bluuebunny/crossref_metadata_2025 huggingface dataset:
Movement disorders: a themed collection
Authors: Haunton Victoria J
Published: October 2019

Movement disorders are a diverse and challenging group of neurological conditions. Geriatricians and allied health professionals play a key role in the care of patients living with these disorders. Age and Ageing is making freely available online a collection of 15 papers that highlight the breadth and depth of this field. Perhaps unsurprisingly papers on Parkinson’s disease predominate, but rarer movement disorders, including those seen following stroke and Huntington’s disease, are also represented. Difficulties in diagnosis are explored, together with innovative approaches to management of both motor and non-motor symptoms. The collection includes qualitative work, longitudinal studies and clinical trials, and both the individual patient perspective and the international perspective are considered. There are papers for generalists, papers for specialists, papers for clinical commissioners and papers for researchers. Comprehensive review articles provide clarity, guidance and pragmatism. Finally, a New Horizons article encourages us to look to the future of movement disorders, which lies not only in developing novel therapies and trials but also in recognising the enormous value of palliative care and the multidisciplinary approach.
Employer Expectations for the MS-Level Cytology Practitioner
Authors: Chiou Paul Z
Published: October 2019

Objectives

The specific aims of the study are to determine skillsets most valuable to regional employers of cytotechnologists and assess the employers’ willingness to use graduating MS cytology practitioners in the expanded scope of practice.

Methods

Data from the greater New York region were collected via a web-based survey distributed to a broad sample of laboratory professionals involved with hiring in a variety of institutions.

Results

The three skillsets most important to New York employers and most employable are fine-needle aspiration adequacy assessment, regulatory acumen, and prescreening cell blocks. The skills that are of least important and least employable are prescreening high-volume tissue biopsy specimens and histology.

Conclusions

The results of this survey shed light on regional employers’ perspectives regarding the skillsets that are most important and marketable in the greater New York region and may be useful for subsequent curriculum development.
Commentary: Necromance
Authors: Hunt Irvin J
Published: October 2019

This article reconsiders the recent turn in political theory to love as a countercapital affect, helping us endure when hope has lost its salience. The article offers the concept of “necromance” to attend to the ways the popular configuration of love as life-giving often overlooks how in the history of slavery and liberal empire love operates as life-taking. Distinct from necromancy, necromance is not a process of reviving the dead but of bringing subjects in ever closer proximity to the dead. Grounded in a reading of W. E. B. Du Bois’s romantic novel The Quest of the Silver Fleece (1911), particularly its vision of a cooperative economy and its response to the evolving meaning of love in American culture at the end of the nineteenth century, necromance is both a structure of feeling and a form of writing. As a resource for activism indebted to the creative powers of melancholic attachments, necromance contests the common conception that in order for grievances to become social movements or collective insurgencies they must be framed to create feelings of outrage, not of grief. By working inside existing conditions of irrevocable loss, necromantic love registers the feeling that the revolution is already here.
Genetic variants in the nucleotide excision repair genes are associated with the risk of developing endometriosis
Authors: Shen Te-Chun , Tsai Chia-Wen , Chang Wen-Shin , Wang Yun-Chi , Hsu Huai-Mei , Li Hsin-Ting , Gu Jian , Bau Da-Tian
Published: October 2019

Endometriosis is a major health issue among women of reproductive age. However, its etiology has not yet been completely understood. We investigated 10 single nucleotide polymorphisms from six novel nucleotide excision repair genes and the susceptibility to endometriosis. A total of 153 patients with endometriosis were recruited during 2000–2010 from central Taiwan. Pathological confirmation was necessary for all patients, and exclusion criteria included the presence of leiomyoma, adenomyosis, or cancer of the uterine, cervix, or ovary and a prescription of hormone therapy. Furthermore, a total of 636 age-matched individuals without endometriosis were recruited during the same time period from central Taiwan. The polymerase chain reaction coupled with restriction fragment length polymorphism methodology was applied for genotyping. The multivariate logistic regression analysis showed that subjects carrying the ERCC1 rs11615 TT (OR = 2.04, 95% CI = 1.36–3.41), ERCC2 rs1799793 AA (OR = 1.86, 95% CI = 1.14–3.11), and ERCC6 rs2228528 AA genotypes (OR = 1.79, 95% CI = 1.13–2.83) exhibited significantly increased risks of developing endometriosis compared with their counterparts carrying the wild-type genotypes. This study suggests that certain single nucleotide polymorphisms of nucleotide excision repair genes excision repair cross-complementation group 1 (ERCC1, ERCC2, and ERCC6) predispose women to the development of endometriosis.
A “Natural Death”: The Political Battlefield of Infections and Migrant Children’s Bodies
Authors: Travassos Mark A
Published: October 2019

