bluuebunny/crossref_metadata_2025 huggingface dataset:
CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains
Authors: Llères David , Moindrot Benoît , Pathak Rakesh , Piras Vincent , Matelot Mélody , Pignard Benoît , Marchand Alice , Poncelet Mallory , Perrin Aurélien , Tellier Virgile , Feil Robert , Noordermeer Daan
Published: December 2019

Background

Genomic imprinting is essential for mammalian development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. So far, the detailed allele-specific chromatin organization of imprinted gene domains has mostly been lacking. Here, we explored the chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints—theIgf2-H19andDlk1-Dio3domains—and assessed the involvement of the insulator protein CTCF in mouse cells.

Results

Both imprinted domains are located within overarching topologically associating domains (TADs) that are similar on both parental chromosomes. At each domain, a single differentially methylated region is bound by CTCF on the maternal chromosome only, in addition to multiple instances of bi-allelic CTCF binding. Combinations of allelic 4C-seq and DNA-FISH revealed that bi-allelic CTCF binding alone, on the paternal chromosome, correlates with a first level of sub-TAD structure. On the maternal chromosome, additional CTCF binding at the differentially methylated region adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal-specific sub-TAD organization. Perturbation of maternal-specific CTCF binding site at theDlk1-Dio3locus, using genome editing, results in perturbed sub-TAD organization and bi-allelicDlk1activation during differentiation.

Conclusions

Maternal allele-specific CTCF binding at the imprintedIgf2-H19and theDlk1-Dio3domains adds an additional layer of sub-TAD organization, on top of an existing three-dimensional configuration and prior to imprinted activation of protein-coding genes. We speculate that this allele-specific sub-TAD organization provides an instructive or permissive context for imprinted gene activation during development.
Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse
Authors: Zhang Jian-Ping , Cheng Xin-Xin , Zhao Mei , Li Guo-Hua , Xu Jing , Zhang Feng , Yin Meng-Di , Meng Fei-Ying , Dai Xin-Yue , Fu Ya-Wen , Yang Zhi-Xue , Arakaki Cameron , Su Ruijun Jeanna , Wen Wei , Wang Wen-Tian , Chen Wanqiu , Choi Hannah , Wang Charles , Gao Guangping , Zhang Lei , Cheng Tao , Zhang Xiao-Bing
Published: December 2019

Background

Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%).

Results

We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects.

Conclusions

These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components.
Reduction of the long-term use of proton pump inhibitors by a patient-oriented electronic decision support tool (arriba-PPI): study protocol for a randomized controlled trial
Authors: Rieckert Anja , Becker Annette , Donner-Banzhof Norbert , Viniol Annika , Bücker Bettina , Wilm Stefan , Sönnichsen Andreas , Barzel Anne
Published: December 2019

Background

Proton pump inhibitors (PPIs) are increasingly being prescribed, although long-term use is associated with multiple side effects. Therefore, an electronic decision support tool with the aim of reducing the long-term use of PPIs in a shared decision-making process between general practitioners (GPs) and their patients has been developed. The developed tool is a module that can be added to the so-called arriba decision support tool, which is already used by GPs in Germany in routine care. In this large-scale cluster-randomized controlled trial we evaluate the effectiveness of this arriba-PPI tool.

Methods

The arriba-PPI tool is an electronic decision support system that supports shared decision-making and evidence-based decisions around the long-term use of PPIs at the point of care. The tool will be evaluated in a cluster-randomized controlled trial involving 210 GP practices and 3150 patients in Germany. GP practices will be asked to recruit 20 patients aged ≥ 18 years regularly taking PPIs for ≥ 6 months. After completion of patient recruitment, each GP practice with enrolled patients will be cluster-randomized. Intervention GP practices will get access to the software arriba-PPI, whereas control GPs will treat their patients as usual. After an observation period of six months, GP practices will be compared regarding the reduction of cumulated defined daily doses of PPI prescriptions per patient.

Discussion

Our principal hypothesis is that the application of the arriba-PPI tool can reduce PPI prescribing in primary care by at least 15% compared to conventional strategies used by GPs. A positive result implies the implementation of the arriba-PPI tool in routine care.

