bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer of mouse blastocysts exposed to ambient oxygen levels can lead to impaired lung development and redox balance
Authors: Karagenç Nedim , Doğan Göksel , Esmen Kerem , Kul Bengi Çınar , Yeşilkaya Hasan , Orman Mehmet Nurullah , Sandıkçı Mustafa , Ünsal Hümeyra , Karagenç Levent 
Published: August 2019

AbstractIn vitro culture under atmospheric oxygen puts embryos under oxidative stress and impairs preimplantation development. However, to what extent this process alters the redox balance in the perinatal period remains largely unknown. The aim of the present study was to examine if the redox balance is altered in the lung tissue of fetuses generated through transfer of mouse embryos exposed to atmospheric oxygen at different stages of development and to determine if this has any effect on lung morphogenesis and gene expression. Two experimental groups (EGs) were generated by transferring in vitro- and in vivo-derived blastocysts to pseudo-pregnant females. In vivo-developed fetuses served as control. Enzymatic/nonenzymatic antioxidants, malondialdehyde (MDA) levels, total antioxidant capacity, stage of lung development and gene expression were evaluated on day 18 of pregnancy. Weight of fetuses was significantly less in both experimental cohorts (ANOVA, P < 0.001 versus control), associated with delayed lung development, higher amounts of MDA (ANOVA, P < 0.001 versus control) and altered expression of several genes in oxidative stress/damage pathways. Evidence gathered in the present study indicates that pre-implantation stress caused by culture under atmospheric oxygen, even for a short period of time, leads to fetal growth restriction, impaired lung development and redox balance along with dysregulation of several genes in oxidative stress response. Absence of an EG in which in vitro embryo culture was performed at 5% oxygen and the use of genetically heterogeneous F2 fetuses are the limitations of the study. In any case, the long-term impact of such dramatic changes in the developmental programming of resulting fetuses warrants further investigations.
Distinct pathways associated with chromosomal aberration frequency in a cohort exposed to genotoxic compounds compared to general population
Authors: Niazi Yasmeen , Thomsen Hauke , Smolkova Bozena , Vodickova Ludmila , Vodenkova Soňa , Kroupa Michal , Vymetalkova Veronika , Kazimirova Alena , Barancokova Magdalena , Volkovova Katarina , Staruchova Marta , Hoffmann Per , Nöthen Markus M , Dusinska Maria , Musak Ludovit , Vodicka Pavel , Hemminki Kari , Försti Asta 
Published: August 2019

AbstractNon-specific structural chromosomal aberrations (CAs) observed in peripheral blood lymphocytes of healthy individuals can be either chromosome-type aberrations (CSAs) or chromatid-type aberrations (CTAs) depending on the stage of cell division they are induced in and mechanism of formation. It is important to study the genetic basis of chromosomal instability as it is a marker of genotoxic exposure and a predictor of cancer risk. For that purpose, we conducted two genome-wide association studies (GWASs) on healthy individuals in the presence and absence of apparent genotoxic exposure from the Czech Republic and Slovakia. The pre-GWAS cytogenetic analysis reported the frequencies of CSA, CTA and total CA (CAtot). We performed both linear and binary logistic regression analysis with an arbitrary cut-off point of 2% for CAtot and 1% for CSA and CTA. Using the statistical threshold of 1.0 × 10−5, we identified five loci with in silico predicted functionality in the reference group and four loci in the exposed group, with no overlap between the associated regions. A meta-analysis on the two GWASs identified further four loci with moderate associations in each of the studies. From the reference group mainly loci within genes related to DNA damage response/repair were identified. Other loci identified from both the reference and exposed groups were found to be involved in the segregation of chromosomes and chromatin modification. Some of the discovered regions in each group were implicated in tumourigenesis and autism.
Programmed genome rearrangements in Oxytricha produce transcriptionally active extrachromosomal circular DNA
Authors: Yerlici V Talya , Lu Michael W , Hoge Carla R , Miller Richard V , Neme Rafik , Khurana Jaspreet S , Bracht John R , Landweber Laura F 
Published: August 2019

