bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth trajectories and oxygen use in neuroendocrine cell hyperplasia of infancy
Authors: Nevel Rebekah J. , Garnett Errine T. , Schaudies Deneen A. , Young Lisa R.
Published: February 2018

Rationale

Neuroendocrine cell hyperplasia of infancy (NEHI) typically presents in infancy with tachypnea, retractions, and hypoxemia. Some infants have failure to thrive, yet the frequency of this and other non‐respiratory phenotypic features have not been delineated. While gradual improvement occurs, the clinical course is variable and the duration of supplemental oxygen requirement has not been defined.

Objectives

Our objective was to identify factors in NEHI that may drive differences in clinical course. We hypothesized that failure to thrive would be associated with greater duration of supplemental oxygen use.

Methods

Children with NEHI were identified as a nested retrospective cohort within an ongoing observational prospective study. An electronic questionnaire evaluating health status was distributed to the parents/guardians. Clinical data were obtained via chart review and parent interview.

Results

Of 42 children, 74% had a diagnosis of failure to thrive during their clinical course. Time to event analysis demonstrated that 50% discontinued daytime and nighttime oxygen at 32 and 87.5 months after initiation, respectively. Diagnosis of failure to thrive was associated with longer continuous oxygen supplementation, P = 0.03. Additional parental concerns identified through the electronic questionnaire included developmental delays, multiple hospitalizations, and delays in diagnosis.

Conclusions

NEHI is associated with substantial respiratory and extra‐pulmonary morbidity. Failure to thrive may be associated with greater respiratory morbidity, though further studies are required to define this interaction. Determining the association of these comorbidities and respiratory course in NEHI may enable development of strategies to improve these modifiable factors and potentially pulmonary outcomes.
The transformed gamma process for degradation phenomena in presence of unexplained forms of unit‐to‐unit variability
Authors: Giorgio Massimiliano , Guida Maurizio , Pulcini Gianpaolo
Published: February 2018

The transformed gamma process is a suitable model for degradation phenomena where damages accumulate gradually over time in a sequence of tiny increments. Attractiveness of the transformed gamma process mainly lies in the fact that it provides a relatively easy way for dealing with phenomena in which the degradation increments over disjoint time intervals are not independent. The transformed gamma process is also a very flexible model. In fact, it is indexed by 2 functions, the “age function” and the “state function,” whose mathematical form can be chosen ad hoc for modeling the dependence of the future degradation increment of a unit on its current age and state, respectively. In this paper, the transformed gamma process is adopted to describe the degradation paths of degrading units in the presence of an unexplained form of unit‐to‐unit variability. The degradation path of each unit is described via a transformed gamma process. Heterogeneity among paths of different units is accounted for by assuming that the scale parameters of the age and state functions vary randomly from unit to unit. Under these assumptions, a quite mathematically tractable model is obtained. The main properties of the proposed model are discussed, and inferential procedures based on the maximum likelihood criterion are implemented. A simple test is presented to check the goodness of fit of the proposed model. Three applicative examples, based on real degradation data, are developed.
Ex Vivo Expansion of CD34+CD90+CD49f+ Hematopoietic Stem and Progenitor Cells from Non-Enriched Umbilical Cord Blood with Azole Compounds
Authors: Bari Sudipto , Zhong Qixing , Fan Xiubo , Poon Zhiyong , Lim Alvin Soon Tiong , Lim Tse Hui , Dighe Niraja , Li Shang , Chiu Gigi Ngar Chee , Chai Christina Li Lin , Hwang William Ying Khee
Published: February 2018