Trial registration

German Clinical Trials Register, DRKS00016364. Registered on 31 January 2019.
Multicenter randomized study on the comparison between electronic and traditional chest drainage systems
Authors: Marulli Giuseppe , Comacchio Giovanni M. , Nosotti Mario , Rosso Lorenzo , Mendogni Paolo , Natale Giuseppe , Andriolo Luigi , Imbriglio Giovanna , Larocca Valentina , Brascia Debora , Rea Federico
Published: December 2019

Background

In patients submitted to major pulmonary resection, the postoperative length of stay is mainly influenced by the duration of air leaks and chest tube removal. The measurement of air leaks largely relies on traditional chest drainage systems which are prone to subjective interpretation. Difficulty in differentiating between active air leaks and bubbles due to a pleural space effect may also lead to tentative drain clamping and prolonged time for chest drain removal. New digital systems allow continuous monitoring of air leaks, identifying subtle leakage that may be not visible during daily patient evaluation. Moreover, an objective assessment of air leaks may lead to a reduced interobserver variability and to an optimized timing for chest tube removal.

Methods

This study is a prospective randomized, interventional, multicenter trial designed to compare an electronic chest drainage system (Drentech™ Palm Evo) with a traditional system (Drentech™ Compact) in a cohort of patients undergoing pulmonary lobectomy through a standard three-port video-assisted thoracic surgery approach for both benign and malignant disease. The study will enroll 382 patients in three Italian centers. The duration of chest drainage and the length of hospital stay will be evaluated in the two groups. Moreover, the study will evaluate whether the use of a digital chest system compared with a traditional system reduces the interobserver variability. Finally, it will evaluate whether the digital drain system may help in distinguishing an active air leak from a pleural space effect, by the digital assessment of intrapleural differential pressure, and in identifying potential predictors of prolonged air leaks.

Discussion

To date, few studies have been performed to evaluate the clinical impact of digital drainage systems. The proposed prospective randomized trial will provide new knowledge to this research area by investigating and comparing the difference between digital and traditional chest drain systems. In particular, the objectives of this project are to evaluate the feasibility and usefulness of digital chest drainages and to provide new tools to identify patients at higher risk of developing prolonged air leaks.

Trial registration

ClinicalTrials.gov, NCT03536130. Retrospectively registered on 24 May 2018.
Determining the effects of exercise after smoking cessation therapy completion on continuous abstinence from smoking: Japanese study protocol
Authors: Ozaki Yuka , Komiyama Maki , Ueshima Kenji , Iso Hiroyasu , Sakata Satoko , Morino Ayumi , Takahara Mitsuyoshi , Noguchi Satoshi , Kuwabara Yoshihiro , Takahashi Yuko , Hasegawa Koji
Published: December 2019

Background

Despite a steady world-wide decline over recent decades, rates of smoking remain high in developed countries. In Japan, 30% of men and 10% of women are smokers. Based on these rates, 18.8 million (14.06 million men and 4.74 million women) in Japan are smokers. The rate of success for smoking cessation has recently improved due to the widespread availability of drug therapy; however, the success rate for quitting smoking one year after beginning therapy is only around 50%. Previous studies have demonstrated that exercise can relieve mental stress during continuous abstinence from smoking and curb smoking resumption. To date, no large-scale, randomized controlled trials have examined the effects of exercise on smoking cessation. The present study aims to determine the effects of exercise instruction on continuous abstinence from smoking after completion of smoking cessation therapy.

Methods

This is a multicenter, prospective, parallel-group, randomized controlled trial in Japan. We will enroll 300 individuals visiting a smoking cessation clinic (over 3 months) who have abstained from smoking in the second month after their initial visit as potential participants. Participants will not habitually exercise and will need to consent to participate. Participants will be randomly assigned to the exercise intervention group or control group. The intervention group will receive instruction on exercises that can be incorporated into their daily lives. The control group will be followed during the standard smoking cessation support program. The primary endpoint will be the continuous abstinence rate, and secondary endpoints will be weight, blood pressure, exhaled carbon monoxide concentration, psychological state, and blood test results. These indices will be compared between the intervention and control groups, with follow-up periods of 9 months in both groups.

Discussion

By examining the effects of exercise instruction after completion of 12-week smoking cessation therapy, this study should yield quality information that can be used to develop protocols to improve the continuous abstinence rate and inhibit weight gain after smoking cessation therapy.

Trial registration

UMIN Clinical Trials Registry,UMIN000014615. Registered on 1 October 2014.
Reporting quality and adherence of randomized controlled trials about statins and/or fibrates for diabetic retinopathy to the CONSORT checklist
Authors: Mozetic Vânia , Leonel Letícia , Leite Pacheco Rafael , de Oliveira Cruz Latorraca Carolina , Guimarães Taís , Logullo Patricia , Riera Rachel
Published: December 2019

Background

A considerable amount of randomized controlled trials (RCTs) have been published on statins and/or fibrates for diabetic retinopathy, a clinical condition associated with high social and economic burden. Adherence to the CONSORT statement items is imperative to ensure transparency and reproducibility in clinical research. The aim of this study is to assess the reporting quality and the adherence to CONSORT of RCTs assessing statins and/or fibrates for diabetic retinopathy.

