bluuebunny/crossref_metadata_2025 huggingface dataset:
High Turnover Among State Health Officials/Public Health Directors: Implications for the Public's Health
Authors: Halverson Paul K. , Lumpkin John R. , Yeager Valerie A. , Castrucci Brian C. , Moffatt Sharon , Tilson Hugh
Published: July 2017

Context:

State health officials (SHOs) serve a critical role as the leaders of state public health systems. Despite their many responsibilities, there is no formal process for preparation to become an SHO, and few requirements influence the selection of an SHO. Furthermore, to date, no studies have examined SHO tenure or their experiences.

Objective:

This study examines SHO tenure over time and the relationship between SHO tenure and organizational and state attributes.

Design:

This longitudinal study employed primary data on SHOs and secondary data from the Association of State and Territorial Health Officials on organizational attributes of state public health agencies.

Setting:

This study examines SHOs within the United States.

Participants:

SHOs who served in years 1980-2017.

Main Outcome Measures:

Annual average SHO tenure; average SHO tenure by state.

Results:

In the 38 years of this study, 508 individuals served as SHOs in the 50 states and the District of Columbia. The average tenure over this period was 4.1 years, with a median tenure of 2.9 years. During the study period, almost 20% of SHOs served terms of 1 year or less. A total of 32 SHOs (32/508 or 6.3%) served for 10 years or longer. Excluding SHOs who served 10 years or longer (n = 32 SHOs who had a collective 478 years of tenure) reduces the average term in office to 3.5 years. The average number of new SHOs per year is 12.3. SHOs appointed by a board of health averaged more than 8 years in office compared with averages just under 4 years for those appointed by governors or secretaries of state agencies.

Conclusions:

There are notable differences in SHO tenure across states. Future research is needed to further examine SHO tenure, effectiveness, job satisfaction, transitions, and the relationship between SHOs and state health. It may be valuable to expand on opportunities for new SHOs to learn from peers who have moderate to long tenures as well as SHO alumni. Given that average SHO tenure is approximately 4 years and that an SHO could be thrust into the national spotlight at a moment's notice, governors may want to consider experience over partisanship as they appoint new SHOs.
Aquatic Exercises in the Treatment of Low Back Pain
Authors: Shi Zhongju , Zhou Hengxing , Lu Lu , Pan Bin , Wei Zhijian , Yao Xue , Kang Yi , Liu Lu , Feng Shiqing
Published: July 2017

Objective

Low back pain is the most common musculoskeletal condition with a high prevalence. There was no sufficient evidence to recommend that aquatic exercise was potentially beneficial to patients with low back pain. The aim of this study was to systematically analyze all evidence available in the literature about effectiveness of the aquatic exercise.

Design

A comprehensive search of PubMed, the Cochrane Library, Embase, and Cumulative Index to Nursing and Allied Health was conducted from their inceptions to November 2016 for randomized controlled trials, which concerned the therapeutic aquatic exercise for low back pain. The results were expressed in terms of standardized mean difference and the corresponding 95% confidence interval.

Results

Eight trials involving 331 patients were included in the meta-analysis, and the results showed a relief of pain (standardized mean difference = −0.65, 95% confidence interval = −1.16 to −0.14) and physical function (standardized mean difference = 0.63, 95% confidence interval = 0.17 to 1.09) after aquatic exercise. However, there was no significant effectiveness with regard to general mental health in aquatic group (standardized mean difference = 0.46; 95% confidence interval = −0.22 to 1.15).

Conclusions

Aquatic exercise can statistically significantly reduce pain and increase physical function in patients with low back pain. Further high-quality investigations on a larger scale are required to confirm the results.
Quality and Safety in Health Care, Part XXIX
Authors: Harolds Jay A.
Published: July 2017

The American College of Cardiology, the Society of Thoracic Surgeons, and other organizations cooperated to form the Transcatheter Valve Therapy Registry. This registry studies information on the outcome of valve therapy device placement with a transcatheter approach. The companies that manufacture these devices can use the registry to meet the post–product sale surveillance requirements of the US Food and Drug Administration. There will also be linkage to the registry information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database, which has information on open cardiac valve surgery.
Swedish Children's Lived Experience of Ulcerative Colitis
Authors: Vejzovic Vedrana , Bramhagen Ann-Cathrine , Idvall Ewa , Wennick Anne
Published: July 2017

Inflammatory bowel disease (IBD) is increasing in children. When this lifelong illness is diagnosed in childhood, especially during adolescence, it may have a negative impact on children's quality of life. The aim of the present study was to illuminate the meaning of children's lived experience of ulcerative colitis. Seven children aged between 10 and 18 years were recruited from University Hospital South Sweden and interviewed about the phenomenon under scrutiny. Data were analyzed by means of a phenomenological hermeneutical method. The meaning of the children's lived experience of ulcerative colitis was summed up as a main theme. A daily struggle to adapt and be perceived as normal consisted of 4 subthemes: being healthy despite the symptoms, being healthy despite being afraid, being healthy despite a sense of being different, and being healthy despite needing support. The children strove to perceive themselves as healthy, and they needed to be perceived as healthy, especially when experiencing symptoms of inflammatory bowel disease. Children with inflammatory bowel disease confront various problems, such as ambitions and goals that are hard to achieve, due to reduced abilities as a result of the illness or an insufficiently adapted environment.
Chronic inflammatory demyelinating polyneuropathy
Authors: Lewis Richard A.
Published: July 2017

