bluuebunny/crossref_metadata_2025 huggingface dataset:
Super-enhancers in transcriptional regulation and genome organization
Authors: Wang Xi , Cairns Murray J , Yan Jian
Published: October 2019

Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term ‘super-enhancer’ has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.
miRTarBase 2020: updates to the experimentally validated microRNA–target interaction database
Authors: Huang Hsi-Yuan , Lin Yang-Chi-Dung , Li Jing , Huang Kai-Yao , Shrestha Sirjana , Hong Hsiao-Chin , Tang Yun , Chen Yi-Gang , Jin Chen-Nan , Yu Yuan , Xu Jia-Tong , Li Yue-Ming , Cai Xiao-Xuan , Zhou Zhen-Yu , Chen Xiao-Hang , Pei Yuan-Yuan , Hu Liang , Su Jin-Jiang , Cui Shi-Dong , Wang Fei , Xie Yue-Yang , Ding Si-Yuan , Luo Meng-Fan , Chou Chih-Hung , Chang Nai-Wen , Chen Kai-Wen , Cheng Yu-Hsiang , Wan Xin-Hong , Hsu Wen-Lian , Lee Tzong-Yi , Wei Feng-Xiang , Huang Hsien-Da
Published: October 2019

MicroRNAs (miRNAs) are small non-coding RNAs (typically consisting of 18–25 nucleotides) that negatively control expression of target genes at the post-transcriptional level. Owing to the biological significance of miRNAs, miRTarBase was developed to provide comprehensive information on experimentally validated miRNA–target interactions (MTIs). To date, the database has accumulated >13,404 validated MTIs from 11,021 articles from manual curations. In this update, a text-mining system was incorporated to enhance the recognition of MTI-related articles by adopting a scoring system. In addition, a variety of biological databases were integrated to provide information on the regulatory network of miRNAs and its expression in blood. Not only targets of miRNAs but also regulators of miRNAs are provided to users for investigating the up- and downstream regulations of miRNAs. Moreover, the number of MTIs with high-throughput experimental evidence increased remarkably (validated by CLIP-seq technology). In conclusion, these improvements promote the miRTarBase as one of the most comprehensively annotated and experimentally validated miRNA–target interaction databases. The updated version of miRTarBase is now available at http://miRTarBase.cuhk.edu.cn/.
Why does the mind wander?
Authors: Shepherd Joshua
Published: October 2019

I seek an explanation for the etiology and the function of mind wandering episodes. My proposal—which I call the cognitive control proposal—is that mind wandering is a form of non-conscious guidance due to cognitive control. When the agent’s current goal is deemed insufficiently rewarding, the cognitive control system initiates a search for a new, more rewarding goal. This search is the process of unintentional mind wandering. After developing the proposal, and relating it to the literature on mind wandering and on cognitive control, I discuss explanations the proposal affords, testable predictions the proposal makes, and philosophical implications the proposal has.
Converting Pediatric Patients and Young Adults From a Shunt to a Third Ventriculostomy: A Multicenter Evaluation
Authors: Hersh David S , Dave Pooja , Weeks Matt , Hankinson Todd C , Karimian Brandon , Staulcup Susan , Van Poppel Mark D , Wait Scott D , Vaughn Brandy N , Klimo Paul
Published: October 2019

BACKGROUND

Endoscopic third ventriculostomy (ETV) is an effective primary treatment for certain forms of hydrocephalus. However, its use in children with an existing shunt is less well known.

OBJECTIVE

To report a multicenter experience in attempting to convert patients from shunt dependence to a third ventriculostomy and to determine predictors of success.

METHODS

Three participating centers provided retrospectively collected information on patients with an attempted conversion from a shunt to an ETV between December 1, 2008, and April 1, 2018. Demographic, clinical, and radiological data were recorded. Success was defined as shunt independence at the last follow-up.

RESULTS

Eighty patients with an existing ventricular shunt underwent an ETV. The median age at the time of the index ETV was 9.9 yr, and 44 (55%) patients were male. The overall success rate was 64% (51/80), with a median duration of follow-up of 2.0 yr (range, 0.1-9.4 yr). Four patients required a successful repeat ETV at a median of 1.7 yr (range, 0.1-5.7 yr) following the index ETV. Only age was predictive of ETV failure on multivariate analysis (odds ratio 0.86 [95% CI 0.78-0.94], P = .005). No patient less than 6 mo of age underwent an ETV, and of the 5 patients between 6 and 12 mo of age, 4 failed.