Methods

We conducted a critical appraisal study at Discipline of Evidence-based Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp). A sensitive literature search was performed to identify all relevant RCTs, with no time or language limits. Two authors independently evaluated the reporting quality of the selected RCTs using the CONSORT statement as a standard.

Results

Thirteen reports of RCTs were included in this study. The adherence of the reports to CONSORT items ranged from 24% to 68%. The median score was 11 (interquartile range (IQR) 8 to 13). When analyzed separately, the methods sections of the reports had a median of three items (IQR 2 to 4) judged adherent to the methods items of CONSORT (items 3 to 12). The most underreported items were those related to trial design, title and abstract, allocation concealment, implementation of the randomization sequence, and blinding. Other important items, such as the one related to the description of the inclusion criteria, also had low adherence.

Conclusions

The overall adherence to the CONSORT checklist items was poor, especially in the items related to the methods section. RCT reports on statins and/or fibrates for diabetic retinopathy must be optimized to avoid reporting biases and to improve transparency and reproducibility.
Assessing the blood meal hosts of Culex quinquefasciatus and Aedes taeniorhynchus in Isla Santa Cruz, Galápagos
Authors: Asigau Samoa , Salah Sawsan , Parker Patricia G.
Published: December 2019

Background

Blood meal host selection by mosquito vectors is an important component in understanding disease dynamics of pathogens that threaten endemic fauna in isolated islands such as Galápagos. Research on the feeding behavior of mosquitoes can provide clues to the hosts and vectors involved in disease transmission. This information is particularly critical for endemic wildlife fauna in island systems that have evolved without resistance to novel diseases such as avian malaria. The aims of this study were to determine the blood-feeding patterns of two species of mosquitoes found in Galápagos and discuss how their feeding behavior may influence the transmission of pathogens such as avian malaria.

Methods

In the summer of 2015, we sampled two mosquito species (Aedes taeniorhynchusandCulex quinquefasciatus) across 18 different sites on Isla Santa Cruz, which is the second largest island in Galápagos and has the largest human population. We trapped mosquitoes using CDC light traps and CDC gravid traps and identified sources of blood meals for engorged mosquitoes by sequencing a portion of the vertebrate mitochondrial cytochromebgene.

Results

Out of 947 female mosquitoes captured, 320 were blood-fed, and PCR amplifications were successful for 301 of the blood meals. Results revealed that bothAedes taeniorhynchusandCulex quinquefasciatusfeed from a variety of vertebrate taxa, numerically dominated by humans on Isla Santa Cruz.

Conclusions

The high proportion of mammalian blood meals could represent locally available and abundant hosts on Santa Cruz. However, host surveys and estimates of relative abundances of vertebrate species will need to accompany mosquito trapping studies on non-inhabited and inhabited islands in Galápagos to further validate this.
Sex aggregation and species segregation cues in swarming mosquitoes: role of ground visual markers
Authors: Poda Serge B. , Nignan Charles , Gnankiné Olivier , Dabiré Roch K. , Diabaté Abdoulaye , Roux Olivier
Published: December 2019

Background

Mating swarm segregation in closely related insect species may contribute to reproductive isolation. Visual markers are used for swarm formation; however, it is unknown whether they play a key role in swarm location, species segregation and sex aggregation.

Methods

Using two sympatric closely related species of theAnopheles gambiaecomplex,An. coluzziiandAn. gambiae(s.s.), we investigated in both laboratory and semi-field conditions (i) whether males of the two species use visual markers (black cloths) to locate their swarm; and (ii) whether the presence/absence and size of the marker may differentially affect swarm characteristics. We also investigated whether conspecific virgin females use these markers to join male swarm sites.

Results

We showed that males of the two species used visual markers but in different ways:An. coluzziiswarm right above the marker whereasAn. gambiae(s.s.) locate their swarm at a constant distance of 76.4 ± 0.6 cm from a 20 × 20 cm marker in the laboratory setup and at 206 ± 6 cm from a 60 × 60 cm marker in the semi-field setup. Although increased marker size recruited more mosquitoes and consequently increased the swarm size in the two species,An. coluzziiswarms flew higher and were stretched both vertically and horizontally, whileAn. gambiae(s.s.) swarms were only stretched horizontally. Virgin females displayed a swarm-like behavior with similar characteristics to their conspecific males.