Umbilical cord blood (UCB) transplants in adults have slower hematopoietic recovery compared to bone marrow (BM) or peripheral blood (PB) stem cells mainly due to low number of total nucleated cells and hematopoietic stem and progenitor cells (HSPC). As such in this study, we aimed to perform ex vivo expansion of UCB HSPC from non-enriched mononucleated cells (MNC) using novel azole-based small molecules. Freshly-thawed UCB–MNC were cultured in expansion medium supplemented with small molecules and basal cytokine cocktail. The effects of the expansion protocol were measured based on in vitro and in vivo assays. The proprietary library of >50 small molecules were developed using structure-activity-relationship studies of SB203580, a known p38-MAPK inhibitor. A particular analog, C7, resulted in 1,554.1 ± 27.8-fold increase of absolute viable CD45+CD34+CD38–CD45RA– progenitors which was at least 3.7-fold higher than control cultures (p < .001). In depth phenotypic analysis revealed >600-fold expansion of CD34+/CD90+/CD49f+ rare HSPCs coupled with significant (p < .01) increase of functional colonies from C7 treated cells. Transplantation of C7 expanded UCB grafts to immunodeficient mice resulted in significantly (p < .001) higher engraftment of human CD45+ and CD45+CD34+ cells in the PB and BM by day 21 compared to non-expanded and cytokine expanded grafts. The C7 expanded grafts maintained long-term human multilineage chimerism in the BM of primary recipients with sustained human CD45 cell engraftment in secondary recipients. In conclusion, a small molecule, C7, could allow for clinical development of expanded UCB grafts without pre-culture stem cell enrichment that maintains in vitro and in vivo functionality.
Construction of 3D Skeleton for Polymer Composites Achieving a High Thermal Conductivity
Authors: Yao Yimin , Sun Jiajia , Zeng Xiaoliang , Sun Rong , Xu Jian‐Bin , Wong Ching‐Ping
Published: February 2018

Owing to the growing heat removal issue in modern electronic devices, electrically insulating polymer composites with high thermal conductivity have drawn much attention during the past decade. However, the conventional method to improve through‐plane thermal conductivity of these polymer composites usually yields an undesired value (below 3.0 Wm−1 K−1). Here, construction of a 3D phonon skeleton is reported composed of stacked boron nitride (BN) platelets reinforced with reduced graphene oxide (rGO) for epoxy composites by the combination of ice‐templated and infiltrating methods. At a low filler loading of 13.16 vol%, the resulting 3D BN‐rGO/epoxy composites exhibit an ultrahigh through‐plane thermal conductivity of 5.05 Wm−1 K−1 as the best thermal‐conduction performance reported so far for BN sheet‐based composites. Theoretical models qualitatively demonstrate that this enhancement results from the formation of phonon‐matching 3D BN‐rGO networks, leading to high rates of phonon transport. The strong potential application for thermal management has been demonstrated by the surface temperature variations of the composites with time during heating and cooling.
Morphology Characterization of Bulk Heterojunction Solar Cells
Authors: Song Jingnan , Zhang Ming , Yuan Meng , Qian Yuhao , Sun Yanming , Liu Feng
Published: February 2018

Revealing the nanostructure of bulk‐heterojunction (BHJ) photovoltaic blends is a critical task in the field of organic photovoltaics. The complicated morphology, ranging from binary blends to ternary mixtures, shows quite varied structural details that need to be fully characterized in terms of correlating them with device performance. The nonequilibrium nature of the BHJ thin‐film morphology makes the structure optimization difficult, and fundamental principles that relate to chemical structure, processing methods, and device performances have not yet been fully understood. On the other hand, various high‐powered techniques ranging from in‐house instrumentation to synchrotron techniques have been applied to this tremendously difficult research topic. More structural details, including length scale of phase separation, structural ordering, chain/molecular orientation, surface topology, etc., can be obtained in a quantitative manner, which finally allows the structure–property relationships to be determined. Here, the most important characterization techniques in understanding the morphology of BHJ solar cells are summarized, targeting chemists and materials scientists.
Hydropower and high productivity in the Hanford Reach: A synthesis of how flow management may benefit fall Chinook Salmon in the Columbia River, USA
Authors: Langshaw Russell B. , Graf Peter J. , Pearsons Todd N.
Published: February 2018

The fall Chinook Salmon (Oncorhynchus tshawytscha) population that spawns in the Hanford Reach of the Columbia River, USA is paradoxical because it is located above 4 and below 10 main stem Columbia River dams and yet is one of the largest and most productive C. salmon populations in the Pacific Northwest. A synthesis of information collected in the Hanford Reach reveals that the hydrosystem above the Hanford Reach and the management of river flows may have contributed to the recent size and productivity of this salmon population. Mechanisms for high survival and capacity at each freshwater life stage have been identified. Plausible mechanisms for contributing to high spawning capacity include: (a) more spawning habitat available during the spawning period. Plausible mechanisms for high egg‐to‐presmolt survival include: (a) reduced desiccation of redds, (b) reduced scour of redds, (c) reduced sedimentation in redds, (d) improved flow exchange within redds, and (e) increased food availability. Smolt survival may also be enhanced through the large size they attain in the Hanford Reach. This synthesis of information provides an uncommon assessment of some the positive effects of flow management from hydropower dams on a valued native fish that has occurred over the last three decades. WIREs Water 2018, 5:e1275. doi: 10.1002/wat2.1275

This article is categorized under:

Water and Life > Stresses and Pressures on Ecosystems

Water and Life > Conservation, Management, and Awareness
Silk nanofibril self‐assembly versus electrospinning
Authors: Humenik Martin , Lang Gregor , Scheibel Thomas
Published: February 2018

Natural silk fibers represent one of the most advanced blueprints for (bio)polymer scientists, displaying highly optimized mechanical properties due to their hierarchical structures. Biotechnological production of silk proteins and implementation of advanced processing methods enabled harnessing the potential of these biopolymer not just based on the mechanical properties. In addition to fibers, diverse morphologies can be produced, such as nonwoven meshes, films, hydrogels, foams, capsules and particles. Among them, nanoscale fibrils and fibers are particularly interesting concerning medical and technical applications due to their biocompatibility, environmental and mechanical robustness as well as high surface‐to‐volume ratio. Therefore, we introduce here self‐assembly of silk proteins into hierarchically organized structures such as supramolecular nanofibrils and fabricated materials based thereon. As an alternative to self‐assembly, we also present electrospinning a technique to produce nanofibers and nanofibrous mats. Accordingly, we introduce a broad range of silk‐based dopes, used in self‐assembly and electrospinning: natural silk proteins originating from natural spinning glands, natural silk protein solutions reconstituted from fibers, engineered recombinant silk proteins designed from natural blueprints, genetic fusions of recombinant silk proteins with other structural or functional peptides and moieties, as well as hybrids of recombinant silk proteins chemically conjugated with nonproteinaceous biotic or abiotic molecules. We highlight the advantages but also point out drawbacks of each particular production route. The scope includes studies of the natural self‐assembly mechanism during natural silk spinning, production of silk fibrils as new nanostructured non‐native scaffolds allowing dynamic morphological switches, as well as studying potential applications.

This article is categorized under:

 Biology‐Inspired Nanomaterials > Peptide‐Based Structures

 Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

 Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures
High-level recombinant production of squalene using selectedSaccharomyces cerevisiaestrains
Authors: Han Jong Yun , Seo Sung Hwa , Song Jae Myeong , Lee Hongweon , Choi Eui-Sung
Published: February 2018

For recombinant production of squalene, which is a triterpenoid compound with increasing industrial applications, in microorganisms generally recognized as safe, we screened Saccharomyces cerevisiae strains to determine their suitability. A strong strain dependence was observed in squalene productivity among Saccharomyces cerevisiae strains upon overexpression of genes important for isoprenoid biosynthesis. In particular, a high level of squalene production (400 ± 45 mg/L) was obtained in shake flasks with the Y2805 strain overexpressing genes encoding a bacterial farnesyl diphosphate synthase (ispA) and a truncated form of hydroxyl-3-methylglutaryl-CoA reductase (tHMG1). Partial inhibition of squalene epoxidase by terbinafine further increased squalene production by up to 1.9-fold (756 ± 36 mg/L). Furthermore, squalene production of 2011 ± 75 or 1026 ± 37 mg/L was obtained from 5-L fed-batch fermentations in the presence or absence of terbinafine supplementation, respectively. These results suggest that the Y2805 strain has potential as a new alternative source of squalene production.
Climate change as a possible driver of invasion and differential in HSP70 expression in two genetically distinct populations of the invasive killer shrimp, Dikerogammarus villosus
Authors: Hupało Kamil , Riss H. Wolfgang , Grabowski Michał , Thiel Jacqueline , Bącela-Spychalska Karolina , Meyer Elizabeth I.
Published: February 2018

Global climate change is known to affect physiological processes in charge of cellular stress response. That often results in forcing many organisms to shift their biogeographic distribution ranges. It also holds true for euryoecious and highly invasive species like the killer shrimp,Dikerogammarus villosus.In this study we compare the level of response to thermal stress in two genetically diversified populations of the amphipodD. villosuson the cellular level, namely HSP70 expression. The results show clear difference in HSP70 expression, that can be a direct consequence of the different climatic conditions both populations faced along their invasion routes. We conclude that the eastern population ofD. villosusis more sensitive to thermal stress than the western population, hence its invasion potential may be lower than that of the latter. Considering the thermal tolerance of both populations and global warming, we can make some predictions about further spread ofD. villosus, including the possibility of an emergence of the super-invader that may arise after cross-breeding of both populations, imposing even larger threat to the freshwater ecosystems.
Radiogenic Isotope Geology
Authors: Dickin Alan P.
Published: February 2018