Before September 2018, no child had died in United States Border Patrol custody in a decade. Since then, 7 detained children have died in the past 10 months. Migrant children’s bodies have become the latest political battlefield, and these children have been caught in the crossfire. This piece focuses on the recent deaths of several migrant children from overwhelming infections in United States detainment centers. The circumstances surrounding these illnesses bring to the fore concerns about the care of these children, suggesting infectious disease outbreaks in these detainment centers, delays in bringing children to medical attention, and inadequate medical expertise in their care. There is an urgent need for advocacy by clinicians and professional societies to resolve this crisis.
Sex-Specific Effects of Apolipoprotein ε4 Allele on Mortality in Very Old and Centenarian Japanese Men
Authors: Sasaki Takashi , Nishimoto Yoshinori , Abe Yukiko , Takayama Michiyo , Hirose Nobuyoshi , Okano Hideyuki , Arai Yasumichi
Published: October 2019

The apolipoprotein E4 (APOE ε4) allele has attracted attention as an age-related genetic factor, both in neurology and gerontology. To understand the effects of the APOE ε4 allele on mortality in elderly individuals, we combined Japanese prospective cohort studies comprising 535 very old individuals (85–99 years of age) and 930 centenarians (over 100 years of age) and analyzed the association between mortality rates and candidate factors, including the APOE ε4 allele. APOE genotyping revealed an inverse correlation between the APOE ε4 allele carrier rate and age. Additionally, APOE ε4 allele carrier rate in centenarian men was significantly lower than that in centenarian women. The association analysis between APOE ε4 allele carriers and all-cause mortality indicated that APOE ε4 carriers showed significantly higher mortality rates than the APOE ε4 noncarriers among men in the very old group. Further analysis using Cox proportional hazard models indicated that cause-specific mortalities, including pneumonia and severe dementia, were associated with APOE ε4 carriers. These findings indicate that the APOE ε4 allele shows phenotypic male-specific adverse effects in the very old, which would explain the high mortality rate observed in this group, resulting in a low APOE ε4 allele carrier rate in centenarian men.
China's ivory bans: enhancing soft power through wildlife conservation
Authors: Gamso Jonas
Published: October 2019

China has been a major market for elephant ivory for centuries. However, the Chinese government recently enacted bans on imports and exports of ivory (2015) and on the domestic ivory trade (2017). These bans appear to have come in response to intensive influence campaigns and public shaming from domestic and foreign activists, who cited declining elephant populations and highlighted China's role. However, this shaming-narrative is at odds with conventional wisdom regarding Chinese policy-making: China typically resists international pressures and its authoritarian government is thought to be largely insulated from domestic efforts by civil society groups. This article reconciles Beijing's ivory policy with these conventional beliefs about policy-making in China. I argue that the Chinese government saw unique benefits to banning the ivory trade, under growing international scrutiny, as doing so enhanced Chinese soft power while having very little impact on its sovereignty or development. Non-government organizations (NGOs) operating both inside and outside of China played a role as well: NGOs in China helped to shift Chinese public opinion towards favouring the bans, while those operating abroad led public relations efforts to publicize Chinese demand for ivory to foreign audiences. Efforts by the latter group of NGOs intensified pressure on the Chinese government to rein in the ivory market, while increasing the soft power benefits that banning ivory would bring to Beijing.
Rebel diplomacy and digital communication: public diplomacy in the Sahel
Authors: Bos Michèle , Melissen Jan
Published: October 2019

Most research on social media as a tool for public diplomacy focuses on its use by recognized international actors to advance their national interest and reputation, deliver foreign policy objectives or promote their global interests. This article highlights the need for paying more attention to non-state diplomacy in conflict situations outside the western world. We examine how rebel groups use new media to enhance their communications, and what the motivations behind this are. Our public diplomacy perspective helps convey the scope of rebel communications with external actors and provides insights for policy-makers seeking to ascertain the nature, intentions and capacities of myriad rebel groups. Our focus is on the Sahel region, where numerous such groups vying for international attention and support make use of multiple social media channels. We analyse two groups in Mali: the MNLA, a Tuareg secessionist group; and Ansar Dine, a Salafist insurgency with ties to Al-Qaeda in the Islamic Maghreb. Our qualitative analysis of Ansar Dine and MNLA communications on several digital platforms helps identify these African rebel groups' international and local framing activities. Rebel groups use public diplomacy nimbly and pragmatically. The digital age has fundamentally changed which stakeholders such groups can reach, and we suggest that social media increase the power they are able to carve out for themselves on the international stage.
Scientific and Regulatory Considerations for Efficacy Studies of Cytomegalovirus Vaccines
Authors: Krause Philip R , Roberts Jeff
Published: October 2019