Conclusions

Our results provided experimental evidence that bothAn. coluzziiandAn. gambiae(s.s.) males use ground visual markers to form and locate their swarm at species-specific locations. Moreover, the marker size differentially affected swarm characteristics in the two species. Our results also showed that virgin females displayed a swarm-like behavior. However, these “swarms” could be due to the absence of males in our experimental conditions. Nevertheless, the fact that females displayed these “swarms” with the same characteristics as their respective males provided evidence that visual markers are used by the two sexes to join mating spots. Altogether, this suggests that visual markers and the way species and sexes use them could be key cues in species segregation, swarm location and recognition.
Genetic and antigenic variation of the bovine tick-borne pathogen Theileria parva in the Great Lakes region of Central Africa
Authors: Amzati Gaston S. , Djikeng Appolinaire , Odongo David O. , Nimpaye Herman , Sibeko Kgomotso P. , Muhigwa Jean-Berckmans B. , Madder Maxime , Kirschvink Nathalie , Marcotty Tanguy
Published: December 2019

Background

Theileria parvacauses East Coast fever (ECF), one of the most economically important tick-borne diseases of cattle in sub-Saharan Africa. A live immunisation approach using the infection and treatment method (ITM) provides a strong long-term strain-restricted immunity. However, it typically induces a tick-transmissible carrier state in cattle and may lead to spread of antigenically distinct parasites. Thus, understanding the genetic composition ofT. parvais needed prior to the use of the ITM vaccine in new areas. This study examined the sequence diversity and the evolutionary and biogeographical dynamics ofT. parvawithin the African Great Lakes region to better understand the epidemiology of ECF and to assure vaccine safety. Genetic analyses were performed using sequences of two antigen-coding genes,Tp1andTp2, generated among 119T. parvasamples collected from cattle in four agro-ecological zones of DRC and Burundi.

Results

The results provided evidence of nucleotide and amino acid polymorphisms in both antigens, resulting in 11 and 10 distinct nucleotide alleles, that predicted 6 and 9 protein variants inTp1andTp2, respectively.Theileria parvasamples showed high variation within populations and a moderate biogeographical sub-structuring due to the widespread major genotypes. The diversity was greater in samples from lowlands and midlands areas compared to those from highlands and other African countries. The evolutionary dynamics modelling revealed a signal of selective evolution which was not preferentially detected within the epitope-coding regions, suggesting that the observed polymorphism could be more related to gene flow rather than recent host immune-based selection. Most alleles isolated in the Great Lakes region were closely related to the components of the trivalent Muguga vaccine.

Conclusions

Our findings suggest that the extensive sequence diversity ofT. parvaand its biogeographical distribution mainly depend on host migration and agro-ecological conditions driving tick population dynamics. Such patterns are likely to contribute to the epidemic and unstable endemic situations of ECF in the region. However, the fact that ubiquitous alleles are genetically similar to the components of the Muguga vaccine together with the limited geographical clustering may justify testing the existing trivalent vaccine for cross-immunity in the region.
Performance of cytokine models in predicting SLE activity
Authors: Ruchakorn Nopparat , Ngamjanyaporn Pintip , Suangtamai Thanitta , Kafaksom Thanuchporn , Polpanumas Charin , Petpisit Veerachat , Pisitkun Trairak , Pisitkun Prapaporn
Published: December 2019

Background

Identification of universal biomarkers to predict systemic lupus erythematosus (SLE) flares is challenging due to the heterogeneity of the disease. Several biomarkers have been reported. However, the data of validated biomarkers to use as a predictor for lupus flares show variation. This study aimed to identify the biomarkers that are sensitive and specific to predict lupus flares.

Methods

One hundred and twenty-four SLE patients enrolled in this study and were prospectively followed up. The evaluation of disease activity achieved by the SLE disease activity index (SLEDAI-2K) and clinical SLEDAI (modified SLEDAI). Patients with active SLE were categorized into renal or non-renal flares. Serum cytokines were measured by multiplex bead-based flow cytometry. The correlation and logistic regression analysis were performed.

Results

Levels of IFN-α, MCP-1, IL-6, IL-8, and IL-18 significantly increased in active SLE and correlated with clinical SLEDAI. Complement C3 showed a weakly negative relationship with IFN-α and IL-18. IL-18 showed the highest positive likelihood ratios for active SLE. Multiple logistic regression analysis showed that IL-6, IL-8, and IL-18 significantly increased odds ratio (OR) for active SLE at baseline while complement C3 and IL-18 increased OR for active SLE at 12 weeks. IL-18 and IL-6 yielded higher sensitivity and specificity than anti-dsDNA and C3 to predict active renal and active non-renal, respectively.

