bluuebunny/crossref_metadata_2025 huggingface dataset:
Atractylenolide II reverses the influence of lncRNA XIST/miR‐30a‐5p/ROR1 axis on chemo‐resistance of colorectal cancer cells
Authors: Zhang Ruijuan , Wang Zhijun , Yu Qianyun , Shen Jun , He Wenji , Zhou Dongqing , Yu Qingqing , Fan Jiawei , Gao Shurong , Duan Lihong
Published: March 2019

This investigation was conducted to elucidate whether atractylenolide II could reverse the role of lncRNA XIST/miR‐30a‐5p/ROR1 axis in modulating chemosensitivity of colorectal cancer cells. We totally collected 294 pairs of colorectal cancer tissues and adjacent normal tissues and also purchased colorectal cancer cell lines and human embryonic kidney cell line. 5‐fluorouracil, cisplatin, mitomycin and adriamycin were designated as the chemotherapies for colorectal cell lines, and atractylenolides were arranged as the Chinese drug. The expressions of XIST, miR‐30a‐5p and ROR1 were quantified with aid of qRT‐PCR or Western blot, and luciferase reporter gene assay was implemented to determine the relationships among XIST, miR‐30a‐5p and ROR1. Our results demonstrated that XIST and ROR1 expressions were dramatically up‐regulated, yet miR‐30a‐5p expression was down‐regulated within colorectal cancer tissues (P < 0.05). The overexpressed XIST and ROR1, as well as under‐expressed miR‐30a‐5p, were inclined to promote viability and proliferation of colorectal cells under the influence of chemo drugs (P < 0.05). In addition, XIST could directly target miR‐30a‐5p, and ROR1 acted as the targeted molecule of miR‐30a‐5p. Interestingly, atractylenolides not only switched the expressions of XIST, miR‐30a‐5p and ROR1 within colorectal cancer cells but also significantly intensified the chemosensitivity of colorectal cancer cells (P < 0.05). Finally, atractylenolide II was discovered to slow down the viability and proliferation of colorectal cancer cells (P < 0.05). In conclusion, the XIST/miR‐30a‐5p/ROR1 axis could be deemed as pivotal markers underlying colorectal cancer, and administration of atractylenolide II might improve the chemotherapeutic efficacy for colorectal cancer.
SP/NK‐1R promotes gallbladder cancer cell proliferation and migration
Authors: Deng Xue‐Ting , Tang Si‐Min , Wu Pei‐Yao , Li Quan‐Peng , Ge Xian‐Xiu , Xu Bo‐Ming , Wang Hui‐Shan , Miao Lin
Published: March 2019

Aberrant substance P/neurokinin‐1 receptor (SP/NK‐1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK‐1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK‐1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK‐1R. The results showed that SP and NK‐1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK‐1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF‐κB p65 and the tumor‐associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF‐κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF‐κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK‐1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF‐κB pathway.
MicroRNA‐92a promotes vascular smooth muscle cell proliferation and migration through the ROCK/MLCK signalling pathway
Authors: Wang Jingyu , Zhang Chenxu , Li Cai , Zhao Dandan , Li Shuyao , Ma Le , Cui Ying , Wei Xiaoqing , Zhao Ying , Gao Ying
Published: March 2019

To identify the interaction between known regulators of atherosclerosis, microRNA‐92a (miR‐92a), Rho‐associated coiled‐coil‐forming kinase (ROCK) and myosin light chain kinase (MLCK), we examined their expressions during proliferation and migration of platelet‐derived growth factor‐BB (PDGF‐BB)‐regulated vascular smooth muscle cells (VSMCs), both in vivo and in vitro. During the formation of atherosclerosis plaque in mice, a parallel increase in expression levels of MLCK and miR‐92a was observed while miR‐92a expression was reduced in ML‐7 (an inhibitor of MLCK) treated mice and in MLCK‐deficient VSMCs. In vitro results indicated that both MLCK and miR‐92a shared the same signalling pathway. Transfection of miR‐92a mimic partially restored the effect of MLCK's deficiency and antagonized the effect of Y27632 (an inhibitor of ROCK) on the down‐regulation of VSMCs activities. ML‐7 increased the expression of Kruppel‐like factor 4 (KLF4, a target of miR‐92a), and siRNA‐KLF4 increased VSMCs' activity level. Consistently, inhibition of either MLCK or ROCK enhanced the KLF4 expression. Moreover, we observed that ROCK/MLCK up‐regulated miR‐92a expression in VSMCs through signal transducer and activator of transcription 3 (STAT3) activation. In conclusion, the activation of ROCK/STAT3 and/or MLCK/STAT3 may up‐regulate miR‐92a expression, which subsequently inhibits KLF4 expression and promotes PDGF‐BB‐mediated proliferation and migration of VSMCs. This new downstream node in the ROCK/MLCK signalling pathway may offer a potential intervention target for treatment of atherosclerosis.
Birth weight, verbal cognition in early adolescence, and lexical and reading skills in late adolescence: a formal mediation analysis using a potential outcomes approach
Authors: Silva Anderson Ribeiro da , Puglisi Marina Leite , Pompéia Sabine , Ploubidis George B. , Swardfager Walter , Cogo‐Moreira Hugo
Published: March 2019

Background

Oral and written language in late adolescence are influenced by many pre‐ and postnatal factors, including cognitive performance at earlier ages. We investigated whether the association between birth weight and lexical knowledge and reading comprehension in late adolescence (14–16 years) is mediated by verbal cognition during early adolescence (10–11 years).