The considerable public health burden due to cytomegalovirus (CMV) supports current interest in vaccine development. Clinical studies intended to support regulatory action should be designed to demonstrate substantial evidence of effectiveness. However, design and conduct of clinical endpoint studies may be hampered by low incidence of disease, especially for congenital CMV. Discussion and experience from other vaccines directed against congenital disease (including rubella and Zika) may be instructive. This article summarizes current scientific and US regulatory considerations related to design of studies of vaccines intended to prevent congenital CMV and complications of CMV in transplantation, as discussed at the 2018 workshop entitled “Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment.”
Modeling Approaches to Predicting Persistent Hotspots in SCORE Studies for Gaining Control of Schistosomiasis Mansoni in Kenya and Tanzania
Authors: Shen Ye , Sung Meng-Hsuan , King Charles H , Binder Sue , Kittur Nupur , Whalen Christopher C , Colley Daniel G
Published: October 2019

Background

Some villages, labeled “persistent hotspots (PHS),” fail to respond adequately in regard to prevalence and intensity of infection to mass drug administration (MDA) for schistosomiasis. Early identification of PHS, for example, before initiating or after 1 or 2 years of MDA could help guide programmatic decision making.

Methods

In a study with multiple rounds of MDA, data collected before the third MDA were used to predict PHS. We assessed 6 predictive approaches using data from before MDA and after 2 rounds of annual MDA from Kenya and Tanzania.

Results

Generalized linear models with variable selection possessed relatively stable performance compared with tree-based methods. Models applied to Kenya data alone or combined data from Kenya and Tanzania could reach over 80% predictive accuracy, whereas predicting PHS for Tanzania was challenging. Models developed from one country and validated in another failed to achieve satisfactory performance. Several Year-3 variables were identified as key predictors.

Conclusions

Statistical models applied to Year-3 data could help predict PHS and guide program decisions, with infection intensity, prevalence of heavy infections (≥400 eggs/gram of feces), and total prevalence being particularly important factors. Additional studies including more variables and locations could help in developing generalizable models.
Immune predictors of mortality following RNA virus infection
Authors: Graham Jessica B , Swarts Jessica L , Menachery Vineet D , Gralinski Lisa E , Schäfer Alexandra , Plante Kenneth S , Morrison Clayton R , Voss Kathleen M , Green Richard , Choonoo Gabrielle , Jeng Sophia , Miller Darla R , Mooney Michael A , McWeeney Shannon K , Ferris Martin T , Pardo-Manuel de Villena Fernando , Gale Michael , Heise Mark T , Baric Ralph S , Lund Jennifer M
Published: October 2019

Background

Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines, as well as the early identification of individuals with the highest risk that may require supportive treatment.

Methods

We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, SARS-coronavirus, and West Nile virus.

Results

CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality following infection and strains exhibiting no mortality. We then used comprehensive pre-infection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection.

Conclusions

These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.
Historical Biogeography of Holarctic Cymbiodyta Water Scavenger Beetles in the Times of Cenozoic Land Bridge Dispersal Routes
Authors: Toussaint Emmanuel F A , Short Andrew E Z
Published: October 2019

The genus Cymbiodyta Bedel, 1881 (Coleoptera: Hydrophilidae: Enochrinae) comprises 31 species distributed in both the Old and New World portions of the Holarctic realm. Although the species and taxonomy are relatively well known, the phylogenetic relationships among Cymbiodyta and the evolutionary history of the genus remain unexplored. To understand the systematics and evolution of this lineage, we sequenced five gene fragments for about half of the species in the genus, including most major morphological groups. We also estimated divergence times to test the hypothesis that Cymbiodyta beetles took advantage of the different land bridges connecting the Palearctic and Nearctic regions, that became subaerial in the Cretaceous and Paleocene. Our results recover the eastern Nearctic genus Helocombus Horn, 1890 nesting within Cymbiodyta. Therefore, we synonymize Helocombus syn. n. with Cymbiodyta, resulting in one new combination, Cymbiodyta bifidus (LeConte 1855) comb. n. Our dating analyses and ancestral range estimation support a Nearctic origin of Cymbiodyta in the late Cretaceous about 100 million year ago. The placement of the unique Palearctic species on a long branch as sister to the rest of the clade and the dating results cannot reject a role of the De Geer and/or Thulean routes in the colonization of the Palearctic region from the Nearctic; however, they do not support a role for Beringia in the more recent colonization of the Oriental region.
Augmented renal clearance of aminoglycosides using population-based pharmacokinetic modelling with Bayesian estimation in the paediatric ICU
Authors: Avedissian Sean N , Rhodes Nathaniel J , Kim Yuna , Bradley John , Valdez Joshua L , Le Jennifer
Published: October 2019

Objective

To evaluate augmented renal clearance (ARC) using aminoglycoside clearance (CLAMINO24h) derived from pharmacokinetic (PK) modelling.

Methods

A retrospective study at two paediatric hospitals of patients who received tobramycin or gentamicin from 1999 to 2016 was conducted. Compartmental PK models were constructed using the Pmetrics package, and Bayesian posteriors were used to estimate CLAMINO24h. ARC was defined as a CLAMINO24h of ≥130 mL/min/1.73 m2. Risk factors for ARC were identified using multivariate logistic regression.