Conclusion

The heterogeneity of SLE pathogenesis leads to different signaling mechanisms and mediates through several cytokines. The monitoring of cytokines increases the sensitivity and specificity to determine SLE disease activity. IL-18 predicts the risk of active renal SLE while IL-6 and IL-8 predict the risk of active non-renal. The sensitivity and specificity of these cytokines are higher than the anti-dsDNA or C3. We propose to use the serum level of IL-18, IL-6, and IL-8 to monitor SLE disease activity in clinical practice.
Arterial stiffness correlates with progressive nailfold capillary microscopic changes in systemic sclerosis: results from a cross-sectional study
Authors: Soulaidopoulos Stergios , Pagkopoulou Eleni , Katsiki Niki , Triantafyllidou Eva , Karagiannis Asterios , Garyfallos Alexandros , Kitas George D. , Dimitroulas Theodoros
Published: December 2019

Background

While microangiopathy is well-documented in systemic sclerosis (SSc), a potential link between SSc and macrovascular disease is highly debated and remains to be established. The aim of the present study is to investigate the association between micro- and macrovascular involvement in the setting of SSc.

Methods

Consecutive, consenting SSc patients were assessed by nailfold video-capillaroscopy (NVC) to evaluate the microcirculation. The number of capillaries per mm2 and the capillaroscopic skin ulcer risk index (CSURI) were measured, and findings were also classified into three scleroderma patterns (i.e., early, active, and late). Carotid intima-media thickness (IMT), aortic augmentation index corrected for a heart rate of 75 beats per minute (AIx-75), carotid-femoral pulse wave velocity (PWV), and central systolic and diastolic blood pressure were also determined to assess macrovascular function.

Results

A total of 37 patients were studied. A significant correlation was observed between AIx and the average number of capillaries per mm2 (r = − 0.34, p = 0.047) and between AIx and CSURI (r = 0.35, p = 0.044). Patients with the “early” scleroderma pattern had lower AIx values compared with “active” (20.5 ± 11.4 vs 34.1 ± 11.5%, p = 0.02) and “late” (20.5 ± 11.4 vs 33.4 ± 8.8%, p = 0.05) patterns. No other significant correlations were found between macrovascular biomarkers (PWV, carotid IMT, systolic and diastolic central blood pressure) and the capillaroscopic measurements.

Conclusions

These data suggest that arterial stiffness (as assessed by AIx-75) correlates with microvascular damage in patients with SSc.
Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer
Authors: Das Debodipta , Ghosh Sahana , Maitra Arindam , Biswas Nidhan K. , Panda Chinmay K. , Roy Bidyut , Sarin Rajiv , Majumder Partha P.
Published: December 2019

Background

Gingivo-buccal oral squamous cell carcinoma (OSCC-GB) is the most common cancer among men in India and is associated with high mortality. Although OSCC-GB is known to be quite different from tongue cancer in its genomic presentation and its clinical behavior, it is treated identically as tongue cancer. Predictive markers of prognosis and therapy that are specific to OSCC-GB are, therefore, required. Although genomic drivers of OSCC-GB have been identified by whole exome and whole genome sequencing, no epigenome-wide study has been conducted in OSCC-GB; our study has filled this gap, and has discovered and validated epigenomic hallmarks of gingivobuccal oral cancer.

Methods

We have carried out integrative analysis of epigenomic (n = 87) and transcriptomic (n = 72) profiles of paired tumor-normal tissues collected from OSCC-GB patients from India. Genome-wide DNA methylation assays and RNA-sequencing were performed on high-throughput platforms (Illumina) using a half-sample of randomly selected patients to discover significantly differentially methylated probes (DMPs), which were validated on the remaining half-sample of patients.

Results

About 200 genes showed significant inverse correlation between promoter methylation and expression, of which the most significant genes included genes that act as transcription factors and genes associated with other cancer types. Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation.

Conclusions

In OSCC-GB patients, there are significant alterations in expression of key genes that (a) regulate normal cell division by maintenance of balanced DNA methylation and transcription process, (b) maintain normal physiological signaling (PPAR, B cell receptor) and metabolism (arachidonic acid) pathways, and (c) provide immune protection against antigens, including tumor cells. These findings indicate novel therapeutic targets, including immunotherapeutic, for treatment of OSCC-GB.
Septo-optic dysplasia with amniotic band syndrome sequence: a case report
Authors: Amiji Insiyah A. , Mohamed Ummulkheir H. , Rutashobya Adelina G. , Mngoya Mariam , Schoenmann Nicole , Naburi Helga E. , Manji Karim P.
Published: December 2019

Introduction

De Morsier syndrome, or septo-optic dysplasia, is a rare, heterogeneous, complex condition with a highly variable phenotype. It is characterized by optic nerve hypoplasia, pituitary gland hypoplasia, and midline brain abnormalities, including absence of septum pellucidum and corpus callosum dysgenesis. Diagnosis is made clinically by the presence of any two or more features from the clinical triad.