CONCLUSION

Although not every shunted patient will be a candidate for an ETV, nor will they be successfully converted, an ETV should at least be considered in every child who presents with a shunt malfunction or who has an externalized shunt.
Vertical structure and kinematics of the Galactic outer disk
Authors: Sakai Nobuyuki , Nagayama Takumi , Nakanishi Hiroyuki , Koide Nagito , Kurayama Tomoharu , Izumi Natsuko , Hirota Tomoya , Yoshida Toshihiro , Shibata Katsunori M , Honma Mareki
Published: October 2019

We report on measurements of parallax and proper motion for four 22 GHz water maser sources as part of the VERA Outer Rotation Curve project. All the sources show Galactic latitudes of >2° and Galactocentric distances of >11 kpc at the Galactic longitude range of 95° < l < 126°. The sources trace the Galactic warp reaching to 200–400 pc, and also the signature of the warp to 600 pc toward the north Galactic pole. The new results, along with previous results in the literature, show that the maximum height of the Galactic warp increases with Galactocentric distance. Also, we examined velocities perpendicular to the disk for the sample, and found oscillatory behavior between the vertical velocities and Galactic heights. This behavior suggests the existence of bending (vertical density) waves, possibly induced by a perturbing satellite (e.g., the passage of the Sagittarius dwarf galaxy).
Zika virus in India: past, present and future
Authors: Gupta N , Kodan P , Baruah K , Soneja M , Biswas A
Published: October 2019

Zika virus (ZIKV) is an arthropod-borne flavivirus that presents with acute febrile illness associated with rash, arthralgia and conjunctivitis. After years of sporadic reports in Africa, the three major outbreaks of this disease occurred in Yap Islands (2007), French Polynesia (2013–14) and South Americas (2015–16). Although, serological surveys suggested the presence of ZIKV in India in 1950s, cross-reactivity could not be ruled out. The first four proven cases of ZIKV from India were reported in 2017. This was followed by major outbreaks in the states of Rajasthan and Madhya Pradesh in 2018. Fortunately, the outbreaks in India were not associated with neurological complications. These outbreaks in India highlighted the spread of this disease beyond geographical barriers owing to the growing globalization, increased travel and ubiquitous presence of its vector, the Aedes mosquito. In this review, we discuss the epidemiology, clinical features and management of ZIKV in India.
UvCom1 Is an Important Regulator Required for Development and Infection in the Rice False Smut Fungus Ustilaginoidea virens
Authors: Chen Xiaoyang , Hai Du , Tang Jintian , Liu Hao , Huang Junbin , Luo Chaoxi , Hsiang Tom , Zheng Lu
Published: October 2019

Ustilaginoidea virens is an economically important biotrophic fungal pathogen that causes rice false smut worldwide. However, the regulatory mechanisms of smut ball formation under U. virens infection remain unclear. Here, we identified an important transcription factor, UvCom1, from this pathogen, which regulates the formation of smut balls on rice spikelets. UvCom1 contains two conserved internal repeat 1 (RPT) domains and is found only in fungi, with specific conservation in species of Basidiomycetes and Ascomycetes. UvCom1 protein N- or C-terminal fusion vectors both showed transactivation activity in yeast. Deletion of UvCom1 significantly affected the vegetative growth and conidiation of U. virens. UvCom1 negatively regulated the responses to oxidative, osmotic, and cell wall stresses. Remarkably, UvCom1 was found to be essential for the formation of rice smut balls, and UvCom1 deletion mutants lost the ability to stably utilize nutrients from the rice host. UvCom1 was also highly expressed at the mycelial expansion stage. Transcriptomic analysis and quantitative real-time PCR revealed that UvCom1 could affect the expression of genes significantly enriched in transmembrane transport. This study demonstrates that UvCom1 is a key transcription factor governing smut ball formation of this biotrophic fungus.
Estimating Real World Performance of a Predictive Model: A Case-Study in Predicting End-of-Life
Authors: Major Vincent J , Jethani Neil , Aphinyanaphongs Yindalon
Published: October 2019

Objective

The main criteria for choosing how models are built is the subsequent effect on future (estimated) model performance. In this work, we evaluate the effects of experimental design choices on both estimated and actual model performance.

Materials and Methods

Four years of hospital admissions are used to develop a 1 year end-of-life prediction model. Two common methods to select appropriate prediction timepoints (backwards-from-outcome and forwards-from-admission) are introduced and combined with two ways of separating cohorts for training and testing (internal and temporal). Two models are trained in identical conditions, and their performances are compared. Finally, operating thresholds are selected in each test set and applied in a final, ‘real-world’ cohort consisting of one year of admissions.

Results

Backwards-from-outcome cohort selection discards 75% of candidate admissions (n=23,579), whereas forwards-from-admission selection includes many more (n=92,148). Both selection methods produce similar global performances when applied to an internal test set. However, when applied to the temporally defined ‘real-world’ set, forwards-from-admission yields higher areas under the ROC and precision recall curves (88.3 and 56.5% vs. 83.2 and 41.6%).

Discussion

A backwards-from-outcome experiment effectively transforms the training data such that it no longer resembles real-world data. This results in optimistic estimates of test set performance, especially at high precision. In contrast, a forwards-from-admission experiment with a temporally separated test set consistently and conservatively estimates real-world performance.