The third edition of Radiogenic Isotope Geology examines revolutionary changes in geochemical thinking that have occurred over the past fifteen years. Extinct-nuclide studies on meteorites have called into question fundamental geochemical models of the Earth, while new dating methods have challenged conventional views of Earth history. At the same time, the problem of global warming has raised new questions about the causes of past and present climate change. In the new edition, these and other recent issues are evaluated in their scholarly and historical context, so readers can understand the development of current ideas. Controversial theories, new analytical techniques, classic papers, and illustrative case studies all come under scrutiny in this book, providing an accessible introduction for students and critical commentary for researchers.
An Innovative Approach to Sex Trafficking Research: The Methodological Advancement of Attride-Stirling’s Thematic Network Analysis
Authors: Mano Avekadavie Parasramsingh
Published: February 2018

Research into sex trafficking is considerably lacking despite its increasing global relevance. The trafficking in human beings has been documented within the literature as a form of modern-day slavery. It is commonly described as a form of organized crime that is highly profitable, involving the active participation of corrupt officials, politicians, financial institutions and criminal networks that facilitate document forgery, illegal border crossings, money laundering and the return of escaped victims. This paper discusses the thematic network analysis of recently collected qualitative data on sex trafficking in Belize. Jennifer Attride-Stirling’s (2001) thematic network analysis was applied to data gathered from face-to-face, semi-structured interviews with four distinct groups within the sex industry: sex traffickers, sex workers, clients and knowledgeable locally based officials Given the expansive nature of this research, thematic network analysis has been advanced to accommodate the specificities of each group, creating what has been termed here as asupra-global theme. This innovative approach facilitates the emergence of a deeper, more pertinent understanding of the intrinsic realities characteristic of Belize’s sex industry and may be applied to similar multi-group research.
fastPACE Train-the-Trainer: A scalable new educational program to accelerate training in biomedical innovation, entrepreneurship, and commercialization
Authors: Servoss Jonathan , Chang Connie , Fay Jonathan , Lota Kanchan Sehgal , Mashour George A. , Ward Kevin R.
Published: February 2018

Introduction

The Institute of Medicine recommended the advance of innovation and entrepreneurship training programs within the Clinical & Translational Science Award (CTSA) program; however, there remains a gap in adoption by CTSA institutes. The University of Michigan’s Michigan Institute for Clinical & Health Research and Fast Forward Medical Innovation (FFMI) partnered to develop a pilot program designed to teach CTSA hubs how to implement innovation and entrepreneurship programs at their home institutions.

Materials and methods

The program provided a 2-day onsite training experience combined with observation of an ongoing course focused on providing biomedical innovation, commercialization and entrepreneurial training to a medical academician audience (FFMI fastPACE).

Results

All 9 participating CTSA institutes reported a greater connection to biomedical research commercialization resources. Six launched their own version of the FFMI fastPACE course or modified existing programs. Two reported greater collaboration with their technology transfer offices.

Conclusion

The FFMI fastPACE course and training program may be suitable for CTSA hubs looking to enhance innovation and entrepreneurship within their institutions and across their innovation ecosystems.
Training in patient-centered outcomes research for specific researcher communities
Authors: Landsittel Douglas P. , Kessler Larry , Schmid Christopher H. , Marantz Paul , Suarez-Almazor Maria E. ,   the Investigators and Program Partners from the Expanding National Capacity in PCOR through Training (ENACT); Patient Centered Outcomes Research Partnership (PCORP); Evidence Synthesis Academy; Education and Training Program in Patient-Centered Outcomes Research; and the Methods Training in Patient-Centered Cancer Outcomes Research Programs
Published: February 2018

A number of publications have discussed approaches to training the scientific workforce in comparative effectiveness research (CER) and patient-centered outcomes research (PCOR). To meet this need, funders have offered resources for developing educational materials and establishing training programs. To extend these efforts into specific researcher communities, the Agency for Healthcare Research and Quality developed an R25 Funding Opportunity Announcement that called for basic, advanced, and experiential training for a specific researcher community in collaboration with associated program partners. This paper describes the strategies developed by the 5 subsequently funded programs, their specific researcher communities and program partners, and the challenges associated with developing in-person and online programs. We focus on lessons learned that can be translated into developing training programs nationwide and on training for the special populations of interest. We also discuss the creation of a sustainable network for training and the conduct of comparative effectiveness research/patient-centered outcomes research in targeted communities.
Small-scale dynamics of settling, bidisperse particles in turbulence
Authors: Dhariwal Rohit , Bragg Andrew D.
Published: February 2018