Case presentation

We report a case of a premature African newborn male baby born to nonconsanguineous parents who presented to our institution with agenesis of the septum pellucidum, unilateral optic nerve hypoplasia, and pituitary stalk hypoplasia. However, he had intact central endocrine function. He also presented with limb defects due to constricting amniotic band syndrome. Other dysmorphic features were low-set ears, microcephaly, and bilateral talipes equinovarus. He otherwise had a normal neurological examination result. Over time, he had an adequate weight gain and was managed by a multidisciplinary team.

Conclusion

De Morsier syndrome still represents a diagnostic challenge, despite advances in neuroimaging and genetic studies, due to the heterogeneous nature of the disorder. This case adds to existing knowledge on the vascular pathogenesis of septo-optic dysplasia.
Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway
Authors: Zhao Chen , Du Feng , Zhao Yang , Wang Shanshan , Qi Ling
Published: December 2019

Background

MicroRNA (miR)-containing exosomes released by acute myeloid leukemia (AML) cells can be delivered into hematopoietic progenitor cells to suppress normal hematopoiesis. Herein, our study was performed to evaluate the effect of exosomal miR-4532 secreted by AML cells on hematopoiesis of hematopoietic stem cells.

Methods

Firstly, differentially expressed miRs related to AML were identified using microarray analysis. Subsequently, AML cell lines were collected, and CD34+ HSCs were isolated from healthy pregnant women. Then, miR-4532 expression was measured in AML cells and AML cell-derived exosomes and CD34+ HSCs, together with evaluation of the targeting relationship between miR-4532 and LDOC1. Then, AML cells were treated with miR-4532 inhibitor, and exosomes were separated from AML cells and co-cultured with CD34+ HSCs. Gain- and loss-function approaches were employed in CD34+ HSCs. Colony-forming units (CFU) and expression of dickkopf-1 (DKK1), a hematopoietic inhibiting factor associated with pathogenesis of AML, were determined in CD34+ HSCs, as well as the extents of JAK2 and STAT3 phosphorylation and LDOC1 expression.

Results

miR-4532 was found to be upregulated in AML cells and AML cell-derived exosomes, while being downregulated in CD34+ HSCs. In addition, exosomes released by AML cells targeted CD34+ HSCs to decrease the expression of CFU and increase the expression of DKK1. miR-4532 was delivered into CD34+ HSCs to target LDOC1 via AML cell-released exosomes. AML cell-derived exosomes containing miR-4532 inhibitor increased CFU but reduced DKK1 in CD34+ HSCs. Inhibition of miR-4532 or JAK2, or ectopic expression of LDOC1 upregulated CFU and downregulated DKK1 expression as well as the extents of JAK2 and STAT3 phosphorylation in CD34+ HSCs.

Conclusion

In conclusion, AML cell-derived exosomes carrying miR-4532 repress normal HSC hematopoiesis via activation of the LDOC1-dependent STAT3 signaling pathway.
Sex differences in clinical presentation of systemic lupus erythematosus
Authors:   the DISSECT consortium, Ramírez Sepúlveda Jorge I. , Bolin Karin , Mofors Johannes , Leonard Dag , Svenungsson Elisabet , Jönsen Andreas , Bengtsson Christine , Nordmark Gunnel , Rantapää Dahlqvist Solbritt , Bengtsson Anders A. , Rönnblom Lars , Sjöwall Christopher , Gunnarsson Iva , Wahren-Herlenius Marie
Published: December 2019

Objective

Systemic lupus erythematosus (SLE) predominantly affects women, but previous studies suggest that men with SLE present a more severe disease phenotype. In this study, we investigated a large and well-characterized patient group with the aim of identifying sex differences in disease manifestations, with a special focus on renal involvement.

Methods

We studied a Swedish multi-center SLE cohort including 1226 patients (1060 women and 166 men) with a mean follow-up time of 15.8 ± 13.4 years. Demographic data, disease manifestations including ACR criteria, serology and renal histopathology were investigated. Renal outcome and mortality were analyzed in subcohorts.

