bluuebunny/crossref_metadata_2025 huggingface dataset:
MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autism
Authors: Cai Dan-Chao , Wang Zhiwei , Bo Tingting , Yan Shengyao , Liu Yilin , Liu Zhaowen , Zeljic Kristina , Chen Xiaoyu , Zhan Yafeng , Xu Xiu , Du Yasong , Wang Yingwei , Cang Jing , Wang Guang-Zhong , Zhang Jie , Sun Qiang , Qiu Zilong , Ge Shengjin , Ye Zheng , Wang Zheng
Published: August 2019

MECP2 gain- and loss-of-function in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that MECP2 coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in MECP2 overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map MECP2-related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.

One sentence summary

We identify shared circuit-level abnormalities between MECP2 transgenic monkeys and a stratified subgroup of human autism, and demonstrate the translational need of a multimodal approach to capture multifaceted effects triggered by a single genetic event in a genetically-engineered primate model.
Widespread transcriptional responses to the thermal stresses are prewired in human 3D genome
Authors: Li Xiaoli , Xu Bingxiang , Li Xiao , Wang Danyang , An Ziyang , Jia Yan , Niu Jing , Gao Juntao , Zhang Michael Q , Li Feifei , Zhang Zhihua
Published: August 2019

Temperature changes is one of the most common environmental stress that consequences with massive phenotypic responses for almost all the life forms. The dysregulation of heat shock (HS) response genes had been found associated with various severe diseases, including cancer. Although the HS response has been well studied in animal cells, it remains elusive whether or not the cells response to cold shock (CS) similarly. Here, we comprehensively compared the changes of gene expression, epigenetic marks (H3K4me3 and H3K27ac), binding of genome architecture proteins (CTCF, SMC3 and Pol II) and chromatin conformation after HS and CS in human cells. Widespread expression change was observed after both HS and CS. Remarkably, we identified distinguished characters in those thermal stress responded genes at nearly all levels of chromatin architecture,i.e, the compartment, topological associated domain, chromatin loops and transcription elongation regulators, in the normal condition. However, the global chromatin architecture remains largely stable after both CS and HS. Interestingly, the thermal stresses responded genes are prone to spatial clustering even before the temperature changes. Our data suggested that the transcriptional response to the thermal stresses maybe independent to the changes of the high-level chromatin architecture, e.g., compartments and TAD, while it may be more dependent on the precondition of the chromatin and epigenetic settings at the normal condition.
Structural insights into the molecular mechanisms of the Mycobacterium evolvability factor Mfd
Authors: Putta Sivasankar , Prabha Swayam , Bhat Vinayak , Fox Gavin C. , Walsh Martin A. , Rao Desirazu N. , Nagaraja Valakunja , Natesh Ramanathan
Published: August 2019

Mfd is a highly conserved ATP dependent DNA translocase that mediates the role of Transcription-Coupled-DNA-Repair(TCR) in bacteria. The molecular mechanisms and conformational remodelling that occurs in Mfd upon ATP binding, hydrolysis, and DNA translocation are poorly defined. Here we report a series of crystal and electron microscopy(EM) structures of Mfd from Mycobacterium tuberculosis (MtbMfd) and Mycobacterium smegmatis Mfd, solved in both the apo and nucleotide-bound states. The structures reveal the mechanism of nucleotide-binding, which lead to the remodeling of the Walker A motif at the catalytic pocket, inducing a flip-flop action of the hinge and flexible linker regions. Specifically, nucleotide binding unlocks the Translocation in RecG motif of the D6-domain to induce a ratchet-like motion. Functional studies of MtbMfd-RNAP complexes show that MtbMfd rescues stalled Transcription Elongation Complexes. We also report negative-stain and cryo-EM single particle reconstructions of MtbMfd higher order oligomer, that reveal an unexpected dodecameric assembly state. Given that Mfd accelerates the evolution of antimicrobial resistance(AMR), our results establish a framework for the design of new “anti-evolution” therapeutics to counter AMR.
Mesenchymal Stem/ Stromal Cells metabolomic and bioactive factors profiles: a comparative analysis on the Umbilical Cord and Dental Pulp derived Stem/ Stromal Cells secretome
Authors: Caseiro AR , Pedrosa SS , Ivanova G , Branquinho MV , Almeida A , Faria F , Amorim I , Pereira T , Maurício AC
Published: August 2019

Mesenchymal Stem/ Stromal Cells assume a supporting role to the intrinsic mechanisms of tissue regeneration, a feature mostly assigned to the contents of their secretome. A comparative study on the metabolomic and bioactive molecules/factors content of the secretome of Mesenchymal Stem/ Stromal Cells derived from two expanding sources: the umbilical cord stroma and the dental pulp is presented and discussed. The metabolic profile (Nuclear Magnetic Resonance Spectroscopy) evidenced some differences in the metabolite dynamics through the conditioning period, particularly on the glucose metabolism. Despite, overall similar profiles are suggested. More prominent differences are highlighted for the bioactive factors (Multiplexing Laser Bear Analysis), in which Follistatin, Growth Regulates Protein, Hepatocyte Growth Factor, Interleukin-8 and Monocyte Chemotactic Protein-1 dominate in Umbilical Cord Mesenchymal Stem/ Stromal Cells secretion, while in Dental Pulp Stem/ Stromal Cells the Vascular Endothelial Growth Factor-A and Follistatin are more evident. The distinct secretory cocktail did not result in significantly different effects on endothelial cell populations dynamics including proliferation, migration, tube formation capacity and in vivo angiogenesis, or in chemotaxis for both Mesenchymal Stem/ Stromal Cells populations.
Computational modelling of the long-term effects of brain stimulation on the local and global structural connectivity of epileptic patients
Authors: Giannakakis Emmanouil , Hutchings Frances , Papasavvas Christoforos A. , Han Cheol E. , Weber Bernd , Zhang Chencheng , Kaiser Marcus
Published: August 2019

In patients with drug resistant focal epilepsy, targeted weak stimulation of the affected brain regions has been proposed as an alternative to surgery. However, the effectiveness of stimulation as a treatment presents great variation from patient to patient. In this study, brain activity is simulated for a period of one day using a network of Wilson-Cowan oscillators coupled according to diffusion imaging based structural connectivity. We use this computational model to examine the potential long-term effects of stimulation on brain connectivity. Our findings indicate that the overall simulated effect of stimulation is heavily dependent on the excitability of the stimulated regions. Additionally, stimulation seems to lead to long-term effects in the connectivity of secondary (non-stimulated) regions in epileptic patients. These effects are correlated with a worse surgery outcome in some patients, which suggests that long-term simulations could be used as a tool to determine suitability for surgery/stimulation.
Breeding of a high-yield strain for commercial cultivation by crossing Pholiota adiposa and P. limonella
Authors: Rong Chengbo , Song Shuang , Yang Li , Zhang Jiachan , Niu Yurong , Pan Xuejiao , Song Qinggang , Liu Yu , Wang Shouxian
Published: August 2019

Pholiota adiposa is an edible mushroom with excellent nutritional and medicinal properties. However, fruiting body yields are low, and the commercial cultivation potential of this fungus is limited. In the present study, 279 crossbred strains were obtained by mono-mono crossing of monokaryotic strains derived from P. adiposa HS5 and P. limonella HS4. Ligninolytic enzymes and mycelial growth rate were used as markers to screen the crossbred strains, and 18 were selected for further analysis. Crossbred strain A10B4 displayed the highest yield, i.e., 165.91 ± 12.56 g per bag, which was 31.34 g and 74.48 g more than that of strains HS5 and HS4, respectively. The mycelial colonization time of A10B4 was 25.18 ± 1.33 days, which was 5.64 days shorter than that of HS5. A10B4 was characterized by inter-simple sequence repeat molecular markers and antagonism tests. Differences in PCR products from parental and crossbred strains were observed. Therefore, the newly developed hybrid strain A10B4, named P. adiposa-limonella HS54 and having a high yield and desirable traits, might be suitable for commercial cultivation.
A Tukey’s g-and-h distribution based approach with PSO for degradation reliability modeling
Authors: Zhang Jinbao , Zhao Yongqiang , Liu Ming , Kong Lingxian
Published: August 2019

Purpose

A generalized distribution with wide range of skewness and elongation will be suitable for the data mining and compatible for the misspecification of the distribution. Hence, the purpose of this paper is to present a distribution-based approach for estimating degradation reliability considering these conditions.

Design/methodology/approach

Tukey’s g-and-h distribution with the quantile expression is introduced to fit the degradation paths of the population over time. The Newton–Raphson algorithm is used to approximately evaluate the reliability. Simulation verification for parameter estimation with particle swarm optimization (PSO) is carried out. The effectiveness and validity of the proposed approach for degradation reliability is verified by the two-stage verification and the comparison with others’ work.

Findings

Simulation studies have proved the effectiveness of PSO in the parameter estimation. Two degradation datasets of GaAs laser devices and crack growth are performed by the proposed approach. The results show that it can well match the initial failure time and be more compatible than the normal distribution and the Weibull distribution.

Originality/value

Tukey’s g-and-h distribution is first proposed to investigate the influence of the tail and the skewness on the degradation reliability. In addition, the parameters of the Tukey’s g-and-h distribution is estimated by PSO with root-mean-square error as the object function.
Cross-border M&As: integration practices from emerging economies
Authors: Jain Samta , Kashiramka Smita , Jain P.K.
Published: August 2019

Purpose

The purpose of the study is to gain insights into the post-acquisition integration practices of Indian multinational companies involved in cross-border acquisitions.

Design/methodology/approach

The study is based on the primary data from a sample of Indian companies engaged in cross-border acquisitions. A survey (based on a structured questionnaire) method has been used to collect the relevant data.

Findings

Majority of the sample companies have successfully managed the post-acquisition phase and realized the anticipated synergies. These companies recognize the importance of cultural integration, people/HR integration and formal communication channel during the post-acquisition phase. Despite the integration strategy being profoundly influenced by cultural differences between two companies, the emphasis on these cultural differences especially during the due-diligence stage is lacking. These aspects have not been examined adequately during the due-diligence phase.

Practical implications

Based on the findings, a model of cross-border acquisition and integration process (AIP) in the context of emerging economies has been proposed; the model is expected to be applicable across all industries and organizations, especially in emerging economies. The proposed model should essentially help senior and middle managers to develop successful integration strategies. Moreover, the study holds immense potential for practitioners and academicians by providing them with a new thought on executing successful acquisitions.

Originality/value

To the best of the authors’ knowledge, no study has examined the post-acquisition integration approach in emerging economies. Moreover, rarely has any AIP model applicable across several organizations of all sizes and types from emerging economies been suggested in the literature. The suggested AIP model is the unique proposition of the paper.
An update on customer value: state of the art, revised typology, and research agenda
Authors: Leroi-Werelds Sara
Published: August 2019

Purpose

The context of marketing and service research is rapidly changing as a result of advances in academic research and business practice. This has implications for our understanding of customer value. The purpose of this paper is to provide an update on customer value given today’s context (including recent advances such as technologies, human contact, collaborative consumption, service ecosystems and transformative service research); to revise Holbrook’s value typology; and to propose a research agenda.

Design/methodology/approach

This paper uses a conceptual approach that is rooted in the service and marketing literature.

Findings

The contribution of this paper is threefold. First, this paper presents an evolved view on customer value which accounts for recent advances in academic research and business practice. Second, this paper updates Holbrook’s value typology by revising existing value types as well as identifying additional value types; and offers guidelines for measuring and modeling customer value. Third, this paper proposes a research agenda to guide and stimulate future value research.

Originality/value

This paper provides an update on customer value, which is one of the most fundamental concepts in service and marketing research. This updated perspective has been approved and applauded by Morris B. Holbrook, one of the founding fathers of value research.
Utilising community engagement approaches to influence public mental health policy in a rural setting
Authors: Thirlwall Claire , Whitelaw Sandy
Published: August 2019

Purpose

Drawing on the notion of “mental health policy participation”, the purpose of this paper is to describe and reflect on a regional case study of a community engagement approach that explored community perspectives on mental health and the factors that influence it. It established three expectations, that: the development of the Dumfries and Galloway Public Mental Health Strategy is informed by project outputs; services and innovations are based on what people want; active involvement of local people in decision making around mental health services and strategy is achieved.

Design/methodology/approach

A “participatory appraisal” approach was used to engage with communities. A three-day “Training of Trainers” exercise was undertaken. These individuals then accessed a number of community groups. Data collection was based on five key questions. A total of 443 were engaged in the process. Insights were reviewed by 20 stakeholders from a range of services to identify key actions. This led to the development of the mental health forum and, in turn, a Public Mental Health Strategy for Dumfries and Galloway. Community members were further included in processes through feedback mechanisms.

Findings

Factors of resilience, support of families and friends, social inclusion, access to social and leisure opportunities were most important. This was followed by structural issues like fear of judgement, lack of transport, discrimination and financial support. Finally, individual factors (sleep, meaningful hobbies and health) were highlighted.

Originality/value

This approach sought to go beyond a traditional focus to explore broader community perspectives on mental health and the factors that influence it.
Comparison of the change in interpretative stances of lifelog photos versus manually captured photos over time
Authors: Lee Ahreum , Ryu Hokyoung
Published: August 2019

Purpose

The purpose of this paper is to explore how people differently create meaning from photos taken by either a lifelogging camera (LC) (i.e. automatic capture) or a mobile phone camera (MC) (i.e. manual capture). Moreover, the paper investigates the different changes in the interpretative stance of lifelog photos and manually captured photos over time to figure out how the LC application could support the users’ iconological interpretation of their past.

Design/methodology/approach

A 200-day longitudinal study was conducted with two different user groups that took and reviewed photos taken by either a LC or a MC. The study was structured in two phases: a photo collection phase, which lasted for five days (Day 1‒Day 5), and a three-part semi-structured interview phase, which was conducted on Days 8, 50 and 200.

Findings

Results revealed that the interpretative stance of the LC group changed greatly compared to the MC group that kept a relatively consistent interpretative stance over time. A significant difference between the two groups was revealed on Day 200 when the lifelog photos provoked a more iconological and less pre-iconographical interpretative stance. This stance allowed the viewers of lifelog photos to systemically interpret the photos and look back upon their past with different viewpoints that were not recognized before.

Originality/value

This paper contributes to further understand the dynamic change in interpretative stance of lifelog photos compared to manually captured photos through a longitudinal study. The results of this study can support the design guidelines for a LC application that could give opportunities for users to create rich interpretations from lifelog photos.
Optimisation of screen printing process for functional printing
Authors: Ali Muhammad , Lin Long , Faisal Saira , Sahito Iftikhar Ali , Ali Syed Imran
Published: August 2019

Purpose

The purpose of this study is to explain the effects of screen printing parameters on the quantity of ink deposited and the print quality in the context of printing of functional inks. Both these aspects of printing are crucial in the case of conventional and functional printing. This is because, in the case of conventional printing, the quantity of ink deposit affects the color strength while in the case of functional printing, it directly affects the resulting functionality of the ink layer.

Design/methodology/approach

In this work, an automatic lab-scale screen printer was used to print functional inks on a paper board substrate. The printing parameters, i.e. printing pressure and squeegee angle were altered and the resulting effects on the quantity of ink that was deposited were recorded. The quantity of ink deposit was related to its surface resistivity. In addition, the quality of the print was also assessed by examining the design registration quality.

Findings

The authors found that altering the squeegee angle has a significant effect on the properties of the resulting ink deposit. More importantly, the authors found that the deflection in the rubber blade squeegee was greatly dependent on the initial angle of the squeegee at the start of the printing stroke. For each set value of the squeegee angle that was considered, the actual angle during printing was recorded and used in the analysis. A printing pressure of three bars and squeegee angle of 20° resulted in the maximum weight of ink deposit with a correspondingly lowest surface resistivity.

Practical implications

This study is envisaged to have considerable practical implications in the rapidly growing field of functional printing of flexible substrates including, but not limited to, textiles. This is because, the study provides an insight into the effects of printing parameters on the characteristics of a functional ink deposit.

Originality/value

Screen printing of flexible substrates is a well-developed and arguably the most widely used printing technique, particularly for textiles. Numerous studies report on the analysis of various aspects of screen printing. However, to the best of the knowledge, the effects of printing parameters on the characteristics of functional inks, such as electrically conductive inks, have not been studied in this manner.
Clinical characteristics and treatment of 52 cases of phakomatosis pigmentovascularis
Authors: Shin Hyoseung , Kim Young Gull , Kim Ye Eun , Park Hyunsun
Published: August 2019

Phakomatosis pigmentovascularis is a rare syndrome characterized by widespread capillary malformation and pigmented nevus. The objective of this study was to evaluate its characteristics and treatment. Fifty‐two patients presenting between 2003 and 2017 were retrospectively reviewed. Type IIa (port‐wine stain and dermal melanocytosis with oculocutaneous involvement) was most common. Systemic involvement was observed in 17.3% and it was not significantly correlated to extent of capillary malformation or pigmented nevus. However, systemic involvement was significantly frequent in patients with nevus of Ota and in patients with pigmented nevus located on the head and neck (P = 0.004 and 0.035, respectively). Capillary malformation was almost cleared in 28.6% of patients using pulsed dye laser, whereas pigmented nevus was almost cleared in 23.7% and completely cleared in 42.1% of patients using Q‐switched neodymium:yttrium–aluminum–garnet laser. Treatment outcome score showed significant inverse correlation with the extent of port‐wine stain or pigmented nevus (P = 0.047, ρ = −0.308 and P = 0.011, ρ = −0.410, respectively). Pigmented nevus demonstrated better treatment response to lasers than did capillary malformation. Smaller lesions tended to show better treatment outcomes for both capillary malformation and pigmented nevus.
Increased risk of cardiovascular comorbidities in hidradenitis suppurativa: A nationwide, population‐based, cohort study in Taiwan
Authors: Hung Chih‐Tsung , Chiang Chien‐Ping , Chung Chi‐Hsiang , Tsao Chang‐Huei , Chien Wu‐Chien , Wang Wei‐Ming
Published: August 2019

Hidradenitis suppurativa (HS) has been reported to be associated with metabolic syndrome and coronary artery disease (CAD). Nevertheless, a nationwide study of this relationship in the Asian population has not been conducted. The aim of the present study was to clarify the cardiovascular disease risk factors, and the occurrence of CAD and cerebral infarction among patients with HS by using a nationwide database in Taiwan. We obtained data from the National Health Insurance Research Database of Taiwan. After adjusting for confounding factors, we used Cox proportional hazards analysis to reveal the risk of incident hypertension (HTN), diabetes mellitus (DM), dyslipidemia, CAD and cerebral infarction in HS patients. We identified 478 patients with newly diagnosed HS and 1912 patients in the control cohort during the 10‐year follow‐up period. Compared with the controls, HS patients had a higher risk of dyslipidemia (adjusted hazard ratio [aHR], 3.858; 95% confidence interval [CI], 2.785–5.346; P < 0.001), HTN (aHR, 1.910; 95% CI, 1.463–2.493; P < 0.001), DM (aHR, 1.709; 95% CI, 1.127–2.591; P = 0.012). Regarding comorbidities, our results also revealed a higher risk of CAD in HS patients (aHR, 2.722; 95% CI, 1.628–4.553; P < 0.001), but not cerebral infarction (aHR, 0.514; 95% CI, 0.119–2.231; P = 0.375). Our results indicate that there is a higher risk of dyslipidemia, HTN, DM and CAD in HS patients.
Diagnoses, damned diagnoses and statistics: Dealing with disparate diagnostic coding systems within the New South Wales Emergency Department Data Collection
Authors: Dinh Michael M , Berendsen Russell Saartje , Bein Kendall J
Published: August 2019

Objectives

The aims of the present study were to describe the distribution of Systematised Nomenclature of Medicine – Clinical Terms (SNOMED‐CT) codes used in the current New South Wales Emergency Department Data Collection (NSW EDDC) and classify duplicate and redundant terms into clinically meaningful sub‐groups for future analyses.

Methods

This was an analysis of ED diagnosis codes using a large state‐wide administrative ED dataset between 2015 and 2018.

Results

A total of 7.4 million (77%) of ED episode diagnoses were coded with SNOMED‐CT. Of those coded with SNOMED‐CT, 12 152 unique codes were identified. Around 1000 of the most frequently used codes accounted for 90% of the presentations coded with SNOMED‐CT and 5000 codes accounted for 99.8% of these. Around 7000 codes were deemed to be redundant, and duplication in terms exists across all sub‐groups.

Conclusion

The use of SNOMED‐CT in the NSW EDDC has resulted in substantial use of non‐specific, duplicate and redundant codes, limiting the capacity of the NSW EDDC to be used for effective data analysis.
Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15
Authors: Guo Yuna , Ayers Jessica L. , Carter Kelly T. , Wang Ting , Maden Sean K. , Edmond Darwin , Newcomb P Polly , Li Christopher , Ulrich Cornelia , Yu Ming , Grady William M.
Published: August 2019

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.
Transforming the Classic Political Forest: Contentious Territories in Java
Authors: Lukas Martin C. , Peluso Nancy Lee
Published: August 2019

Java’s extensive political forests and their contentious social relations have been profoundly transformed since the turn of the 21st century. This paper analyses new forms of forest land use, control, and revenue distribution, shaping and shaped by political‐economic changes and neoliberal‐era reforms. Villagers’ expanded uses, access to, and control of the forest understory under the violently thinned out canopies of the main tree species has generated newly spatialised forest politics, with new institutions and forest labour practices. The changes in land, species, and labour controls, and in villagers’ access to forest products and revenues define this historical transformation in the constitution of Java’s classic political forest. Contentious co‐production has resulted in fragmented territories and a momentary (at least) weakening of state controls within the old imperial political forest.
The impact of smoking and smoking cessation on disease outcomes in ulcerative colitis: a nationwide population‐based study
Authors: Blackwell Jonathan , Saxena Sonia , Alexakis Christopher , Bottle Alex , Cecil Elizabeth , Majeed Azeem , Pollok Richard C.
Published: August 2019

Background

Smokers are less likely to develop ulcerative colitis (UC) but the impact of smoking and subsequent cessation on clinical outcomes in UC is unclear.

Aim

To evaluate the effect of smoking status and smoking cessation on disease outcomes.

Methods

Using a nationally representative clinical research database, we identified incident cases of UC during 2005‐2016. Patients were grouped as never‐smokers, ex‐smokers and smokers based on smoking status recorded in the 2 years preceding UC diagnosis. We defined subgroups of persistent smokers and smokers who quit within 2 years after diagnosis. We compared the rates of overall corticosteroid use, corticosteroid‐requiring flares, corticosteroid dependency, thiopurine use, hospitalisation and colectomy between these groups.

Results

We identified 6754 patients with a new diagnosis of UC over the study period with data on smoking status, of whom 878 were smokers at diagnosis. Smokers had a similar risk of corticosteroid‐requiring flares (OR 1.16, 95% CI 0.92‐1.25), thiopurine use (HR 0.84, 95% CI 0.62‐1.14), corticosteroid dependency (HR 0.85, 95% CI 0.60‐1.11), hospitalisation (HR 0.92, 95% CI 0.72‐1.18) and colectomy (HR 0.78, 95% CI 0.50‐1.21) in comparison with never‐smokers. Rates of flares, thiopurine use, corticosteroid dependency, hospitalisation and colectomy were not significantly different between persistent smokers and those who quit smoking after a diagnosis of UC.

Conclusions

Smokers and never‐smokers with UC have similar outcomes with respect to flares, thiopurine use, corticosteroid dependency, hospitalisation and colectomy. Smoking cessation was not associated with worse disease course. The risks associated with smoking outweigh any benefits. UC patients should be counselled against smoking.
Why is the therapeutic effect of acute antimigraine drugs delayed? A review of controlled trials and hypotheses about the delay of effect
Authors: Tfelt‐Hansen Peer , Messlinger Karl
Published: August 2019

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (Tmax) at 2 hours increases from 2 to 4 hours in RCTs. To check whether such a delayed effect is also present for other oral antimigraine drugs, we hand‐searched the literature for publications on RCTs reporting efficacy. Two triptans, 3 nonsteroidal anti‐inflammatory drugs (NSAIDs), a triptan combined with an NSAID and a calcitonin gene–related peptide receptor antagonist were evaluated for their therapeutic gain with determination of time to maximum effect (Emax). Emax was compared with known Tmax from pharmacokinetic studies to estimate the delay to pain‐free. The delay in therapeutic gain varied from 1–2 hours for zolmitriptan 5 mg to 7 hours for naproxen 500 mg. An increase in effect from 2 to 4 hours was observed after eletriptan 40 mg, frovatriptan 2.5 mg and lasmiditan 200 mg, and after rizatriptan 10 mg (Tmax = 1 h) from 1 to 2 hours. This strongly indicates a general delay of effect in oral antimigraine drugs. A review of 5 possible effects of triptans on the trigemino‐vascular system did not yield a simple explanation for the delay. In addition, Emax for triptans probably depends partly on the rise in plasma levels and not only on its maximum. The most likely explanation for the delay in effect is that a complex antimigraine system with more than 1 site of action is involved.
Biogenetic ties and parent‐child relationships: The misplaced critique
Authors: Murphy Timothy F.
Published: August 2019

According to an almost axiomatic standard in bioethics, moral commitment should ground parents’ relationship with their children, rather than biogenetic relatedness. This standard has been used lately to express skepticism about extending existing assisted reproductive treatments (ARTs) to same‐sex couples and to research into novel fertility interventions for those couples, but this skepticism is misplaced on several grounds. As a matter of access and equity, same‐sex couples seem presumptively entitled to genetic relatedness to their children as far as possible both in regard to existing ARTs and to novel ARTs under investigation. For those worried about the effects of trying to secure biogenetic relatedness for same‐sex couples, it may be noted that same‐sex couples will only ever be a fraction of the parents implicated in propping up “biologism,” as the expectation of biogenetic relatedness it is sometimes called. The cultural force of biologism would survive almost intact even if no same‐sex couples were ever to have genetically related children. It is therefore hard to see why same‐sex couples should forfeit aspirations to biogenetic relationships with their children or enjoy less subsidy for ARTs than the subsidy given to different‐sex couples. As matter of moral consistency, the full implications of the biologism critique have yet to be evaluated relative to different‐sex couples.
Institutional refusal to offer assisted dying: A response to Shadd and Shadd
Authors: Sumner L.W.
Published: August 2019

Ever since medical assistance in dying (MAID) became legal in Canada in 2016, controversy has enveloped the refusal by many faith‐based institutions to allow this service on their premises. In a recent article in this journal, Philip and Joshua Shadd have proposed ‘changing the conversation’ on this issue, reframing it as an exercise not of conscience but of an institutional right of self‐governance. This reframing, they claim, will serve to show how health‐care institutions may be justified in refusing to provide MAID on moral or religious grounds. I argue that it will not make it easier to justify institutional refusal, and is likely to make it harder.
Cardiac expression of HMOX1 and PGF in sickle cell mice and haem‐treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2)
Authors: Gbotosho Oluwabukola T. , Ghosh Samit , Kapetanaki Maria G. , Lin Yu , Weidert Frances , Bullock Grant C. , Ofori‐Acquah Solomon F. , Kato Gregory J.
Published: August 2019

Haemolysis is a major feature of sickle cell disease (SCD) that contributes to organ damage. It is well established that haem, a product of haemolysis, induces expression of the enzyme that degrades it, haem oxygenase‐1 (HMOX1). We have also shown that haem induces expression of placental growth factor (PGF), but the organ specificity of these responses has not been well‐defined. As expected, we found high level expression of Hmox1 and Pgf transcripts in the reticuloendothelial system organs of transgenic sickle cell mice, but surprisingly strong expression in the heart (P < 0·0001). This pattern was largely replicated in wild type mice by intravenous injection of exogenous haem. In the heart, haem induced unexpectedly strong mRNA responses for Hmox1 (18‐fold), Pgf (4‐fold), and the haem transporter Slc48a1 (also termed Hrg1; 2·4‐fold). This was comparable to the liver, the principal known haem‐detoxifying organ. The NFE2L2 (also termed NRF2) transcription factor mediated much of the haem induction of Hmox1 and Hrg1 in all organs, but less so for Pgf. Our results indicate that the heart expresses haem response pathway genes at surprisingly high basal levels and shares with the liver a similar transcriptional response to circulating haem. The role of the heart in haem response should be investigated further.
The role of parental acute psychological distress in paediatric burn re‐epithelialization
Authors: Brown Erin A. , De Young Alexandra , Kimble Roy , Kenardy Justin
Published: August 2019

Objectives

Following a paediatric burn, parents commonly experience high levels of acute psychological distress, which has been shown to increase child psychological distress as well as child procedural distress. The influence of psychological stress and perceived pain on wound healing has been demonstrated in several laboratory and medical populations. This paper investigates the influence of parental acute psychological distress and procedural behaviour on the child's rate of re‐epithelialization, after controlling for child procedural distress.

Design

A prospective observational study with longitudinal outcome.

Methods

Eighty‐three parents of children 1–6 years old reported acute psychological distress (post‐traumatic stress symptoms [PTSS], guilt, pre‐procedural fear, general anxiety/depression symptoms) in relation to their child's burn. A researcher observed parent–child behaviour at the first dressing change, and parents and nurses reported child procedural distress (pre‐, peak‐, and post‐procedural pain and fear). These variables, along with demographic and injury information, were tested for predicting time to re‐epithelialization. Date of re‐epithelialization was determined by the treating consultant.

Results

Days to re‐epithelialization ranged from 3 to 35 days post‐injury. A hierarchical multiple regression analysis found wound depth and size significantly accounted for 28% of the variance in time to re‐epithelialization. In Block 2, child peak‐procedural pain significantly accounted for 6% additional variance. In Block 3, parental PTSS significantly accounted for 5% additional variance.

Conclusions

Parental PTSS appears to be an important but under‐recognized factor that may influence their child's burn re‐epithelialization. Further investigation is required to understand the mechanisms contributing to this association.

Statement of contribution

What is already known on this subject?

Psychological stress delays wound healing, and this relationship has been found in paediatric burn populations with procedural pain. Parental psychological stress is often present after a child's burn and is related to the child's procedural coping and distress.

What does this study add?

Parental post‐traumatic stress is related to delayed child burn re‐epithelialization.

This association is in addition to procedural pain delaying re‐epithelialization.
Andrographolide alleviates Parkinsonism in MPTP‐PD mice via targeting mitochondrial fission mediated by dynamin‐related protein 1
Authors: Geng Ji , Liu Wen , Gao Jian , Jiang Chunhong , Fan Ting , Sun Yang , Qin Zheng‐Hong , Xu Qiang , Guo Wenjie , Gao Jing
Published: August 2019

Background and Purpose

Accumulating evidence indicates that mitochondrial dynamics play an important role in the progressive deterioration of dopaminergic neurons. Andrographolide has been found to exert neuroprotective effects in several models of neurological diseases. However, the mechanism of how andrographolide protects neurons in Parkinson's disease (PD) remains not fully understood.

Experimental Approach

Behavioural experiments were performed to examine the effect of andrographolide in 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐PD mice. Mitochondrial mass and morphology were visualized using transmission electron microscopy (TEM). SH‐SY5Y cells and primary mouse neurons were exposed to rotenone to mimic PD in vitro. Western blotting, co‐immunoprecipitation and immunofluorescence were performed. The target protein of andrographolide was identified by biotin‐andrographolide pulldown assay as well as drug affinity responsive target stability (DARTS), cellular thermal shift (CETSA), and surface plasmon resonance (SPR) assays.

Key Results

Andrographolide administration improved behavioural deficits and attenuated loss of dopaminergic neurons in MPTP‐exposed mice and reduced cell death induced by rotenone in vitro. An increased mitochondrial mass, and decreased surface area were found in the striatum from MPTP‐PD mice, as well as in rotenone‐treated primary neurons and SH‐SY5Y cells, while andrographolide treatment preserved mitochondrial mass and morphology. Dynamin‐related protein 1 (DRP1) was identified as a target protein of andrographolide. Andrographolide bound to DRP1 and inhibited its GTPase activity, thereby preventing excessive mitochondria fission and neuronal damage in PD.

Conclusions and Implications

Our findings suggest that andrographolide may protect neurons against rotenone‐ or MPTP‐induced damage in vitro and in vivo through inhibiting mitochondrial fission.
The stratigraphic record of minibasin subsidence, Precaspian Basin, Kazakhstan
Authors: Jackson Christopher A.‐L. , Duffy Oliver B. , Fernandez Naiara , Dooley Tim P. , Hudec Michael R. , Jackson Martin P. A. , Burg George
Published: August 2019

Minibasins are fundamental components of many salt‐bearing sedimentary basins, where they may host large volumes of hydrocarbons. Although we understand the basic mechanics governing their subsidence, we know surprisingly little of how minibasins subside in three‐dimensions over geological timescales, or what controls such variability. Such knowledge would improve our ability to constrain initial salt volumes in sedimentary basins, the timing of salt welding and the distribution and likely charging histories of suprasalt hydrocarbon reservoirs. We use 3D seismic reflection data from the Precaspian Basin, onshore Kazakhstan to reveal the subsidence histories of 16, Upper Permian‐to‐Triassic, suprasalt minibasins. These minibasins subsided into a Lower‐to‐Middle Permian salt layer that contained numerous relatively strong, clastic‐dominated minibasins encased during an earlier, latest Permian phase of diapirism; because of this, the salt varied in thickness. Suprasalt minibasins contain a stratigraphic record of symmetric (bowl‐shaped units) and then asymmetric (wedge‐shaped units) subsidence, with this change in style seemingly occurring at different times in different minibasins, and most likely prior to welding. We complement our observations from natural minibasins in the Precaspian Basin with results arising from new physical sandbox models; this allows us to explore the potential controls on minibasin subsidence patterns, before assessing which of these might be applicable to our natural example. We conclude that due to uncertainties in the original spatial relationships between encased and suprasalt minibasins, and the timing of changes in style of subsidence between individual minibasins, it is unclear why such complex temporal and spatial variations in subsidence occur in the Precaspian Basin. Regardless of what controls the observed variability, we argue that vertical changes in minibasin stratigraphic architecture may not record the initial (depositional) thickness of underlying salt or the timing of salt welding; this latter point is critical when attempting to constrain the timing of potential hydraulic communication between sub‐salt source rocks and suprasalt reservoirs. Furthermore, temporal changes in minibasin subsidence style will likely control suprasalt reservoir distribution and trapping style.
Impact of a pre‐existing transverse drainage system on active rift stratigraphy: An example from the Corinth Rift, Greece
Authors: Somerville David J. P. , Mountney Nigel P. , Colombera Luca , Collier Richard E. Ll.
Published: August 2019

Models to explain alluvial system development in rift settings commonly depict fans that are sourced directly from catchments formed in newly uplifted footwalls, which leads to the development of steep‐sided talus‐cone fans in the actively subsiding basin depocentre. The impact of basin evolution on antecedent drainage networks orientated close to perpendicular to a rift axis, and flowing over the developing hangingwall dip slope, remains relatively poorly understood. The aim of this study is to better understand the responses to rift margin uplift and subsequent intrabasinal fault development in determining sedimentation patterns in alluvial deposits of a major antecedent drainage system. Field‐acquired data from a coarse‐grained alluvial syn‐rift succession in the western Gulf of Corinth, Greece (sedimentological logging and mapping) has allowed analysis of the spatial distribution of facies associations, stratigraphic architectural elements and patterns of palaeoflow. During the earliest rifting phase, newly uplifted footwalls redirected a previously established fluvial system with predominantly southward drainage. Footwall uplift on the southern basin margin at an initially relatively slow rate led to the development of an overfilled basin, within which an alluvial fan prograded to the south‐west, south and south‐east over a hangingwall dip slope. Deposition of the alluvial system sourced from the north coincided with the establishment of small‐scale alluvial fans sourced from the newly uplifted footwall in the south. Deposits of non‐cohesive debris flows close to the proposed hangingwall fan apex pass gradationally downstream into predominantly bedload conglomerate deposits indicative of sedimentation via hyperconcentrated flows laden with sand‐ and silt‐grade sediment. Subsequent normal faulting in the hangingwall resulted in the establishment of further barriers to stream drainage, blocking flow routes to the south. This culminated in the termination of sediment supply to the basin depocentre from the north, and the onset of underfilled basin conditions as signified by an associated lacustrine transgression. The evolution of the fluvial system described in this study records transitions between three possible end‐member types of interaction between active rifting and antecedent drainage systems: (a) erosion through an uplifted footwall, (b) drainage diversion away from an uplifted footwall and (c) deposition over the hangingwall dip slope. The orientation of antecedent drainage pathways at a high angle to the trend of a developing rift axis, replete with intrabasinal faulting, exerts a primary control on the timing and location of development of overfilled and underfilled basin states in evolving depocentres.
Contested Spaces: Intimate Segregation and Environmental Gentrification on Chicago's 606 Trail
Authors: Harris Brandon , Schmalz Dorothy , Larson Lincoln , Fernandez Mariela , Griffin Sarah
Published: August 2019

The 606, a greenway in Chicago, has been lauded as a transformative revitalization project that provides diverse benefits and connects communities. However, the greenway has become a source of conflict among Latinx residents who question the trail's value and influence on their communities. Using observations and interviews with users and residents, this study examined potential consequences of The 606, including intimate segregation, which occurs when individuals use social and physical barriers to stratify themselves in a shared environment, and impacts of environmental gentrification. Results revealed division along The 606 with Latinx users isolating themselves in western trail segments, citing feelings of exclusion, discrimination, and resistance to gentrification. Conversely, white users were found to avoid western trail segments due to fear and pervasive stereotypes. The study highlights the urban park paradox, where green space provides benefits to communities while simultaneously generating unintentional consequences that potentially reinforce segregation and social inequities.