Conclusion

Experimental design choices impose bias upon selected cohorts. A forwards-from-admission experiment, validated temporally, can conservatively estimate real-world performance.
Bringing Critical Race Praxis into the Study of Electrophysiological Substrate of Sudden Cardiac Death: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Jensen Kelly , Howell Stacey J. , Phan Francis , Khayyat-Kholghi Maedeh , Wang Linda , Haq Kazi T. , Johnson John , Tereshchenko Larisa G.
Published: October 2019

Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological (EP) substrate with SCD varies between black and white individuals. Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,408; age 54±6 y; 74% white) were included. EP substrate was characterized by traditional 12-lead ECG and vectorcardiographic metrics. Two competing outcomes were adjudicated SCD and non-sudden cardiac death (nonSCD). Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease (CVD), risk factors, and incident non-fatal CVD. At the baseline visit linear regression analysis, adjusted for age, sex, and study center, showed black individuals had larger Spatial Ventricular Gradient magnitude by 0.30 (95%CI 0.25-0.34) mV, SAI QRST by 18.4 (13.7-23.0) mV*ms, Cornell voltage by 0.30 (95%CI 0.25-0.35) mV than white individuals. Over a median follow-up of 24.4 years, SCD incidence was higher in black (2.86; 95%CI 2.50-3.28 per 1000 person-years) than white individuals (1.37; 95%CI 1.22-1.53 per 1000 person-years). Black individuals with hypertension had the highest rate of SCD: 4.26; 95%CI 3.66-4.96 per 1000 person-years. Race did not modify associations of EP substrate with SCD and nonSCD. EP substrate does not explain racial disparities in SCD rate.
Improved Alzheimer’s disease versus frontotemporal lobar degeneration differential diagnosis combining EEG and neurochemical biomarkers
Authors: Laton Jorne , Van Schependom Jeroen , Goossens Joery , Wiels Wietse , Sieben Anne , De Deyn Peter Paul , Goeman Johan , Streffer Johannes , van der Zee Julie , Martin Jean-Jacques , Van Broeckhoven Christine , De Vos Maarten , Bjerke Maria , Nagels Guy , Engelborghs Sebastiaan
Published: October 2019

Introduction

Distinguishing between two of the most common causes of dementia, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD), on clinical diagnostic criteria alone has poor diagnostic accuracy. Promising tools to increase the diagnostic accuracy of AD are the use of cerebrospinal fluid (CSF) biomarkers and electroencephalography (EEG), which is being investigated as a diagnostic tool for neurodegenerative brain disorders. In this study, we investigated the utility of EEG-based biomarkers in comparison and in addition to established neurochemical biomarkers in the AD versus FTLD differential diagnosis.

Methods

Our study cohort comprised 37 AD and 32 FTLD patients, of which 19 AD and 11 FTLD had definite diagnoses. All these participants had CSF biomarker analyses resulting in four neurochemical (NCM) biomarkers (Aβ1-42, T-tau, P-tau181 and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks (DFP) were extracted in four regions resulting in four dominant frequencies (in left-temporal, frontal, right-temporal and parieto-occipital regions). This yielded a total of eight features (4 NCM + 4 EEG), which we used to train and test a classifier and assess the diagnostic value of the markers separately (using only the NCM or EEG subset) and combined.

Results

The classification accuracies were much higher when training and testing on the definite subgroup than on the whole group. Furthermore, we found that the NCM feature subset allowed a better accuracy than the EEG feature subset, both when training and testing on the whole group (NCM 82% vs EEG 72%), as on the definite group only (92% vs 86%). Using both feature subsets together increased the accuracy to 86% in the whole group and 94% in the definite subgroups. Another interesting finding was the presence of two spectral peaks in a considerable number of patients in both groups.

Conclusion

Combining EEG with neurochemical biomarkers resulted in differential diagnostic accuracies of 86% in clinically diagnosed AD and FTD patients and of 94% in patients having a definite diagnosis. Furthermore, we found evidence that the slowing down of the dominant EEG rhythm might be a gradual appearance of a slow rhythm and fading out of the normal ground rhythm, rather than a gradual slowing down of the ground rhythm. Finally, we have discovered two differences in the occurrence of the dominant EEG frequency: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. These unexpected but interesting findings need to be explored further.
Point-of-care serodiagnostic test for early-stage Lyme disease using a multiplexed paper-based immunoassay and machine learning
Authors: Joung Hyou-Arm , Ballard Zachary S. , Wu Jing , Tseng Derek K. , Teshome Hailemariam , Zhang Linghao , Horn Elizabeth J , Arnaboldi Paul M. , Dattwyler Raymond J. , Garner Omai B. , Carlo Dino Di , Ozcan Aydogan
Published: October 2019

Caused by the tick-borne spirochete, Borrelia burgdorferi, Lyme disease (LD) is the most common vector-borne infectious disease in North America and Europe. Though timely diagnosis and treatment are effective in preventing disease progression, current tests are insensitive in early-stage LD, with a sensitivity <50%. Additionally, the serological testing currently recommended by the US Center for Disease Control has high costs (>$400/test) and extended sample-to-answer timelines (>24 hours). To address these challenges, we created a cost-effective and rapid point-of-care (POC) test for early-stage LD that assays for antibodies specific to seven Borrelia antigens and a synthetic peptide in a paper-based multiplexed vertical flow assay (xVFA). We trained a deep learning-based diagnostic algorithm to select an optimal subset of antigen/peptide targets, and then blindly-tested our xVFA using human samples (N(+) = 42, N(−)= 54), achieving an area-under-the-curve (AUC), sensitivity, and specificity of 0.950, 90.5%, and 87.0% respectively, outperforming previous LD POC tests. With batch-specific standardization and threshold tuning, the specificity of our blind-testing performance improved to 96.3%, with an AUC and sensitivity of 0.963 and 85.7%, respectively.
Randomized controlled trial combining constraint-induced movement therapy and action-observation training in unilateral cerebral palsy: clinical effects and influencing factors of treatment response
Authors: Simon-Martinez Cristina , Mailleux Lisa , Hoskens Jasmine , Ortibus Els , Jaspers Ellen , Wenderoth Nicole , Sgandurra Giuseppina , Cioni Giovanni , Molenaers Guy , Klingels Katrijn , Feys Hilde
Published: October 2019