Results

The final population model was fitted to 275 aminoglycoside serum concentrations. Overall clearance (L/h) was=CL0 × (TBW/70)0.75 × AGEH/(TMH + AGEH) + CL1 (0.5/SCr), where TBW is total body weight, H is the Hill coefficient, TM is a maturation term and SCr is serum creatinine. Median CLAMINO24h in those with versus without ARC was 157.36 and 93.42 mL/min/1.73 m2, respectively (P < 0.001). ARC was identified in 19.5% of 118 patients. For patients with ARC, median baseline SCr was lower than for those without ARC (0.38 versus 0.41 mg/dL, P = 0.073). Risk factors for ARC included sepsis [adjusted OR (aOR) 3.77, 95% CI 1.01–14.07, P = 0.048], increasing age (aOR 1.11, 95% CI 1–1.23, P = 0.04) and low log-transformed SCr (aOR 0.16, 95% CI 0.05–0.52, P = 0.002). Median 24 h AUC (AUC24h) was significantly lower in patients with ARC at 45.27 versus 56.95 mg·h/L, P  < 0.01.

Conclusions

ARC was observed in one of every five patients. Sepsis, increasing age and low SCr were associated with ARC. Increased clearance was associated with an attenuation of AUC24h in this population. Future studies are needed to define optimal dosing in paediatric patients with ARC.
ANISEED 2019: 4D exploration of genetic data for an extended range of tunicates
Authors: Dardaillon Justine , Dauga Delphine , Simion Paul , Faure Emmanuel , Onuma Takeshi A , DeBiasse Melissa B , Louis Alexandra , Nitta Kazuhiro R , Naville Magali , Besnardeau Lydia , Reeves Wendy , Wang Kai , Fagotto Marie , Guéroult-Bellone Marion , Fujiwara Shigeki , Dumollard Rémi , Veeman Michael , Volff Jean-Nicolas , Roest Crollius Hugues , Douzery Emmanuel , Ryan Joseph F , Davidson Bradley , Nishida Hiroki , Dantec Christelle , Lemaire Patrick
Published: October 2019

ANISEED (https://www.aniseed.cnrs.fr) is the main model organism database for the worldwide community of scientists working on tunicates, the vertebrate sister-group. Information provided for each species includes functionally-annotated gene and transcript models with orthology relationships within tunicates, and with echinoderms, cephalochordates and vertebrates. Beyond genes the system describes other genetic elements, including repeated elements and cis-regulatory modules. Gene expression profiles for several thousand genes are formalized in both wild-type and experimentally-manipulated conditions, using formal anatomical ontologies. These data can be explored through three complementary types of browsers, each offering a different view-point. A developmental browser summarizes the information in a gene- or territory-centric manner. Advanced genomic browsers integrate the genetic features surrounding genes or gene sets within a species. A Genomicus synteny browser explores the conservation of local gene order across deuterostome. This new release covers an extended taxonomic range of 14 species, including for the first time a non-ascidian species, the appendicularian Oikopleura dioica. Functional annotations, provided for each species, were enhanced through a combination of manual curation of gene models and the development of an improved orthology detection pipeline. Finally, gene expression profiles and anatomical territories can be explored in 4D online through the newly developed Morphonet morphogenetic browser.
Cigarette Smokers Versus Cousers of Cannabis and Cigarettes: Exposure to Toxicants
Authors: Meier Ellen , Vandrey Ryan , Rubin Nathan , Pacek Lauren R , Jensen Joni A , Donny Eric C , Hecht Stephen S , Carmella Steven G , Murphy Sharon E , Luo Xianghua , Stepanov Irina , Ikuemonisan Joshua , Severson Herb , Al’absi Mustafa , Hatsukami Dorothy K
Published: October 2019

Introduction

Cannabis and tobacco couse is common and could expose users to higher levels of toxicants. No studies have examined biomarkers of toxicant exposure in cousers of cannabis and cigarettes, compared with cigarette smokers (CS).

Aims and Methods

Adult daily CS were recruited from 10 US sites for a study of reduced nicotine cigarettes. In this analysis of baseline data, participants were categorized as either cousers of cannabis and tobacco (cousers; N = 167; urine positive for 11-nor-9-carboxy-Δ 9-tetrahydrocannnabinol and self-reported cannabis use ≥1×/week), or CS (N = 911; negative urine and no self-reported cannabis use). Participants who did not meet either definition (N = 172) were excluded. Self-reported tobacco and cannabis use and tobacco and/or combustion-related biomarkers of exposure were compared between groups.

