bluuebunny/crossref_metadata_2025 huggingface dataset:
Psoriatic arthritis screening: a systematic review and meta-analysis
Authors: Iragorri Nicolas , Hazlewood Glen , Manns Braden , Danthurebandara Vishva , Spackman Eldon
Published: September 2018

Objective

To systematically review the accuracy and characteristics of different questionnaire-based PsA screening tools.

Methods

A systematic review of MEDLINE, Excerpta Medical Database, Cochrane Central Register of Controlled Trials and Web of Science was conducted to identify studies that evaluated the accuracy of self-administered PsA screening tools for patients with psoriasis. A bivariate meta-analysis was used to pool screening tool-specific accuracy estimates (sensitivity and specificity). Heterogeneity of the diagnostic odds ratio was evaluated through meta-regression. All full-text records were assessed for risk of bias with the QUADAS 2 tool.

Results

A total of 2280 references were identified and 130 records were assessed for full-text review, of which 42 were included for synthesis. Of these, 27 were included in quantitative syntheses. Of the records, 37% had an overall low risk of bias. Fourteen different screening tools and 104 separate accuracy estimates were identified. Pooled sensitivity and specificity estimates were calculated for the Psoriatic Arthritis Screening and Evaluation (cut-off = 44), Psoriatic Arthritis Screening and Evaluation (47), Toronto Psoriatic Arthritis Screening (8), Psoriasis Epidemiology Screening Tool (3) and Early Psoriatic Arthritis Screening Questionnaire (3). The Early Psoriatic Arthritis Screening Questionnaire reported the highest sensitivity and specificity (0.85 each). The I2 for the diagnostic odds ratios varied between 76 and 90.1%. Meta-regressions were conducted, in which the age, risk of bias for patient selection and the screening tool accounted for some of the observed heterogeneity.

Conclusions

Questionnaire-based tools have moderate accuracy to identify PsA among psoriasis patients. The Early Psoriatic Arthritis Screening Questionnaire appears to have slightly better accuracy compared with the Toronto Psoriatic Arthritis Screening, Psoriasis Epidemiology Screening Tool and Psoriatic Arthritis Screening and Evaluation. An economic evaluation could model the uncertainty and estimate the cost-effectiveness of PsA screening programs that use different tools.
Depo-Provera increases neural activity in the central amygdala of reindeer bulls
Authors: Ziegler R L , Austin K J , Blake J E , Rowell J E , Cupp A S , Shipka M P , Alexander B M
Published: September 2018

Reindeer bulls are difficult to manage and dangerous to handlers during the rutting period. Progesterone agonists have been used anecdotally in the field to favorably influence behavior, but effects on reproductive signaling have not been determined. The objective of this study was to determine the effects of Depo-Provera (medroxyprogesterone acetate) on neural activity in the amygdala of reindeer bulls in the early (n = 4) and full (n = 4) rut. Treated bulls (n = 4) were injected with a single injection of Depo-Provera (400 mg i.m.) approximately 2 wk before rut was initiated. Control bulls were untreated. Bulls were exsanguinated and brains collected. Neural activity in the amygdala was determined using c-fos immunohistochemistry. Neural activity did not differ by treatment (P ≥ 0.5), collection period (P ≥ 0.5), or their interaction (P ≥ 0.3) in the medial and cortical amygdala nuclei. A treatment × time interaction (P = 0.009) was observed in the central amygdala. The amygdala nuclei are interconnected allowing for integration of sensory stimuli with a direct connection between the medial amygdala and the olfactory bulb. The central amygdala is responsible for alerting, fear, and initiating a state of arousal towards nonspecific stimuli in the surrounding environment. In wildlife, the central amygdala has a role in recognizing threats in the environment such as predators. During the rut, bulls normally have a decreased sense of fear and elevated aggressive behavior with Depo-Provera treatment seemly able to diminish that aggression. Although it is unlikely that this observed change in neural activity fully explains the decreased aggressive behavior noted in bulls treated with Depo-Provera, neural networks of aggression include the amygdala. It is possible that further changes in c-fos activity will be noted in other areas of the brain known to be necessary for processing social cues. Bulls treated with Depo-Provera maintain sexual interest and have offspring. Depo-Prevera increases the neural activity within the central amygdala and may partially account for their altered aggressive behavior during the rut.
Impact of 24-h feed or water, or both, deprivation on feed intake, metabolic, and inflammatory response in beef heifers
Authors: Rett B , Marques R S , Brandão A P , de Sousa O A , Schumaher T F , Cooke R F , Bohnert D W
Published: September 2018

This experiment evaluated the effects of 24-h feed or water, or both, restriction on hay intake, metabolic, and inflammatory response in growing beef heifers. Forty Angus × Hereford heifers were ranked by initial body weight (BW) (275 ± 6 kg) and age (278 ± 6 d) and randomly allocated to 20 drylot pens (two heifers per pen) in 5, consecutively run, 4 × 4 Latin squares containing four periods of 17 d each. From days 5 to 0 of each period, all pens were offered alfalfa-grass hay ad libitum plus 454 g of dried distillers’ grains with solubles (as-fed basis) per heifer/d. On day 0 of each period, pens received one of the four treatments: 1) feed and water restriction for 24 h (FWR), 2) feed restriction for 24 h (FR), 3) water restriction for 24 h (WR), or 4) full access to feed and water (CON). Treatments were concurrently applied from days 0 to 1. Heifer full BW was collected for two consecutive days (days 6 and 5), before (day 0) and after (day 1) treatment application, and on days 3, 6, and 10 of each period. Hay dry matter intake was recorded daily from days 5 to 10. Blood was collected on days 5, 0, 1, 3, 6, and 10 of each experimental period. Following treatment on day 1, BW loss was greater, and heifer BW was less (P < 0.01), for WR, FWR, and FR compared with CON, whereas similar (P > 0.13) for BW loss and heifer BW among heifers that received nutrient restriction. No treatment effects were detected (P = 0.88) for overall ADG. Plasma cortisol concentration was greater (P < 0.01) in FR and FWR vs. WR and CON on day 1, and similar (P = 0.46) between CON and WR. Serum NEFA concentration was greater (P < 0.01) in FR and FWR vs. WR and CON on day 1, and also greater (P < 0.01) in WR vs. CON heifers on day 1. No treatment effects were detected (P = 0.53) for plasma haptoglobin concentration. Hence, feed or water, or both, restriction for 24 h did not affect hay intake and ADG, whereas metabolic results suggest that nutrient deprivation is the major contributor to the increased cortisol and NEFA response of growing beef heifers.
Time of rumen fluid collection relative to feeding alters in vitro fermentation gas parameters
Authors: Brewster A N , Pless L A , McLean D J , Armstrong S A
Published: September 2018

The objective of this study was to determine the effect of time of rumen fluid collection relative to feeding on gas production kinetics for in vitro rumen fermentation. Three ruminally cannulated Holstein heifers were rumen fluid donors. Feed was removed from heifers 12 h prior to feeding, rumen fluid was collected from each heifer before feeding (0 h), and at 2, 4, and 6 h after feeding, repeated on three separate incubation days. Buffered rumen fluid (100 mL) was incubated in 250-mL bottles containing 1.4 g of dried TMR, in duplicate for each heifer at each collection time. All bottles were incubated for 24 h at 39°C and constant agitation (60 rpm), and capped with monitors to capture temperature and pressure every 15 min (RF1, Ankom Technology, Macedon, NY). At the end of incubation, final pH was recorded. Gas data were fit with nonlinear regression comparison of fit in GraphPad Prism 7 to find best fit regression. The formula with best fit was as follows: y = Vm(1 − (e(−Kd(x − lag)))), where y is gas produced at time X (mmol), Vm is the asymptotic gas production (mmol), Kd indicates the fractional rate of gas production (mmol/h), X is time (h), and lag refers to the lag time before the start of fermentation (h) as indicated by positive gas production (R2 = 0.98). Data were analyzed using PROC GLIMMIX of SAS, with donor as the experimental unit and day as the random blocking factor; significance is defined as P ≤ 0.05. Time of rumen fluid collection significantly affected gas production kinetics (lag P = 0.01, VmP = 0.03, KdP <0.0001). Gas production was highest in fermenter units fed with rumen fluid collected 2-h post-feeding. Fractional rate of fermentation (Kd) was fastest in rumen fluid collected at 0 h. Lag time was longest in rumen fluid collected at 4-h post-feeding and slowest in rumen fluid collected at 0 h. Time of rumen fluid collection did not alter final pH. Our findings suggest that gas production is maximized when rumen fluid is collected between 2 and 4 h after feeding.
Time of rumen fluid collection relative to feeding alters in vitro fermentation volatile fatty acid production
Authors: Pless L A , Brewster A N , McLean D J , Armstrong S A
Published: September 2018

The objective of this study was to determine the effect of time of rumen fluid collection relative to feeding on volatile fatty acid (VFA) production for in vitro rumen fermentation. Three ruminally cannulated Holstein heifers were used as rumen fluid donors. Feed was removed from heifers 12 h prior to feeding, rumen fluid was collected from each heifer before feeding (0 h), and at 2, 4, and 6 h after feeding, repeated on three separate incubation days. Buffered rumen fluid (100 mL) was incubated in 250-mL bottles containing 1.4 g of dried TMR, in duplicate for each heifer at each collection time. All bottles were incubated for 24 h at 39°C and constant agitation (60 rpm), and capped with monitors to capture temperature and pressure every 15 min (RF1, Ankom Technology, Macedon, NY). At the end of incubation, final pH and a sample of rumen fluid were collected for VFA and ammonia nitrogen. Data were analyzed using PROC GLIMMIX of SAS, with donor as the experimental unit and day as the random blocking factor; significance is defined as P ≤ 0.05. Time of rumen fluid collection significantly affected acetate (mmol/liter; P = 0.0004), propionate (mmol/liter; P = 0.02), isobutyrate (mmol/liter; P < 0.0001), valerate (mmol/liter; P = 0.004), isovalerate (mmol/liter; P < 0.00001), and total VFA concentrations (mmol/liter; P = 0.004). All VFA relative proportions were altered due to time of rumen fluid collection (P < 0.02). VFA production was highest when rumen fluid was collected 4-h post-feeding. There was little to no effect on pH. Our findings suggest that VFA production is maximized when rumen fluid is collected between 2 and 4 h after feeding.
Molecular Mapping of a Recessive Powdery Mildew Resistance Gene in Wheat Cultivar Tian Xuan 45 Using Bulked Segregant Analysis with Polymorphic Single Nucleotide Polymorphism Relative Ratio Distribution
Authors: Chao Kaixiang , Su Wenwen , Wu Lei , Su Bei , Li Qiang , Wang Baotong , Ma Dongfang
Published: September 2018

Powdery mildew is a destructive foliar disease of wheat worldwide. Wheat cultivar Tian Xuan 45 exhibits resistance to the highly virulent isolate HY5. Genetic analysis of the F2 and F2:3 populations of a cultivar Ming Xian 169/Tian Xuan 45 cross revealed that the resistance to HY5 was controlled by a single recessive gene, temporarily designated as PmTx45. A Manhattan plot with the relative frequency distribution of single nucleotide polymorphisms (SNPs) was used to rapidly narrow down the possible chromosomal regions of the associated genes. This microarray-based bulked segregant analysis (BSA) largely improved traditional analytical methods. PmTx45 was located in chromosomal bin 4BL5-0.86-1.00 and was flanked by SNP marker AX-110673642 and intron length polymorphism (ILP) marker ILP-4B01G269900 with genetic distances of 3.0 and 2.6 cM, respectively. Molecular detection in a panel of wheat cultivars using the markers linked to PmTx45 showed that the presence of PmTx45 in commercial wheat cultivars was rare. Resistance spectrum and chromosomal position analyses indicated that PmTx45 may be a novel recessive gene with moderate powdery mildew resistance. This new microarray-based BSA method is feasible and effective and has the potential application for mapping genes in wheat in marker-assisted breeding.
Surgical Technique for Closed Reduction and Percutaneous Pinning of Pediatric Lateral Humeral Condyle Fractures
Authors: Prusick Vincent W. , Dantzker Nicholas J. , Hysong Alexander A. , Johnson Megan , Mencio Gregory A. , Stutz Christopher M. , Schoenecker Jonathan G.
Published: September 2018

Lateral condyle fractures are intra-articular injuries of the distal humerus and are the second most common elbow fracture in pediatric patients. When these fractures involve significant displacement, anatomic reduction of the lateral condyle fragment is commonly achieved using open reduction techniques. Although a technique for closed reduction of lateral condyle fractures has been proposed in the literature, an instructional, step-by-step description of such a technique has yet to be published. We have built upon the previously published closed reduction technique by focusing on the pathomechanism of injury, with the goal of making successful closed reduction more reliably reproducible across treating surgeons. Specifically, this article provides step-by-step descriptions of the proposed mechanism of injury, reduction technique, pinning technique, arthrogram/casting technique, and suggested follow-up for pediatric patients with lateral humeral condyle fractures.
Use of a 3D-Printed Custom Reverse Shoulder Arthroplasty
Authors: De Boer Friso A. , Huijsmans Pol E.
Published: September 2018

Reverse shoulder arthroplasty is an established treatment for rotator cuff tear arthropathy of the shoulder. In cases of deformity of the glenoid with limited bone stock, implantation of a noncustomized glenoid implant could be challenging. In this technique article, we report 2 cases with severe glenoid deformity. The first case is a 74-year-old woman presenting with rotator cuff tear arthropathy of the shoulder with a severly deformed glenoid. The second case is a 63-year-old woman with deformity of the glenoid after hemiarthroplasty of the shoulder. Both patients were succesfully treated with a 3D-printed customized glenoid implant, combined with a noncustom glenosphere and humeral stem.
Dynamic Prediction of Survival in Cystic Fibrosis
Authors: Keogh Ruth H. , Seaman Shaun R. , Barrett Jessica K. , Taylor-Robinson David , Szczesniak Rhonda
Published: September 2018

Background:

Cystic fibrosis (CF) is an inherited, chronic, progressive condition affecting around 10,000 individuals in the United Kingdom and over 70,000 worldwide. Survival in CF has improved considerably over recent decades, and it is important to provide up-to-date information on patient prognosis.

Methods:

The UK Cystic Fibrosis Registry is a secure centralized database, which collects annual data on almost all CF patients in the United Kingdom. Data from 43,592 annual records from 2005 to 2015 on 6181 individuals were used to develop a dynamic survival prediction model that provides personalized estimates of survival probabilities given a patient’s current health status using 16 predictors. We developed the model using the landmarking approach, giving predicted survival curves up to 10 years from 18 to 50 years of age. We compared several models using cross-validation.

Results:

The final model has good discrimination (C-indexes: 0.873, 0.843, and 0.804 for 2-, 5-, and 10-year survival prediction) and low prediction error (Brier scores: 0.036, 0.076, and 0.133). It identifies individuals at low and high risk of short- and long-term mortality based on their current status. For patients 20 years of age during 2013–2015, for example, over 80% had a greater than 95% probability of 2-year survival and 40% were predicted to survive 10 years or more.

Conclusions:

Dynamic personalized prediction models can guide treatment decisions and provide personalized information for patients. Our application illustrates the utility of the landmarking approach for making the best use of longitudinal and survival data and shows how models can be defined and compared in terms of predictive performance.
Countering Unprofessional Behaviors Among Nurses in the Workplace
Authors: Filipova Anna A.
Published: September 2018

OBJECTIVE:

This study investigates the association of authentic leadership (AL) and perceived organizational support to workplace bullying among a sample of licensed practical nurses (LPNs).

BACKGROUND:

Workplace bullying is a serious problem in the workplace that harms nurses' physical and psychological well-being.

METHODS:

A cross-sectional survey design was implemented. A simple random sample of 855 was drawn from a population of 4306 LPNs in a single US Midwestern state. A total of 168 usable questionnaires were returned (19.65% response rate).

RESULTS:

Forty-three percent of nurses experienced at least 2 negative behaviors on a weekly/daily basis; 12% self-identified as a victim. The moral component of AL was a major determinant of overall workplace bullying (β = −.59), person-related bullying (β = −.70), and physical intimidation (β = −.58). Perceived support was a major determinant of work-related bullying (β = −.40).

CONCLUSIONS:

Organizational support initiatives and AL training for nurse leaders should be considered to reduce bullying.
Leadership Practices and Engagement Among Magnet® Hospital Chief Nursing Officers
Authors: Prado-Inzerillo MariLou , Clavelle Joanne T. , Fitzpatrick Joyce J.
Published: September 2018

OBJECTIVE

Describe the relationship between leadership practices and engagement of chief nursing officers (CNOs) in Magnet® organizations.

BACKGROUND

Transformational leadership practices and CNO engagement are vital in influencing nursing practice.

METHODS

Magnet hospital CNOs were invited to participate in a quantitative descriptive study via an online survey published in 2 newsletters.

RESULTS

The CNOs rated their leadership practices high across all dimensions; the top leadership practice of Magnet CNOs was enabling others to act. There was a strong positive correlation between the vigor of engagement and the challenge the process leadership practice.

CONCLUSION

This is the 1st study of Magnet CNOs transformational leadership practices and their work engagement and therefore adds to our understanding of the important characteristics to build future leadership development programs for nurse leaders at the executive level. Particularly noteworthy for the development of future nurse executives is the strong link between vigor and challenging the process.
Effects of Twitch Contraction Induced by Magnetic Stimulation on Expression of Skeletal Muscle Fibrosis Related Genes and Limited Range of Motion in Rats
Authors: Kubo Kiyoko , Sakamoto Junya , Honda Ayana , Honda Yuichiro , Kataoka Hideki , Nakano Jiro , Okita Minoru
Published: September 2018

Objective

We examined the effects of twitch contraction induced by lumbar spinal root magnetic stimulation on immobilization-induced limited range of motion and skeletal muscle fibrosis in rat soleus muscle.

Design

The groups included male Wistar rats (controls), rats with both bilateral ankle joints immobilized with plaster casts for 4 wks (immobilization [IM]), and rats in which twitch contraction of the soleus muscle was induced by lumbar magnetic stimulation for 4 wks of immobilization (twitch contraction [TC]). Group differences in ankle dorsiflexion range of motion, collagen content as determined by hydroxyproline assay, and the expression of fibrosis-related genes as determined by reverse transcription-polymerase chain reaction (hypoxia inducible factor 1α, α-smooth muscle actin, and types I and III collagen) in the soleus muscle were examined after the 4-wk-long experiment.

Results

Range of motion in the TC group was significantly greater than that in the IM group. The hydroxyproline content and the expressions of fibrosis-related genes decreased significantly in the TC group compared with those in the IM group. No significant differences were seen in the expression of transforming growth factor β mRNA.

Conclusions

These results suggest that twitch contraction induced by lumbar spinal root magnetic stimulation may reduce immobilization-induced limited range of motion and skeletal muscle fibrosis.
State of the States: Growing Physiatry
Authors: Perret Danielle , Sunico Rachel , Knowlton Tiffany , Kezar Laura , Worsowicz Gregory , Whyte John
Published: September 2018

The growth of physiatry in the United States is dependent on academic exposure at both the undergraduate and graduate medical education levels. Undergraduate medical education provides students with knowledge of physiatry, as well as proper understanding of human function, medical rehabilitation treatments, and of physiatrists as consultants. Graduate medical education contributes more directly to the total number of practicing physiatrists. This article presents disparities in medical student exposure to physiatry, physical medicine and rehabilitation residency positions, the number of practicing physiatrists, and physical medicine and rehabilitation–relevant patient care needs, by state. In the model, these disparities are highlighted to provide guidance and expose gaps/opportunities for targeted physiatric growth.
Motor Control Training Compared With Transcutaneous Electrical Nerve Stimulation in Patients With Disc Herniation With Associated Radiculopathy
Authors: França Fábio Jorge Renovato , Callegari Bianca , Ramos Luiz Armando Vidal , Burke Thomaz Nogueira , Magalhães Maurício Oliveira , Comachio Josielli , CarvalhoSilva Ana Paula Moura Campos , Almeida Gabriel Peixoto Leão , Marques Amélia Pasqual
Published: September 2018

Objective

The aim of the study was to compare the effectiveness of motor control training and transcutaneous electrical nerve stimulation in relieving pain, reducing functional disability, and improving transversus abdominis activation in patients with lumbar disc herniation with associated radiculopathy.

Design

This is a randomized controlled trial.

Methods

Forty patients diagnosed with lumbar disc herniation were randomly divided into two groups: motor control training group (n = 20) and transcutaneous electrical nerve stimulation group (n = 20).

Interventions

The motor control training group and transcutaneous electrical nerve stimulation group attended 60 mini sessions twice a week for 8 wks, totaling to 16 sessions.

Main Outcome Measures

The main outcome measures are pain, functional disability, and transversus abdominis activation capacity.

Results

Differences between both groups were observed after 8 wks, favoring the motor control training group. Motor control training was more effective than transcutaneous electrical nerve stimulation in relieving pain (mean difference = 3.3 points, 95% confidence interval = 2.12–4.48), reducing functional disability (mean difference = 8.4 points, 95% confidence interval = 5.44–11.36), improving the quality of pain (mean difference = 17 points, 95% confidence interval = 7.93–26.07), sensory quality of pain (mean difference = 10.3 points, 95% confidence interval = 5.55–15.05), and transversus abdominis activation (mean difference = 1.5 points, 95% confidence interval = 0.90–2.10).

Conclusions

The results suggest that motor control training is more effective than transcutaneous electrical nerve stimulation with respect to relieving pain, reducing functional disability, and improving transversus abdominis activation in patients with lumbar disc herniation.
The Effect of Abdominal Massage on Constipation in the Elderly Residing in Rest Homes
Authors: Çevik Kıvan , Çetinkaya Aynur , Yiğit Gökbel Kübra , Menekşe Başak , Saza Saadet , Tıkız Canan
Published: September 2018

Constipation is a health problem commonly seen in the elderly. In the present study, the effect of abdominal massage on constipation in the elderly was examined. The study sample consisted of 22 elderly people residing in a nursing home in the province of Manisa who were suffering from constipation in June 2014 to February 2015. The following were used to collect data: a case identification form; the Rome III Functional Constipation Diagnosis Criteria Form; the Bristol Stool Scale, consisting of the Recall Bias and Visual Scale Analog; and the Standard Diary Constipation Monitoring Form. The comparison of the mean scores obtained before, during, and after the implementation of abdominal massage in the elderly revealed that the number of bowel movements, stool weight, and stool consistency scores increased during and after the implementation. The differences between the mean intra- and postimplementation scores in terms of stool weight and between the pre- and postimplementation mean scores in terms of stool consistency were not statistically significant. There was a statistically significant difference between straining scores except for those obtained during intra- and postimplementation application. It was determined that abdominal massage increased the number of bowel movements, stool weight, and stool consistency, decreased the mean scores for straining, and decreased inability to completely empty the bowels (except on the implementation days).
Mastocytosis
Authors: Birn Cathy S.
Published: September 2018

Mastocytosis is a rare and underdiagnosed disorder characterized by mast cell proliferation in the tissues and organs of the body. The gastrointestinal manifestations of the disease can be noted in approximately 70%–80% of those patients diagnosed with the disorder. Symptomatic manifestations of systemic mastocytosis can either be triggered spontaneously or be precipitated by a variety of situations, stimuli, and exposures. Common gastrointestinal complaints include abdominal pain, diarrhea, nausea, vomiting, and gastrointestinal reflux disease. Substantial numbers of mast cells have been noted in patients who have been diagnosed with gastritis, ulcerative colitis, and Crohn disease. Irreversible, with symptoms that run the gamut from the merely annoying to the severely life-threatening, mastocytosis is a disease that prevents an individual from leading a normal life. As the prevalence of gastrointestinal symptomatology in those patients who have been diagnosed with mastocytosis is so significant, it is an important and relevant disease of which gastroenterology nurses should be cognizant.
Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping
Authors: Kikuchi Masataka , Hara Norikazu , Hasegawa Mai , Miyashita Akinori , Kuwano Ryozo , Ikeuchi Takeshi , Nakaya Akihiro
Published: September 2018

Background:

Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer’s disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops.

Results:

We examined enhancer locations that were predicted in 127 human tissues or cell types, including ten brain tissues, and identified chromatin-chromatin interactions by Hi-C experiments. We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes.

Conclusion:

Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.
Directed Nucleosome Sliding in SV40 Minichromosomes During the Formation of the Virus Particle Exposes DNA Sequences Required for Early Transcription
Authors: Kumar Meera Ajeet , Kasti Karine , Balakrishnan Lata , Milavetz Barry
Published: September 2018

Simian Virus 40 (SV40) exists as chromatin throughout its life cycle, and undergoes typical epigenetic regulation mediated by changes in nucleosome location and associated histone modifications. In order to investigate the role of epigenetic regulation during the encapsidation of late stage minichromosomes into virions, we have mapped the location of nucleosomes containing acetylated or methylated lysines in the histone tails of H3 and H4 present in the chromatin from 48-hour post-infection minichromosomes and disrupted virions. In minichromosomes obtained late in infection, nucleosomes were found carrying various histone modifications primarily in the regulatory region with a major nucleosome located within the enhancer and other nucleosomes at the early and late transcriptional start sites. The nucleosome found in the enhancer would be expected to repress early transcription by blocking access to part of the SP1 binding sites and the left side of the enhancer in late stage minichromosomes while also allowing late transcription. In chromatin from virions, the principal nucleosome located in the enhancer was shifted ~ 70 bases in the late direction from what was found in minichromosomes and the level of modified histones was increased throughout the genome. The shifting of the enhancer-associated nucleosome to the late side would effectively serve as a switch to relieve the repression of early transcription found in late minichromosomes while likely also repressing late transcription by blocking access to necessary regulatory sequences. This epigenetic switch appeared to occur during the final stage of virion formation.
High-Throughput ChIPmentation: freely scalable, single day ChIPseq data generation from very low cell-numbers
Authors: Gustafsson Charlotte , Paepe Ayla De , Schmidl Christian , Månsson Robert
Published: September 2018

Chromatin immunoprecipitation coupled to sequencing (ChIP-seq) is widely used to map histone modifications and transcription factor binding on a genome-wide level. Here, we present high-throughput ChIPmentation (HT-ChIPmentation) that eliminates the need for DNA purification prior to library amplification and reduces reverse-crosslinking time from hours to minutes. The resulting workflow is easily established, extremely rapid, and compatible with requirements for very low numbers of FACS sorted cells, high-throughput applications and single day data generation.
Towards inferring causal gene regulatory networks from single cell expression Measurements
Authors: Qiu Xiaojie , Rahimzamani Arman , Wang Li , Mao Qi , Durham Timothy , McFaline-Figueroa José L , Saunders Lauren , Trapnell Cole , Kannan Sreeram
Published: September 2018

Single-cell transcriptome sequencing now routinely samples thousands of cells, potentially providing enough data to reconstruct causal gene regulatory networks from observational data. Here, we present Scribe, a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs Restricted Directed Information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. We apply Scribe and other leading approaches for causal network reconstruction to several types of single-cell measurements and show that there is a dramatic drop in performance for "pseudotime” ordered single-cell data compared to true time series data. We demonstrate that performing causal inference requires temporal coupling between measurements. We show that methods such as “RNA velocity” restore some degree of coupling through an analysis of chromaffin cell fate commitment. These analyses therefore highlight an important shortcoming in experimental and computational methods for analyzing gene regulation at single-cell resolution and point the way towards overcoming it.
Verifying, Challenging, and Discovering New Synapses among Fully EM-Reconstructed Neurons in the Leech Ganglion
Authors: Pipkin Jason E. , Bushong Eric A. , Ellisman Mark H. , Kristan William B.
Published: September 2018

Neural circuits underpin the production of animal behavior, largely based upon the precise pattern of synaptic connectivity among the neurons involved. For large numbers of neurons, determining such “connectomes” by direct physiological means is difficult, as physiological accessibility is ultimately required to verify and characterize the function of synapses. We collected a volume of images spanning an entire ganglion of the juvenile leech nervous system via serial blockface electron microscopy (SBEM). We validated this approach by reconstructing a well-characterized circuit of motor neurons involved in the swimming behavior of the leech by locating the synapses among them. We confirm that there are multiple synaptic contacts between connected pairs of neurons in the leech, and that these synapses are widely distributed across the region of neuropil in which the neurons’ arbors overlap. We verified the anatomical existence of connections that had been described physiologically among longitudinal muscle motor neurons. We also found that some physiological connections were not present anatomically. We then drew upon the SBEM dataset to design additional physiological experiments. We reconstructed an uncharacterized neuron and one of its presynaptic partners identified from the SBEM dataset. We subsequently interrogated this cell pair via intracellular electrophysiology in an adult ganglion and found that the anatomically-discovered synapse was also functional physiologically. Our findings demonstrate the value of combining a connectomics approach with electrophysiology in the leech nervous system.

Significance Statement

The function of any nervous system depends on the arrangement of its component neurons into circuits. Determining this precise pattern requires an account of which neurons are linked by synapses, and where. Here we use serial electron microscopy to confirm, challenge, and discover synapses in the neuropil of one ganglion from a juvenile leech. Relying on the homology of the ganglion from animal to animal, we demonstrate that we can identify synapses we knew existed from previous physiological work, and that we can confirm a new anatomically-discovered synapse by subsequently recording from the same neurons in a different animal. Here we show how analyses of anatomical detail and physiologically determined interactions complementarily yield insight into how neural circuits produce behavior.
AIM-SNPtag: a computationally efficient approach for developing ancestry-informative SNP panels
Authors: Zhao Shilei , Shi Cheng-Min , Ma Liang , Liu Qi , Liu Yongming , Wu Fuquan , Chi Lianjiang , Chen Hua
Published: September 2018

Inferring an individual’s ancestry or group membership using a small set of highly informative genetic markers is very useful in forensic and medical genetics. However, given the huge amount of SNP data available from a diverse of populations, it is challenging to develop informative panels by exhaustively searching for all possible SNP combination. In this study, we formulate it as an algorithm problem of selecting an optimal set of SNPs that maximizes the inference accuracy while minimizes the set size. Built on this conception, we develop a computational approach that is capable of constructing ancestry informative panels from multi-population genome-wide SNP data efficiently. We evaluate the performance of the method by comparing the panel size and membership inference accuracy of the constructed SNP panels to panels selected through empirical procedures in former studies. For the membership inference of population groups including Asian, European, African, East Asian and Southeast Asian, a 36-SNP panel developed by our approach has an overall accuracy of 99.07%, and a 21-SNP subset of the panel has an overall accuracy of 95.36%. In comparison, the existing panel requires 74 SNPs to achieve an accuracy of 94.14% on the same set of population groups. We further apply the method to four subpopulations within Europe (Finnish, British, Spain and Italia); a 175-SNP panel can discriminate individuals of those European subpopulations with an accuracy of 99.36%, of which a 68-SNP subset can achieve an accuracy of 95.07%. We expect our method to be a useful tool for constructing ancestry informative markers in forensic genetics.
Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning
Authors: Li Dong , Zavaglia Melissa , Wang Guangyu , Hu Yi , Xie Hong , Werner Rene , Guan Ji-Song , Hilgetag Claus C.
Published: September 2018

The laminar organization of the cerebral cortex is a fundamental characteristic of the brain, with essential implications for cortical function. Due to the rapidly growing amount of high-resolution brain imaging data, a great demand arises for automated and flexible methods for discriminating the laminar texture of the cortex. Here, we propose a combined approach of unsupervised and supervised machine learning to discriminate the hierarchical cortical laminar organization in high-resolution 2-photon microscopic neural image data without observer bias, that is, without the prerequisite of manually labeled training data. For local cortical foci, we modify an unsupervised clustering approach to identify and represent the laminar cortical structure. Subsequently, supervised machine learning is applied to transfer the resulting layer labels across different locations and image data, to ensure the existence of a consistent layer label system. By using neurobiologically meaningful features, the discrimination results are shown to be consistent with the layer classification of the classical Brodmann scheme, and provide additional insight into the structure of the cerebral cortex and its hierarchical organization. Thus, our work paves a new way for studying the anatomical organization of the cerebral cortex, and potentially its functional organization.
Niche maintenance of germline stem cells inC. elegansmales
Authors: Crittenden Sarah L. , Lee ChangHwan , Mohanty Ipsita , Battula Sindhu , Kimble Judith
Published: September 2018

Stem cell maintenance by niche signaling is a common theme across phylogeny. In theCaenorhabditis elegansgonad, the broad outlines of germline stem cell (GSC) regulation are the same for both sexes: GLP-1/Notch signaling from the mesenchymal Distal Tip Cell (DTC) niche maintains GSCs in the distal gonad of both sexes (Austin andKimble1987), and does so via two key stem cell regulators, SYGL-1 and LST-1 (Kershneret al. 2014). Most analyses of niche signaling and GSC regulation have focused on XX hermaphrodites, an essentially female sex making sperm in larvae and oocytes in adults. Here we focus on XO males, which are sexually dimorphic in all tissues, including the distal gonad. The architecture of the male niche and the cellular behavior of GSCs are sex-specific. Despite these differences, males maintain a GSC pool similar to the hermaphrodite with respect to size and cell number and the male GSC response to niche signaling is also remarkably similar.
Mathematical Models for the Influence of Cytarabine on White Blood Cell Dynamics in Acute Myeloid Leukemia
Authors: Jost Felix , Schalk Enrico , Rinke Kristine , Fischer Thomas , Sager Sebastian
Published: September 2018

We investigate the personalisation and prediction accuracy of mathematical models for white blood cell (WBC) count dynamics during consolidation treatment using intermediate or high-dose cytarabine (Ara-C) in acute myeloid leukemia (AML). Ara-C is the clinically most relevant cytotoxic agent for AML treatment.

We extend the gold-standard model of myelosuppression and a pharmacokinetic model of Ara-C with different hypotheses of Ara-C’s pharmacodynamic effects. We cross-validate 12 mathematical models using dense WBC count measurements from 23 AML patients. Surprisingly, the prediction accuracies are similarly good despite different modelling hypotheses. Therefore, we compare average clinical and calculated WBC recovery times for different Ara-C schedules as a successful methodology for model discrimination. As a result, a new hypothesis of a secondary pharmacodynamic effect on the proliferation rate seems plausible. Furthermore, we demonstrate how personalized predictions of the impact of treatment timing on subsequent nadir values could be used for clinical decision support.

Author summary

The major obstacle in accurately predicting the outcome of a medical therapy is the vast variation in individual response patterns. It concerns both the subjective experience of the patient and the objectively measurable achievement of a clinical remission with restoration of normal blood counts. Here, we address acute myeloid leukemia (AML)-chemotherapy using cytarabine (Ara-C) as this drug is this most important component of AML-treatment. In addition to the wide spectrum of genetic aberrations involved in pathogenesis leading to variations in patient response patterns, another facet of personalised medicine awaits exploration of its full potential: a systematic, mathematical approach to understand and manipulate the dynamics of relevant biomarkers. We use personalised mathematical models to describe and predict white blood cell (WBC) counts during AML consolidation treatment. We analyse why and to what extent low WBC counts, a serious adverse event during therapy, occur. In a comprehensive approach we investigate published models, compare them with our extended models and outline the impact of modelling assumptions and varying chemotherapy schedules on prediction accuracy and model discrimination. Our numerical results confirm the clinical finding that a newly proposed schedule is superior with respect to WBC recovery and shed new light on the reasons why.
Elimination of peripheral auditory pathway activation does not affect motor responses from ultrasound neuromodulation
Authors: Mohammadjavadi Morteza , Peiyong Ye Patrick , Xia Anping , Brown Julian , Popelka Gerald , Pauly Kim Butts
Published: September 2018

Recent studies in a variety of animal models including rodents, monkeys, and humans suggest that transcranial focused ultrasound (tFUS) has considerable promise for non-invasively modulating neural activity with the ability to target deep brain structures. However, concerns have been raised that motor responses evoked by tFUS may be due to indirect activation of the auditory pathway rather than direct activation of motor circuits. In this study, tFUS-induced electromyography (EMG) signals were recorded and analyzed in wild-type (WT) normal hearing mice and two strains of genetically deaf mice to examine the involvement of the peripheral auditory system in tFUS-stimulated motor responses. In addition, auditory brainstem responses (ABRs) were measured to elucidate the effect of the tFUS stimulus envelope on auditory and motor responses. We also varied the tFUS stimulation duration to measure its effect on motor response duration. We show, first, that the sharp edges in a tFUS rectangular envelope stimulus activate the peripheral afferent auditory pathway and, second, that smoothing these edges eliminates the auditory responses without affecting the motor responses in normal hearing WT mice. We further show that by eliminating peripheral auditory activity using two different strains of deaf knockout mice, motor responses are the same as in normal hearing WT mice. Finally, we demonstrate a high correlation between tFUS pulse duration and EMG response duration. These results support the concept that tFUS-evoked motor responses are not a result of stimulation of the peripheral auditory system.
Towards Decoding the Metabolic Plasticity in Cancer: Coupling of Gene Regulation and Metabolic Pathways
Authors: Jia Dongya , Lu Mingyang , Jung Kwang Hwa , Park Jun Hyoung , Yu Linglin , Onuchic José N. , Kaipparettu Benny Abraham , Levine Herbert
Published: September 2018

Metabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities for better survival. Here, we establish a theoretical framework to model the coupling of gene regulation and metabolic pathways in cancer. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis respectively, with the activities of three metabolic pathways: glucose oxidation, glycolysis and fatty acid oxidation (FAO). Guided by the model, we develop metabolic pathway signatures to quantify the activities of glycolysis, FAO and the citric acid cycle of tumor samples by evaluating the expression levels of enzymes involved in corresponding processes. The association of AMPK/HIF-1 activity with metabolic pathway activity, predicted by the model and verified by analyzing the gene expression and metabolite abundance data of patient samples, is further validated by in vitro studies of aggressive triple negative breast cancer cell lines.
V1 neurons encode the perceptual compensation of “false torsion” arising from Listing’s law
Authors: Khazali Mohammad Farhan , Thier Peter
Published: September 2018

We try to deploy the retinal fovea to optimally scrutinize an object of interest by directing our eyes to it. Horizontal and vertical components of these fixation eye movements are determined by the object’s location. However, fixation eye movements also involve a torsional component, which according to Listing’s law is fully determined by the 2D eye position acquired. According to Von Helmholtz knowledge of the torsion provided by this law alleviates the perceptual interpretation of the image tilt that changes with fixation, a view supported by psychophysical experiments he pioneered. We address the question where and how Listing’s law is implemented in the visual system and we show that neurons in monkey area V1 use knowledge of torsion to compensate the image tilt associated with specific eye positions as set by Listing’s law.