibitors suppression of epithelial cell apoptosis in vitro. Results of current study indicated that TSA or VPA inhibited apoptosis of renal tubular epithelial cells via promoting the level of BMP-7 epigenetically through targeting HDAC2. Hence, HDAC inhibitors could be useful therapeutic agents for the prevention of cisplatin nephrotoxicity.
MiR-106a-5p inhibits the cell migration and invasion of renal cell carcinoma through targeting PAK5
Authors: Pan Yao-Jie , Wei Lu-Lu , Wu Xiao-Jin , Huo Fu-Chun , Mou Jie , Pei Dong-Sheng
Published: October 2017

MicroRNA-106a-5p (MiR-106a-5p), a small non-coding RNA, has been reported to be downregulated in astrocytoma, osteosarcoma and colorectal cancer. However, the expression levels and biological function in renal cell carcinoma (RCC) have not been studied yet. In this study, we found that the miR-106a-5p was significantly downregulated in RCC tissues and cell lines, and that overexpression of miR-106a-5p led to decreased cell metastasis ability in a xenograft model. Inhibition of miR-106a-5p in RCC cell lines altered the cell migration, invasion and wound healing abilities. Mechanistic studies demonstrated that miR-106a-5p directly bound to the 3′-UTR of the PAK5 mRNA and mediated a decrease in the protein expression of PAK5. We further proved that PAK5 protein levels were negatively correlated with the miR-106a-5p expression in both patient samples and xenograft model. In epigenetics, methylation specific PCR experiments indicated that the upstream gene promoter of miR-106a-5p was hypermethylated in RCC, which might be responsible for its downregulation. Our findings suggested that miR-106a-5p might be a potential gene therapy target for the treatment of RCC metastasis.
Correction: Corrigendum: MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells
Authors: Lai Xianning , Broderick Ronan , Bergoglio Valérie , Zimmer Jutta , Badie Sophie , Niedzwiedz Wojciech , Hoffmann Jean-Sébastien , Tarsounas Madalena
Published: October 2017

Nature Communications 8: Article number: 15983 (2017); Published: 17 July 2017; Updated: 26 October 2017 In this Article, there are errors in the labelling of the y axis in Fig. 1a and Supplementary Fig. 1b. The labels ‘20’, ‘40’, ‘60’, ‘80’ and ‘100’ should have been ‘0.5’, ‘1.0’ and ‘1.5’ in Fig. 1a and the labels ‘50’, ‘100’, ‘150’ and ‘200’ should have been ‘1’, ‘2’ and ‘3’ in Supplementary Fig.
Quantitative structural mechanobiology of platelet-driven blood clot contraction
Authors: Kim Oleg V. , Litvinov Rustem I. , Alber Mark S. , Weisel John W.
Published: October 2017

Blood clot contraction plays an important role in prevention of bleeding and in thrombotic disorders. Here, we unveil and quantify the structural mechanisms of clot contraction at the level of single platelets. A key elementary step of contraction is sequential extension–retraction of platelet filopodia attached to fibrin fibers. In contrast to other cell–matrix systems in which cells migrate along fibers, the “hand-over-hand” longitudinal pulling causes shortening and bending of platelet-attached fibers, resulting in formation of fiber kinks. When attached to multiple fibers, platelets densify the fibrin network by pulling on fibers transversely to their longitudinal axes. Single platelets and aggregates use actomyosin contractile machinery and integrin-mediated adhesion to remodel the extracellular matrix, inducing compaction of fibrin into bundled agglomerates tightly associated with activated platelets. The revealed platelet-driven mechanisms of blood clot contraction demonstrate an important new biological application of cell motility principles.
Role of influenza A virus NP acetylation on viral growth and replication
Authors: Giese Sebastian , Ciminski Kevin , Bolte Hardin , Moreira Étori Aguiar , Lakdawala Seema , Hu Zehan , David Quinnlan , Kolesnikova Larissa , Götz Veronika , Zhao Yongxu , Dengjel Jörn , Chin Y. Eugene , Xu Ke , Schwemmle Martin
Published: October 2017

Lysine acetylation is a post-translational modification known to regulate protein functions. Here we identify several acetylation sites of the influenza A virus nucleoprotein (NP), including the lysine residues K77, K113 and K229. Viral growth of mutant virus encoding K229R, mimicking a non-acetylated NP lysine residue, is severely impaired compared to wildtype or the mutant viruses encoding K77R or K113R. This attenuation is not the result of decreased polymerase activity, altered protein expression or disordered vRNP co-segregation but rather caused by impaired particle release. Interestingly, release deficiency is also observed mimicking constant acetylation at this site (K229Q), whereas virus encoding NP-K113Q could not be generated. However, mimicking NP hyper-acetylation at K77 and K229 severely diminishes viral polymerase activity, while mimicking NP hypo-acetylation at these sites has no effect on viral replication. These results suggest that NP acetylation at K77, K113 and K229 impacts multiple steps in viral replication of influenza A viruses.
Acoel regeneration mechanisms indicate an ancient role for muscle in regenerative patterning
Authors: Raz Amelie A. , Srivastava Mansi , Salvamoser Ranja , Reddien Peter W.
Published: October 2017

Positional information is required for animal regeneration, yet how it is harbored in adult tissues is poorly understood. In planarians, positional control genes (PCGs) control regeneration outcomes and are regionally expressed predominately in the musculature. Acoels are early diverging bilaterally symmetric animals, having separated from other bilaterians > 550 million years ago. Here, we find that PCGs in the acoel Hofstenia miamia are expressed together and specifically in a primary differentiated cell type: muscle. The vast majority of Hofstenia muscle cells in regions tested express PCGs, suggesting positional information is a major feature of muscle. PCG expression domains are dynamic in muscle after injury, consistent with known PCG roles in guiding regeneration. These data demonstrate an instructive positional role for Hofstenia muscle and this similarity with planarians suggests mesodermal muscle originated at the base of the Bilateria not only for contraction, but also as the source of positional information guiding regeneration.
Combating subclonal evolution of resistant cancer phenotypes
Authors: Brady Samuel W. , McQuerry Jasmine A. , Qiao Yi , Piccolo Stephen R. , Shrestha Gajendra , Jenkins David F. , Layer Ryan M. , Pedersen Brent S. , Miller Ryan H. , Esch Amanda , Selitsky Sara R. , Parker Joel S. , Anderson Layla A. , Dalley Brian K. , Factor Rachel E. , Reddy Chakravarthy B. , Boltax Jonathan P. , Li Dean Y. , Moos Philip J. , Gray Joe W. , Heiser Laura M. , Buys Saundra S. , Cohen Adam L. , Johnson W. Evan , Quinlan Aaron R. , Marth Gabor , Werner Theresa L. , Bild Andrea H.
Published: October 2017

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer’s ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.