Results

Compared to CS, cousers were younger (couser Mage = 38.96, SD = 13.01; CS Mage = 47.22, SD = 12.72; p < .001) and more likely to be male (cousers = 67.7%, CS = 51.9%, p < .001). There were no group differences in self-reported cigarettes/day, total nicotine equivalents, or breath carbon monoxide, but cousers had greater use of non-cigarette tobacco products. Compared to CS, cousers had higher concentrations of 3-hydroxypropylmercapturic acid, 2-cyanoethylmercapturic acid, S-phenylmercapturic acid, 3-hydroxy-1-methylpropylmercapturic acid (ps < .05), and phenanthrene tetraol (p < .001). No biomarkers were affected by number of cannabis use days/week or days since last cannabis use during baseline (ps > .05).

Conclusions

Cousers had higher concentrations of biomarkers of exposure than CS, but similar number of cigarettes per day and nicotine exposure. Additional studies are needed to determine whether cannabis and/or alternative tobacco products are driving the increased toxicant exposure.

Implications

Cousers of cannabis and tobacco appear to be exposed to greater levels of harmful chemicals (ie, volatile organic compounds and polycyclic aromatic hydrocarbons), but similar levels of nicotine as CS. It is unclear if the higher levels of toxicant exposure in cousers are due to cannabis use or the increased use of alternative tobacco products compared with CS. It is important for studies examining biomarkers of exposure among CS to account for cannabis use as it may have a significant impact on outcomes. Additionally, further research is needed examining exposure to harmful chemicals among cannabis users.
Characterization of Anti–Interferon-γ Antibodies in HIV-Negative Patients Infected With Disseminated Talaromyces marneffei and Cryptococcosis
Authors: Zeng Wen , Qiu Ye , Tang Shudan , Zhang Jianquan , Pan Mianluan , Zhong Xiaoning
Published: October 2019

Background

Few reports of Talaromyces marneffei (TM) or cryptococcosis infections among HIV-negative patients with high-titeranti–IFN-γautoantibodies (nAIGAs) have been published. We investigated the clinical manifestations of patients with nAIGAs and TM infections.

Methods

HIV-negative adults (≥18 years) were enrolled if they haddisseminated TM infection (group 1; further divided into nAIGAs positive [group 1P] and negative [group 1N]); cryptococcosis(pulmonary cryptococcosis and/or cryptococcosis of the brain)(group 2); pulmonary tuberculosis (group 3); and healthy controls (group 4) with nAIGAs detected. Complete histories, physical examinations, and routine clinical laboratory tests were obtained at baseline.

Results

Overall, 88 participants were in the four groups (20,13,23, and 32 in groups 1 to 4, respectively). Significant differences occurred between groups with higher nAIGAs titers (P < 0.001), and higher total white-cell and absolute neutrophil counts (P < 0.001) in group1. Lungs (90.0%), lymph nodes (60.0%), skin (55.0%), and bones (50.0%) were most common sites of involvement. Significant differences in total white-cell and absolute neutrophil counts occurred between groups IP and 1N.Patients with recurrent TM infections, particularly group 1P, had higher initial nAIGA titer.

Conclusions

Patients with persistent infection who died tended to have positive initial nAIGA titer. It suggests that nAIGAs may play a critical role in the pathogenesis of TM infections, and may be associated with more severe, refractory infection.
Effect of hypoxia on human equilibrative nucleoside transporters hENT1 and hENT2 in breast cancer
Authors: Krys Daniel , Hamann Ingrit , Wuest Melinda , Wuest Frank
Published: October 2019

Elevated proliferation rates in cancer can be visualized with positron emission tomography (PET) using 3‘‐deoxy‐3‘‐l‐[18F]fluorothymidine ([18F]FLT). This study investigates whether [18F]FLT transport proteins are regulated through hypoxia. Expression and function of human equilibrative nucleoside transporter (hENT)‐1, hENT2, and thymidine kinase 1 (TK1) were studied under normoxic and hypoxic conditions, and assessed with [18F] FLT‐PET in estrogen receptor positive (ER+)‐MCF7, triple‐negative MDA‐MB231 breast cancer (BC) cells, and MCF10A cells (human mammary epithelial cells). Functional involvement of hENT2 [18F]FLT transport was demonstrated in all cell lines. In vitro [18F]FLT uptake was higher in MDA‐MB231 than in MCF7:242 ± 9 vs. 147 ± 18% radioactivity/mg protein after 60 min under normoxia. Hypoxia showed no significant change in radiotracer uptake. Protein analysis revealed increased hENT1 (P < 0.0963) in MDA‐MB231. Hypoxia did not change expression of either hENT1, hENT2, or TK1. In vitro inhibition experiments suggested involvement of hENT1, hENT2, and human concentrative nucleoside transporters during [18F]FLT uptake into all cell lines. In vivo PET imaging revealed comparable tumor uptake in MCF7 and MDA‐MB231 tumors over 60 min, reaching standardized uptake values of 0.96 ± 0.05 vs. 0.89 ± 0.08 (n = 3). Higher hENT1 expression in MDA‐MB231 seems to drive nucleoside transport, whereas TK1 expression in MCF7 seems responsible for comparable [18F]FLT retention in ER+ tumors. Our study demonstrates that hypoxia does not significantly affect nucleoside transport as tested with [18F]FLT in BC.—Krys, D., Hamann, I., Wuest, M., Wuest, F. Effect of hypoxia on human equilibrative nucleoside transporters hENT1 and hENT2 in breast cancer. FASEB J. 33, 13837‐13851 (2019). www.fasebj.org
EphrinB2/ephB2‐mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS
Authors: Zhang Lei , Wang Ruiyun , Bai Tao , Xiang Xuelian , Qian Wei , Song Jun , Hou Xiaohua
Published: October 2019