Introduction

Constraint-induced movement therapy (CIMT) improves upper limb (UL) motor execution in unilateral cerebral palsy (uCP). As these children also show motor planning deficits, action-observation training (AOT) might be of additional value. Here, we investigated the combined effect of AOT to CIMT and identified factors influencing treatment response.

Methods

Forty-four children with uCP (mean 9y6m, SD 1y10m) participated in a 9-day camp wearing a splint for 6 hours/day and were allocated to the CIMT+AOT (n=22) and the CIMT+placebo group (n=22). The CIMT+AOT group received 15 hours of AOT (i.e. video-observation) and executed the observed tasks, whilst the CIMT+AOT group watched videos free of biological motion and executed the same tasks. The primary outcome measure was bimanual performance. Secondary outcomes included measures at body function and activity level assessed before (T1), after (T2) the intervention, and at 6 months follow-up (T3). Influencing factors included behavioural and neurological characteristics.

Results

Although no between-groups differences were found (p>0.05), the addition of AOT led to higher gains in children with initially poorer bimanual performance (p=0.02). Both groups improved in all outcome measures after the intervention and retained the gains at follow up (p<0.01). Poor sensory function resulted in larger improvements in the total group (p=0.03) and high amount of mirror movements tended to result in better response to the additional AOT training (p=0.06). Improvements were similar irrespective of the type of brain lesion or corticospinal tract wiring pattern.

Conclusions

Adding AOT to CIMT, resulted in better outcome for children with poor motor function and high amount of mirror movements. CIMT with or without AOT seems to be more beneficial for children with poor sensory function.

Trial registration

Registered at ClinicalTrials.gov on 22nd August 2017 (Identifier: NCT03256357).
Independent and Joint Associations of Sedentary Behavior and Physical Activity with Cardiometabolic Health Markers in the 1970 British Birth Cohort
Authors: Huang Bo-Huei , Hamer Mark , Chastin Sebastien , Koster Annemarie , Pearson Natalie , Stamatakis Emmanuel
Published: October 2019

Objective

To examine the independent and joint associations thigh-worn accelerometry assessed sedentary time and moderate to vigorous physical activity with cardiometabolic health markers.

Design

Cross-sectional study embedded in the age-46 wave an established birth cohort, the 1970 British Birth Cohort.

Setting

Population-based sample from Great Britain (England, Scotland, and Wales).

Methods

Outcome measures included: body mass index, waist-to-hip ratio, blood pressure, glycated hemoglobin, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and c-reactive protein. Sedentary behavior and other physical activity exposures, recorded by a thigh-worn activPAL3 accelerometry, included: daily sedentary time, breaks in sedentary time, daily time spent in moderate-to-vigorous physical activity. Multiple linear regression analyses, multiple logistic regression analyses, and general linear models were conducted as applicable.

Results

4,634 participants were available for the final analysis. After adjusting for potential confounders and moderate-to-vigorous physical activity, daily sedentary time was positively associated with triglycerides (β=0.052 [0.015, 0.089]) and inversely associated with high-density lipoprotein cholesterol (β=-0.015 [-0.022, -0.010]). Daily prolonged sedentary time (≥ 60 minutes) was positively associated with both glycated hemoglobin and log-transformed c-reactive protein (β=0.240 [0.030, 0.440] and 0.026 [0.007, 0.045], respectively) and inversely associated with systolic blood pressure and high-density lipoprotein cholesterol (β=-0.450 [-0.760, -0.150] and -0.013 [-0.022, -0.003], respectively). After adjusting for potential confounders and daily sedentary time, daily breaks in sedentary time were inversely associated with glycated hemoglobin (β=-0.020 [-0.037, -0.003]), and positively associated with both triglycerides and systolic blood pressure (β=0.006 [0.002, 0.010] and 0.030 [0.002, 0.050], respectively). The joint associations of prolonged sedentary time and moderate-to-vigorous physical activity with the prevalence of diabetes were not statistically significant.