Mixing and collisions of inertial particles at the small scales of turbulence can be investigated by considering how pairs of particles move relative to each other. In real problems the two particles will have different sizes, i.e. they are bidisperse, and the effect of gravity on their motion is often important. However, how turbulence and gravity compete to control the motion of bidisperse inertial particles is poorly understood. Motivated by this, we use direct numerical simulations (DNS) to investigate the dynamics of settling, bidisperse particles in isotropic turbulence. In agreement with previous studies, we find that without gravity (i.e. $Fr=\infty$, where $Fr$ is the Froude number), bidispersity leads to an enhancement of the relative velocities, and a suppression of their spatial clustering. For $Fr<1$, the relative velocities in the direction of gravity are enhanced by the differential settling velocities of the bidisperse particles, as expected. However, we also find that gravity can strongly enhance the relative velocities in the ‘horizontal’ directions (i.e. in the plane normal to gravity). This non-trivial behaviour occurs because fast settling particles experience rapid fluctuations in the fluid velocity field along their trajectory, leading to enhanced particle accelerations and relative velocities. Indeed, the results show that even when $Fr\ll 1$, turbulence can still play an important role, not only on the horizontal motion, but also on the vertical motion of the particles. This is related to the fact that $Fr$ only characterizes the importance of gravity compared with some typical acceleration of the fluid, yet accelerations in turbulence are highly intermittent. As a consequence, there is a significant probability for particles to be in regions of the flow where the Froude number based on the local, instantaneous fluid acceleration is ${>}1$, even though the typically defined Froude number is $\ll 1$. This could imply, for example, that extreme events in the mixing of settling, bidisperse particles are only weakly affected by gravity even when $Fr\ll 1$. We also find that gravity drastically reduces the clustering of bidisperse particles. These results are strikingly different to the monodisperse case, for which recent results have shown that when $Fr<1$, gravity strongly suppresses the relative velocities in all directions, and can enhance clustering. Finally, we consider the implications of these results for the collision rates of settling, bidisperse particles in turbulence. We find that for $Fr=0.052$, the collision kernel is almost perfectly predicted by the collision kernel for bidisperse particles settling in quiescent flow, such that the effect of turbulence may be ignored. However, for $Fr=0.3$, turbulence plays an important role, and the collisions are only dominated by gravitational settling when the difference in the particle Stokes numbers is ${\geqslant}O(1)$.
Racism in Singapore: A Review and Recommendations for Future Research
Authors: Chew Peter K.H.
Published: February 2018

Racism refers to ‘the differential treatment enacted by an individual, group, or organization on individuals based on assumptions of a group's phenotypic, linguistic, or cultural differences’ (Gamst, Liang, & Der-Karabetian, 2011 , p. 251). Currently, there is a lack of psychological research investigating racism in Singapore. The available research, narrative reviews, qualitative studies, and quantitative studies have yielded limited and inconclusive results. These researches are critically evaluated to provide four recommendations for a psychological research agenda: (a) develop a reliable and valid instrument to assess racism, (b) conduct experimental research to examine racism perpetuated by the majority or institutions, (c) examine the negative effects of racism, and (d) develop and evaluate interventions for racism.
THE COHOMOLOGY RING OF ORBIT SPACES OF FREE -ACTIONS ON SOME DOLD MANIFOLDS
Authors: MORITA ANA MARIA M. , DE MATTOS DENISE , PERGHER PEDRO L. Q.
Published: February 2018

We determine the possible $\mathbb{Z}_{2}$-cohomology rings of orbit spaces of free actions of $\mathbb{Z}_{2}$ (or fixed point free involutions) on the Dold manifold $P(1,n)$, where $n$ is an odd natural number.
THE QUEER -SCHUR SUPERALGEBRA
Authors: DU JIE , WAN JINKUI
Published: February 2018

As a natural generalisation of $q$-Schur algebras associated with the Hecke algebra ${\mathcal{H}}_{r,R}$ (of the symmetric group), we introduce the queer $q$-Schur superalgebra associated with the Hecke–Clifford superalgebra ${\mathcal{H}}_{r,R}^{\mathsf{c}}$, which, by definition, is the endomorphism algebra of the induced ${\mathcal{H}}_{r,R}^{\mathsf{c}}$-module from certain $q$-permutation modules over ${\mathcal{H}}_{r,R}$. We will describe certain integral bases for these superalgebras in terms of matrices and will establish the base-change property for them. We will also identify the queer $q$-Schur superalgebras with the quantum queer Schur superalgebras investigated in the context of quantum queer supergroups and provide a constructible classification of their simple polynomial representations over a certain extension of the field $\mathbb{C}(\mathbf{v})$ of complex rational functions.
Building collaborative capacity: supporting tribal agriculture and natural resources in a changing climate
Authors: Reyes Julian J , Wiener John D. , Doan-Crider Diana , Novak Rachael
Published: February 2018