Results

Female SLE patients presented more often with malar rash (p < 0.0001), photosensitivity (p < 0.0001), oral ulcers (p = 0.01), and arthritis (p = 0.007). Male patients on the other hand presented more often with serositis (p = 0.0003), renal disorder (p < 0.0001), and immunologic disorder (p = 0.04) by the ACR definitions. With regard to renal involvement, women were diagnosed with nephritis at an earlier age (p = 0.006), while men with SLE had an overall higher risk for progression into end-stage renal disease (ESRD) with a hazard ratio (HR) of 5.1 (95% CI, 2.1–12.5). The mortality rate among men with SLE and nephritis compared with women was HR 1.7 (95% CI, 0.8–3.8).

Conclusion

SLE shows significant sex-specific features, whereby men are affected by a more severe disease with regard to both renal and extra-renal manifestations. Additionally, men are at a higher risk of developing ESRD which may require an increased awareness and monitoring in clinical practice.
PRC1 promotes GLI1-dependent osteopontin expression in association with the Wnt/β-catenin signaling pathway and aggravates liver fibrosis
Authors: Rao Shenzong , Xiang Jie , Huang Jingsong , Zhang Shangang , Zhang Min , Sun Haoran , Li Jian
Published: December 2019

Background

PRC1 (Protein regulator of cytokinesis 1) regulates microtubules organization and functions as a novel regulator in Wnt/β-catenin signaling pathway. Wnt/β-catenin is involved in development of liver fibrosis (LF). We aim to investigate effect and mechanism of PRC1 on liver fibrosis.

Methods

Carbon tetrachloride (CCl4)-induced mice LF model was established and in vitro cell model for LF was induced by mice primary hepatic stellate cell (HSC) under glucose treatment. The expression of PRC1 in mice and cell LF models was examined by qRT-PCR (quantitative real-time polymerase chain reaction), western blot and immunohistochemistry. MTT assay was used to detect cell viability, and western blot to determine the underlying mechanism. The effect of PRC1 on liver pathology was examined via measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and hydroxyproline, as well as histopathological analysis.

Results

PRC1 was up-regulated in CCl4-induced mice LF model and activated HSC. Knockdown of PRC1 inhibited cell viability and promoted cell apoptosis of activated HSC. PRC1 expression was regulated by Wnt3a signaling, and PRC1 could regulate downstream β-catenin activation. Moreover, PRC1 could activate glioma-associated oncogene homolog 1 (GLI1)-dependent osteopontin expression to participate in LF. Adenovirus-mediated knockdown of PRC1 in liver attenuated LF and reduced collagen deposition.

Conclusions

PRC1 aggravated LF through regulating Wnt/β-catenin mediated GLI1-dependent osteopontin expression, providing a new potential therapeutic target for LF treatment.
Asymptotic properties of wavelet estimators in heteroscedastic semiparametric model based on negatively associated innovations
Authors: Hu Xueping , Zhong Jinbiao , Ren Jiashun , Shi Bing , Yu Keming
Published: December 2019

Consider the heteroscedastic semiparametric regression model $y_{i}=x_{i}\beta+g(t_{i})+\varepsilon_{i}$yi=xiβ+g(ti)+εi, $i=1, 2, \ldots, n$i=1,2,…,n, where β is an unknown slope parameter, $\varepsilon_{i}=\sigma_{i}e_{i}$εi=σiei, $\sigma^{2}_{i}=f(u_{i})$σi2=f(ui), $(x_{i},t_{i},u_{i})$(xi,ti,ui) are nonrandom design points, $y_{i}$yi are the response variables, f and g are unknown functions defined on the closed interval $[0,1]$[0,1], random errors $\{e_{i} \}${ei} are negatively associated (NA) random variables with zero means. Whereas kernel estimators of β, g, and f have attracted a lot of attention in the literature, in this paper, we investigate their wavelet estimators and derive the strong consistency of these estimators under NA error assumption. At the same time, we also obtain the Berry–Esséen type bounds of the wavelet estimators of β and g.
Nonoscillatory solutions to fourth-order neutral dynamic equations on time scales
Authors: Qiu Yang-Cong
Published: December 2019

In this paper, we present some sufficient conditions and necessary conditions for the existence of nonoscillatory solutions to a class of fourth-order nonlinear neutral dynamic equations on time scales by employing Banach spaces and Krasnoselskii’s fixed point theorem. Two examples are given to illustrate the applications of the results.
Diversity, evolution, and classification of virophages uncovered through global metagenomics
Authors: Paez-Espino David , Zhou Jinglie , Roux Simon , Nayfach Stephen , Pavlopoulos Georgios A. , Schulz Frederik , McMahon Katherine D. , Walsh David , Woyke Tanja , Ivanova Natalia N. , Eloe-Fadrosh Emiley A. , Tringe Susannah G. , Kyrpides Nikos C.
Published: December 2019

Background

Virophages are small viruses with double-stranded DNA genomes that replicate along with giant viruses and co-infect eukaryotic cells. Due to the paucity of virophage reference genomes, a collective understanding of the global virophage diversity, distribution, and evolution is lacking.

