bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbiota differences of the comb jelly Mnemiopsis leidyi in native and invasive sub-populations
Authors: Jaspers Cornelia , Weiland-Bräuer Nancy , Fischer Martin , Künzel Sven , Schmitz Ruth A. , Reusch Thorsten B.H.
Published: April 2019

The translocation of non-indigenous species around the world, especially in marine systems, is a matter of concern for biodiversity conservation and ecosystem functioning. While specific traits are often recognized to influence establishment success of non-indigenous species, the impact of the associated microbial community for the fitness, performance and invasion success of basal marine metazoans remains vastly unknown. In this study we compared the microbiota community composition of the invasive ctenophore Mnemiopsis leidyi in different native and invasive sub-populations along with characterization of the genetic structure of the host. By 16S rRNA gene amplicon sequencing we showed that the sister group to all metazoans, namely ctenophores, harbored a distinct microbiota on the animal host, which significantly differed across two major tissues, namely epidermis and gastrodermis. Additionally, we identified significant differences between native and invasive sub-populations of M. leidyi, which indicate, that the microbiota community is likely influenced by the genotypic background of the ctenophore. To test the hypothesis that the microbiota is genotypically selected for by the ctenophore host, experiments under controlled environments are required.
Differential Inhibition of E-S Potentiation and Long-term Potentiation by Cell-derived and Arctic Amyloid Beta
Authors: Orr Adrienne L. , Clark Jason K. , Madison Daniel V.
Published: April 2019

Soluble oligomers of amyloid-beta peptide (Abeta) have been implicated in the onset of memory deficits in Alzheimer’s disease, perhaps due to their reported ability to impair long-term potentiation (LTP) of synaptic strength. We previously showed the effect of Abeta on LTP depends on the strength of LTP induction. Furthermore, Abeta affects EPSP-Spike (E-S) potentiation more robustly than LTP, suggesting that E-S potentiation may be equally important to learning and memory in the context of Alzheimer’s disease. Here we extend our findings to two additional forms of Abeta that form higher concentrations of soluble Abeta oligomers and show that they also affect E-S potentiation at induction strengths where there is no effect on LTP in hippocampal slices.
Alternative Polyadenylation Regulates Patient-specific Tumor Growth by Individualizing the MicroRNA Target Site Landscape
Authors: Kim Soyeon , Bai Yulong , Fan Zhenjiang , Diergaarde Brenda , Tseng George C. , Park Hyun Jung
Published: April 2019

Background

Alternative polyadenylation (APA) shortens or lengthens the 3’-untranslated region (3’-UTR) of hundreds of genes in cancer. While APA genes modify microRNA target sites in the 3’-UTRs to promote tumorigenesis, previous studies have focused on a subset of the modification landscape.

Method

For comprehensive understanding of the function of global APA events, we consider the total target site landscape of microRNAs that are significantly and collectively modified by global APA genes. To identify such microRNAs in spite of complex interactions between microRNAs and the APA genes, we developedProbabilisticInference ofMicroRNATarget Site Modification throughAPA(PRIMATA-APA).

Results

Running PRIMATA-APA on TCGA breast cancer data, we identified that global APA events concentrate to modify target sites of particular microRNAs (target-site-modified-miRNAor tamoMiRNA). TamoMiRNAs are enriched for microRNAs known to regulate cancer etiology and treatments. Also, their target genes are enriched in cancer-associated pathways, suggesting that APA modifies target sites of tamoMiRNAs to progress tumors. Knockdown of NUDT21, a master 3’-UTR regulator in HeLa cells, confirmed the causal role of tamoMiRNAs for tumor growth.

Conclusions

Further, the expressions of tamoMiRNA target genes, enriched in cancer-associated pathways, vary across tumor samples as a function of patient-specific APA events, suggesting that APA is a novel regulatory axis for interpatient tumor heterogeneity.
3′-UTR shortening contributes to subtype-specific cancer growth by breaking stable ceRNA crosstalk of housekeeping genes
Authors: Fan Zhenjiang , Kim Soyeon , Bai Yulong , Diergaarde Brenda , Oesterreich Steffi , Park Hyun Jung
Published: April 2019

Shortening of 3′UTRs (3′US) through alternative polyadenylation (APA) is a post-transcriptional mechanism that regulate expression of hundreds of genes in human cancers. In breast cancer, different subtypes of tumor samples, such as estrogen receptor positive and negative (ER+ and ER-), are characterized by distinct molecular mechanisms, suggesting possible differences in the post-transcriptional regulation between the subtype tumors. In this study, based on the profound tumorigenic role of 3′US interacting with competing-endogenous RNA (ceRNA) network (3′US-ceRNA effect), we hypothesize that the 3′US-ceRNA effect drives subtype-specific tumor growth. However, we found that the subtypes are available in different sample size, biasing the ceRNA network size and disabling the fair comparison of the 3′US-ceRNA effect. Using normalized Laplacian Matrix Eigenvalue Distribution, we addressed this bias and built the tumor ceRNA networks comparable between the subtypes. Based on the comparison, we identified a novel role of housekeeping (HK) genes as stable and strong miRNA sponges (sponge HK genes) that synchronize the ceRNA networks of normal samples (adjacent to ER+ and ER- tumor samples). We further found that distinct 3′US events in the ER- tumor break the stable sponge effect of HK genes in a subtype-specific fashion, especially in association with the aggressive and metastatic phenotypes. Knockdown of NUDT21, a master 3′-UTR regulator in HeLa cells, confirmed the causal role of 3′US-ceRNA effect repressing HK genes for tumor growth. In this study, we identified 3′US-ceRNA effect on the sponge HK genes for subtype-specific growth of ER- tumors.
Investigating Biomechanical Properties of A. tortilis as Related to their Habitat: A novel approach to characterize bending
Authors: Faris Ahmed , Altoum Rani , Salameh Iyad , Salameh Mohammed , Al-Mohannadi Saif , Mahmoud Abdulla
Published: April 2019

The biomechanical properties of Acacia tortilis were investigated considering its habitat (wild vs. nursery). The plant materials were collected from partially urbanized area in Doha city and from Qatar Foundation Nursery. The results show that Acacia grown in field are more flexible than those grown in nursery. Young’s Modulus of Elasticity was found to be 191 MPa and 617 MPa and the Flexural Modulus was found to be 49 MPa and 575 MPa and the breaking force was found to be 210 and 550 N for nursery and field Acacia, respectively. The deflection angle was measured using sensitive flex sensors connected to Arduino boards and was found to be higher for field Acacia (50∘). Image processing techniques were used to mathematically describe the branch motion versus time diagrams.

The plant part being investigated was covered with red tape and videotaped while subjected to a force causing it to bend. The stem was divided into 745 successive points and the change in their position with time taken frame by frame was converted into a change in position expressed through mathematical parameters. The bending movement of the branch was found to follow a power function H = (4001 − e0.06m).

Highlight

Field grown Acacia have higher values of Young’s and Flexural Moduli than nursery grown ones thus conferring them more elasticity and flexibility.
Quantifying the contribution of sequence variants with regulatory and evolutionary significance to 34 bovine complex traits
Authors: Xiang Ruidong , Van Den Berg Irene , MacLeod Iona M. , Hayes Benjamin J. , Prowse-Wilkins Claire P. , Wang Min , Bolormaa Sunduimijid , Liu Zhiqian , Rochfort Simone J. , Reich Coralie M. , Mason Brett A. , Vander Jagt Christy J. , Daetwyler Hans D. , Lund Mogens S. , Chamberlain Amanda J. , Goddard Michael E.
Published: April 2019

Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (eQTLs) and concentration of metabolites (mQTLs), and under histone modification marks in several tissues were discovered from multi-omics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants and for each set we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent (r>0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone modification marks and selection signatures. From these results, we defined aFunctional-And-EvolutionaryTraitHeritability (FAETH) score indicating the functionality and predicted heritability of each variant. In 7,551 Danish cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution and trait heritability to rank variants and the publicly available FAETH data provides a set of biological priors for cattle genomic selection worldwide.
The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin
Authors: Urquhart Andrew S. , Hu Jinyu , Chooi Yit-Heng , Idnurm Alexander
Published: April 2019

Background

Viriditoxin is one of the ‘classical’ secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown.

Results

Here, a gene cluster responsible for its synthesis was identified, using bioinformatic approaches from two species that produce viriditoxin and then through gene disruption and metabolite profiling. All eight genes in the cluster inPaecilomyces variotiiwere mutated, revealing their roles in the synthesis of this molecule and establishing its biosynthetic pathway which includes an interesting Baeyer-Villiger monooxygenase catalyzed reaction. Additionally, a candidate catalytically-inactive hydrolase was identified as being required for the stereoselective biosynthesis of (M)-viriditoxin. The localization of two proteins were assessed by fusing these proteins to green fluorescent protein, revealing that at least two intracellular structures are involved in the compartmentalization of the synthesis steps of this metabolite.

Conclusions

The full pathway for synthesis of viriditoxin was established by a combination of genomics, bioinformatics, gene disruption and chemical analysis processes. Hence, this work reveals the basis for the synthesis of an understudied class of fungal secondary metabolites and provides a new model species for understanding the synthesis of biaryl compounds with a chiral axis.
Pooled-parent exome sequencing to prioritise de novo variants in genetic disease
Authors: Dashnow Harriet , Bell Katrina M. , Stark Zornitza , Tan Tiong Y. , White Susan M. , Oshlack Alicia
Published: April 2019

In the clinical setting, exome sequencing has become standard-of-care in diagnosing rare genetic disorders, however many patients remain unsolved. Trio sequencing has been demonstrated to produce a higher diagnostic yield than singleton (proband-only) sequencing. Parental sequencing is especially useful when a disease is suspected to be caused by a de novo variant in the proband, because parental data provide a strong filter for the majority of variants that are shared by the proband and their parents. However the additional cost of sequencing the parents makes the trio strategy uneconomical for many clinical situations. With two thirds of the sequencing budget being spent on parents, these are funds that could be used to sequence more probands. For this reason many clinics are reluctant to sequence parents.

Here we propose a pooled-parent strategy for exome sequencing of individuals with likely de novo disease. In this strategy, DNA from all the parents of a cohort of unrelated probands is pooled together into a single exome capture and sequencing run. Variants called in the proband can then be filtered if they are also found in the parent pool, resulting in a shorter list of prioritised variants. To evaluate the pooled-parent strategy we performed a series of simulations by combining reads from individual exomes to imitate sample pooling. We assessed the recall and false positive rate and investigated the trade-off between pool size and recall rate. We compared the performance of GATK HaplotypeCaller individual and joint calling, and FreeBayes to genotype pooled samples. Finally, we applied a pooled-parent strategy to a set of real unsolved cases and showed that the parent pool is a powerful filter that is complementary to other commonly used variant filters such as population variant frequencies.
A field and video analysis guide for diver operated stereo‐video
Authors: Goetze Jordan S. , Bond Todd. , McLean Dianne L. , Saunders Benjamin J. , Langlois Tim J. , Lindfield Steve , Fullwood Laura. A. F. , Driessen Damon , Shedrawi George , Harvey Euan S.
Published: April 2019

There has been rapid uptake of stereo‐video‐based sampling techniques to collect species, abundance and body‐size information on fish assemblages and their associated habitats. Stereo‐video methods provide highly accurate estimates of body‐size, range and sampling area as well as a permanent record that can be cross‐checked or resampled for additional data. Due to these advantages, diver‐operated stereo‐video (stereo‐DOV) is becoming an increasingly popular alternative to underwater visual census.

We provide a comprehensive guide for researchers using stereo‐DOVs to survey fish assemblages and their associated habitat. Information on stereo‐DOV design, video camera settings, field operations and video analysis are outlined.

Stereo–DOV surveys permit rapid and simultaneous collection of data on fish diversity, abundance, length and behaviour as well as their associated habitat. However, biases associated with diver presence in the water and variation in detectability should be considered and are dependent on the location and focal species of the survey.

We recommend using stereo‐DOVs for diver‐based surveys of non‐cryptic fish assemblages, given the advantages described. An increased uptake of this methodology, following the standard procedures described herein, will reduce variation in methodology, assist in the synthesis of data on continental and global scales and provide accurate information to improve fisheries management and conservation.
Structural brain characteristics of anabolic–androgenic steroid dependence in men
Authors: Hauger Lisa E. , Westlye Lars T. , Fjell Anders M. , Walhovd Kristine B. , Bjørnebekk Astrid
Published: April 2019

Aim

To identify differences in brain morphology between dependent and non‐dependent male anabolic–androgenic steroid (AAS) users.

Design

This study used cross‐sectional data from a longitudinal study on male weightlifters.

Participants

Oslo University Hospital, Norway.

Setting

Eighty‐one AAS users were divided into two groups; AAS‐dependent (n = 43) and AAS‐non‐dependent (n = 38).

Measurements

Neuroanatomical volumes and cerebral cortical thickness were estimated based on magnetic resonance imaging (MRI) using FreeSurfer. Background and health information were obtained using a semi‐structured interview. AAS‐dependence was evaluated in a standardized clinical interview using a version of the Structured Clinical Interview for DSM‐IV, adapted to apply to AAS‐dependence.

Findings

Compared with non‐dependent users, dependent users had significantly thinner cortex in three clusters of the right hemisphere and in five clusters of the left hemisphere, including frontal, temporal, parietal and occipital regions. Profound differences were seen in frontal regions (left pars orbitalis, cluster‐wise P < 0.001, right superior frontal, cluster‐wise P < 0.001), as has been observed in other dependencies. Group differences were also seen when excluding participants with previous or current non‐AAS drug abuse (left pre‐central, cluster‐wise P < 0.001, left pars orbitalis, cluster‐wise P = 0.010).

Conclusion

Male dependent anabolic–androgenic steroid users appear to have thinner cortex in widespread regions, specifically in pre‐frontal areas involved in inhibitory control and emotional regulation, compared with non‐dependent anabolic–androgenic steroid users.
Composition and ecological drivers of the kwongan scrub and woodlands in the northern Swan Coastal Plain, Western Australia
Authors: Tsakalos James L. , Renton Michael , Dobrowolski Mark P. , Veneklaas Erik J. , Macintyre Paul D. , Broomfield Sarah J. , Mucina Ladislav
Published: April 2019

The nature of community patterns and environmental drivers in kwongan mediterranean‐type shrubland on nutrient‐poor soils occurring in Western Australia remain poorly examined. We aimed to determine whether (i) classification of the kwongan vegetation of the northern Swan Coastal Plain would be ecologically informative and (ii) which environmental drivers underpin the plant community patterns. The study area was positioned on the northern Swan Coastal Plain, locality of Cooljarloo (30°39′ S, 115°22′ E), situated 170 km north of Perth, Western Australia. Compositional (518 species × 337 relevés) and environmental data set (29 variables × 87 relevés) describing time since last fire, soil chemical and physical properties, and terrain characteristics were analysed using classification and ordination techniques. OptimClass assisted in the selection of a robust data transformation, resemblance function and clustering algorithm to identify the vegetation patterns. Major ecological drivers of the vegetation patterns were detected using distance‐based redundancy analysis (db‐RDA). Classification revealed major groupings of Wet Heath and Banksia Woodland distinguishable by the high prevalence of myrtyoid and proteoid taxa, respectively. On floristic‐sociological grounds, we recognised four Wet Heath and two Banksia Woodland communities. The Wet Heath was constrained to areas of higher litter depth (db‐RDA axis 1: 9%). Soil chemical and physical properties explained the highest proportion (17%) of the compositional variance, while the terrain‐ and fire‐related variables explained 2% and <0.001%, respectively. While fire explained little compositional variance overall, a separate db‐RDA analysis found that it may play an important pattern‐structuring role within Banksia Woodlands. Fine‐scale compositional patterns correspond only to a small extent to environmental data; the substantial unexplained variance may be due to slow‐acting neutral and stochastic processes.
Umbilical artery pH and base excess at birth are poor predictors of neurodevelopmental morbidity in early childhood
Authors: Leinonen Elina , Gissler Mika , Haataja Leena , Andersson Sture , Rahkonen Petri , Rahkonen Leena , Metsäranta Marjo
Published: April 2019

Aim

We sought to evaluate the associations between umbilical artery pH and base excess and neurodevelopmental outcome at four years of age.

Methods

This study comprised 84 588 singleton children born alive at term in 2005–2011 in the hospital district of Helsinki and Uusimaa in Finland. Data from the maternity hospital information system were linked to the data from the Medical Birth Register and the Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual or sensorineural impairment.

Results

After adjustment for maternal and perinatal factors, a combination of pH <7.00 and base excess <−16.00 was associated with infant death (adjusted odds ratio 19.97; 95% confidence interval 5.38–74.17). Values of pH 7.00–7.10 were associated with cerebral palsy (adjusted odds ratio 2.40; 95% confidence interval 1.05–5.47). A combination of low five‐minute Apgar score and umbilical artery base excess <−16.00 showed the highest positive predictive value (9.1%) for neurodevelopmental impairments. When umbilical artery pH <7.00 was included, a positive predictive value of 25.0% was observed for infant mortality.

Conclusion

Low umbilical artery pH and base excess at birth were the poor predictors of long‐term neurodevelopmental morbidity in an unselected population. However, these parameters might be useful in assessing the risk of infant mortality.
Trajectories of pain predict disabilities affecting daily living in arthritis
Authors: James Richard J. E. , Walsh David A. , Ferguson Eamonn
Published: April 2019

Purpose

To examine the interplay between pain and disability in arthritis when adjusting for patient heterogeneity in pain progression. There is consistent evidence to suggest that people experience osteoarthritis heterogeneously, with subgroups of people having different trajectories of pain. However, at present it is unclear how these pain trajectories are related to functional disability. We ask the question: Do levels of disability track changes in pain across different pain trajectories?

Methods

Secondary analysis of a subset (n = 889) from a cohort of older English adults, representative of the general population (the English Longitudinal Study of Ageing). The relationship between pain and functional disability was compared in three domains of disability: mobility, activities of daily living (ADL) and instrumental ADL. These represent increasingly complex forms of self‐care required for independent living. Data analysis compared the heterogeneous analysis of pain (different trajectories) and disability compared to treating pain as a simpler homogenous construct.

Results

On a population level, pain was significantly positively correlated with increased disability in all three domains, and the relationship remained stable over time. However, when heterogeneity was examined respondents whose pain improved did not show a corresponding improvement in disability in two domains (ADL and mobility).

Conclusions

These findings highlight how, for some people, alleviating pain, the main symptom of arthritis, might not prevent the persistence or progression of disability. Even when pain improves, further interventions that improve disability are likely to be required.

Statement of contribution

What is already known on this subject?

Pain and functional limitation in daily living are common symptoms of arthritis.

Arthritis pain is heterogeneous – there are trajectories of people whose pain gets better or worse.

However, to date no study has looked at the relationship between trajectories of arthritis pain and functional disability outside of the minority of people with rheumatoid arthritis.

What does this study add?

Treating pain as heterogeneous explained disability better than treating pain as a single entity.

Respondents in a trajectory of worsening pain reported functional disability in two domains (mobility and activities of daily living) also got worse over time.

People in a trajectory of decreasing pain over time did not experience a reduction in disability, despite pain being the most common reason for why people limit their daily functioning.

This suggests further intervention is required for people with arthritis, even when the most visible symptoms have been alleviated.
Development and validation of the Health Visual Information Preference Scale
Authors: Jones Annie S. K. , Kleinstäuber Maria , Martin Leslie R. , Norton Sam , Fernandez Justin , Petrie Keith J.
Published: April 2019

Objective

Patients are likely to have individual preferences for learning about health, which may influence their comprehension and utilization of health information. Some patients may prefer visual health information, which can make complex health information easier to understand. Aligning health information presentation with preferences may increase understanding and improve health outcomes, yet no scale measures preferences for visual health information.

Design

Two studies examined the psychometric properties of the Health Visual Information Preference Scale (Health VIPS), a new measure designed to assess preferences for visual health information.

Methods

In Study 1, 103 undergraduate students and 97 patients undergoing colorectal and gynaecological oncology surgery completed the Health VIPS. Exploratory factor analyses (EFA) were conducted for both samples. Internal consistency, test–retest reliability, and validity were assessed in the student sample. In Study 2, 196 outpatients completed the Health VIPS. Confirmatory factor analysis (CFA) was performed on this sample, in addition to measures of reliability and validity.

Results

In Study 1, EFA analysis suggested a two‐factor structure. The Health VIPS demonstrated good internal consistency in both the student sample (α = .70–.80) and patient sample (α = .80), and good test–retest reliability in the student sample (r = .63, p < .001). Convergent validity and discriminant validity were also established. In Study 2, the CFA confirmed a two‐factor structure is the best model fit for the Health VIPS. The Health VIPS also demonstrated discriminant and convergent validity. Scale item means in all samples were positively skewed, suggesting a general preference for visual health information.

Conclusions

Initial evidence suggests the Health VIPS has good psychometric properties. This scale could identify patients who would benefit from additional visual aids when receiving health information.

Statement of contribution

What is already known on this subject?

Poor comprehension of health information can lead to misunderstandings of illness and treatment, and potentially non‐adherence.

It is likely that patients have distinct preferences for how they would choose to receive health information, including information format.

Visual health information is becoming more widely used to communicate information about health and illness to patients, although there is no measure to identify those who prefer this information format to standard written health materials.

What does this study add?

This study describes the first scale to assess preferences for visual health information.

This scale could identify patients who would benefit from supplementary visual information in consultations.
Olanzapine induced autophagy through suppression of NF‐κB activation in human glioma cells
Authors: Zhu Ying , Zhao Yi‐Fan , Liu Rui‐Si , Xiong Ya‐Jie , Shen Xiao , Wang Yan , Liang Zhong‐Qin
Published: April 2019

Aims

Our laboratory previously reported that olanzapine treatment inhibited growth of glioma cell lines and hypothesized that autophagy may be involved in the proliferation inhibitory effects of olanzapine. However, the mechanisms of olanzapine‐contributed autophagy activation are unclear.

Methods

The inhibitory effects of olanzapine on glioma cells were evaluated by CCK8 assay, Hoechst 33258 staining and annexin V‐FITC/PI staining. Western blotting, nuclear separation techniques, and immunofluorescence assays were used to investigate the relationship between the inhibition of NF‐κB and autophagy activation by olanzapine.

Results

In this work, we verified that olanzapine increased autophagic flux and autophagic vesicles. In addition, we confirmed that autophagy was related to NF‐κB inhibition in cancer progression, especially with the nuclear translocation of p65. Furthermore, we demonstrated that autophagy induced by olanzapine could be impaired with TNFα cotreatment. We also found that olanzapine had an inhibitory effect on T98 cells with positive MGMT protein expression, which may involve the inhibition of MGMT through effects on NF‐κB.

Conclusions

Our findings identify a pathway by which olanzapine induces autophagy by depressing NF‐κB in a glioma cell line, providing evidence which supports the use of olanzapine as a potential anticancer drug.
CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model
Authors: Liu Zhi‐Yuan , Song Zhi‐Wen , Guo Shi‐Wu , He Jun‐Sheng , Wang Shen‐Yu , Zhu Jian‐Guo , Yang Hui‐Lin , Liu Jin‐Bo
Published: April 2019

Background

Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms.

Methods

Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c‐Fos and CGRP to evaluate the sensitization of neurons by RT‐PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba‐1. The mRNA levels of the pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT‐PCR.

Results

First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c‐Fos, GFAP, and iba‐1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba‐1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c‐Fos, CGRP, GFAP, iba‐1, and pro‐inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased.

Conclusion

We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain.
Anastomotic leak after transanal total mesorectal excision: grading of severity and management aimed at preservation of the anastomosis
Authors: Guel‐Klein S. , Biebl M. , Knoll B. , Dittrich L. , Weiß S. , Pratschke J. , Aigner F.
Published: April 2019

Aim

The transanal approach to total mesorectal excision (TaTME) as an alternative to conventional anterior resection offers an improved view to otherwise restricted anatomical regions in obese and narrow male pelves and unfavourable tumour locations. Guidelines for the management of anastomotic leakage (AL) following low rectal resections are scarce.

Patients and methods

Prospectively collected data of all consecutive patients undergoing TaTME between December 2014 and April 2017 in our centre were analysed retrospectively. Existing classification systems for AL were modified with regard to transanal anastomotic‐preserving management.

Results

TaTME was performed in 66 patients with a median age of 56.2 years. The overall incidence of AL was 12.1% (n = 8). AL grading was differentiated in Grades I to V according to the severity of necrosis and abscess development. Two patients suffered from AL Grade II, one patient from Grade III, three patients from Grade IV and two patients from Grade V. Preservation of the anastomosis following AL was achieved by the damage control concept in six of eight patients (75%) with a median duration of hospital stay of 36 days. Two patients received a Hartmann procedure (Grades IV and V).

Conclusion

Our study demonstrates that management of AL following TaTME is challenging but definitely amenable to strategies aimed at preserving the anastomosis by appropriate damage control. The modified classification system might serve as guidance for anastomosis‐preserving management.
Shiga‐like toxin I exerts specific and potent anti‐tumour efficacy against gastric cancer cell proliferation when driven by tumour‐preferential Frizzled‐7 promoter
Authors: Xu Hongpan , Peng Lijun , Shen Mengjiao , Xia Yanyan , Li Zhiyang , He Nongyue
Published: April 2019

Objectives

Tumour‐targeted gene therapy is a promising approach for effective control of gastric cancer cell proliferation. Our study aims to develop a cancer therapy which combines tumour‐targeting promoters with cytotoxins.

Methods

The expression of globotriaosylceramide (Gb3), which is a Shiga‐like toxin I (Stx1) receptor, was verified in gastric cancer compared with normal stomach tissues as assessed by flow cytometry and immunohistochemical analysis. We therefore constructed the recombinant pFZD7‐Stx1 plasmid vectors with tumour‐preferential Frizzled‐7 promoter and Stx1. pFZD7‐Stx1 was used to treat gastric cancer in vitro and in vivo. The gastric cancer cell proliferation and tumour growth were identified after the transfection with the pFZD7‐Stx1.

Results

Globotriaosylceramide was obviously increased in gastric cancer compared with normal stomach. The gastric cancer cell proliferation and tumour growth decreased significantly after the transfection with the pFZD7‐Stx1.

Conclusion

Frizzled‐7 promoter is preferentially active, and Gb3 is abundant in gastric cancer cells. Frizzled‐7 promoter and Stx1 may be used to determine a novel and relatively specific and potent gastric cancer therapeutic strategy.
The v‐DECAF score can predict 90‐day all‐cause mortality in patients with COPD exacerbation requiring invasive mechanical ventilation
Authors: Shi Qi‐fang , Sheng Ying , Zhu Nian , Tan Yan , Xie Xiao‐Hong , Wang Shu‐yun , Cai Jin‐fang
Published: April 2019

Introduction

The DECAF score is a simple and effective tool for predicting mortality in patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (AECOPD); however, the DECAF score has not been validated in AECOPD patients requiring invasive mechanical ventilation (IMV). We devised the ventilator (v)‐DECAF score, in which “anemia” replaces “acidaemia,” for use in AECOPD patients requiring IMV. The objective of this study was to compare the predictive efficacy of the v‐DECAF score and the DECAF score.

Methods

This study prospectively recruited 112 consecutive AECOPD patients requiring IMV from a single center. The clinical endpoint was 90‐day all‐cause mortality. Demographic and clinical data were recorded, as well as APACHE II, GCS, CURB‐65, BAP‐65 and DECAF scores, and the newly devised v‐DECAF score. The discriminatory value of the scoring systems in predicting 90‐day all‐cause mortality was determined using the area under the receiver operating characteristic (AUROC) curve.

Results

In multivariate logistic regression analysis, the v‐DECAF score was an independent predictor of 90‐day all‐cause mortality (odds ratio 3.004, 95% CI 1.658‐5.445, P < 0.001). The AUROC of the v‐DECAF and DECAF scores were 0.852 (95% CI 0.766‐0.938) and 0.777 (95%CI: 0.676‐0.878), respectively. The v‐DECAF score had a better predictive value for 90‐day all‐cause mortality compared to the DECAF score (Z = 2.338, P = 0.019).

Conclusion

The v‐DECAF score had good discriminatory power in predicting 90‐day all‐cause mortality in AECOPD patients requiring IMV.
Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice
Authors: Fu Qiang , Chen Mingqing , Anderson Jason T. , Sun Xinxin , Hu Shuiying , Sparreboom Alex , Baker Sharyn D.
Published: April 2019

Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.
Persistent C‐peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?
Authors: Marren S. M. , Hammersley S. , McDonald T. J. , Shields B. M. , Knight B. A. , Hill A. , Bolt R. , Tree T. I. , Roep B. O. , Hattersley A. T. , Jones A. G. , Oram R. A. ,   on behalf of the TIGI consortium
Published: April 2019

Aims

Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c, hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C‐peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes.

Methods

We conducted a cross‐sectional case–control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C‐peptide after a mixed‐meal tolerance test. We compared self‐reported hypoglycaemia (n = 160), HbA1c, insulin dose and microvascular complications (n = 140) in those with preserved and low C‐peptide.

Results

Stimulated median (IQR) C‐peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C‐peptide respectively. Participants with preserved C‐peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C‐peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06).

Conclusions

Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self‐reported hypoglycaemic episodes, but no difference in HbA1c. This is consistent with non‐intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin.
Suppression of bacteriocin resistance using live, heterospecific competitors
Authors: Bhattacharya Amrita , Stacy Alexander , Bashey Farrah
Published: April 2019

Rapidly spreading antibiotic resistance has led to the need for novel alternatives and sustainable strategies for antimicrobial use. Bacteriocins are a class of proteinaceous anticompetitor toxins under consideration as novel therapeutic agents. However, bacteriocins, like other antimicrobial agents, are susceptible to resistance evolution and will require the development of sustainable strategies to prevent or decelerate the evolution of resistance. Here, we conduct proof‐of‐concept experiments to test whether introducing a live, heterospecific competitor along with a bacteriocin dose can effectively suppress the emergence of bacteriocin resistance in vitro. Previous work with conventional chemotherapeutic agents suggests that competition between conspecific sensitive and resistant pathogenic cells can effectively suppress the emergence of resistance in pathogenic populations. However, the threshold of sensitive cells required for such competitive suppression of resistance may often be too high to maintain host health. Therefore, here we aim to ask whether the principle of competitive suppression can be effective if a heterospecific competitor is used. Our results show that a live competitor introduced in conjunction with low bacteriocin dose can effectively control resistance and suppress sensitive cells. Further, this efficacy can be matched by using a bacteriocin‐producing competitor without any additional bacteriocin. These results provide strong proof of concept for the effectiveness of competitive suppression using live, heterospecific competitors. Currently used probiotic strains or commensals may provide promising candidates for the therapeutic use of bacteriocin‐mediated competitive suppression.
Molecular insights into the role of the polyalanine region in mediating PHOX2B aggregation
Authors: Pirone Luciano , Caldinelli Laura , Di Lascio Simona , Di Girolamo Rocco , Di Gaetano Sonia , Fornasari Diego , Pollegioni Loredano , Benfante Roberta , Pedone Emilia
Published: April 2019

About 90% of congenital central hypoventilation syndrome (CCHS) patients show polyalanine triplet expansions in the coding region of transcription factor PHOX2B, which renders this protein an intriguing target to understand the insurgence of this syndrome and for the design of a novel therapeutical approach. Consistently with the role of PHOX2B as a transcriptional regulator, it is reasonable that a general transcriptional dysregulation caused by the polyalanine expansion might represent an important mechanism underlying CCHS pathogenesis. Therefore, this study focused on the biochemical characterization of different PHOX2B variants, such as a variant containing the correct C‐terminal (20 alanines) stretch, one of the most frequent polyalanine expansions (+7 alanines), and a variant lacking the complete alanine stretch (0 alanines). Comparison of the different variants by a multidisciplinary approach based on different methodologies (including circular dichroism, spectrofluorimetry, light scattering, and Atomic Force Microscopy studies) highlighted the propensity to aggregate for the PHOX2B variant containing the polyalanine expansion (+7‐alanines), especially in the presence of DNA, while the 0‐alanines variant resembled the protein with the correct polyalanine length. Moreover, and unexpectedly, the formation of fibrils was revealed only for the pathological variant, suggesting a plausible role of such fibrils in the insurgence of CCHS.
Bio‐derived hydroxystearic acid ameliorates skin age spots and conspicuous pores
Authors: Schütz R. , Rawlings A.V. , Wandeler E. , Jackson E. , Trevisan S. , Monneuse J.‐M. , Bendik I. , Massironi M. , Imfeld D.
Published: April 2019

Introduction

We report on the preparation and efficacy of 10‐hydroxystearic acid (HSA) that improves facial age spots and conspicuous pores.

Methods

The hydration of oleic acid into HSA was catalyzed by the oleate hydratase from Escherichia coli. Following treatment with HSA, collagen type I and type III was assessed in primary human dermal fibroblasts together with collagen type III, p53 protein levels and sunburn cells (SBC) after UVB irradiation (1 J cm−2) by immunohistochemistry on human ex vivo skin. UVB‐induced expression of matrix metalloprotease‐1 (MMP‐1) was determined from full thickness skin by RT‐qPCR. Modification of the fibroblast secretome by HSA was studied by mass‐spectrometry‐based proteomics. In a full‐face, double blind, vehicle‐controlled trial HSA was assessed for its effects on conspicuous facial pore size and degree of pigmentation of age spots in Caucasian women over an 8‐week period.

Results

HSA was obtained in enantiomeric pure, high yield (≥80%). Collagen type I and type III levels were dose‐dependently increased (96% and 244%; P < 0.01) in vitro and collagen type III in ex vivo skin by +57% (P < 0.01) by HSA. HSA also inhibited UVB‐induced MMP‐1 gene expression (83%; P < 0.01) and mitigated SBC induction (−34% vs. vehicle control) and reduced significantly UV‐induced p53 up‐regulation (−46% vs. vehicle control; P < 0.01) in irradiated skin. HSA modified the fibroblast secretome with significant increases in proteins associated with the WNT pathway that could reduce melanogenesis and proteins that could modify dermal fibroblast activity and keratinocyte differentiation to account for the alleviation of conspicuous pores. Docking studies in silico and EC50 determination in reporter gene assays (EC50 5.5 × 10−6 M) identified HSA as a peroxisomal proliferator activated receptor‐α (PPARα) agonist. Clinically, HSA showed a statistically significant decrease of surface and volume of skin pores (P < 0.05) after 8 weeks of application and age spots became significantly less pigmented than the surrounding skin (contrast, P < 0.05) after 4 weeks.

Conclusion

HSA acts as a PPARα agonist to reduce the signs of age spots and conspicuous pores by significantly modulating the expression of p53, SBC, MMP‐1 and collagen together with major changes in secreted proteins that modify keratinocyte, melanocyte and fibroblast cell behavior.
Correlation between polishing pad’s properties and material removal during full‐aperture polishing
Authors: Ren Lele , Zhang Feihu , Zhao Shijie , Liao Defeng , Xie Ruiqing , Wang Jian , Xu Qiao
Published: April 2019

Polishing pad plays a vital role in the fabrication of large flat optical elements during full‐aperture polishing. Material removal rate (MRR) and material removal distribution (MRD) describe the material removal process from the point of the global average removal rate and the spatial distribution of removed material, respectively. The pad's mechanical property characterized by compression modulus and morphological characteristic indicated by material ratio curve are used to qualitatively clarify the degression of MRR at different rough polishing stage. Moreover, the novel MRD model is proposed to quantitatively correlate the pad's mechanical and morphological characteristic with MRD. The radial surface profile predicted by MRD model meets well with the experimental results. Furthermore, the influence of pad viscoelastic property is used to explain the generation of additional MRD in experiment at the edge of workpiece.