Methods

We conducted a mediation analysis via a potential outcomes approach to data from three United Kingdom (UK) prospective birth cohorts – The National Child Development Study (NCDS; year of birth (Y.B.) = 1,958; analytic sample size (A.N.) = 9,399; original sample size (O.N.) = 18,558), British Cohort Study (BCS70; Y.B. = 1,970; A.N. = 6,591; O.N. = 17,196), and Millennium Cohort Study (MCS; Y.B. = 2,000–2,001; A.N. = 3,950; O.N. = 18,552) – to evaluate the indirect effects of birth weight on lexical knowledge (BCS and MCS) and reading comprehension measures (NCDS) in adolescence.

Results

We found an indirect effect but no statistically significant direct effects for the BCS and MCS cohorts. The proportion of the effect of birth weight on oral and written language in late adolescence mediated by early adolescence verbal cognition was 59.19% (BCS) and 8.41% (MCS) for lexical knowledge and 61.00% when the outcome was reading comprehension (NCDS). Sensitivity analyses, used to assess whether unmeasured variables could have affected our mediation estimates, showed that for reading comprehension, in NCDS, the indirect effect is robust; only unmeasured confounders highly correlated with the mediator and outcome (ρ = .68) would explain away the indirect effect. For lexical knowledge, smaller correlations with hypothetical confounders (ρ = .33 for BCS) would suffice to render the indirect effect non‐significant; the indirect effect for MCS non statistical significant.

Conclusions

Birth weight affects oral and written language skills (lexical knowledge and reading comprehension) in late adolescence via verbal cognition in early adolescence in two cohorts born in 1958 and 1970, but not in a cohort born at the turn of the millennium. These indirect effects were stronger than the direct effects and are unlikely to be explained by unmeasured confounders when the outcome involves complex skills such as reading comprehension.
A case–control study of risk factors associated with Zoon balanitis in men
Authors: Piaserico S. , Orlando G. , Linder M.D. , Cappozzo P. , Zarian H. , Iafrate M.
Published: March 2019

Background

Zoon balanitis (ZB) is a chronic inflammatory benign mucositis. Its etiopathogenesis still remains hypothetical and speculative.

Objectives

To determine risk factors associated with genital ZB in men.

Methods

This is a case–control study including 30 patients diagnosed with ZB and 54 patients with dermatological diseases other than ZB enrolled in the Dermatological Clinic of the University of Padova, Italy, from September 2015 to June 2018. Univariate and multivariate logistic regression analyses were used for analysis of data collected.

Results

According to multivariate logistic regression analysis, risk factors for ZB were as follows: the mean daily cigarettes consumption (OR 1.065; 95% CI 1.8‐11.4; P = 0.006) and the number of weekly foreskin retractions (OR 0.847; 95% CI 5.5–24.1; P = 0.003). There were no statistically significant differences between cases and controls according to age, presence of circumcision as well in number of sexual partners.

Conclusions

To our knowledge, this is the first case–control study showing that smoking and poor genital hygiene are associated with being affected by ZB.
Association of sensitive skin with sensitive corneas and sensitive eyelids
Authors: Misery L. , Cochener B. , Brenaut E. , Séité S. , Taieb C.
Published: March 2019

Background

Sensitive scalp or irritable bowel syndrome has been previously shown to be associated with sensitive skin. We wondered whether sensitive eyelids and sensitive eyes could also be associated with sensitive skin.

Methods

A cross‐sectional epidemiological study was carried out on a representative sample of French people, according to the quota method, using a questionnaire.

Results

A total of 2048 subjects were included in the present study. Notably, 52.2% declared sensitive eyes, which was more frequent in women than in men. The subjects who reported sensitive eyes were more numerous according to the severity of skin sensitivity, the severity of sleep disorders and the presence of bright eyes. More than half of the subjects with sensitive eyes thought that they were sensitive to sun exposure, dust, computer or touch pads or dry air. The presence of sensitive eyelids was reported by 18.65% (more frequent in women) and was associated with sensitive skin and sensitive eyes, sun exposure and exposure to dust.

Conclusion

This study is the first to investigate sensitive eyelids or sensitive eyes. Sensitive eyelids can be considered a localization of sensitive skin. The concept of sensitive eyes is not commonly used by ophthalmologists and remains to be more precisely defined.
Cholelithiasis: Presentation and Management
Authors: Littlefield Amber , Lenahan Christy
Published: March 2019