Purpose of review

As a syndrome with typical and atypical cases, chronic inflammatory demyelinating polyneuropathy (CIDP) has been a difficult disorder to diagnose and treat. The pathophysiologic basis for CIDP has not been established, contributing to the challenges in dealing with these patients. However, as one of only a handful of treatable peripheral neuropathies, there has been a tendency to diagnose CIDP to attempt a therapeutic intervention. We are also aware that there has also been overtreatment of some patients. This combination of overdiagnosis and prolonged treatment has been a concern. This chapter will review these challenges and discuss recent findings that will lead to improved diagnosis and treatment.

Recent findings

The factors leading to misdiagnosis of CIDP were explored in a cohort of patients referred to a neuromuscular center. On a more positive note, the identification of two disorders with antibodies directed at paranodal constituents has excited the field. Treatment options have increased and been clarified. Pulse corticosteroids have been compared with oral prednisone and with intravenous immunoglobulin. The clinical trial of subcutaneous immunoglobulin in CIDP has shown both efficacy and a very low side effect profile adding to our therapeutic options.

The current review will identify recent developments that show both the challenges and the exciting growth in our ability to diagnose and treat CIDP.
Update on diagnostics of metabolic myopathies
Authors: Toscano Antonio , Barca Emanuele , Musumeci Olimpia
Published: July 2017

Purpose of review

This review aims to highlight the most relevant clinical and laboratory findings, regarding acute and progressive metabolic myopathies, and to develop an algorithm addressing clinicians to clinical practice.

Recent findings

Although diagnosis of metabolic myopathies remains still challenging, the recent identification of new disorders has increased the number of patients requiring specific investigations. Nowadays, a more detailed characterization of the clinical spectrum of metabolic myopathies improved awareness as well as a deeper knowledge on their natural history or multisystem involvement. Diagnostic procedures, as first-line screening tests are necessary for an earlier and more accurate diagnostic work up, not only in infantile cases, but also in adults with suspected metabolic myopathies. New generation diagnostic techniques such as NGS (Next Generation Sequencing) and whole exome/genome sequencing have emerged as innovative tools to extensively evaluate either known genes variants or new candidate genes as possible causes of metabolic myopathies.

Diagnosis of metabolic myopathies is still challenging for clinicians because of rarity and clinical heterogeneity which is often overlapping with other neuromuscular disorders. Detailed algorithms supported by advanced laboratory investigations may be helpful to timely reach a diagnosis, so allowing an earlier therapeutic decision.
Beyond the Hype: Deep Neural Networks Outperform Established Methods Using A ChEMBL Bioactivity Benchmark Set
Authors: Lenselink Eelke B. , Dijke Niels ten , Bongers Brandon , Papadatos George , van Vlijmen Herman W.T. , Kowalczyk Wojtek , IJzerman Adriaan P. , van Westen Gerard J.P.
Published: July 2017

The increase of publicly available bioactivity data in recent years has fueled and catalyzed research in chemogenomics, data mining, and modeling approaches. As a direct result, over the past few years a multitude of different methods have been reported and evaluated, such as target fishing, nearest neighbor similarity-based methods, and Quantitative Structure Activity Relationship (QSAR)-based protocols. However, such studies are typically conducted on different datasets, using different validation strategies, and different metrics.

In this study, different methods were compared using one single standardized dataset obtained from ChEMBL, which is made available to the public, using standardized metrics (BEDROC and Matthews Correlation Coefficient). Specifically, the performance of Naive Bayes, Random Forests, Support Vector Machines, Logistic Regression, and Deep Neural Networks was assessed using QSAR and proteochemometric (PCM) methods. All methods were validated using both a random split validation and a temporal validation, with the latter being a more realistic benchmark of expected prospective execution.

Deep Neural Networks are the top performing classifiers, highlighting the added value of Deep Neural Networks over other more conventional methods. Moreover, the best method (‘DNN_PCM’) performed significantly better at almost one standard deviation higher than the mean performance. Furthermore, Multi task and PCM implementations were shown to improve performance over single task Deep Neural Networks. Conversely, target prediction performed almost two standard deviations under the mean performance. Random Forests, Support Vector Machines, and Logistic Regression performed around mean performance. Finally, using an ensemble of DNNs, alongside additional tuning, enhanced the relative performance by another 27% (compared with unoptimized DNN_PCM).

Here, a standardized set to test and evaluate different machine learning algorithms in the context of multitask learning is offered by providing the data and the protocols.
Conventional and hyperspectral time-series imaging of maize lines widely used in field trials
Authors: Liang Zhikai , Pandey Piyush , Stoerger Vincent , Xu Yuhang , Qiu Yumou , Ge Yufeng , Schnable James C.
Published: July 2017

Maize (Zea maysssp.mays) is one of three crops, along with rice and wheat, responsible for more than 1/2 of all calories consumed around the world. Increasing the yield and stress tolerance of these crops is essential to meet the growing need for food. The cost and speed of plant phenotyping is currently the largest constraint on plant breeding efforts. Datasets linking new types of high throughput phenotyping data collected from plants to the performance of the same genotypes under agronomic conditions across a wide range of environments are essential for developing new statistical approaches and computer vision based tools. A set of maize inbreds – primarily recently off patent lines – were phenotyped using a high throughput platform at University of Nebraska-Lincoln. These lines have been previously subjected to high density genotyping, and scored for a core set of 13 phenotypes in field trials across 13 North American states in two years by the Genomes to Fields consortium. A total of 485 GB of image data including RGB, hyperspectral, fluorescence and thermal infrared photos has been released. Correlations between image-based measurements and manual measurements demonstrated the feasibility of quantifying variation in plant architecture using image data. However, naive approaches to measuring traits such as biomass can introduce nonrandom measurement errors confounded with genotype variation. Analysis of hyperspectral image data demonstrated unique signatures from stem tissue. Integrating heritable phenotypes from high-throughput phenotyping data with field data from different environments can reveal previously unknown factors influencing yield plasticity.
Emphasizing the ‘positive’ in positive reinforcement: Using non-binary rewarding for training monkeys on cognitive tasks
Authors: Fischer Benjamin , Wegener Detlef
Published: July 2017

Non-human primates constitute an indispensable model system for studying higher brain functions at the neurophysiological level. They can be trained on highly demanding cognitive tasks, and studies involving these animals elucidated the neuronal mechanisms of various cognitive and executive functions, such as visual attention, working memory, and decision-making. The training of behavioral tasks used to study these processes builds on reinforcement learning and involves many discrete stages. It may takes several months, but frequently lasts a year or longer. The training is usually based on applying a liquid reward as the reinforcer to strengthen the desired behavior, and absence of the reward if the animal’s response was wrong. We here propose an alternative, non-binary rewarding scheme that aims to minimize unrewarded behavior. We show the potential of this alternative scheme to significantly speed up the training of an animal at various stages, without trade-off in accessible task difficulty or task performance.
Creating a highly directional anti-tumor immunity
Authors: Buts Vyacheslav A. , Skibenko Klavdiya P.
Published: July 2017

A simple method of creating a highly directional anti-tumor immunity is proposed. It is shown that under the influence of ultrasound of small and medium intensity, it is possible to tear off antigens from the cell surface (surface antigens (SA)). It was found that the immunogenicity of these SAs is not less than the immunogenicity of intact cells. These results give a new opportunity for creating specific, acute-directed immunity against malignant tumors.
Paradoxical Associations Between Familial Affective Responsiveness, Stress, and Amygdala Reactivity
Authors: Farber Madeline J. , Romer Adrienne L. , Justin Kim M. , Knodt Annchen R. , Elsayed Nourhan M. , Williamson Douglas E. , Hariri Ahmad R.
Published: July 2017

Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving shapes threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability, but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development.
Computational design of Small Transcription Activating RNAs (STARs) for versatile and dynamic gene regulation
Authors: Chappell James , Westbrook Alexandra , Verosloff Matthew , Lucks Julius B.
Published: July 2017

A longstanding goal of synthetic biology has been the programmable control of cellular functions. Central to this goal is the creation of versatile regulatory toolsets that allow for programmable control of gene expression. Of the many regulatory molecules available, RNA regulators offer the intriguing possibility ofde novodesign – allowing for the bottom-up molecular-level design of genetic control systems. Here we present a computational design approach for the creation of a bacterial regulator called Small Transcription Activating RNAs (STARs) and create a library of high-performing and orthogonal STARs that achieve up to ∼9000-fold gene activation. We then demonstrate the versatility of RNA-based transcription control by showing the broad utility of STARs – from acting synergistically with existing constitutive and inducible regulators, to reprogramming cellular phenotypes and controlling multigene metabolic pathway expression. Finally, we combine these new STARs with themselves and CRISPRi transcriptional repressors to deliver new types of RNA-based genetic circuitry that allow for sophisticated and temporal control of gene expression.
Comprehensive Characterization of Toxicity of Fermentative Metabolites on Microbial Growth
Authors: Wilbanks Brandon , Trinh Cong T.
Published: July 2017

Background

Volatile carboxylic acids, alcohols, and esters are natural fermentative products, typically derived from anaerobic digestion. These metabolites have important functional roles to regulate cellular metabolisms and broad use as food supplements, flavors and fragrances, solvents, and fuels. Comprehensive characterization of toxic effects of these metabolites on microbial growth under similar conditions is very limited.

Results

We characterized a comprehensive list of 32 short-chain carboxylic acids, alcohols, and esters on microbial growth ofEscherichia coliMG1655 under anaerobic conditions. We analyzed toxic effects of these metabolites onE. colihealth, quantified by growth rate and cell mass, as a function of metabolite types, concentrations, and physiochemical properties including carbon chain lengths and associated functional groups, chain branching features, hydrophobicity, and energy density. Strain characterization reveals these metabolites exerted distinct toxic effects onE. colihealth. We find that higher concentrations and/or longer carbon lengths of metabolites cause more severe growth inhibition. For the same carbon lengths and metabolite concentrations, alcohols are most toxic followed by acids then esters. We also discover that branched chain metabolites are less toxic than linear chain metabolites for the same carbon lengths and metabolite concentrations. Remarkably, shorter alkyl esters (e.g., ethyl butyrate) are found to be less toxic than longer alkyl esters (e.g., butyl acetate) for the same carbon lengths and metabolite concentrations. Regardless of metabolite types, longer chain metabolites are less soluble and have higher energy densities but are more toxic to microbial growth.

Conclusions

Metabolite hydrophobicity, correlated with carbon chain length, associated functional group, chain branching feature, and energy density, is a good quantitative index to evaluate toxic effect of a metabolite on microbial health. The results provide better understanding of degrees of toxicity of fermentative metabolites on microbial growth and further help selection of desirable metabolites and hosts for industrial fermentation to overproduce them.
Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation
Authors: You Wanli , Tang Zhiye , Chang Chia-en A.
Published: July 2017

The kinetics of ligand dissociation has been found to be crucial for a good drug candidate. Therefore, examining the underlying free energy profile of the dissociation that governs the kinetics becomes important. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems. The potential of mean force (PMF) computed from US seems to always produce binding affinity and energy barriers that more or less agree with experiments. However, such PMFs are influenced by many practical aspects, like the method used to generate the initial dissociation pathway, collective variables (CVs) that used to describe the reaction coordinate (RC), and how intensive the sampling is in the conformational space restrained by the CVs. These critical factors were rarely studied. Here we applied US to study the dissociation processes of β-cyclodextrin (β-CD) and p38α complex systems. For β-CD, we used three different β-CD conformations to generate the dissociation path manually. For p38α, we generated the dissociation pathway using accelerated molecular dynamics (AMD) followed by conformational relaxing with short conventional molecular dynamics (MD), steered molecular dynamics (SMD) and manual pulling. We found that even for small β-CD complexes, different β-CD conformations will alter the height of the PMF and different dissociation directions result in appearance/disappearance of local minima. SMD poorly samples the residue sidechain movement, leading to overestimated height of PMF. On the other hand, the AMD pathway relaxed by short conventional MD sampled more accurate structures, resulting in reasonable PMF.
Recasting the cancer stem cell hypothesis: unification using a continuum model of microenvironmental forces
Authors: Scott Jacob G. , Dhawan Andrew , Hjelmeland Anita , Lathia Justin , Chumakova Anastasia , Hitomi Masahiro , Fletcher Alexander G. , Maini Philip K. , Anderson Alexander R. A.
Published: July 2017

Since the first evidence for cancer stem cells in leukemia, experimentalists have sought to identify tumorigenic subpopulations in solid tumors. In parallel, scientists have argued over the implications of the existence of this subpopulation. On one side, the cancer stem cell hypothesis posits that a small subset of cells within a tumor are responsible for tumorigenesis and are capable of recapitulating the entire tumor on their own. Under this hypothesis, a tumor may be conceptualized as a series of coupled compartments, representing populations of progressively differentiated cell types, starting from stem cells. The allure of this model is that it elegantly explains our therapeutic failures: we have been targeting the wrong cells. Alternatively, the stochastic model states that all cells in a tumor can have stem-like properties, and have an equally small capability of forming a tumor. As tumors are, by nature, heterogeneous, there is ample evidence to support both hypotheses. We propose a mechanistic mathematical description that integrates these two theories, settling the dissonance between the schools of thought and providing a road map for integrating disparate experimental results into a single theoretical framework. We present experimental results from clonogenic assays that demonstrate the importance of defining this novel formulation, and the clarity that is provided when interpreting these results through the lens of this formulation.
Neuronal origin of the temporal dynamics of spontaneous BOLD activity correlation
Authors: Matsui Teppei , Murakami Tomonari , Ohki Kenichi
Published: July 2017

Resting-state functional connectivity (FC) has become a major fMRI method to study network organization of human brains. There has been recent interest in the temporal fluctuations of FC calculated using short time windows (“dynamic FC”) because this method could provide information inaccessible with conventional “static” FC, which is typically calculated using the entire scan lasting several tens of minutes. Although multiple studies have revealed considerable temporal fluctuations in FC, it is still unclear whether the fluctuations of FC measured in hemodynamics reflect the dynamics of underlying neural activity. We addressed this question using simultaneous imaging of neuronal calcium and hemodynamic signals in mice and found coordinated temporal dynamics of calcium FC and hemodynamic FC measured in the same short time windows. Moreover, we found that variation in transient neuronal coactivation patterns (CAPs) was significantly related to temporal fluctuations of sliding window FC in hemodynamics. Finally, we show that the observed dynamics of FC cannot be fully accounted for by simulated data assuming stationary FC. These results provide evidence for the neuronal origin of dynamic FC and further suggest that information relevant to FC is condensed in temporally sparse events that can be extracted using a small number of time points.
First Characterization of a Biphasic, Switch-like DNA Amplification
Authors: Özay Burcu , Robertus Cara M , Negri Jackson L , McCalla Stephanie E
Published: July 2017

We report the first DNA amplification chemistry with switch-like characteristics: the chemistry is biphasic, with an expected initial phase followed by an unprecedented high gain burst of product oligonucleotide in a second phase. The first and second phases are separated by a temporary plateau, with the second phase producing 10 to 100 times more product than the first. The reaction is initiated when an oligonucleotide binds and opens a palindromic looped DNA template with two binding domains. Upon loop opening, the oligonucleotide trigger is rapidly amplified through cyclic extension and nicking of the bound trigger. Loop opening and DNA association drive the amplification reaction, such that reaction acceleration in the second phase is correlated with DNA association thermodynamics. Without a palindromic sequence, the chemistry resembles the exponential amplification reaction (EXPAR). EXPAR terminates at the initial plateau, revealing a previously unknown phenomenon that causes early reaction cessation in this popular oligonucleotide amplification reaction. Here we present two distinct types of this biphasic reaction chemistry and propose dominant reaction pathways for each type based on thermodynamic arguments. These reactions create an endogenous switch-like output that reacts to approximately 1pM oligonucleotide trigger. The chemistry is isothermal and can be adapted to respond to a broad range of input target molecules such as proteins, genomic bacterial DNA, viral DNA, and microRNA. This rapid DNA amplification reaction could potentially impact a variety of disciplines such as synthetic biology, biosensors, DNA computing, and clinical diagnostics.
Anticipating complexity in the deployment of gene drive insects in agriculture
Authors: Baltzegar Jennifer , Barnes Jessica Cavin , Elsensohn Johanna E. , Gutzmann Nicole , Jones Michael S. , King Sheron , Sudweeks Jayce
Published: July 2017

Insects cause substantial losses to agricultural crops each year and require intensive management approaches. Genetic pest management (GPM) has emerged as a viable, non-chemical alternative for managing insect pests. The development of engineered gene drives for agricultural use is promising, though unproven, and has the potential to impact farmers as well as broader socio-ecological systems in several ways. Drawing on lessons from the deployment of other pest control technologies, this paper considers how gene drive insects could intersect with some of the complexities that characterize agricultural systems. The development of gene drives is emerging in a landscape of pest management shaped by past and current approaches, experiences, regulations, public opinion and pest invasions. Because gene drive insects may spread well beyond their release area, stakeholder groups at different spatial scales need to be engaged in decisions about their deployment. This new paradigm both complicates and offers great promise for future pest management efforts.
Tropomyosin and α-actinin cooperation inhibits fimbrin association with actin filament networks in fission yeast
Authors: Christensen Jenna R. , Homa Kaitlin E. , O’Connell Meghan E. , Kovar David R.
Published: July 2017

We previously discovered that competition between fission yeast actin binding proteins (ABPs) for association with F-actin helps facilitate their sorting to different F-actin networks. Specifically, competition between actin patch ABPs fimbrin Fim1 and cofilin Adf1 enhances each other’s activities, and rapidly displaces tropomyosin Cdc8 from the F-actin network. However, these interactions don’t explain how Fim1, a robust competitor, is prevented from associating equally well with other F-actin networks. Here, with a combination of fission yeast genetics, live cell fluorescent imaging, and in vitro TIRF microscopy, we identified the contractile ring ABP α-actinin Ain1 as a key sorting factor. Fim1 competes with Ain1 for association with F-actin, which is dependent upon their residence time on F-actin. Remarkably, although Fim1 outcompetes both contractile ring ABPs Ain1 and Cdc8 individually, Cdc8 enhances the bundling activity of Ain1 10-fold, allowing the combination of Ain1 and Cdc8 to inhibit Fim1 association with contractile ring F-actin.
Estrogen repressesTgfbr1andBmpr1aexpression via estrogen receptor beta in MC3T3-E1 cells
Authors: He Hanliang , Wang Chunqing , Tang Qifeng , Yang Fan , Xu Youjia
Published: July 2017

MC3T3-E1 is a clonal pre-osteoblastic cell line derived from newborn mouse calvaria, which is commonly used in osteoblast studies. To investigate the effects of estrogen on osteoblasts, we treated MC3T3-E1 cells with various concentrations of estrogen and assessed their proliferation. Next, we performed RNA deep sequencing to investigate the effects on estrogen target genes.Bmpr1aandTgfbr1, important participants in the TGF-beta signaling pathway, were down-regulated in our deep sequencing results. Bioinformatics analysis revealed that estrogen receptor response elements (EREs) were present in theBmpr1aandTgfbr1promoters. Culturing the cells with the estrogen receptor (ER) alpha or beta antagonists 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) or 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-alpha]pyrimidin-3-yl] phenol (PTHPP), respectively, demonstrated that ER beta is involved in the estrogen-mediated repression ofTgfbr1andBmpr1a.The chromatin immunoprecipitation (ChIP) results were consistent with the conclusion that E2 increased the binding of ER beta at the EREs located in theTgfbr1andBmpr1apromoters. Our research provides new insight into the role of estrogen in bone metabolisms.
The Na+(K+)/H+ exchanger Nhx1 controls multivesicular body-vacuolar lysosome fusion
Authors: Karim Mahmoud Abdul , Brett Christopher Leonard
Published: July 2017

Loss-of-function mutations in human endosomal Na+(K+)/H+ Exchangers (NHEs) NHE6 and NHE9 are implicated in neurological disorders including Christianson Syndrome, autism and attention deficit and hyperactivity disorder (ADHD). These mutations disrupt retention of surface receptors within neurons and glial cells by affecting their delivery to lysosomes for degradation. However, the molecular basis of how these endosomal NHEs control endocytic trafficking is unclear. Using Saccharomyces cerevisiae as a model, we conducted cell-free organelle fusion assays to show that transport activity of the orthologous endosomal NHE Nhx1 is important for multivesicular body (MVB)-vacuolar lysosome fusion, the last step of endocytosis required for surface protein degradation. We find that deleting Nhx1 disrupts the fusogenicity of the MVB, not vacuole, by targeting pH-sensitive machinery downstream of the Rab-GTPase Ypt7 needed for SNARE-mediated lipid bilayer merger. All contributing mechanisms are evolutionarily conserved offering new insight into the etiology of human disorders linked to loss of endosomal NHE function.
Protein–ligand complex structure from serial femtosecond crystallography using soaked thermolysin microcrystals and comparison with structures from synchrotron radiation
Authors: Naitow Hisashi , Matsuura Yoshinori , Tono Kensuke , Joti Yasumasa , Kameshima Takashi , Hatsui Takaki , Yabashi Makina , Tanaka Rie , Tanaka Tomoyuki , Sugahara Michihiro , Kobayashi Jun , Nango Eriko , Iwata So , Kunishima Naoki
Published: July 2017

Serial femtosecond crystallography (SFX) with an X-ray free-electron laser is used for the structural determination of proteins from a large number of microcrystals at room temperature. To examine the feasibility of pharmaceutical applications of SFX, a ligand-soaking experiment using thermolysin microcrystals has been performed using SFX. The results were compared with those from a conventional experiment with synchrotron radiation (SR) at 100 K. A protein–ligand complex structure was successfully obtained from an SFX experiment using microcrystals soaked with a small-molecule ligand; both oil-based and water-based crystal carriers gave essentially the same results. In a comparison of the SFX and SR structures, clear differences were observed in the unit-cell parameters, in the alternate conformation of side chains, in the degree of water coordination and in the ligand-binding mode.
Placental abruption in parents who were born small: registry‐based cohort study
Authors: Rasmussen S , Ebbing C , Linde LE , Baghestan E
Published: July 2017

Objective

To assess whether parents who were born small for gestational age (below the 10th birthweight centile, SGA) have increased risk of severe or mild placental abruption. To assess whether a history of SGA in other family members modifies this intergenerational effect.

Design

Prospective population‐based observational study.

Setting

The Medical Birth Registry of Norway.

Population

From 1967 to 2013, 785 333 mother–offspring pairs, 643 066 father–offspring pairs, 272 941 maternal tetrads (i.e. her offspring, sibling, and niece/nephew), and 265 505 paternal tetrads were identified.

Methods

Cohort study based on linked data from the Medical Birth Registry of Norway.

Main outcome measures

Relative risk (RR) of severe placental abruption (preterm birth, birthweight below the 10th centile, or perinatal death) and mild placental abruption (other cases) in families with SGA.

Results

Mothers who were born SGA had increased risk of severe placental abruption (RR 1.5; 95% confidence interval, 95% CI 1.3–1.8), but not mild abruption. The paternal effects were weaker. The combined effect of SGA in the mother and her sibling on severe abruption was twofold (RR 2.4; 95% CI 1.7–3.3) compared with birthweight centiles ≥10 for both. Similarly, the effect of adding an SGA niece/nephew was twofold (RR 2.3; 95% CI 1.3–3.9), whereas the combined effect of SGA in the mother, her sibling and her niece/nephew was fourfold (RR 3.6; 95% CI 1.9–6.8).

Conclusions

Women who were born SGA have an increased risk of severe placental abruption. The corresponding paternal effect was modest. A history of SGA in other family members increases the generational effect.

Tweetable abstract

Women born small for gestational age have excess risk of placental abruption.
High expression of long non‐coding HOX antisense transcript RNA and its clinical significance in cancer tissues: A meta‐analysis
Authors: Wang Lei , Zhao Yandong , Qin Yi , Xuan Yunpeng , Qiu Tong , Fu Bo , Ren Xiaoyang , Jiao Wenjie
Published: July 2017

Background

HOX antisense transcript RNA (HOTAIR) is a 2148 nt long, intergenic, non‐coding RNA molecule, which is reported to be highly expressed in many types of cancers. This meta‐analysis summarizes its expression in cancer.

Methods

We searched all eligible papers on the prognostic impact of HOTAIR in cancer from inception to 30 September 2015 in PubMed, CBMdisc, and the CNKI database. Only full texts were included. Revman 5.3 was used for meta‐analysis.

Results

A total of 11 studies of 1010 cases were included in the meta‐analysis. HOTAIR expression was higher in: cancer tissues in than adjacent or normal tissues (odds ratio [OR] 37.52, 95% confidence interval [CI] 18.94–74.31;
P
 < 0.00001); in cancer tissues with lymph node metastasis than in those without lymph node metastasis (OR 3.37, 95% CI 2.36–4.82;
P
 < 0.00001); and in histological grades II–III than in histological gradeI(OR 0.47, 95% CI 0.29–0.75;
P
 = 0.002).

Conclusion

This study shows that HOTAIR may play an important role in cancer occurrence and development, but whether it is a marker of cancer diagnosis and reliable prognosis remains to be confirmed. More rigorous design and meticulous quality epidemiological studies are required.
The role of anaplastic lymphoma kinase in pediatric cancers
Authors: Takita Junko
Published: July 2017

The anaplastic lymphoma kinase (ALK) gene was initially identified as a fusion partner of the nucleophosmin gene in anaplastic large‐cell lymphoma with t(2;5)(p23;q35) translocation, and then described with different genetic abnormalities in a number of tumors. Although ALK is known to be involved in the pathogenesis of neuroblastoma through activating mutations or gene amplification, its role in the pathogenesis of other pediatric cancers is still elusive. In addition to neuroblastoma, the high‐grade amplification of ALK has been described in a subset of rhabdomyosarcoma cases. Normal ALK protein expression is restricted to the nervous systems of adult mammals, but the aberrant expression of ALK has been observed in a variety of pediatric cancers, including glioma and Ewing sarcoma. The discovery of oncogenic activation of ALK in neuroblastoma suggests that this cancer could be potentially treated with an ALK inhibitor, as could other cancers, such as non‐small‐cell lung cancer and anaplastic large‐cell lymphoma. However, cellular responses to mutant ALK are complex when compared to rearranged ALK, and treatment remains a challenge. This review focuses on the biology of ALK in pediatric cancers and possible therapeutic strategies for ALK‐associated tumors.
Double‐edged sword of mesenchymal stem cells: Cancer‐promoting versus therapeutic potential
Authors: Lee Hwa‐Yong , Hong In‐Sun
Published: July 2017

Mesenchymal stem cells (MSCs) derived from adipose tissue, bone marrow, cord blood, and other tissues, have recently attracted much attention as potential therapeutic agents in various diseases because of their trans‐differentiation capacity. However, recent studies have suggested that MSCs also appear to contribute to tumor pathogenesis by supporting tumor microenvironments, increasing tumor growth, and eliciting antitumor immune responses. Although some studies suggest that MSCs have inhibitory effects on tumor development, they are overwhelmed by a number of studies showing that MSCs exert stimulatory effects on tumor pathogenesis. In the present review, we summarize a number of findings to provide current information about the therapeutic potential of MSCs in various diseases. We then discuss the potential roles of MSCs in tumor progression.
Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors
Authors: Liu Sha , Ji Sen , Yu Zhu‐Jun , Wang Hua‐Li , Cheng Xu , Li Wei‐Jian , Jing Li , Yu Yamei , Chen Qiang , Yang Ling‐Ling , Li Guo‐Bo , Wu Yong
Published: July 2017

Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism‐related diseases. Small‐molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of newly synthesized (E)‐2‐cyano‐N‐phenyl‐3‐(5‐phenylfuran‐2‐yl)acrylamide derivatives/analogues were carried out structure–activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5.59 ± 0.75 μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl‐lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics.
Accurate quantification of 5 German cockroach (GCr) allergens in complex extracts using multiple reaction monitoring mass spectrometry (MRM MS)
Authors: Mindaye S. T. , Spiric J. , David N. A. , Rabin R. L. , Slater J. E.
Published: July 2017

Background

German cockroach (GCr) allergen extracts are complex and heterogeneous products, and methods to better assess their potency and composition are needed for adequate studies of their safety and efficacy.

Objective and Methods

The objective of this study was to develop an assay based on liquid chromatography and multiple reaction monitoring mass spectrometry (LC‐MRM MS) for rapid, accurate, and reproducible quantification of 5 allergens (Bla g 1, Bla g 2, Bla g 3, Bla g 4, and Bla g 5) in crude GCr allergen extracts.

Results

We first established a comprehensive peptide library of allergens from various commercial extracts as well as recombinant allergens. Peptide mapping was performed using high‐resolution MS, and the peptide library was then used to identify prototypic and quantotypic peptides to proceed with MRM method development. Assay development included a systematic optimization of digestion conditions (buffer, digestion time, and trypsin concentration), chromatographic separation, and MS parameters. Robustness and suitability were assessed following ICH (Q2 [R1]) guidelines. The method is precise (RSD < 10%), linear over a wide range (r > 0.99, 0.01‐1384 fmol/μL), and sensitive (LLOD and LLOQ <1 fmol/μL). Having established the parameters for LC‐MRM MS, we quantified allergens from various commercial GCr extracts and showed considerable variability that may impact clinical efficacy.

Conclusions and Clinical Relevance

Our data demonstrate that the LC‐MRM MS method is valuable for absolute quantification of allergens in GCr extracts and likely has broader applicability to other complex allergen extracts. Definitive quantification provides a new standard for labelling of allergen extracts, which will inform patient care, enable personalized therapy, and enhance the efficacy of immunotherapy for environmental and food allergies.
Factors influencing the quality of Myrmecia pilosula (Jack Jumper) ant venom for use in in vitro and in vivo diagnoses of allergen sensitization and in allergen immunotherapy
Authors: Wanandy T. , Dwyer H. E. , McLean L. , Davies N. W. , Nichols D. , Gueven N. , Brown S. G. A. , Wiese M. D.
Published: July 2017

Background

Allergen immunotherapy uses pharmaceutical preparations derived from naturally occurring source materials, which contain water‐soluble allergenic components responsible for allergic reactions. The success of in vivo and in vitro diagnoses in allergen sensitization and allergen immunotherapy largely depends on the quality, composition and uniformity of allergenic materials used to produce the active ingredients, and the formulation employed to prepare finished products.

Objectives

We aimed to examine the factors influencing batch‐to‐batch consistency of Jack Jumper (Myrmecia pilosula) ant venom (JJAV) in the form of active pharmaceutical ingredient (AI) and informed whether factors such as temperature, artificial light and container materials influence the quality of JJAV AIs. We also aimed to establish handling and storage requirements of JJAV AIs to ensure preservation of allergenic activities during usage in the diagnosis of allergen sensitization and in allergen immunotherapy.

Methods

The quality and consistency of JJAV AIs were analysed using a combination of bicinchoninic acid assay for total protein quantification, HPLC‐UV for JJAV allergen peptides quantification, ELISA inhibition for total allergenic potency, SDS‐PAGE, AU‐PAGE and immunoblot for qualitative assessment of JJAV components, and Limulus Amebocyte Lysate assay for the quantification of endotoxin concentration. API‐ZYM and Zymogram assays were used to probe the presence of enzymatic activities in JJAV.

Results

Pharmaceutical‐grade JJAV for allergen immunotherapy has good batch‐to‐batch consistency. Temporary storage at 4°C and light exposure do not affect the quality of JJAV. Exposure to temperature above 40°C degrades high MW allergens in JJAV. Vials containing JJAV must be stored frozen and in upright position during long‐term storage.

Conclusions and Clinical Relevance

We have identified factors, which can influence the quality and consistency of JJAV AIs, and provided a framework for appropriate handling, transporting and storage of JJAV to be used for the diagnosis of allergen sensitization and in AIT.
DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood
Authors: Barton S. J. , Ngo S. , Costello P. , Garratt E. , El‐Heis S. , Antoun E. , Clarke‐Harris R. , Murray R. , Bhatt T. , Burdge G. , Cooper C. , Inskip H. , van der Beek E. M. , Sheppard A. , Godfrey K. M. , Lillycrop K. A. ,   the EpiGen Consortium
Published: July 2017

Background

There is now increasing evidence that asthma and atopy originate in part in utero, with disease risk being associated with the altered epigenetic regulation of genes.

Objective and Methods

To determine the relationship between variations in DNA methylation at birth and the development of allergic disease, we examined the methylation status of CpG loci within the promoter regions of Th1/2 lineage commitment genes (GATA3, IL‐4, IL‐4R, STAT4 and TBET) in umbilical cord DNA at birth in a cohort of infants from the Southampton Women's Survey (n = 696) who were later assessed for asthma, atopic eczema and atopy.

Results

We found that higher methylation of GATA3 CpGs −2211/−2209 at birth was associated with a reduced risk of asthma at ages 3 (median ratio [median methylation in asthma group/median methylation in non‐asthma group] = 0.74, P = .006) and 6‐7 (median ratio 0.90, P = .048) years. Furthermore, we demonstrated that the GATA3 CpG loci associated with later risk of asthma lie within a NF‐κB binding site and that methylation here blocks transcription factor binding to the GATA3 promoter in the human Jurkat T‐cell line. Associations between umbilical cord methylation of CpG loci within IL‐4R with atopic eczema at 12 months (median ratio 1.02, P = .028), and TBET with atopy (median ratio 0.98, P = .017) at 6‐7 years of age were also observed.

Conclusions and Clinical Relevance

Our findings provide further evidence of a developmental contribution to the risk of later allergic disorders and suggest that involvement of epigenetic mechanisms in childhood asthma is already demonstrable at birth.