AbstractExtrachromosomal circular DNA (eccDNA) is both a driver of eukaryotic genome instability and a product of programmed genome rearrangements, but its extent had not been surveyed in Oxytricha, a ciliate with elaborate DNA elimination and translocation during development. Here, we captured rearrangement-specific circular DNA molecules across the genome to gain insight into its processes of programmed genome rearrangement. We recovered thousands of circularly excised Tc1/mariner-type transposable elements and high confidence non-repetitive germline-limited loci. We verified their bona fide circular topology using circular DNA deep-sequencing, 2D gel electrophoresis and inverse polymerase chain reaction. In contrast to the precise circular excision of transposable elements, we report widespread heterogeneity in the circular excision of non-repetitive germline-limited loci. We also demonstrate that circular DNAs are transcribed in Oxytricha, producing rearrangement-specific long non-coding RNAs. The programmed formation of thousands of eccDNA molecules makes Oxytricha a model system for studying nucleic acid topology. It also suggests involvement of eccDNA in programmed genome rearrangement.
Molecular basis of abasic site sensing in single-stranded DNA by the SRAP domain of E. coli yedK
Authors: Wang Na , Bao Hongyu , Chen Liu , Liu Yanhong , Li Yue , Wu Baixing , Huang Hongda 
Published: August 2019

AbstractHMCES and yedK were recently identified as sensors of abasic sites in ssDNA. In this study, we present multiple crystal structures captured in the apo-, nonspecific-substrate-binding, specific-substrate-binding, and product-binding states of yedK. In combination with biochemical data, we unveil the molecular basis of AP site sensing in ssDNA by yedK. Our results indicate that yedK has a strong preference for AP site-containing ssDNA over native ssDNA and that the conserved Glu105 residue is important for identifying AP sites in ssDNA. Moreover, our results reveal that a thiazolidine linkage is formed between yedK and AP sites in ssDNA, with the residues that stabilize the thiazolidine linkage important for the formation of DNA-protein crosslinks between yedK and the AP sites. We propose that our findings offer a unique platform to develop yedK and other SRAP domain-containing proteins as tools for detecting abasic sites in vitro and in vivo.
Gene silencing by double-stranded RNA from C. elegans neurons reveals functional mosaicism of RNA interference
Authors: Ravikumar Snusha , Devanapally Sindhuja , Jose Antony M 
Published: August 2019

AbstractDelivery of double-stranded RNA (dsRNA) into animals can silence genes of matching sequence in diverse cell types through mechanisms that have been collectively called RNA interference. In the nematode Caenorhabditis elegans, dsRNA from multiple sources can trigger the amplification of silencing signals. Amplification occurs through the production of small RNAs by two RNA-dependent RNA polymerases (RdRPs) that are thought to be tissue-specific - EGO-1 in the germline and RRF-1 in somatic cells. Here we demonstrate that EGO-1 can compensate for the lack of RRF-1 when dsRNA from neurons is used to silence genes in intestinal cells. However, the lineal origins of cells that can use EGO-1 varies. This variability could be because random sets of cells can either receive different amounts of dsRNA from the same source or use different RdRPs to perform the same function. Variability is masked in wild-type animals, which show extensive silencing by neuronal dsRNA. As a result, cells appear similarly functional despite underlying differences that vary from animal to animal. This functional mosaicism cautions against inferring uniformity of mechanism based on uniformity of outcome. We speculate that functional mosaicism could contribute to escape from targeted therapies and could allow developmental systems to drift over evolutionary time.
A Constructive Proof of Helmholtz’s Theorem
Authors: De La Calle Ysern Bernardo , Sabina De Lis José C 
Published: August 2019

Summary
It is a known result that any vector field ${\boldsymbol{u}}$ that is locally Hölder continuous on an arbitrary open set $\Omega\subset \mathbb{R}^3$ can be written on $\Omega$ as the sum of a gradient and a curl. Should $\Omega$ be unbounded, no conditions are required on the behaviour of ${\boldsymbol{u}}$ at infinity. We present a direct, self-contained proof of this theorem that only uses elementary techniques and has a constructive character. It consists in patching together local solutions given by the Newtonian potential that are then modified by harmonic approximations—based on solid spherical harmonics—to assure convergence near infinity for the resulting series.
Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis
Authors: Boutet Marie-Astrid , Nerviani Alessandra , Lliso-Ribera Gloria , Lucchesi Davide , Prediletto Edoardo , Ghirardi Giulia Maria , Goldmann Katriona , Lewis Myles , Pitzalis Costantino 
Published: August 2019

Abstract

Objectives
IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy.

Methods
Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes.

Results
PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts.