Patients with irritable bowel syndrome (IBS) show pain hypersensitivity and smooth muscle hypercontractility in response to colorectal distension (CRD). Synaptic plasticity, a key process of memory formation, in the enteric nervous system may be a novel explanation. This study aimed to explore the regulatory role of ephrinB2/ephB2 in enteric synaptic plasticity and colonic hyperreactive motility in IBS. Postinfectious (PI)‐IBS was induced by Trichinella spiralis infection in rats. Isometric contractions of colonic circular muscle strips, particularly neural‐mediated contractions, were recorded ex vivo. Meanwhile, ephrinB2/ephB2‐mediated enteric structural and functional synaptic plasticity were assessed in the colonic muscularis, indicating that ephrinB2 and ephB2 were located on enteric nerves and up‐regulated in the colonic muscularis of PI‐IBS rats. Colonic hypersensitivity to CRD and neural‐mediated colonic hypercontractility were present in PI‐IBS rats, which were correlated with increased levels of cellular homologous fos protein (c‐fos) and activity‐regulated cystoskeleton‐associated protein (arc), the synaptic plasticity‐related immediate early genes, and were ameliorated by ephB2Fc (an ephB2 receptor blocker) or MK801 (an NMDA receptor inhibitor) exposure. EphrinB2/ephB2 facilitated synaptic sprouting and NMDA receptor‐mediated synaptic potentiation in the colonic muscularis of PI‐IBS rats and in the longitudinal muscle‐myenteric plexus cultures, involving the Erk‐MAPK and PI3K‐protein kinase B pathways. In conclusion, ephrinB2/ephB2 promoted the synaptic sprouting and potentiation of myenteric nerves involved in persistent muscle hypercontractility and pain in PI‐IBS. Hence, ephrinB2/ephB2 may be an emerging target for the treatment of IBS.—Zhang, L., Wang, R., Bai, T., Xiang, X., Qian, W., Song, J., Hou, X. EphrinB2/ephB2‐mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS. FASEB J. 33, 13644‐13659 (2019). www.fasebj.org
Quality of life for patients with fibromyalgia
Authors: Armstrong Faith E.
Published: October 2019

Consider applying the Neuman systems model to provide holistic care for more positive outcomes.
Bridging the Knowledge Gap: An Examination of the Ideal Postoperative Autologous Breast Reconstruction Educational Material with A/B Testing
Authors: Fan Kenneth L. , Black Cara K. , DeFazio Michael V. , Luvisa Kyle , Camden Rachel , Song David H.
Published: October 2019

Background:

Poor health literacy is an epidemic in the United States, associated with higher mortality rates and poor postoperative care. Autologous breast reconstruction is highly complex, and the identification of complications is difficult even for non–plastic surgeon practitioners. The authors sought to explore the problem of health literacy in this context and identify the ideal postoperative patient education materials.

Methods:

Available online postoperative patient education materials for autologous breast reconstruction and corresponding readability scores were assessed. To derive the ideal formula for materials, the authors crowd-sourced quizzes with A/B testing, a method to examine the outcome of two versions of a single variable. The authors implemented their findings and compared performance on postoperative quizzes with and without oral reinforcement.

Results:

Of the 12 postoperative flap complication patient education materials found through an Internet search, the average grade level readability level was 9.9. Only one of 12 (8.3 percent) mentioned symptoms and signs of flap compromise. The A/B tests result revealed that text approximately 400 to 800 words written on a sixth-grade level led to the highest quiz scores. Patients scored significantly higher on the postoperative day–2 quiz when patient education materials, modeled after these findings, were reinforced with oral presentation (p = 0.0059). Retention of high quiz scores remained at postoperative day 10.

Conclusions:

Currently available patient education materials are at a high reading level and lack specific information on the identification of flap compromise. The authors propose the most effective postoperative instructions to be approximately 400 to 800 words written on a grade-six level with images and oral reinforcement.
Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia
Authors: Karlsson Leif , Barbaro Michela , Ewing Ewoud , Gomez-Cabrero David , Lajic Svetlana
Published: October 2019

Background

Patients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome.