A working group was held during the 2017 National Adaptation Forum to build collaborative capacity on issues related to Tribal agriculture and natural resource management in a changing climate. We developed three synthetic themes from these discussions and dialogue to highlight on-going opportunities, but also demonstrate areas for continued engagement with Tribes related to effective agricultural and natural resource management. We hope this forum demonstrates the critical importance of partnerships, and motivates further coordination and collaboration among Tribes, universities and Federal agencies.
The Structure of the Rosenberg Self-Esteem Scale
Authors: Gnambs Timo , Scharl Anna , Schroeders Ulrich
Published: February 2018

Abstract. The Rosenberg Self-Esteem Scale (RSES; Rosenberg, 1965 ) intends to measure a single dominant factor representing global self-esteem. However, several studies have identified some form of multidimensionality for the RSES. Therefore, we examined the factor structure of the RSES with a fixed-effects meta-analytic structural equation modeling approach including 113 independent samples (N = 140,671). A confirmatory bifactor model with specific factors for positively and negatively worded items and a general self-esteem factor fitted best. However, the general factor captured most of the explained common variance in the RSES, whereas the specific factors accounted for less than 15%. The general factor loadings were invariant across samples from the United States and other highly individualistic countries, but lower for less individualistic countries. Thus, although the RSES essentially represents a unidimensional scale, cross-cultural comparisons might not be justified because the cultural background of the respondents affects the interpretation of the items.
How to Identify Hot Topics in Psychology Using Topic Modeling
Authors: Bittermann André , Fischer Andreas
Published: February 2018

Abstract. Latent topics and trends in psychological publications were examined to identify hotspots in psychology. Topic modeling was contrasted with a classification-based scientometric approach in order to demonstrate the benefits of the former. Specifically, the psychological publication output in the German-speaking countries containing German- and English-language publications from 1980 to 2016 documented in the PSYNDEX database was analyzed. Topic modeling based on latent Dirichlet allocation (LDA) was applied to a corpus of 314,573 publications. Input for topic modeling was the controlled terms of the publications, that is, a standardized vocabulary of keywords in psychology. Based on these controlled terms, 500 topics were determined and trending topics were identified. Hot topics, indicated by the highest increasing trends in this data, were facets of neuropsychology, online therapy, cross-cultural aspects, traumatization, and visual attention. In conclusion, the findings indicate that topics can reveal more detailed insights into research trends than standardized classifications. Possible applications of this method, limitations, and implications for research synthesis are discussed.
Effect Size Estimation Fromt-Statistics in the Presence of Publication Bias
Authors: Ulrich Rolf , Miller Jeff , Erdfelder Edgar
Published: February 2018

Abstract. Publication bias hampers the estimation of true effect sizes. Specifically, effect sizes are systematically overestimated when studies report only significant results. In this paper we show how this overestimation depends on the true effect size and on the sample size. Furthermore, we review and follow up methods originally suggested by Hedges (1984) , Iyengar and Greenhouse (1988) , and Rust, Lehmann, and Farley (1990) allowing the estimation of the true effect size from published test statistics (e.g., from the t-values of reported significant results). Moreover, we adapted these methods allowing meta-analysts to estimate the percentage of researchers who consign undesired results in a research domain to the file drawer. We also apply the same logic to the case when significant results tend to be underreported. We demonstrate the application of these procedures for conventional one-sample and two-sample t-tests. Finally, we provide R and MATLAB versions of a computer program to estimate the true unbiased effect size and the prevalence of publication bias in the literature.
An Update of a Meta-Analysis on the Clinical Outcomes of Deep Transcranial Magnetic Stimulation (DTMS) in Major Depressive Disorder (MDD)
Authors: Gellersen Helena M. , Kedzior Karina Karolina
Published: February 2018