Conclusion
The impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.
Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis
Authors: Nair Nisha , Plant Darren , Verstappen Suzanne M , Isaacs John D , Morgan Ann W , Hyrich Kimme L , Barton Anne , Wilson Anthony G ,   the MATURA investigators
Published: August 2019

AbstractObjectivesIdentifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.MethodsDNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.ResultsIn the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.ConclusionThese data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.
The Relationship Between Level of Catastrophizing and Mental Health Comorbidity in Individuals With Whiplash Injuries
Authors: Paré Catherine , Thibault Pascal , Côté Pierre , Pimentel Stephania D. , Shen Shiyang , Yakobov Esther , Sullivan Michael J.L. 
Published: August 2019

Objectives:
Pain catastrophizing has been shown to be correlated with measures of mental health problems such as depression and post-traumatic stress disorder (PTSD). However, the clinical implications of findings reported to date remain unclear. To date, no study has been conducted to determine meaningful cut-scores on measures of catastrophizing indicative of the heightened risk of mental health comorbidity. One objective of the present study was to identify the cut-score on the Pain Catastrophizing Scale (PCS) indicative of the heightened risk of the comorbidity of depression and PTSD. A second objective was to determine whether mental health comorbidity mediated the relationship between catastrophizing and occupational disability.

Materials and Methods:
The sample consisted of 143 individuals with whiplash injuries. Pain severity, pain catastrophizing, depression, and post-traumatic stress symptoms were assessed after admission to a rehabilitation program. Mental health comorbidity was operationally defined as obtaining a score above the clinical threshold on measures of depressive and/or post-traumatic stress symptom severity.

Results:
A receiver operating characteristic curve analysis revealed that a PCS score of 22 best distinguished between participants with and without mental health comorbidity. Results also revealed that mental health comorbidity mediated the relationship between catastrophizing and occupational disability.

Discussion:
The findings suggest that a score of ≥22 on the PCS should alert clinicians to the possibility that patients might also be experiencing clinically significant symptoms of depression or PTSD. Greater attention to the detection and treatment of mental health conditions associated with whiplash injury might contribute to more positive recovery outcomes.
A New Test for the Detection of Direct Oral Anticoagulants (Rivaroxaban and Apixaban) in the Emergency Room Setting
Authors: Frydman Galit H. , Ellett Felix , Van Cott Elizabeth M. , Hayden Douglas , Majmudar Maulik , Vanderburg Charles R. , Dalzell Haley , Padmanabhan Divya L. , Davis Nick , Jorgensen Julianne , Toner Mehmet , Fox James G. , Tompkins Ronald G. 
Published: August 2019

Objectives:
Determining whether a patient has taken a direct oral anticoagulant (DOAC) is critical during the periprocedural and preoperative period in the emergency department. However, the inaccessibility of complete medical records, along with the generally inconsistent sensitivity of conventional coagulation tests to these drugs, complicates clinical decision making and puts patients at risk of uncontrollable bleeding. In this study, we evaluate the utility of inhibitor-II-X (i-II-X), a novel, microfluidics-based diagnostic assay for the detection and identification of Factor Xa inhibitors (FXa-Is) in an acute care setting.

Design:
First-in-human, 91-patient, single-center retrospective pilot study.

Setting:
Emergency room.

Patients:
Adult patients admitted into the emergency department, which received any clinician-ordered coagulation test requiring a 3.2% buffered sodium citrate blood collection tube.

Interventions:
None.

Measurements and Main Results:
Plasma samples from patients admitted to the emergency department were screened for the use of FXa-Is, including apixaban and rivaroxaban, within the past 24 hours using our new i-II-X microfluidic test. i-II-X results were then compared with results from conventional coagulation tests, including prothrombin time (PT) and international normalized ratio (INR), which were ordered by treating clinicians, and an anti-Xa assay for rivaroxaban. The i-II-X test detected DOACs in samples collected from the emergency department with 95.20% sensitivity and 100.00% specificity. Unlike PT and INR, i-II-X reliably identified patients who had prolonged clotting times secondary to the presence of a FXa-I.

Conclusions:
The i-II-X test overcomes the limitations of currently available coagulation tests and could be a useful tool by which to routinely screen patients for DOACs in emergency and critical care settings. Our new diagnostic approach is particularly relevant in clinical situations where medical records may be unavailable, or where precautions need to be taken prior to invasive interventions, such as specific reversal agent administration.
A Review of the Literature on the Global Epidemiology of Corneal Blindness
Authors: Porth Julia M. , Deiotte Erin , Dunn Matthew , Bashshur Ramona 
Published: August 2019

Purpose:
This study seeks to review published research on the global epidemiology of corneal blindness, with a specific focus on the available published estimates of incidence, prevalence, and trends in incidence or prevalence, as well as the contribution of corneal causes to overall burden of blindness.

Methods:
A scoping review was conducted of the published literature on the global epidemiology of corneal blindness, with emphasis on prevalence and incidence studies. Four databases were searched using both epidemiological and corneal blindness keywords. This review was limited to studies with a primary aim of determining the incidence, prevalence, or trends in corneal blindness or the percentage of blindness due to corneal causes. Only conditions considered to signify current blindness were included, not diseases that eventually could lead to blindness if left untreated.