Cholelithiasis affects approximately 15% of the US population. Rising trends in obesity and metabolic syndrome have contributed to an increase in diagnosis of cholelithiasis. There are several risk factors for cholelithiasis, both modifiable and nonmodifiable. Women are more likely to experience cholelithiasis than are men. Pregnancy, increasing parity, and obesity during pregnancy further increase the risk that a woman will develop cholelithiasis. The classic presentation of persons experiencing cholelithiasis, specifically when gallstones obstruct the common bile duct, is right upper quadrant pain of the abdomen that is often elicited upon palpation during physical examination and documented as a positive Murphy's sign. Referred pain to the right supraclavicular region and/or shoulder, nausea, and vomiting are also frequently reported by persons with cholelithiasis. Cholelithiasis can result in complications, including cholecystitis (inflammation of the gallbladder) and cholangitis (inflammation of the bile duct). Lack of physical examination findings does not rule out a diagnosis of cholelithiasis. Laboratory tests such as white blood cell count, liver enzymes, amylase, and lipase may assist the clinician in diagnosing cholelithiasis; however, ultrasonography is the gold standard for diagnosis. Management is dependent on severity and frequency of symptoms. Lifestyle and dietary modifications combined with medication management, such as use of gallstone dissolution agents, may be recommended for persons who have a single symptomatic episode. If symptoms become severe and/or are recurrent, laparoscopic cholecystectomy is recommended. It is recommended that individuals with an established diagnosis of cholelithiasis be referred to a surgeon and/or gastroenterologist within 2 weeks of initial presentation regardless of severity or frequency of symptoms.
Human factors awareness and recognition during multidisciplinary team meetings
Authors: Oeppen Rachel S. , Davidson Mike , Scrimgeour Duncan S. , Rahimi Siavash , Brennan Peter A.
Published: March 2019

Multidisciplinary team (MDT) meetings are widely used throughout medicine and dentistry, bringing together expertise and different opinions across many disciplines to benefit patient care. Depending on the cancer site and specialties involved, some MDTs can last for several hours, especially if there are many complex patients to discuss. However, concentration and attention can vary and distraction is almost inevitable with separate conversations between MDT members and the ever‐increasing use of smartphones. The role of human factors (HF) in contributing to error is well known in high‐risk activities including medicine and surgery. Surprisingly, while there is increasing awareness of their importance by medical and dental professionals to enhance patient safety, to our knowledge nothing to date has been published about the possible effect and role of HF at MDTs. Here we provide a brief HF overview and focus on the factors at an MDT that could lead to distraction, providing suggestions (including some from aviation) for possible ways to enhance and improve discussion during these often‐long meetings. It is hoped that this paper will generate some thought and discussion around the current “normal” MDT practice in head and neck and other specialties and challenge colleagues to embrace HF and safety principles in a just and learning culture.
Adolescent Social Norms and Alcohol Use: Separating Between‐ and Within‐Person Associations to Test Reciprocal Determinism
Authors: Meisel Samuel N. , Colder Craig R.
Published: March 2019

Despite perceived drinking norms being robust predictors of adolescent alcohol use, few studies have assessed the development of perceived norms across adolescence and processes accounting for the strong associations between perceived norms and drinking. Using reciprocal determinism as a theoretical basis for understanding the development of adolescent drinking norms, this study examined reciprocal associations across nine waves of data spanning early to late adolescence. Bivariate latent curve models with structured residuals demonstrated consistent within‐person reciprocal associations between descriptive and injunctive norms and alcohol use after accounting for growth in norms and alcohol use. Results suggest the need for developmentally informed intervention efforts targeting perceived drinking norms during early and middle adolescence.
Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury
Authors: Han Dong , Wang Yongjun , Chen Jiangwei , Zhang Jibin , Yu Peng , Zhang Ran , Li Shuang , Tao Bo , Wang Yabin , Qiu Ya , Xu Mengqi , Gao Erhe , Cao Feng
Published: March 2019

Accumulated pieces of evidence have proved the beneficial effects of melatonin on myocardial ischemia/reperfusion (MI/R) injury, and these effects were largely dependent on melatonin membrane receptor activation. In humans and other mammals, there are two types of melatonin receptors, including the melatonin receptor 1 (MT1, melatonin receptor 1a or MTNR1A) and melatonin receptor 1 (MT2, melatonin receptor 1b or MTNR1B) receptor subtypes. However, which receptor mediates melatonin‐conferred cardioprotection remains unclear. In this study, we employed both loss‐of‐function and gain‐of‐function approaches to reveal the answer. Mice (wild‐type; MT1 or MT2 silencing by in vivo minicircle vector; and those overexpressing MT1 or MT2 by in vivo AAV9 vector) were exposed to MI/R injury. Both MT1 and MT2 were present in wild‐type myocardium. MT2, but not MT1, was essentially upregulated after MI/R Melatonin administration significantly reduced myocardial injury and improved cardiac function after MI/R Mechanistically, melatonin treatment suppressed MI/R‐initiated myocardial oxidative stress and nitrative stress, alleviated endoplasmic reticulum stress and mitochondrial injury, and inhibited myocardial apoptosis. These beneficial actions of melatonin were absent in MT2‐silenced heart, but not the MT1 subtype. Furthermore, AAV9‐mediated cardiomyocyte‐specific overexpression of MT2, but not MT1, mitigated MI/R injury and improved cardiac dysfunction, which was accompanied by significant amelioration of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. Mechanistically, MT2 protected primary cardiomyocytes against hypoxia/reoxygenation injury via MT2/Notch1/Hes1/RORα signaling. Our study presents the first direct evidence that the MT2 subtype, but not MT1, is a novel endogenous cardiac protective receptor against MI/R injury. Medications specifically targeting MT2 may hold promise in fighting ischemic heart disease.
Genetic analysis of the Linnaean Ulva lactuca (Ulvales, Chlorophyta) holotype and related type specimens reveals name misapplications, unexpected origins, and new synonymies
Authors: Hughey Jeffery R. , Maggs Christine A. , Mineur Frédéric , Jarvis Charlie , Miller Kathy Ann , Shabaka Soha Hamdy , Gabrielson Paul W.
Published: March 2019