Results

Here we screened a public collection of over 14,000 metagenomes using the virophage-specific major capsid protein (MCP) as “bait.” We identified 44,221 assembled virophage sequences, of which 328 represent high-quality (complete or near-complete) genomes from diverse habitats including the human gut, plant rhizosphere, and terrestrial subsurface. Comparative genomic analysis confirmed the presence of four core genes in a conserved block. We used these genes to establish a revised virophage classification including 27 clades with consistent genome length, gene content, and habitat distribution. Moreover, for eight high-quality virophage genomes, we computationally predicted putative eukaryotic virus hosts.

Conclusion

Overall, our approach has increased the number of known virophage genomes by 10-fold and revealed patterns of genome evolution and global virophage distribution. We anticipate that the expanded diversity presented here will provide the backbone for further virophage studies.
Fathers today: design of a randomized controlled trial examining the role of oxytocin and vasopressin in behavioral and neural responses to infant signals
Authors: Witte Annemieke M. , de Moor Marleen H. M. , van IJzendoorn Marinus H. , Bakermans-Kranenburg Marian J.
Published: December 2019

Background

Previous research has mostly focused on the hormonal, behavioral and neural correlates of maternal caregiving. We present a randomized, double-blind, placebo-controlled within-subject design to examine the effects of intranasal administration of oxytocin and vasopressin on parenting behavior and the neural and behavioral responses to infant cry sounds and infant threat. In addition, we will test whether effects of oxytocin and vasopressin administration are moderated by fathers’ early childhood experiences.

Methods

Fifty-five first-time fathers of a child between two and seven months old will participate in three experimental sessions with intervening periods of one to two weeks. Participants self-administer oxytocin, vasopressin or a placebo. Infant-father interactions and protective parenting responses are observed during play. Functional Magnetic Resonance Imaging (fMRI) is used to examine the neural processing of infant cry sounds and infant threat. A handgrip dynamometer is used to measure use of handgrip force when listening to infant cry sounds. Participants report on their childhood experiences of parental love-withdrawal and abuse and neglect.

Discussion

The results of this study will provide important insights into the hormonal, behavioral and neural correlates of fathers’ parenting behavior during the early phase of fatherhood.

Trial registration

Dutch Trial Register: NTR (ID:NL8124); Date registered: October 30, 2019.
Diagnosis and management of septal deviation and nasal valve collapse - a survey of Canadian otolaryngologists
Authors: Wang Yiqiao , Bonaparte James P.
Published: December 2019

Background

Management of nasal valve collapse (NVC) in patients with a septal deviation can be challenging. Our objective was to determine the opinions of Canadian Otolaryngologists regarding the diagnosis and management of nasal obstruction in patients with septal deviation and NVC.

Methods

A twenty-question survey was developed for the purpose of our study. Questions were divided into the following areas: diagnosis, management and prognosis. We included all otolaryngologists who were members of the Canadian Society of Otolaryngology.

Results

The response rate to our survey was 18%. The most commonly identified cause of a failed septoplasty was incomplete septoplasty (41.9%), followed by nasal valve collapse (25.6%). The Cottle manoeuvre (62.8%) and visual inspection (39.5%) were noted to be the most important diagnostic tools for external and internal NVC respectively. However, physicians often rely on a variable number of different examinations when making a diagnosis of nasal valve collapse. When evaluating which patients with a septal deviation also required nasal valve surgery, 27.9% of responders believed the current physical examination methods provided a high accuracy, while 55.8% indicated moderate accuracy and 16.3% indicated low accuracy. Compared to other subspecialties in Otolaryngology, Facial Plastic and Reconstruction Surgeons noted higher septoplasty failure rates in patients with co-morbid NVC.

Conclusions

NVC is an important concern for otolaryngologists performing septoplasty. Although most physicians believe that the physical exam provides a moderate effectiveness when predicting who requires a functional rhinoplasty, diagnostic methods used for NVC is varied and inconsistent.
Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice
Authors: Zhou Libin , Flores Joseph , Noël Anastasia , Beauchet Olivier , Sjöström P. Jesper , LeBlanc Andrea C.
Published: December 2019

Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.
Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study
Authors: Kelley Christy M. , Perez Sylvia E. , Mufson Elliott J.
Published: December 2019

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1–42and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.