Methods

We analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 ±6.5 years [y]) and 37 population controls (mean age=17.0 ±6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, ±6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment.

Results

We identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035).

Conclusion

In conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH.
Homeostatic regulation of perisynaptic MMP9 activity in the amblyopic visual cortex
Authors: Murase Sachiko , Winkowski Daniel E. , Liu Ji , Kanold Patrick O. , Quinlan Elizabeth M.
Published: October 2019

Dark exposure (DE) followed by light reintroduction (LRx) reactivates robust synaptic plasticity in adult mouse V1, which allows recovery from amblyopia. Previously we showed that LRx-induced perisynaptic proteolysis of extracellular substrates by MMP9 mediates the enhanced plasticity in binocular adult mice (Murase et al., 2017). However, it is unknown if a visual system compromised by amblyopia could engage this pathway. Here we show that LRx to adult amblyopic mice induces perisynaptic MMP2/9 activity and degradation of ECM in the deprived and non-deprived V1. LRx restricted to the amblyopic eye induces equally robust MMP2/9 activity at thalamo-cortical synapses and ECM degradation in deprived V1. Two-photon live imaging demonstrates that the history of visual experience regulates MMP2/9 activity in V1, and that DE lowers the threshold for the proteinase activation. This homeostatic reduction of MMP2/9 activation threshold by DE enables the visual input from the amblyopic pathway to trigger robust perisynaptic proteolysis.
Numerous post-translational modifications of RNA polymerase II subunit Rpb4 link transcription to post-transcriptional mechanisms
Authors: Richard Stephen , Gross Lital , Fischer Jonathan , Bendalak Keren , Ziv Tamar , Urim Shira , Choder Mordechai
Published: October 2019

Rpb4/7 binds RNA Polymerase II (Pol II) transcripts co-transcriptionally and accompanies them throughout their lives. By virtue of its capacity to interact with key regulators (e.g., Pol II, eIF3, Pat1) both temporarily and spatially, Rpb4/7 regulates the major stages of the mRNA lifecycle. Here we show that Rpb4/7 can undergo over 100 combinations of post-translational modifications (PTMs). Remarkably, the Rpb4/7 PTMs repertoire changes as the mRNA/Rpb4/7 complex progresses from one stage to the next. A mutagenesis approach in residues that undergo PTMs suggests that temporal Rpb4 PTMs regulate its interactions with key regulators of gene expression that control transcriptional and post-transcriptional stages. Moreover, one mutant type specifically affects mRNA synthesis despite its normal association with Pol II, whereas the other affects both mRNA synthesis and decay; both types disrupt the balance between mRNA synthesis and decay (‘mRNA buffering’) and the cell’s capacity to respond to the environment. Taken together, we propose that temporal Rpb4/7 PTMs are involved in cross talks among the various stages of the mRNA lifecycle.
Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases
Authors: Perenthaler Elena , Nikoncuk Anita , Yousefi Soheil , Berdowski Woutje M. , Capo Ivan , van der Linde Herma C. , van den Berg Paul , Jacobs Edwin H. , Putar Darija , Ghazvini Mehrnaz , Aronica Eleonora , van IJcken Wilfred F.J. , de Valk Walter G. , Medici-van den Herik Evita , van Slegtenhorst Marjon , Brick Lauren , Kozenko Mariya , Kohler Jennefer N. , Bernstein Jonathan A. , Monaghan Kristin G. , Begtrup Amber , Torene Rebecca , Futaisi Amna Al , Murshedi Fathiya Al , Mani Renjith , Azri Faisal Al , Kamsteeg Erik-Jan , Mojarrad Majid , Eslahi Atieh , Khazaei Zaynab , Darmiyan Fateme Massinaei , Doosti Mohammad , Karimiani Ehsan Ghayoor , Vandrovcova Jana , Zafar Faisal , Rana Nuzhat , Kandaswamy Krishna K. , Hertecant Jozef , Bauer Peter , Efthymiou Stephanie , Houlden Henry , Bertoli-Avella Aida M. , Maroofian Reza , Retterer Kyle , Brooks Alice S. , van Ham Tjakko J. , Barakat Tahsin Stefan
Published: October 2019

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essentialUDP-glucose pyrophosphorylase(UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled during pluripotent stem cell differentiationin vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2bin vivoin zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation inUGP2as a cause of a novel autosomal recessive DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
A hierarchical model of perceptual multistability involving interocular grouping
Authors: Wang Yunjiao , Kilpatrick Zachary P , Josić Krešimir
Published: October 2019