Current usage of the name Ulva lactuca, the generitype of Ulva, remains uncertain. Genetic analyses were performed on the U. lactuca Linnaean holotype, the U. fasciata epitype, the U. fenestrata holotype, the U. lobata lectotype, and the U. stipitata lectotype. The U. lactuca holotype is nearly identical in rbcL sequence to the epitype of U. fasciata, a warm temperate to tropical species, rather than the cold temperate species to which the name U. lactuca has generally been applied. We hypothesize that the holotype specimen of U. lactuca came from the Indo‐Pacific rather than northern Europe. Our analyses indicate that U. fasciata and U. lobata are heterotypic synonyms of U. lactuca. Ulva fenestrata is the earliest name for northern hemisphere, cold temperate Atlantic and Pacific species, with U. stipitata a junior synonym. DNA sequencing of type specimens provides an unequivocal method for applying names to Ulva species.
Frequency Domain Estimation of Continuous Time Cointegrated Models with Mixed Frequency and Mixed Sample Data
Authors: Chambers Marcus J.
Published: March 2019

Recent work by the author on mixed frequency data analysis has focused on the estimation of cointegrated systems in continuous time based on a fully specified dynamic system of equations, while the estimation of cointegrating vectors in a discrete time system has been approached using a semiparametric frequency domain estimator. We extend the latter approach to cover the continuous time case, establishing the asymptotic properties of the frequency domain estimator and explore, in a simulation study, the effects of misspecifying the continuous time dynamic model in discrete time compared to treating the dynamics non‐parametrically. An empirical illustration is also provided.
An outback oasis: the ecological importance of bilby burrows
Authors: Dawson S. J. , Broussard L. , Adams P. J. , Moseby K. E. , Waddington K. I. , Kobryn H. T. , Bateman P. W. , Fleming P. A.
Published: March 2019

Ecosystem engineers are species that have a role in creating and maintaining certain habitat traits that are important for other species. Burrowing species do this by creating subterranean refugia from predation and thermal extremes, but also providing foraging opportunities through soil movement and by increasing local landscape heterogeneity. In this study, we used camera traps to monitor the burrows of greater bilbies (Macrotis lagotis), a vulnerable Australian marsupial, in an area subject to frequent disturbance by fire. We tested the hypothesis that bilby burrows provide refuge for other species and therefore their presence increases biodiversity. In total, 45 taxa – 22 bird, 16 reptile and 7 mammal taxa – were recorded interacting with 127 burrows across 7 sites. Species richness was greater at burrows compared with vegetation away from burrows, while abundance was no different. There was no difference in species assemblage for bilby burrows that were actively maintained by bilbies compared with abandoned burrows, although there was more activity at bilby maintained burrows. A wildfire allowed us to test the ad hoc hypothesis that the use of bilby burrows was greater when vegetation cover was removed by fire. We recorded significant differences in species assemblage interacting with burrows after fire, although overall species richness and abundance did not change. The response of individual species was variable; for example, burrows provide a refuge for smaller species (such as mice and small reptiles), and may therefore protect them from the effects of fire. Where they persist, bilbies provide an important ecosystem engineering service, as their burrows support a broad range of species. Further reduction in the distribution of the bilby is therefore likely to have a flow‐on effect on biodiversity, impacting species that use their burrows for refuge.
Geochemistry of a confirmed Precambrian impact ejecta deposit: The Grænsesø spherule layer, South Greenland
Authors: Huber Matthew S. , Koeberl Christian , Smith Frank C. , Glass Billy P. , Mundil Roland , McDonald Iain
Published: March 2019

Samples from a single outcrop of the Graenseso spherule layer, Midternaes, South Greenland, consist of a spherule‐bearing dolomixtite with matrix‐supported intraclasts up to 1 m in size. In addition to field observations, we performed mineralogical and whole rock geochemical analysis, including electron microprobe, neutron activation analysis, X‐ray fluorescence, and mass spectrometry of the horizon and the overlying and underlying strata. We show that the spherules are petrographically similar to those in the Zaonega spherule layer, Karelia, Russia. Our petrographic and chemical results are consistent with the previous suggestion that the Grænsesø layer correlates with the Zaonega layer, and it is possible that both layers are related to the Vredefort impact event. The samples containing spherules, as well as the overlying rocks, have elevated REEs compared to the underlying pre‐impact layer, suggestive of a new continental source of sediment that may be coincident with the impact event. Zircons separated from the lower part of the Grænsesø spherule layer display complex age patterns suggesting that they have genetically different origins based on distinctly different Th/U ratios. Crystallization ages of all groups are ≥ 2.8 Ga, with ~2.8 Ga representing a time of major crustal growth globally. Therefore, we cannot conclusively determine in this study if the zircons are locally derived or if they are transported with the ejecta. The spherule layer was deposited by a high‐energy, subaqueous debris flow, an origin that is consistent with the hypothesis that the layer was deposited by impact‐induced waves and/or currents.
Linear growth faltering and the role of weight attainment: Prospective analysis of young children recovering from severe wasting in Niger
Authors: Isanaka Sheila , Hitchings Matt D.T. , Berthé Fatou , Briend André , Grais Rebecca F.
Published: March 2019