Conclusion

Prolonged sedentary time (≥ 60 minutes) and daily breaks in sedentary time were deleteriously associated with glycated hemoglobin, although we found no evidence that there were joint moderate-to-vigorous physical activity and sitting associations.
Beware (surprisingly common) left-right flips in your MRI data: an efficient and robust method to check MRI dataset consistency using AFNI
Authors: Glen Daniel R. , Taylor Paul A. , Buchsbaum Bradley R. , Cox Robert W. , Reynolds Richard C.
Published: October 2019

Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets.
Sensory restoration by epidural stimulation of dorsal spinal cord in upper-limb amputees
Authors: Chandrasekaran Santosh , Nanivadekar Ameya C. , McKernan Gina P. , Helm Eric R. , Boninger Michael L. , Collinger Jennifer L. , Gaunt Robert A. , Fisher Lee E.
Published: October 2019

Restoring somatosensory feedback to people with limb amputations is crucial for improving prosthesis acceptance and function. Epidural spinal cord stimulation is a commonly used clinical procedure that targets sensory neural pathways in the dorsal spinal cord to treat pain conditions. A similar approach could be developed as a clinically translatable means to restore somatosensation in amputees. We show that epidural stimulation of the dorsal spinal cord evoked sensory percepts, perceived as emanating from the amputated arm and hand, in four people with upper-limb amputation. After an initial caudal movement immediately following the implantation, the leads stabilized, exhibiting a median migration of <5 mm (each electrode contact is 3 mm long) over the remainder of the study in all the subjects. This was reflected in the consistent locations of evoked percepts in the hand across four subjects throughout the period of implantation, which lasted up to 29 days. The median change in the centroid location was 1.2 to 35.3 mm and the median change in percept area was 0 to 40%. While most of the evoked percepts were paresthetic in nature, a subset was described as naturalistic (e.g. touch or pressure) in three subjects. Modulating the stimulus amplitude affected the perceived intensity of the sensation in all subjects. A variety of sensory percepts were evoked in all subjects irrespective of the level of amputation or the time since amputation, suggesting the approach is amenable to a diverse population of amputees.
COST-EFFECTIVENESS ANALYSIS FOR HPV MITIGATION STRATEGIES IMPLEMENTED IN 2018 IN THE REPUBLIC OF MOLDOVA BASED ON INFECTIOUS DISEASE MODELLING
Authors: Jarynowski Andrzej
Published: October 2019

Human papillomavirus (HPV), is a sexually transmittable virus infection, which is necessary risk factor for developing cervical cancer, first killer in working age women in Moldova. Since 2018 Moldova has modified screening program and vaccination program (mainly externally funded). To assess the performance of the mitigation policy we propose cost-effectiveness analysis according to 2 already implemented strategies. (1) Vaccination of a single age-cohort, although vaccinating a single cohort may not have a substantial effect in other countries with distinct socio-economic situation. (2) Transition to more technologically advance screening ecosystem (changing from Romanowski to Pap smear), which might not necessary be cost-efficient in low resource settings (if GDP per capita will not growth substantially at the same time).

We verified that single cohort vaccination is both cost-beneficial (total costs reduction will balance intervention costs around the year 2040) and cost-efficient (with incremental impact in 20 years perspective on the level of 2300 EUR/QALY). Moreover, we found out that single year cohort is more beneficial than 5-years cohort vaccination scenarios in our mathematical model. This behaviour could be explained by a transitional situation in Moldova (HPV epidemic is near outbreak threshold), still small changes of model parameters and initial conditions could cause strong effect in the epidemiology. However, a definitive answer cannot be given with the chosen methodology.

Transition between Romanowski -> Pap smear cytology in screening benefits unquestionably in epidemiology e.g. due to higher specificity. However, further maintenance and higher procedure costs could exceed treatment costs, hence intervention costs would gather unacceptable share in whole national limited resources dedicated to public health.
Attacks on genetic privacy via uploads to genealogical databases
Authors: Edge Michael D. , Coop Graham
Published: October 2019

Direct-to-consumer (DTC) genetics services are increasingly popular for genetic genealogy, with tens of millions of customers as of 2019. Several DTC genealogy services allow users to upload their own genetic datasets in order to search for genetic relatives. A user and a target person in the database are identified as genetic relatives if the user’s uploaded genome shares one or more sufficiently long segments in common with that of the target person—that is, if the two genomes share one or more long regions identical by state (IBS). IBS matches reveal some information about the genotypes of the target person, particularly if the chromosomal locations of IBS matches are shared with the uploader. Here, we describe several methods by which an adversary who wants to learn the genotypes of people in the database can do so by uploading multiple datasets. Depending on the methods used for IBS matching and the information about IBS segments returned to the user, substantial information about users’ genotypes can be revealed with a few hundred uploaded datasets. For example, using a method we call IBS tiling, we estimate that an adversary who uploads approximately 900 publicly available genomes could recover at least one allele at SNP sites across up to 82% of the genome of a median person of European ancestries. In databases that detect IBS segments using unphased genotypes, approximately 100 uploads of falsified datasets can reveal enough genetic information to allow accurate genome-wide imputation of every person in the database. Different DTC services use different methods for identifying and reporting IBS segments, leading to differences in vulnerability to the attacks we describe. We provide a proof-of-concept demonstration that the GEDmatch database in particular uses unphased genotypes to detect IBS and is vulnerable to genotypes being revealed by artificial datasets. We suggest simple-to-implement suggestions that will prevent the exploits we describe and discuss our results in light of recent trends in genetic privacy, including the recent use of uploads to DTC genetic genealogy services by law enforcement.
Composition dependent phase separation underlies directional flux through the nucleolus
Authors: Riback Joshua A. , Zhu Lian , Ferrolino Mylene C. , Tolbert Michele , Mitrea Diana M. , Sanders David W. , Wei Ming-Tzo , Kriwacki Richard W. , Brangwynne Clifford P.
Published: October 2019