Results:
A total of 185 articles met the selection criteria. Of these, 145 articles investigated all-cause blindness prevalence. Only 10 articles specifically aimed to determine estimates of corneal blindness prevalence, 7 articles provided results for all-cause blindness incidence, and no studies focused on obtaining corneal blindness incidence. Data on corneal blindness were most often present in studies investigating all-cause blindness and in trachoma studies.

Conclusions:
The results demonstrate the somewhat inconsistent and fragmented information regarding corneal causes of vision loss. A significant outcome of this research is the demonstration of a need for further research into global corneal blindness and the necessary steps to address the problem.
The Efficacy of Modafinil as a Cognitive Enhancer
Authors: Kredlow M. Alexandra , Keshishian Ani , Oppenheimer Sarah , Otto Michael W. 
Published: August 2019

Abstract

Background
Animal models and human studies have identified the potential of modafinil as a cognitive enhancing agent, independent of its effects on promoting wakefulness in sleep-deprived samples. Given that single-dose applications of other putative memory enhancers (eg, d-cycloserine, yohimbine, and methylene blue) have shown success in enhancing clinical outcomes for anxiety-related disorders, we conducted a meta-analytic review examining the potential for single-dose effects for modafinil on cognitive functioning in non–sleep-deprived adults.

Methods
A total of 19 placebo-controlled trials that examined the effects of single-dose modafinil versus placebo on the cognitive domains of attention, executive functioning, memory, or processing speed were identified, allowing for the calculation of 67 cognitive domain–specific effect sizes.

Results
The overall positive effect of modafinil over placebo across all cognitive domains was small and significant (g = 0.10; 95% confidence interval, 0.05–0.15; P < 0.001). No significant differences between cognitive domains were found. Likewise, no significant moderation was found for modafinil dose (100 mg vs 200 mg) or for the populations studied (psychiatric vs nonpsychiatric).

Conclusions
In conclusion, the available evidence indicates only limited potential for modafinil to act as a cognitive enhancer outside sleep-deprived populations.
Minimal Effects of Binaural Auditory Beats for Subclinical Insomnia
Authors: Bang Young Rong , Choi Ha yun , Yoon In-Young 
Published: August 2019

Abstract

Background
Auditory binaural beat (BB) stimulation is known to modulate electroencephalographic activity by brain entrainment, but few studies have established whether BB can affect the sleep state. We examined the effect of θ BB in improving sleep disturbances and daytime alertness.

Methods
We conducted double-blind and sham-controlled randomized trial. Subjects with subclinical insomnia were randomly assigned and listened to music for 2 weeks with or without θ BB for 30 minutes before going to sleep.

Results
There were 43 participants (32 female; mean age, 34.3 ± 10.4 years) who finished the trial. The insomnia severity decreased at 2 weeks in both groups without significant differences in Insomnia Severity Index score (4.41 ± 4.32 vs 2.71 ± 4.66, P = 0.656), although the effect was much stronger for the music with the BB group than for the music-only group (Cohen d = 1.02 vs 0.58). In awake electroencephalographic analysis, the relative β power after 2 weeks was higher in the music with the BB group than in the music-only group (0.2 ± 7.02 vs −3.91 ± 6.97, P = 0.041).

Conclusions
Auditory θ BB with music does not induce evident improvement of sleep disturbances more than does pure music, but could alter brain activity toward increasing daytime alertness in subclinical insomnia, which needs to be corroborated in a clinical population.
Learning in anticipation of reward and punishment: Perspectives across the human lifespan
Authors: Betts Matthew J. , Richter Anni , de Boer Lieke , Tegelbeckers Jana , Perosa Valentina , Chowdhury Rumana , Dolan Raymond J. , Seidenbecher Constanze , Schott Björn H. , Düzel Emrah , Guitart-Masip Marc , Krauel Kerstin 
Published: August 2019

AbstractPavlovian biases influence the interaction between action and valence by coupling reward seeking to action invigoration and punishment avoidance to action suppression. In this study we used an orthogonalised go/no-go task to investigate learning in 247 individuals across the human lifespan (7-80 years) to demonstrate that all participants, independently of age, demonstrated an influence of Pavlovian control. Computational modeling revealed peak performance in young adults was attributable to greater sensitivity to both rewards and punishment. However in children and adolescents an increased bias towards action but not reward sensitivity was observed. In contrast, reduced learning in midlife and older adults was accompanied with decreased reward sensitivity and especially punishment sensitivity. These findings reveal distinct learning capabilities across the human lifespan that cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implications in life-long education.