Efforts to reduce the impact of stunting have been largely independent of interventions to reduce the impact of wasting, despite the observation that the conditions can coexist in the same child and increase risk of death. To optimize the management of malnourished children—who can be wasted, stunted, or both—the relationship between stunting and wasting should be elaborated. We aimed to describe the relationship between concurrent weight and height gain during and after rehabilitation from severe wasting. We conducted a secondary analysis of a randomized trial for the outpatient treatment of severe wasting, including 1,542 children who recovered and were followed for 12 weeks. We described the overlap of stunting and severe wasting and the change in stunting over time. We showed the relationship between concurrent weight and height gain using adjusted generalized estimating equations and calculated the mean rate of change in weight‐for‐height z score (WHZ) and height‐for‐age z score (HAZ) during and after rehabilitation. At baseline, 79% (n = 1,223/1,542) and 49% (n = 757/1,542) of children were stunted and severely stunted, respectively. Prevalence increased over time among children <24 months. During rehabilitation when weight was not yet fully recovered, we found rapid WHZ gain but limited HAZ gain. Following successful rehabilitation, WHZ gain slowed. The rate of HAZ gain was negative after rehabilitation but increased relative to the period during treatment. The potential relationship between weight and height gain calls for increased coverage of wasting treatment to not only prevent child mortality but also reduce linear growth faltering.
Bringing meaning to coaching in medical education
Authors: Lovell Ben
Published: March 2019

Lovell reflects on what it means to be a coach is within medical education and the resultant skill set required to be effective
Exomic and transcriptomic alterations of hereditary gingival fibromatosis
Authors: Han Seong Kyu , Kong Jungho , Kim Sanguk , Lee Jae‐Hoon , Han Dong‐Hoo
Published: March 2019

Objective

Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by either localized or generalized gradual, benign, non‐hemorrhagic enlargement of gingivae. Although several genetic causes of HGF are known, the genetic etiology of HGF as a non‐syndromic and idiopathic entity remains uncertain.

Subjects and methods

We performed exome and RNA‐seq of idiopathic HGF patients and controls, and then devised a computational framework that specifies exomic/transcriptomic alterations interconnected by a regulatory network to unravel genetic etiology of HGF. Moreover, given the lack of animal model or large‐scale cohort data of HGF, we developed a strategy to cross‐check their clinical relevance through in silico gene–phenotype mapping with biomedical literature mining and semantic analysis of disease phenotype similarities.

Results

Exomic variants and differentially expressed genes of HGF were connected by members of TGF‐β/SMAD signaling pathway and craniofacial development processes, accounting for the molecular mechanism of fibroblast overgrowth mimicking HGF. Our cross‐check supports that genes derived from the regulatory network analysis have pathogenic roles in fibromatosis‐related diseases.

Conclusions

The computational approach of connecting exomic and transcriptomic alterations through regulatory networks is applicable in the clinical interpretation of genetic variants in HGF patients.
Safety and efficacy of anti‐tachycardia pacing in patients with hypertrophic cardiomyopathy implanted with an ICD
Authors: Adduci Carmen , Semprini Lorenzo , Palano Francesca , Musumeci Maria Beatrice , Volpe Massimo , Autore Camillo , Francia Pietro
Published: March 2019

Background

In hypertrophic cardiomyopathy (HCM) patients implanted with an implantable cardioverter defibrillator (ICD), clinical outcomes of antitachycardia pacing (ATP) have been poorly explored. In a retrospective analysis of a cohort of consecutive HCM patients implanted with an ICD, we aimed to assess the efficacy, safety, and clinical value of ATP.

Methods

The cohort of HCM patients implanted with a transvenous ICD and followed in our center was assessed for device intervention from implantation to last clinical follow‐up.

Results

Overall 77 patients (45 males; mean age: 46 ± 16 years) were analyzed. After 67 ± 41 months, 24 patients had 49 ventricular tachycardia/fibrillation (VT/VF) appropriately treated (5.8% per year). Among 39 monomorphic VTs, ATP was effective in 27 (success rate: 69%). Mean time from VT onset to ATP delivery was 9.1 ± 4.9 s. The only clinical variable improving ATP success was use of beta‐blockers (81% vs 50%; P = .04). Out of 12 ineffectively treated VTs, one was immediately shocked, four self‐terminated after 18 ± 12 s, and seven (18%) were accelerated to a new VT. ATP was also delivered for 27 of 42 inappropriately detected episodes and induced two de novo VTs (7%). In the per patient analysis, 14 out 77 (18%) patients had one or more appropriate and effective ATP (3.4% per year), and only six (8%; 1.4% per year) received more than one ATP.