Intracellular bodies such as nucleoli, Cajal bodies, and various signaling assemblies, represent membraneless organelles, or condensates, that form via liquid-liquid phase separation (LLPS)1,2. Biomolecular interactions, particularly homotypic interactions mediated by self-associating intrinsically disordered protein regions (IDRs), are thought to underlie the thermodynamic driving forces for LLPS, forming condensates that can facilitate the assembly and processing of biochemically active complexes, such as ribosomal subunits within the nucleolus. Simplified model systems3–6have led to the concept that a single fixed saturation concentration (Csat) is a defining feature of endogenous LLPS7–9, and has been suggested as a mechanism for intracellular concentration buffering2,7,8,10. However, the assumption of a fixed Csatremains largely untested within living cells, where the richly multicomponent nature of condensates could complicate this simple picture. Here we show that heterotypic multicomponent interactions dominate endogenous LLPS, and give rise to nucleoli and other condensates that do not exhibit a fixed Csat. As the concentration of individual components is varied, their partition coefficients change, in a manner that can be used to extract thermodynamic interaction energies, that we interpret within a framework we term polyphasic interaction thermodynamic analysis (PITA). We find that heterotypic interactions between protein and RNA components stabilize a variety of archetypal intracellular condensates, including the nucleolus, Cajal bodies, stress granules, and P bodies. These findings imply that the composition of condensates is finely tuned by the thermodynamics of the underlying biomolecular interaction network. In the context of RNA processing condensates such as the nucleolus, this stoichiometric self-tuning manifests in selective exclusion of fully-assembled RNP complexes, providing a thermodynamic basis for vectorial ribosomal RNA (rRNA) flux out of the nucleolus. The PITA methodology is conceptually straightforward and readily implemented, and it can be broadly utilized to extract thermodynamic parameters from microscopy images. These approaches pave the way for a deep understanding of the thermodynamics of multi-component intracellular phase behavior and its interplay with nonequilibrium activity characteristic of endogenous condensates.
Insights into the desert living skin microbiome: geography, soil depth, and crust type affect biocrust microbial communities and networks in Mojave Desert, USA
Authors: Pombubpa Nuttapon , Pietrasiak Nicole , De Ley Paul , Stajich Jason E
Published: October 2019

Biocrusts are the living skin of drylands, comprising diverse microbial communities that are essential to desert ecosystems. Although we have extensive knowledge on biocrust ecosystem function and what drives biodiversity in lichen and moss dominated biocrusts, much less is understood about the impacts of diversity among microbial communities. Moreover, most biocrust microbial composition studies have primarily focused on bacteria. We used amplicon-based metabarcode sequencing to explore composition of both fungal and bacterial communities in biocrusts. Specifically we tested how geography, soil depth, and crust type structured biocrust microbial communities or fungal-bacterial networks. Microbial communities were surveyed from biocrust surface and subsurface soils collected from Joshua Tree National Park, Granite Mountain, Kelso Dunes, and Cima volcanic flows located within the Mojave Desert, USA. Five biocrust types were examined: Light-algal, Cyano-lichen, Green-algal lichen, Smooth moss, and Rough moss crust types. We found the primary characteristics structuring biocrust microbial diversity were 1) geography, as central and southern Mojave sites displayed different community signatures, 2) presence of plant associated fungi (plant pathogens and wood saprotrophs), indicator, and endemic species were identified at each site, 3) soil depth patterns, as surface and subsurface microbial communities were distinctly structured, and 4) the crust type, which predicted distinct microbial compositions. Network analysis showed that Cyanobacteria and Dothideomycetes (Pleosporales) were the major hubs of overall biocrust microbial community. Such hierarchical spatial organization of biocrust communities and their associated biotic networks can have pronounced impacts to ecosystem functions. Our findings provide crucial insights for dryland restoration and sustainable management.
Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation
Authors: Thim-uam Arthid , Prabakaran Thaneas , Tansakul Mookmanee , Makjaroen Jiradej , Wongkongkathep Piriya , Chantaravisoot Naphat , Saethang Thammakorn , Leelahavanichkul Asada , Benjachat Thitima , Paludan Søren , Pisitkun Trairak , Pisitkun Prapaporn
Published: October 2019

SLE (systemic lupus erythematosus) is an autoimmune disease that causes chronic inflammation and leads to fatality if left untreated. Immune complex-mediated inflammation and type I IFN signaling pathways are one of the mechanisms initiating lupus disease. Signaling through stimulator of interferon genes (STING) leads to the production of type I IFN and inflammatory cytokines. However, the role of STING in lupus mouse models is controversy. Here we demonstrated the mechanisms of STING involving in SLE pathogenesis at the molecular level. The disruption of STING signaling rescued lupus disease inFcgr2b-deficient mice. STING activated DC facilitated T cell proliferation, which depended on intrinsic expression of STING on DC but not on T cells. Upon STING activation, LYN was recruited and co-localized with STING in bone marrow-derived dendritic cells (BMDC). STING signaling induced phosphorylated LYN and AKT. The inhibition of LYN prohibited STING-induced DC differentiation. Adoptive transfer of STING-activated BMDC into the FCGR2B and STING double-deficiency mice restored lupus phenotypes. These findings provide the proof of concept that inhibition of STING signaling is a promising therapeutic approach for SLE patients.
The brain of a nocturnal migratory insect, the Australian Bogong moth
Authors: Adden Andrea , Wibrand Sara , Pfeiffer Keram , Warrant Eric , Heinze Stanley
Published: October 2019

Every year, millions of Australian Bogong moths (Agrotis infusa) complete an astonishing journey: in spring, they migrate over 1000 km from their breeding grounds to the alpine regions of the Snowy Mountains, where they endure the hot summer in the cool climate of alpine caves. In autumn, the moths return to their breeding grounds, where they mate, lay eggs and die. These moths can use visual cues in combination with the geomagnetic field to guide their flight, but how these cues are processed and integrated in the brain to drive migratory behavior is unknown. To generate an access point for functional studies, we provide a detailed description of the Bogong moth’s brain. Based on immunohistochemical stainings against synapsin and serotonin (5HT), we describe the overall layout as well as the fine structure of all major neuropils, including the regions that have previously been implicated in compass-based navigation. The resulting average brain atlas consists of 3D reconstructions of 25 separate neuropils, comprising the most detailed account of a moth brain to date. Our results show that the Bogong moth brain follows the typical lepidopteran ground pattern, with no major specializations that can be attributed to their spectacular migratory lifestyle. These findings suggest that migratory behavior does not require widespread modifications of brain structure, but might be achievable via small adjustments of neural circuitry in key brain areas. Locating these subtle changes will be a challenging task for the future, for which our study provides an essential anatomical framework.
High-throughput, temporal and dose dependent, effect of vitamins and minerals on chondrogenesis
Authors: Dennis James E. , Splawn Taylor , Kean Thomas J.
Published: October 2019

Tissue engineered hyaline cartilage is plagued by poor mechanical properties largely due to inadequate type II collagen expression. Of note, commonly used defined chondrogenic media lack 14 vitamins and minerals, some of which are implicated in chondrogenesis. Type II collagen promoter-drivenGaussialuciferase was transfected into ATDC5 cells to create a chondrogenic cell with a secreted-reporter. The reporter cells were used in an aggregate-based chondrogenic culture model to develop a high-throughput analytic platform. This high-throughput platform was used to assess the effect of vitamins and minerals, alone and in combination with TGFβ1, on type II collagen expression. Significant combinatorial effects between vitamins, minerals and TGFβ1 in terms of type II collagen expression and metabolism were discovered. An ‘optimal’ continual supplement of copper and vitamin K in the presence of TGFβ1 gave a 2.5-fold increase in collagen expression over TGFβ1 supplemented media alone.

Current defined chondrogenic culture media lack several vitamins and minerals. Type II collagen is the quintessential marker of articular hyaline cartilage, and is commonly deficient in engineered tissue. A type II collagen promoter driven secreted luciferase construct has been transduced into ATDC5 cells and used to assess vitamin and mineral effects on chondrogenesis in a high-throughput format.
Network analyses implicate a role for PHYTOCHROME-mediated light signaling in the regulation of cuticle development in plant leaves
Authors: Qiao Pengfei , Bourgault Richard , Mohammadi Marc , Smith Laurie G. , Gore Michael A. , Molina Isabel , Scanlon Michael J.
Published: October 2019

Plant cuticles are composed of wax and cutin, and evolved in the land plants as a hydrophobic boundary that reduces water loss from the plant epidermis. The expanding maize adult leaf displays a dynamic, proximodistal gradient of cuticle development, from the leaf base to the tip. Laser microdissection RNA Sequencing (LM-RNAseq) was performed along this proximodistal gradient, and complementary network analyses identified potential regulators of cuticle biosynthesis and deposition. Correlations between cuticle development and cell wall biosynthesis processes were identified, as well as evidence of roles for auxin and brassinosteroids. In addition, our network analyses suggested a previously undescribed function for PHYTOCHROME-mediated light signaling during cuticular wax deposition. Genetic analyses reveal that the phyB1 phyB2 double mutant of maize exhibits abnormal cuticle composition, supporting predictions of our coexpression analyses. Reverse genetic analyses also show that phy mutants of the moss Physcomitrella patens exhibit abnormal cuticle composition, suggesting a role for light-stimulated development of cuticular waxes during plant evolution.
Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction
Authors: Gnan Stefano , Flyamer Ilya M. , Klein Kyle N. , Castelli Eleonora , Rapp Alexander , Maiser Andreas , Chen Naiming , Weber Patrick , Enervald Elin , Cardoso M. Cristina , Bickmore Wendy A. , Gilbert David M. , Buonomo Sara C. B.
Published: October 2019

Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing program and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. RIF1’s role in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing program and nuclear architecture.
A novel method to detect intracellular metabolite alterations in MCF-7 cells by doxorubicin induced cell death
Authors: Kumar Ajay , Patel Sheetal , Bhatkar Devyani , Sharma Nilesh Kumar
Published: October 2019

Metabolic reprogramming within cancer cells is suggested as a potential barrier to chemotherapy. Additionally, metabolic tumor heterogeneity is one of factor behind discernible hallmarks such as drug resistance, relapse of tumor and the formation of secondary tumors. In this paper, cell based assays including PI/annexin V staining and immunoblot assay were performed to show the apoptotic cell death in MCF-7 cells treated with DOX. Further, MCF-7 cells were lysed in hypotonic buffer and whole cell lysate was purified by a novel and specifically designed metabolite (100 to 1000 Da) fractionation system as vertical tube gel electrophoresis (VTGE). Further, purified intracellular metabolites were subjected to identification by LC-HRMS technique. The authors show the presence of cleaved PARP 1 in MCF-7 cells treated with DOX. Concomitantly, data show the absence of active caspase 3 in MCF-7 cells. Novel findings are to identify key intracellular metabolites assisted by VTGE system that include lipid (CDP-DG, phytosphingosine, dodecanamide), non-lipid (N-acetyl-D-glucosamine, N1-acetylspermidine and gamma-L-glutamyl-L-cysteine) and tripeptide metabolites in MCF-7 cells treated by DOX. Interestingly, the authors report a first evidence of doxorubicinone, an aglycone form of DOX in MCF-7 cells that is potentially linked to the mechanism of cell death in MCF-7 cells. This paper reports on novel methods and processes that involve VTGE system based purification of hypotonically lysed novel intracellular metabolites of MCF-7 cells treated by DOX. Here, these identified intracellular metabolites corroborate to caspase 3 independent and mitochondria induced apoptotic cell death in MCF-7 cells.

SIGNIFICANCE STATEMENT

Metabolic reprogramming in cancer cells is implicated in various tumor hallmarks. Interestingly, thousands of research have addressed the molecular basis of drug treatment and resistance in chemotherapy. But, there is a significant gap in the precise methodologies and approaches in addressing intracellular metabolite alterations. This paper reports on a novel approach that helped reveal new findings on intracellular metabolite changes in case of doxorubicin (DOX) induced cell death in MCF-7 cells. This paper highlights the additional insights on debatable findings available in literature in the contexts of DOX induced cell death mechanisms. In this paper, novel and specifically designed vertical tube gel electrophoresis (VTGE) system is claimed to purify intracellular metabolites and this method is compatible with other biological system.
Establishment of the trans-resveratrol-induced mouse pulmonary fibrosis model and its comparison with the bleomycin-induced model
Authors: Yiwen Chen , Chenzhong Zong , Chunrui Sheng , Hongsheng Chang , Shuyan Wang , Hongzhao Zhao , Shanshan Liu , qiaohui Zhang , Ruijuan Dong , Dongyu Ge , Xue Yu , Lina Li
Published: October 2019

Pulmonary fibrosis (PF) is a progressive, fatal disease, and its pathogenic mechanism has not yet been identified. The bleomycin (BLM)-induced animal model has several shortcomings that cannot be overcome. We accidentally found that the continuous oral administration of trans-resveratrol (TR) at levels above the prescribed dose can induce PF within a certain period of time, and this model can be successfully replicated in mice, as indicated by the hydroxyproline (HYP) test and pathological analysis. The TR model requires no anesthesia or surgery and thus causes less damage to mice than the BLM model. The progress of fibrosis in the TR model was slow but progressed steadily compared with the BLM model, and the TR model was more comparable to human PF. Although the pathogenesis is not understood, the TR-induced PF model indicated that there may be a close relationship between PF and tumors and antitumor drugs, which requires further exploration.
A novel toolkit for the efficient delivery of Cas9/sgRNA complexes to chromosomes in cells
Authors: Indikova Ivana , Indik Stanislav
Published: October 2019

Introductory paragraph

The application of gene editing technology is currently limited by the lack of safe and efficient methods to deliver RNA-guided endonucleases to target cells. We engineered lentivirus-based nanoparticles to copackage the U6-sgRNA template and the CRISPR-associated protein 9 (Cas9) fused with a virion-targeted protein Vpr (Vpr.Prot.Cas9), for simultaneous delivery to cells. In addition to Vpr, equal spatiotemporal control of thevpr.prot.cas9andgag/polgene expression of was required for efficient packaging of the fusion protein into virus particles. Transduction of the unconcentrated, Vpr.Prot.Cas9-containing vectors resulted in >98% disruption of theEGFPgene in reporter HEK293-EGFP cells with minimal cytotoxicity. Furthermore, we detected indels in the targeted endogenous loci at frequencies of up to 100% in cell lines derived from lymphocytes and monocytes and up to 15% in primary CD4+ T cells by high-throughput sequencing. This approach may provide a platform for the efficient, safe and selective delivery of genome editing enzymes to cells and it may be suitable for simultaneous gene disruption and transgene delivery.