Ambiguous visual images can generate dynamic and stochastic switches in perceptual interpretation known as perceptual rivalry. Such dynamics have primarily been studied in the context of rivalry between two percepts, but there is growing interest in the neural mechanisms that drive rivalry between more than two percepts. In recent experiments, we showed that split images presented to each eye lead to subjects perceiving four stochastically alternating percepts (Jacot-Guillarmod et al., 2017): two single eye images and two interocularly grouped images. Here we propose a hierarchical neural network model that exhibits dynamics consistent with our experimental observations. The model consists of two levels, with the first representing monocular activity, and the second representing activity in higher visual areas. The model produces stochastically switching solutions, whose dependence on task parameters is consistent with four generalized Levelt Propositions. Our neuromechanistic model also allowed us to probe the roles of inter-actions between populations at the network levels. Stochastic switching at the lower level representing alternations between single eye percepts dominated, consistent with experiments.
Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain
Authors: Zhao Lei , Li Zhongqi , Vong Joaquim S. L. , Chen Xinyi , Lai Hei-Ming , Yan Leo Y. C. , Huang Junzhe , Sy Samuel K. H. , Tian Xiaoyu , Huang Yu , Chan Ho Yin Edwin , So Hon-Cheong , Ng Wai-Lung , Tang Yamei , Lin Wei-Jye , Mok Vincent C.T. , Ko Ho
Published: October 2019

With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail1,2, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases3–7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed – the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions8–17. Furthermore, an overrepresentation of Alzheimer’s disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.
Heterosis indices: What do they really measure?
Authors: de Vienne Dominique , Fiévet Julie B.
Published: October 2019

Heterosis (hybrid vigour) is a universal phenomenon of crucial agro-economic and evolutionary importance. We show that the most common heterosis indices do not properly measure deviation from additivity because they include both a component accounting for “real” heterosis and a term that is not related to heterosis since it is derived solely from parental values. Therefore, these indices are inadequate when the aim of the study is to compare heterosis levels between different traits, environments, genetic backgrounds or developmental stages, as these factors may affect not only heterosis but also parental values. The only relevant index for such comparisons is the so-called “potence ratio”. These observations argue for the careful choice of heterosis indices depending on the purpose of the work.

Highlight

Unlike dominance indices, heterosis indices, with one exception, do not properly measure the level of deviation from additivity, thus making them unsuitable for comparative analyses.
Genetic diversity and thermal performance in invasive and native populations of African fig flies
Authors: Comeault Aaron A. , Wang Jeremy , Tittes Silas , Isbell Kristin , Ingley Spencer , Hurlbert Allen H. , Matute Daniel R.
Published: October 2019

During biological invasions, alien populations can suffer losses of genetic diversity that are predicted to negatively impact their fitness/performance. Using genome sequences, we show that invasive populations of the African fig fly,Zaprionus indianus, have lower levels of genetic diversity compared to native populations, and that genetic diversity is lost more in regions of the genome with low recombination rates. However, genetic diversity remains as high or higher in invasive populations than in populations of non-invasive congeneric species. We then use parameter estimates from thermal performance curves measured for 13 species ofZaprionusto show thatZ. indianushas the broadest thermal niche of measured species, and that performance does not differ between invasive and native populations. These results illustrate how aspects of genetic diversity in invasive species can be decoupled from measures of fitness, and that a broad thermal niche may have helped facilitateZ. indianus’srange expansion.
Modelling Niemann-Pick disease type C in a human haploid cell line allows for patient variant characterization and clinical interpretation
Authors: Erwood Steven , Brewer Reid A. , Bily Teija M.I. , Maino Eleonora , Zhou Liangchi , Cohn Ronald D. , Ivakine Evgueni A.
Published: October 2019

The accurate clinical interpretation of human sequence variation is foundational to personalized medicine. This remains a pressing challenge, however, as genome sequencing becomes routine and new functionally undefined variants rapidly accumulate. Here, we describe a platform for the rapid generation, characterization and interpretation of genomic variants in haploid cells focusing on Niemann-Pick disease type C (NPC) as an example. NPC is a fatal neurodegenerative disorder characterized by a lysosomal accumulation of unesterified cholesterol and glycolipids. In 95% of cases, NPC is caused by mutations in the NPC1 gene, where over 200 unique disease-causing variants have been reported to date. Furthermore, the majority of patients with NPC are compound heterozygotes that often carry at least one private mutation, presenting a challenge for the characterization and classification of individual variants. Here, we have developed the first haploid cell model of NPC. This haploid cell model recapitulates the primary biochemical and molecular phenotypes typically found in patient-derived fibroblasts, illustrating its utility in modelling NPC. Additionally, we demonstrate the power of CRISPR-Cas9-mediated base editing in quickly and efficiently generating haploid cell models of individual patient variants in NPC. These models provide a platform for understanding the disease mechanisms underlying individual NPC1 variants while allowing for definitive clinical variant interpretation for NPC. While this study has focused on modelling NPC, the outlined approach could be translated widely and applied to a variety of genetic disorders or understanding the pathogenicity of somatic mutations in cancer.