Conclusion

ATP is moderately effective for the treatment of monomorphic VTs in HCM patients. However, the rate of appropriate ATP therapies is low, ATP is often prematurely delivered, and ATP‐induced arrhythmia degeneration is of concern.
Quantifying the completeness of the bat fossil record
Authors: Brown Emily E. , Cashmore Daniel D. , Simmons Nancy B. , Butler Richard J.
Published: March 2019

Bats (Chiroptera) are one of the most successful extant mammalian orders, uniquely capable of powered flight and laryngeal echolocation. The timing and evidence for evolution of their novel adaptations have been difficult to ascertain from the fossil record due to chronological gaps and the fragmentary nature of most fossil bat material. Here, we quantify the quality of the bat fossil record using skeletal and character completeness metrics, which respectively document for each taxon what proportion of a complete skeleton is preserved, and the proportion of phylogenetic characters that can be scored. Completeness scores were collected for 441 valid fossil bat species in 167 genera from the Eocene to the Pleistocene. All metrics record similar temporal patterns: peak completeness in the Lutetian stage reflects the presence of Lagerstätten, while subsequent stages have very low completeness, except an Aquitanian high and a Pleistocene peak in skeletal completeness. Bat completeness is not correlated with intensity of sampling through geological time but has a weak negative correlation with publication date. There is no correlation between taxonomic richness and completeness, as the bat record predominately consists of diagnostic but isolated teeth. Consequently, bat skeletal completeness is the lowest of any previously assessed tetrapod group, but character completeness is similar to parareptiles and birds. Bats have significantly higher character completeness in the northern hemisphere, probably due to heightened historical interest and presence of Lagerstätten. Taxa derived from caves are more complete than those from fluviolacustrine and marine deposits, but do not preserve highly complete specimens.
CRISPR‐LbCas12a‐mediated modification of citrus
Authors: Jia Hongge , Orbović Vladimir , Wang Nian
Published: March 2019

Recently, CRISPR‐Cas12a (Cpf1) from Prevotella and Francisella was engineered to modify plant genomes. In this report, we employed CRISPR‐LbCas12a (LbCpf1), which is derived from Lachnospiraceae bacterium ND2006, to edit a citrus genome for the first time. First, LbCas12a was used to modify the CsPDS gene successfully in Duncan grapefruit via Xcc‐facilitated agroinfiltration. Next, LbCas12a driven by either the 35S or Yao promoter was used to edit the PthA4 effector binding elements in the promoter (EBEPthA4‐CsLOBP) of CsLOB1. A single crRNA was selected to target a conserved region of both Type I and Type II CsLOBPs, since the protospacer adjacent motif of LbCas12a (TTTV) allows crRNA to act on the conserved region of these two types of CsLOBP. CsLOB1 is the canker susceptibility gene, and it is induced by the corresponding pathogenicity factor PthA4 in Xanthomonas citri by binding to EBEPthA4‐CsLOBP. A total of seven 35S‐LbCas12a‐transformed Duncan plants were generated, and they were designated as #D35s1 to #D35s7, and ten Yao‐LbCas12a‐transformed Duncan plants were created and designated as #Dyao1 to #Dyao10. LbCas12a‐directed EBEPthA4‐CsLOBP modifications were observed in three 35S‐LbCas12a‐transformed Duncan plants (#D35s1, #D35s4 and #D35s7). However, no LbCas12a‐mediated indels were observed in the Yao‐LbCas12a‐transformed plants. Notably, transgenic line #D35s4, which contains the highest mutation rate, alleviates XccΔpthA4:dCsLOB1.4 infection. Finally, no potential off‐targets were observed. Therefore, CRISPR‐LbCas12a can readily be used as a powerful tool for citrus genome editing.
Elevated CO2 does not affect stem CO2 efflux nor stem respiration in a dry Eucalyptus woodland, but it shifts the vertical gradient in xylem [CO2]
Authors: Salomón Roberto L. , Steppe Kathy , Crous Kristine Y. , Noh Nam Jin , Ellsworth David S.
Published: March 2019

To quantify stem respiration (RS) under elevated CO2 (eCO2), stem CO2 efflux (EA) and CO2 flux through the xylem (FT) should be accounted for, because part of respired CO2 is transported upwards with the sap solution. However, previous studies have used EA as a proxy of RS, which could lead to equivocal conclusions. Here, to test the effect of eCO2 on RS, both EA and FT were measured in a free‐air CO2 enrichment experiment located in a mature Eucalyptus native forest. Drought stress substantially reduced EA and RS, which were unaffected by eCO2, likely as a consequence of its neutral effect on stem growth in this phosphorus‐limited site. However, xylem CO2 concentration measured near the stem base was higher under eCO2, and decreased along the stem resulting in a negative contribution of FT to RS, whereas the contribution of FT to RS under ambient CO2 was positive. Negative FT indicates net efflux of CO2 respired below the monitored stem segment, likely coming from the roots. Our results highlight the role of nutrient availability on the dependency of RS on eCO2 and suggest stimulated root respiration under eCO2 that may shift vertical gradients in xylem [CO2] confounding the interpretation of EA measurements.
Focus stacking photogrammetry for micro‐scale roughness reconstruction: a methodological study
Authors: Olkowicz Marcin , Dabrowski Marcin , Pluymakers Anne
Published: March 2019

In close‐range applications, it is unclear whether optical photogrammetry is capable of accurately reconstructing submillimetre‐scale roughness. This paper presents a study of fine‐scale rock fracture roughness measurements with a careful assessment of the error. The workflow combines the techniques of structure from motion with focus stacking, using consumer‐grade equipment and free or affordable software. The approach is tested firstly with synthetic data to check the influence of the number and position of cameras, object texture and image processing using focus stacking. Secondly, the optimised workflow is used to measure a natural shale rock fracture surface. To estimate the accuracy, the results were compared with a high‐precision reference dataset provided by white‐light interferometry. The standard deviation of error in the method is 6·5 μm, and is related with morphological structures with wavelengths below 150 μm and amplitudes smaller than 10 μm.
Is there evidence for post‐epidemic attenuation in the Dutch elm disease pathogenOphiostoma novo‐ulmi?
Authors: Brasier C. M. , Webber J. F.
Published: March 2019

The first pandemic of Dutch elm disease (DED) in Europe and North America caused by the introducedOphiostoma ulmibegan in the early 1900s but declined unexpectedly in Europe from the 1930s onwards after killing 30–40% of the elms. Later a second pandemic caused by the much more aggressiveOphiostoma novo‐ulmispread across the same areas and by 1990 most of Britain'sc. 30 million mature elms had died. During the second pandemic,O. novo‐ulmiacquired debilitating viruses and changed from being largely clonal to highly heterogeneous through horizontal transfer of novel, sometimes deleterious, genes fromO. ulmi. In the post‐epidemic period a new disease dynamic has emerged, with millions of small recruitment elms repeatedly attacked by sequential cycles of disease. This study investigated the possibility of pathogenic attenuation inO. novo‐ulmias the epidemic has progressed. Isolates collected from the three original outbreak areas in Britain in 1982–3 (early post‐epidemic period) and 2011 (advanced post‐epidemic) were compared for two fitness components: pathogenic aggressiveness andin vitrogrowth rate. Mean aggressiveness of the 2011 isolates to clonal English elm (Ulmus procera) proved not to differ significantly from that of the 1982 isolates, either overall or within each outbreak area. Similarly, the mean growth rates of the 1982 and 2011 samples showed no differences. The implications of these findings are discussed in relation to the future of the currentDEDpandemic in Europe, the decline of the first pandemic, and the difficulty of drawing parallels between different tree–pathogen systems.
Classical conditioning in oddball paradigm: A comparison between aversive and name conditioning
Authors: Pavlov Yuri G. , Kotchoubey Boris
Published: March 2019

The nature of cortical plasticity in learning is one of the most intriguing questions of modern cognitive neuroscience. Classical conditioning (as a typical case of associative learning) and electroencephalography together provide a good framework for expanding our knowledge about fast learning‐related cortical changes. In our experiment, we employed a novel paradigm in which classical conditioning was combined with passive oddball. Nineteen subjects participated in the first experiment (aversive conditioning with painful shock as unconditioned stimulus (US) and neutral tones as conditioned stimulus (CS)), and 22 subjects in the second experiment (with a subject’s own name as US). We used event‐related potentials (ERPs) and time‐frequency analyses to explore the CS‐US interaction. We found a learning‐induced increment of P3a in the first experiment and the late positive potential (LPP) in both experiments. These effects may be related to increased attentional and emotional significance of conditioned stimuli. We showed that the LPP and P3a effects, earlier found only in visual paradigms, generalize to the auditory sensory system. We also observed suppression of the low beta activity to CS+ in aversive conditioning over the hemisphere contralateral to expected electrical shocks, presumably indicating preparation of the somatosensory system to the expected nociceptive US.
A comprehensive study of disorder of sex development in Staffordshire bull terrier dog
Authors: Horňáková Ľubica , Dianovský Ján , Holečková Beáta , Šiviková Katarína
Published: March 2019

An 8‐month‐old female Staffordshire bull terrier was clinically examined because of external sexual organs abnormality—clitoral hypertrophy. As stated by the owner, the female dog had not been in heat yet. Serum profile of testosterone (3.39 ng/ml), as well as an anti‐Műllerian hormone (24.0 ng/ml), suggested the presence of testicular tissue. On the contrary, the estimated level of 17β‐oestradiol (24.6 pg/ml) was approximately two times higher when compared with the normal anoestrus values (5–10 pg/ml). A midline laparotomy was performed to detect the cranial parts of the genital system. Gonads resembling testicle or ovotestis (left) and hypoplastic testicle (right) was visible. Cranial portion of gonads was attached to structures indicative of bilateral epididymidis. The next tubular structures—oviducts were resected along with adherent parts of a hypoplastic uterus. Histological evaluation confirmed that the examined gonad samples were testicles with modified interstitial testicular tissue. Hypertrophy of interstitial space was predominantly formed by Leydig cells. Examination of a cross‐section through the head of suspected epididymidis confirmed their characteristic structures. In addition, the characteristic configuration of the oviducts was presented. The uterus consisted of three walls, in which the endometrium was hypoplastic with the presence of endometrial glands. No Y chromosome was detected by chromosomal analysis using CFA Y probe and the amplification of SRY‐gene coding region (813 bp) indicated genotype 78, XX; SRY‐negative. Sequencing of SOX9 gene exons 1–3 did not reveal any differences in exon 1 and 3. On the contrary, a few changes were determined in the SOX9 exon 2 sequences: G instead of A at position 103; C instead of reference T at position 115; GCG instead of reference CGC at position 138–140; T instead of reference C at positions 161, 164 and 167.
Seed depredation negates the benefits of midstory hardwood removal on longleaf pine seedling establishment
Authors: Willis John L. , Schnake David K. , Wetzstein Branson , Yow Justin , Guinto Daniel , Ulrich Stacy , DePerno Christopher S. , Lashley Marcus A.
Published: March 2019