Abstract. Deep transcranial magnetic stimulation (DTMS) is a noninvasive therapy for treatment-resistant major depressive disorder (MDD). The current study aimed to update a previous meta-analysis by investigating the acute and longer-term clinical outcomes of DTMS and their possible predictors (patient characteristics and stimulation parameters) in unipolar MDD. A systematic literature search identified 11 studies with 282 treatment-resistant, unipolar MDD patients. The clinical outcomes (depression severity, response and remission rates) were evaluated using random-effects meta-analyses. High frequency and intensity DTMS protocol with H1-coil had significant acute antidepressant outcomes and improved some cognitive functions after 20 daily sessions in unipolar MDD. Response rates tended to increase with lower severity of illness. Antidepressant effects were prolonged if maintenance DTMS was used after daily stimulation phases. DTMS consistently improves various symptom domains (antidepressant, cognitive) in treatment-resistant unipolar MDD.
Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe
Authors: Pietrobono Silvia , Santini Roberta , Gagliardi Sinforosa , Dapporto Francesca , Colecchia David , Chiariello Mario , Leone Cosima , Valoti Massimo , Manetti Fabrizio , Petricci Elena , Taddei Maurizio , Stecca Barbara
Published: February 2018

Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling.
Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis
Authors: Gueron Geraldine , Anselmino Nicolás , Chiarella Paula , Ortiz Emiliano G. , Lage Vickers Sofia , Paez Alejandra V. , Giudice Jimena , Contin Mario D. , Leonardi Daiana , Jaworski Felipe , Manzano Verónica , Strazza Ariel , Montagna Daniela R. , Labanca Estefania , Cotignola Javier , D´Accorso Norma , Woloszynska-Read Anna , Navone Nora , Meiss Roberto P. , Ruggiero Raúl , Vazquez Elba
Published: February 2018

An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy.
RAP80 is an independent prognosis biomarker for the outcome of patients with esophageal squamous cell carcinoma
Authors: Yang Qingyuan , Lin Wanrun , Liu Zhiwei , Zhu Jiabei , Huang Nan , Cui Zhongqi , Han Zeping , Pan Qiuhui , Goel Ajay , Sun Fenyong
Published: February 2018

Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues. Moreover, the RAP80 mRNA level was validated to be an independent prognosis biomarker for the overall survival time of ESCC patients. The following biological assays revealed that it promoted cell proliferation both in vitro and in vivo, inhibited cell apoptosis at both early and late stages, and participated in G2/M checkpoint regulation. Even though studies have reported that ATM phosphorylates RAP80 at different serine sites upon DNA damage, the reversal regulation of RAP80 on the activity of ATM has never been investigated. In the study, mechanism explorations revealed that RAP80 positively regulated the ATM activity via proteasome–ubiquitination pathway to promote the transition of G2/M phase in cell cycle. By examining a number of E3 ubiquitination ligases (Ub) and deubiquitination (DUb) enzymes, we found that RAP80 positively regulated the stability of USP13 to promote cell proliferation of EC cells. Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians.
The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance
Authors: Jiang Weiliang , Zhao Senlin , Shen Jia , Guo Lihong , Sun Yi , Zhu Yuntian , Ma Zhixiong , Zhang Xin , Hu Yangyang , Xiao Wenqin , Li Kai , Li Sisi , Zhou Li , Huang Li , Lu Zhanjun , Feng Yun , Xiao Junhua , Zhang Eric Erquan , Yang Lijuan , Wan Rong
Published: February 2018

Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3′-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a ‘miR-135b–BMAL1–YY1’ loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance.
Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9
Authors: Rozenberg Perri , Ziporen Lea , Gancz Dana , Saar-Ray Moran , Fishelson Zvi
Published: February 2018

Cancer cells are commonly more resistant to cell death activated by the membranolytic protein complex C5b-9. Several surface-expressed and intracellular proteins that protect cells from complement-dependent cytotoxicity (CDC) have been identified. In this study, we investigated the function of heat shock protein 90 (Hsp90), an essential and ubiquitously expressed chaperone, overexpressed in cancer cells, in C5b-9-induced cell death. As shown, inhibition of Hsp90 with geldanamycin or radicicol is enhancing sensitivity of K562 erythroleukemia cells to CDC. Similarly, Hsp90 inhibition confers in Ramos B cell lymphoma cells elevated sensitivity to treatment with rituximab and complement. C5b-9 deposition is elevated on geldanamycin-treated cells. Purified Hsp90 binds directly to C9 and inhibits zinc-induced C9 polymerization, indicating that Hsp90 may act directly on the C5b-9 complex. Mortalin, also known as stress protein 70 or GRP75, is a mitochondrial chaperone that confers resistance to CDC. The postulated cooperation between Hsp90 and mortalin in protection from CDC was tested. Geldanamycin failed to sensitize toward CDC cells with knocked down mortalin. Direct binding of Hsp90 to mortalin was shown by co-immunoprecipitation in cell extracts after triggering with complement as well as by using purified recombinant proteins. These results provide an insight into the protective mechanisms utilized by cancer cells to evade CDC. They suggest that Hsp90 protects cells from CDC by inhibiting, together with mortalin, C5b-9 assembly and/or stability at the plasma membrane.
Human immunodeficiency virus Tat impairs mitochondrial fission in neurons
Authors: Rozzi Summer J. , Avdoshina Valeria , Fields Jerel A. , Mocchetti Italo
Published: February 2018

Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls. To provide an experimental clue as to which mechanisms are used by Tat to promote changes in mitochondrial morphology, rat cortical neurons were exposed to Tat (100 nM) for various time points. Within 30 min, Tat caused a significant reduction in mitochondrial membrane potential, a process that is regulated by fusion and fission. To further assess whether Tat changes these processes, fission and fusion proteins dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2), respectively, were measured. We found that Drp1 levels increased beginning at 2 h after Tat exposure while Mfn2 remained unchanged. Moreover, increased levels of an active form of Drp1 were found to be present following Tat exposure. Furthermore, Drp1 and calcineurin inhibitors prevented Tat-mediated effects on mitochondria size. These findings indicate that mitochondrial fission is likely the leading factor in Tat-mediated alterations to mitochondrial morphology. This disruption in mitochondria homeostasis may contribute to the instability of the organelle and ultimately neuronal cell death following Tat exposure.
LARP7 family proteins have conserved function in telomerase assembly
Authors: Collopy Laura C. , Ware Tracy L. , Goncalves Tomas , í Kongsstovu Sunnvør , Yang Qian , Amelina Hanna , Pinder Corinne , Alenazi Ala , Moiseeva Vera , Pearson Siân R. , Armstrong Christine A. , Tomita Kazunori
Published: February 2018

Understanding the intricacies of telomerase regulation is crucial due to the potential health benefits of modifying its activity. Telomerase is composed of an RNA component and reverse transcriptase. However, additional factors required during biogenesis vary between species. Here we have identified fission yeast Lar7 as a member of the conserved LARP7 family, which includes the Tetrahymena telomerase-binding protein p65 and human LARP7. We show that Lar7 has conserved RNA-recognition motifs, which bind telomerase RNA to protect it from exosomal degradation. In addition, Lar7 is required to stabilise the association of telomerase RNA with the protective complex LSm2–8, and telomerase reverse transcriptase. Lar7 remains a component of the mature telomerase complex and is required for telomerase localisation to the telomere. Collectively, we demonstrate that Lar7 is a crucial player in fission yeast telomerase biogenesis, similarly to p65 in Tetrahymena, and highlight the LARP7 family as a conserved factor in telomere maintenance.
Publisher Correction: 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: February 2018

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.
The tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma
Authors: Soncin Irene , Sheng Jianpeng , Chen Qi , Foo Shihui , Duan Kaibo , Lum Josephine , Poidinger Michael , Zolezzi Francesca , Karjalainen Klaus , Ruedl Christiane
Published: February 2018

Circulating CCR2+monocytes are crucial for maintaining the adult tissue-resident F4/80hiMHCIIhimacrophage pool in the intestinal lamina propria. Here we show that a subpopulation of CCR2-independent F4/80hiMHCIIlowmacrophages, which are the most abundant F4/80hicells in neonates, gradually decline in number in adulthood; these macrophages likely represent the fetal contribution to F4/80hicells. In colon adenomas ofApcMin/+mice, F4/80hiMHCIIlowmacrophages are not only preserved, but become the dominant subpopulation among tumour-resident macrophages during tumour progression. Furthermore, these pro-tumoural F4/80hiMHCIIlowand F4/80hiMHCIIhimacrophages can self-renew in the tumour and maintain their numbers mostly independent from bone marrow contribution. Analyses of colon adenomas indicate that CSF1 may be a key facilitator of macrophage self-renewal. In summary, the tumour microenvironment creates an isolated niche for tissue-resident macrophages that favours macrophage survival and self-renewal.
IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation
Authors: Zhao Ming , Tan Yixin , Peng Qiao , Huang Cancan , Guo Yu , Liang Gongping , Zhu Bochen , Huang Yi , Liu Aiyun , Wang Zijun , Li Mengying , Gao Xiaofei , Wu Ruifang , Wu Haijing , Long Hai , Lu Qianjin
Published: February 2018

Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases.