bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial
Authors: Wan Yi , Wang Fenglei , Yuan Jihong , Li Jie , Jiang Dandan , Zhang Jingjing , Li Hao , Wang Ruoyi , Tang Jun , Huang Tao , Zheng Jusheng , Sinclair Andrew J , Mann Jim , Li Duo 
Published: February 2019

ObjectiveTo investigate whether diets differing in fat content alter the gut microbiota and faecal metabolomic profiles, and to determine their relationship with cardiometabolic risk factors in healthy adults whose diet is in a transition from a traditional low-fat diet to a diet high in fat and reduced in carbohydrate.MethodsIn a 6-month randomised controlled-feeding trial, 217 healthy young adults (aged 18–35 years; body mass index <28 kg/m2; 52% women) who completed the whole trial were included. All the foods were provided during the intervention period. The three isocaloric diets were: a lower-fat diet (fat 20% energy), a moderate-fat diet (fat 30% energy) and a higher-fat diet (fat 40% energy). The effects of the dietary interventions on the gut microbiota, faecal metabolomics and plasma inflammatory factors were investigated.ResultsThe lower-fat diet was associated with increased α-diversity assessed by the Shannon index (p=0.03), increased abundance ofBlautia(p=0.007) andFaecalibacterium(p=0.04), whereas the higher-fat diet was associated with increasedAlistipes(p=0.04),Bacteroides(p<0.001) and decreasedFaecalibacterium(p=0.04). The concentration of total short-chain fatty acids was significantly decreased in the higher-fat diet group in comparison with the other groups (p<0.001). The cometabolites p-cresol and indole, known to be associated with host metabolic disorders, were decreased in the lower-fat diet group. In addition, the higher-fat diet was associated with faecal enrichment in arachidonic acid and the lipopolysaccharide biosynthesis pathway as well as elevated plasma proinflammatory factors after the intervention.ConclusionHigher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavourable changes in gut microbiota, faecal metabolomic profiles and plasma proinﬂammatory factors, which might confer adverse consequences for long-term health outcomes.Trial registration numberNCT02355795; Results.
Fold–thrust structures – where have all the buckles gone?
Authors: Butler Robert W. H. , Bond Clare E. , Cooper Mark A. , Watkins Hannah 
Published: February 2019

Abstract
The margins to evolving orogenic belts experience near layer-parallel contraction that can evolve into fold–thrust belts. Developing cross-section-scale understanding of these systems necessitates structural interpretation. However, over the past several decades a false distinction has arisen between some forms of so-called fault-related folding and buckle folding. We investigate the origins of this confusion and seek to develop unified approaches for interpreting fold–thrust belts that incorporate deformation arising both from the amplification of buckling instabilities and from localized shear failures (thrust faults). Discussions are illustrated using short case studies from the Bolivian Subandean chain (Incahuasi anticline), the Canadian Cordillera (Livingstone anticlinorium) and Subalpine chains of France and Switzerland. Only fault–bend folding is purely fault-related and other forms, such as fault-propagation and detachment folds, all involve components of buckling. Better integration of understanding of buckling processes, the geometries and structural evolutions that they generate may help to understand how deformation is distributed within fold–thrust belts. It may also reduce the current biases engendered by adopting a narrow range of idealized geometries when constructing cross-sections and evaluating structural evolution in these systems.
Capsaicin causes robust reduction in glycinergic transmission to rat hypoglossal motor neurons via a TRPV1-independent mechanism
Authors: Thakre Prajwal P. , Bellingham Mark C. 
Published: February 2019

The effect of capsaicin on glycinergic synaptic transmission to juvenile rat hypoglossal motor neurons in acute brainstem slices was evaluated in the presence of TTX. Capsaicin caused a robust decrease in miniature IPSC frequency, amplitude, and half-width, showing that this effect is independent of action potential generation. In the presence of capsazepine, a classic TRPV1 antagonist, capsaicin was still able to reduce spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. We further investigated whether the effect of capsaicin on glycinergic transmission to hypoglossal motor neurons is pre- or postsynaptic in nature by recording pairs of evoked IPSCs. Interestingly, capsaicin also reduced evoked IPSC amplitude without affecting paired-pulse ratio, indicating a postsynaptic mechanism of action. Significant reduction was also observed in evoked IPSC half-width, rise time, and decay tau. We also show that capsaicin does not have any effect on either transient (It) or sustained (Is) potassium currents. Finally, we also show that the hyperpolarization-activated cationic current (Ih) also remains unchanged after capsaicin application. NEW & NOTEWORTHY Capsaicin reduces the amplitude of quantal and evoked glycinergic inhibitory neurotransmission to brainstem motor neurons without altering activity-dependent transmitter release. This effect of capsaicin is not due to activation of TRPV1 receptors, as it is not blocked by capsazepine, a TRPV1 receptor antagonist. Capsaicin does not alter voltage-dependent potassium current or the hyperpolarization-activated cationic current in brainstem motor neurons.
Time-resolved quantification of the dynamic extracellular space in the brain: study of cortical spreading depression
Authors: Zhao Hui-Hui , Du Hong , Cai Yujie , Liu Chao , Xie Zeyu , Chen Kevin C. 
Published: February 2019

Extracellular diffusion in the brain is customarily characterized by two parameters, the extracellular space (ECS) volume fraction α and the diffusion tortuosity λ. How these two parameters are temporarily modified and correlated in a physiological/pathological event remains unclear to date. Using tetramethylammonium (TMA+) as an ECS ion tracer in a newly updated iontophoretic sinusoidal method, we studied in this work the dynamic α( t) and λ( t) in rat somatosensory cortex during spreading depression (SD). Temporal variations of α( t) and λ( t), as evoked by SD, were obtained through analyses of the extracellular TMA+diffusion waveform resulting from a sinusoidally modulated point source. Most of the time, cortical SD induced coordinated α( t) decreases and λ( t) increases. In rare occasions, SD induced sole decreases of α( t) with no changes in λ( t). The independent modulation of α( t) and λ( t) was neither associated with cortical anatomy nor with the specific shape of the SD field potential wave. Changes of α( t) and λ( t) often took place acutely at the onset of SD, followed by a more transient modulation. Compared with the prior iontophoretic methods of TMA+, the sinusoidal method provides time-resolved quantification of α( t) and λ( t) in relative terms but also raises a higher property requirement on the TMA+-selective microelectrode. The sinusoidal method could become a valuable tool in the studies of the dynamic ECS response in various brain events.NEW & NOTEWORTHY An iontophoretic sinusoidal method was applied to study the dynamic changes of two extracellular space parameters, the extracellular volume fraction α( t) and tortuosity λ( t), in the brain during cortical spreading depression. Both parameters showed coordinated (most often) and independent (rarely) modulations in spreading depression. The sinusoidal method is equally applicable to other acute pathological events and a valuable tool to study the functional role of extracellular space in brain events.
Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation
Authors: van den Broeke E. N. , Hartgerink D. M. , Butler J. , Lambert J. , Mouraux A. 
Published: February 2019

High-frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization (CS), manifested as increased pinprick sensitivity of the skin surrounding the site of HFS. Our aim was to assess the effect of CS on pinprick-evoked pupil dilation responses (PDRs) and pinprick-evoked brain potentials (PEPs). We hypothesized that the increase in the positive wave of PEPs following HFS would result from an enhanced pinprick-evoked phasic response of the locus coeruleus-noradrenergic system (LC-NS), indicated by enhanced PDRs. In 14 healthy volunteers, 64- and 96-mN pinprick stimuli were delivered to the left and right forearms, before and 20 minutes after HFS was applied to one of the two forearms. Both PEPs and pinprick-evoked PDRs were recorded. After HFS, pinprick stimuli were perceived as more intense at the HFS-treated arm compared with baseline and control site, and this increase was similar for both stimulation intensities. Importantly, the pinprick-evoked PDR was also increased, and the increase was stronger for 64- compared with 96-mN stimulation. This is in line with our previous results showing a stronger increase of the PEP positivity at 64 vs. 96-mN stimulation and suggests that the increase in PEP positivity observed in previous studies could relate, at least in part, to enhanced LC-NS activity. However, there was no increase of the PEP positivity in the present study, indicating that enhanced LC-NS activity is not the only determinant of the HFS-induced enhancement of PEPs. Altogether, our results indicate that PDRs are more sensitive for detecting CS than PEPs. NEW & NOTEWORTHY We provide the first demonstration in humans that activity-dependent central sensitization increases pinprick-evoked autonomic arousal measured by enhanced pupil dilation response.
Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer
Authors: Kim Bo Ram , Jeong Yoon A. , Jo Min Jee , Park Seong Hye , Na Yoo Jin , Kim Jung Lim , Jeong Soyeon , Yun Hye Kyeong , Kang Sanghee , Lee Dae-Hee , Oh Sang Cheul 
Published: February 2019

Abstract
Despite an increase in the survival rate of patients with cancer owing to the use of current chemotherapeutic agents, adverse effects of cancer therapies remain a concern. Combination therapies have been developed to increase efficacy, reduce adverse effects, and overcome drug resistance. Genipin is a natural product derived from Gardenia jasminoides, which has been associated with anti-inflammatory, anti-angiogenic, and anti-proliferative effects; hypertension; and anti-ischemic brain injuries. However, the enhancement of oxaliplatin sensitivity by genipin remains unexplored. Our study showed that a combination of genipin and oxaliplatin exerts synergistic antitumor effects in vitro and in vivo in colorectal cancer cell lines through the reactive oxygen species (ROS)/endoplasmic reticulum (ER) stress/BIM pathway. Importantly, the combination did not affect normal colon cells. BIM knockdown markedly inhibited apoptosis induced by the combination. In addition, genipin induced ROS by inhibiting superoxide dismutase 3 activity. These findings suggest that genipin may be a novel agent for increasing the sensitivity of oxaliplatin against colorectal cancer. The combination of oxaliplatin and genipin hold significant therapeutic potential with minimal adverse effects.
Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition
Authors: Fischl Anthony S. , Wang Xiaoen , Falcon Beverly L. , Almonte-Baldonado Rowena , Bodenmiller Diane , Evans Glenn , Stewart Julie , Wilson Takako , Hipskind Philip , Manro Jason , Uhlik Mark T. , Chintharlapalli Sudhakar , Gerald Damien , Alsop David C. , Benjamin Laura E. , Bhatt Rupal S. 
Published: February 2019

Abstract
Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.
TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models
Authors: Irie Hiroki , Ito Kimihiro , Fujioka Yayoi , Oguchi Kei , Fujioka Akio , Hashimoto Akihiro , Ohsawa Hirokazu , Tanaka Kenji , Funabashi Kaoru , Araki Hikari , Kawai Yuichi , Shimamura Tadashi , Wadhwa Renu , Ohkubo Shuichi , Matsuo Kenichi 
Published: February 2019

Abstract
Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal–dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken together, our results demonstrated that TAS0728 may offer a promising therapeutic option with improved efficacy as compared with current HER2 inhibitors for HER2-activated cancers. Assessment of TAS0728 in ongoing clinical trials is awaited (NCT03410927).
Immune cytopenia post–cord transplant in Hurler syndrome is a forme fruste of graft rejection
Authors: Deambrosis David , Lum Su Han , Hum Ryan M. , Poulton Kay , Ogden Wendy , Jones Simon , Stanworth Simon , Bonney Denise , Hiwarkar Prashant , Wynn Robert F. 
Published: February 2019

Abstract
Umbilical cord blood (UCB) is the preferred donor cell source for children with Hurler syndrome undergoing transplant, and its use has been associated with improved “engrafted survival” rates. However, as in other pediatric recipients of UCB transplants for nonmalignant disease, immune-mediated cytopenia (IMC) is a significant complication. This article describes 8 episodes of IMC in 36 patients with Hurler syndrome undergoing UCB transplant. The incidence of IMC was increased in those with a higher preconditioning absolute lymphocyte count and in those conditioned with fludarabine-containing regimens rather than cyclophosphamide, and it included red cell alloantibodies directed at cord blood group antigens that are novel to the recipient. In several cases, IMC was a precursor to immune-mediated complete graft rejection. We describe IMC as part of a spectrum of graft rejection by a residual competent host immune system and a forme fruste of complete graft rejection.
Using Twitter to assess attitudes to schizophrenia and psychosis
Authors: Passerello Giorgianna L. , Hazelwood James E. , Lawrie Stephen 
Published: February 2019

Aims and methodSchizophrenia is a psychotic disorder that is stereotypically stigmatised as untreatable and associated with violence. Several authorities have suggested that changing the name, for example to psychosis, would reduce such stigmatisation. We aimed to compare attitudes to schizophrenia and psychosis on Twitter to see if psychosis was associated with less negative attitudes. Tweets containing the terms ‘schizophrenia’, ‘schizophrenic’, ‘psychosis’ or ‘psychotic’ were collected on www.twitter.com and were captured with NCapture. On NVivo, tweets were coded into categories based on user type, tweet content, attitude and stigma type by two independent raters. We compared the content and attitudes of tweets referring to schizophrenia/schizophrenic and psychosis/psychotic.ResultsA total of 1120 tweets referring to schizophrenia/schizophrenic and 1080 referring to psychosis/psychotic were identified over two 7-day periods; 424 original tweets for schizophrenia and 416 original tweets for psychosis were included in the analysis. Psychosis was significantly more commonly included in tweets expressing negative attitudes (n=131, 31.5%) than schizophrenia (n=41, 9.7%) (χ² = 237.03, P < 0.0001). Of the personal opinions or dyadic interactions, 125 (53.4%) in the psychosis data set were stigmatising, compared with 33 (24.6%) of those in the schizophrenia set (χ² = 44.65, P < 0.0001).Clinical implicationsThe terms psychosis/psychotic are associated with a significantly higher number of tweets with negative content than schizophrenia/schizophrenic. Together with other evidence, this suggests that changing the name of schizophrenia to psychosis will not reduce negative attitudes toward the condition.Declaration of interestS.L. has received personal fees from Otsuka and Sunovion, and personal and research fees from Janssen.
2.5 years on: what are the effects of a ‘frequent attenders’ service in the Emergency Department?
Authors: Sousa Soraia , Hilder Tracey , Burdess Christopher , Bolton Philippa 
Published: February 2019

This study focused on an evaluation over 2.5 years to establish if a frequent attenders' service in an Emergency Department (ED) impacted on the overall number of patients attending as well as the numbers of their attendances. For this, three patient lists from April-September 2015 and three lists from a matched period in 2017 were randomly selected and the two samples compared. Results showed both a reduction in the number of total patients identified as frequent attenders as well as a reduction on the number of attendances to ED. The study suggests that the implementation of a frequent attenders' service is associated with benefits, not only for the individual attendances per patient, but also in an overall reduction of the number patients classed as frequent attenders.Declaration of interestThe authors have no conflict of interest to declare regarding this manuscript.
Epigenetic Age Acceleration in Adolescence Associates With BMI, Inflammation, and Risk Score for Middle Age Cardiovascular Disease
Authors: Huang Rae-Chi , Lillycrop Karen A , Beilin Lawrence J , Godfrey Keith M , Anderson Denise , Mori Trevor A , Rauschert Sebastian , Craig Jeffrey M , Oddy Wendy H , Ayonrinde Oyekoya T , Pennell Craig E , Holbrook Joanna D , Melton Phillip E 
Published: February 2019

Abstract

Context
“Accelerated aging,” assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age.

Design
DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA; preserved across cell types) and extrinsic (EEAA; dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development.

Results
In 995 participants (49.6% female; age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ–inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors.

Conclusions
Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.
Advancing the science of outcome measurement in paediatric palliative care
Authors: Harding Richard , Chambers Lizzie , Bluebond-Langner Myra 
Published: February 2019

Background: There is a lack of appropriate, validated person-centred outcome measures (PCOM) for paediatric palliative care in the scientific literature, and as a result there is not a tool to drive and evaluate care of children and young people. Methods: In line with COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidance, an expert group was convened to elicit views on the domains/items to include in a PCOM, implementation challenges and requirements for use in routine care by practitioners. Data were content analysed. Results: 36 UK-wide clinicians, advocates, and researchers participated. 1) Items included were: specific symptoms, education, play and social interaction, parental time for partner and other children, sex and intimacy, and sibling wellbeing. 2) Implementation challenges: supporting children and young people to engage meaningfully, that the instrument could be seen as a ‘test’ of parents' care quality, raising unrealistic expectations, proxy validity. 3) There is a need for clear administration and interpretation guidance and for data ownership/access to be agreed. Conclusions: This expert meeting addressed the initial step in COSMIN guidance, informing face validity and acceptability. It provides the information necessary for the first phase of tool development and informs potential use and implementation.