Midstory hardwoods are traditionally removed to restore longleaf pine on fire‐excluded savannas. However, recent evidence demonstrating midstory hardwood facilitation on longleaf pine seedling survival has brought this practice into question on xeric sites. Also, midstory hardwoods could facilitate longleaf pine seedling establishment, as hardwood litter may conceal seeds from seed predators or improve micro‐environmental conditions for seedling establishment. However, little is known about these potential mechanisms. In this study, we tracked longleaf pine seed depredation and germination in artificially seeded plots (11 seeds/m2) in a factorial design fully crossing hardwood retention or removal with vertebrate seed predator access or exclusion in the Sandhills Ecoregion of North Carolina, U.S.A. Seed depredation averaged 78% across treatments and was greatest in unexcluded plots. Hardwood retention did not affect seed depredation. Longleaf pine averaged 3.6 germinants/4 m2 across treatments, and was six times more abundant where vertebrates had been excluded. Hardwood removal had a strong positive effect on seedling germination, likely due to the removal of litter, but only when vertebrates were excluded. Our results indicated midstory hardwoods are not facilitating longleaf pine seedling establishment. Nevertheless, our results indicated that hardwood removal may not increase longleaf pine seedling establishment, as seed depredation diminished the effectiveness of hardwood removal under mast seed availability. Collectively, these results demonstrate the underlying complexity of the longleaf pine ecosystem, and suggest that planting may need to be part of the restoration strategy on sites where seed depredation limits longleaf pine natural regeneration.
Metabolomics in chronic lung diseases
Authors: Nambiar Shabarinath , Bong How Sze , Gummer Joel , Trengove Robert , Moodley Yuben
Published: March 2019

Chronic lung diseases represent a significant global burden. Their increasing incidence and complexity render a comprehensive, multidisciplinary and personalized approach to each patient, critically important. Most recently, unique biochemical pathways and disease markers have been identified through large‐scale metabolomic studies. Metabolomics is the study of metabolic pathways and the measurement of unique biomolecules in a living system. Analysing samples from different compartments such as bronchoalveolar lavage fluid (BALF) and plasma has proven useful for the characterization of a number of pathological conditions and offers promise as a clinical tool. For example, several studies using mass spectrometry (MS) have shown alterations in the sphingolipid metabolism of chronic obstructive pulmonary disease (COPD) sufferers. In this article, we present a practical review of the application of metabolomics to the study of chronic lung diseases (CLD): COPD, idiopathic pulmonary fibrosis (IPF) and asthma. The insights, which the analytical strategies employed in metabolomics, have provided to the dissection of the biochemistry of CLD and future clinical biomarkers are explored.
Experiments in Lay Cues to the Relative Validity of Positions Taken by Disputing Groups of Scientists
Authors: Johnson Branden B.
Published: March 2019

Risk analysis and hazard management can prompt varied intra‐scientific disputes, some which have or will become public, and thus potentially available for lay judgments of the relative validity of the positions taken. As attentive laypeople may include elites as well as the general public, understanding whether and how cues to credibility of disputing groups of scientists might shape those lay judgments can be important. Relevant literatures from philosophy, social studies of science, risk analysis, and elsewhere have identified potential cues, but not tested their absolute or relative effects. Two experiments with U.S. online panel members tested multiple cues (e.g., credentials, experience, majority opinions, research quality) across topics varying in familiarity subject to actual intra‐science disputes (dark matter, marijuana, sea‐level rise). If cues supported a position, laypeople were more likely to choose it as relatively more valid, with information quality, majority “vote,” experience, and degree source as the strongest, and interest, demographic, and values similarity as the weakest, cues. These results were similar in overall rankings to those from implicit rankings of cue reliability ratings from an earlier U.S. online survey. Proposed moderators were generally nonsignificant, but topic familiarity and subjective topic knowledge tended to reduce cue effects. Further research to confirm and extend these findings can inform both theory about citizen engagement with scientific and risk disputes, and practice in communication about science and risk.
Comparing Kaplan–Meier Curves with Delayed Treatment Effects: Applications in Immunotherapy Trials
Authors: Flandre Philippe , O’Quigley John
Published: March 2019

We consider a comparison of Kaplan–Meier curves from clinical trials in which there may be a delayed treatment effect. Any such delay takes us outside the umbrella of a proportional hazards structure and therefore outside the setting in which the log-rank test would be optimal. The approach of Chauvel and O’Quigley based on Brownian motion approximations enables the construction of powerful tests in situations of non-proportionality and, in particular, a powerful test in the situation of delayed effect. The power of this test is seen to be very close to that of the most powerful test, which, however, is unavailable in practice. We show that the test is unbiased and consistent under general conditions. Under the null, we obtain identical large sample behaviour to the log-rank test so the type 1 error is correctly controlled. Under proportional hazards departures from the null we obtain results that indicate a manageable loss in power compared with the log-rank test. The usual sample size calculations can still provide a useful guide. Support for the theoretical findings are provided by simulations as well as illustrations from three immunotherapy clinical trials.