bluuebunny/crossref_metadata_2025 huggingface dataset:
“Acquired” Type Castellvi-IIIa Lumbarization Transformed From Castellvi-IIa Following Discectomy and Fusion at Lumbosacral Level
Authors: Hou Lisheng , Bai Xuedong , Li Haifeng , Cheng Shi , Wen Tianyong , He Qing , Ruan Dike
Published: May 2018

Study Design.

A retrospective case report.

Objective.

To report a case that transformed from type Castellvi-IIa sacralization to type Castellvi-IIIa after decompression and fusion surgery at transitional disc (TD).

Summary of Background Data.

Traditionally, lumbosacral transitional vertebra has been regarded as a congenital anomaly. No literature has ever reported that transformation from one type lumbosacral transitional vertebra to another would happen after birth.

Methods.

A 60-year-old man presented to our department with the complaint of low back pain and left sciatic pain, and was diagnosed of lumbar disc herniation at L4–5 and L5-S1 levels. Lumbar digital radiography revealed an anomalous articulation formed between sacrum and enlarged right L5 transverse process, exhibiting a typical Castellvi-IIa sacralization. Dynamic lateral radiographs showed mobilization existed at L5-S1 disc which was TD. The patient received posterior lumbar interbody fusion (PLIF) surgery at L4–5 and L5-S1 levels. Postoperative computed tomography examinations were taken to identify the progress of solid fusion at the operated segments.

Results.

After surgery, the patient's symptoms alleviated obviously. As solid fusion developed at intended interbody regions with time, we found that bony bridge passed through the patient's anomalous articulation region gradually, and finally, complete osseous fusion of the right L5 transverse process to the sacrum developed 1 year after surgery.

Conclusion.

Following PLIF surgery at TD segment on a Castellvi-IIa Sacralization case, “acquired” transformation to Castellvi-IIIa might develop.

Level of Evidence: 5
Dietary and serum vitamins A and E and colorectal cancer risk in Chinese population: a case–control study
Authors: Luo Hong , Fang Yu-Jing , Lu Min-Shan , Pan Zhi-Zhong , Huang Jing , Chen Yu-Ming , Zhang Cai-Xia
Published: May 2018

The effect of vitamin A (VA) and vitamin E (VE) on colorectal cancer (CRC) risk is controversial. The aim of this study is to examine the association between serum concentrations and dietary intakes of VA and VE and the risk of CRC in Guangdong, China. A total of 535 cases and 552 sex and age-matched (5-year interval) controls were recruited during July 2010 to September 2014. Dietary information was assessed by face-to-face interviews using a validated food frequency questionnaire. Concentrations of VA and VE were measured by high-performance liquid chromatography. Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders. A higher intake of VA and VE was found to be associated with 52 and 43% reduction in CRC risk. The ORs of the highest quartile compared with the lowest quartile intake were 0.48 (95% CI: 0.31, 0.73, P
trend<0.01) for VA and 0.57 (95% CI: 0.37, 0.88, P
trend<0.01) for VE. An inverse association was also found between serum retinol and CRC risk, with an adjusted OR (95% CI) of 0.28 (0.19–0.43) (P
trend<0.01). However, no statistically significant association was found between serum α-tocopherol and CRC risk. Stratified analysis by sex showed that serum retinol and dietary VA and VE were inversely associated with CRC risk in both sexes. This study supported the hypothesis that lower serum levels of retinol and lower intakes of VA and VE were associated with the risk of CRC in a Chinese population.
Tumour-infiltrating lymphocytes, programmed death ligand 1 and cyclooxygenase-2 expression in skin melanoma of elderly patients: clinicopathological correlations
Authors: Iacono Donatella , Cinausero Marika , Gerratana Lorenzo , Angione Vito , Scott Cathryn Anne , De Maglio Giovanna , Pizzolitto Stefano , Di Loreto Carla , Puglisi Fabio , Fasola Gianpiero , Minisini Alessandro Marco
Published: May 2018

Age is an important prognostic factor in melanoma; notably, elderly patients tend to present with advanced stage skin melanoma (SM) and worse outcome. Moreover, SM is an immunogenic cancer, and its interaction with the aging immune system could have an effect on biologic behaviour of this disease. Tumour-infiltrating lymphocytes (TILs) could represent the host response in SM; it has been shown that higher grade of TILs is associated with better survival. Moreover, programmed death ligand 1 (PD-L1) and cyclooxygenase-2 (COX-2) are potential markers of host immune response and inflammation. We retrospectively reviewed 113 consecutive cases of early-stage SM that occurred in patients aged greater than or equal to 65 years at the time of diagnosis, followed between January 2010 and March 2014 at the University and General Hospital of Udine, Italy. The aim of this study was to evaluate TILs grade, PD-L1 expression on TILs and tumour expression of PD-L1 and COX-2 and their prognostic value in elderly patients with early SM. A better disease-free survival as well as melanoma-specific survival (MSS) was significantly associated with TILs [hazard ratios (HR): 0.41, 95% confidence interval (CI): 0.20–0.84, P=0.02 and HR: 0.37, 95% CI: 0.17–0.82, P=0.01, respectively]. PD-L1 positivity on TILs was associated with a better MSS (HR: 0.41, 95% CI: 0.17–0.97, P=0.04). Moreover, among patients with TILs, those showing COX-2 positivity on tumour cells and no PD-L1 expression on TILs had a worse disease-free survival and MSS (HR: 5.18, 95% CI: 1.33–20.23, P=0.018; HR: 6.21, 95% CI: 1.20–32.24, P=0.03; respectively). Immune and inflammatory markers deserve further investigation in aging patients with melanoma.
What do clinicians consider when assessing chronic low back pain? A content analysis of multidisciplinary pain centre team assessments of functioning, disability, and health
Authors: Bagraith Karl S. , Strong Jenny , Meredith Pamela J. , McPhail Steven M.
Published: May 2018

Beyond expert suggestions as to the appropriate subject matter for chronic pain assessments, little is known about the actual content of multidisciplinary pain centre (MPC) clinical assessments. The International Classification of Functioning, Disability and Health Low Back Pain Core Set (ICF LBP-CS) provides a universal language to support the consistent description of LBP-related assessments across disciplines within multidisciplinary teams (MDTs). This study sought to map the content of MPC clinical assessments to the ICF to: (1) identify and compare the content of clinical MDT assessments using a cross-disciplinary framework and (2) examine the content validity of the LBP-CS. A qualitative examination of MPC team clinical assessments of chronic low back pain was undertaken. Multidisciplinary team (pain medicine, psychiatry, nursing, physiotherapy, occupational therapy, and psychology) assessments were audio-recorded and transcribed. Concepts were extracted from transcripts using a meaning condensation procedure and then linked to the ICF. Across 7 MDT assessments, comprised 42 discipline-specific assessments and 241,209 transcribed words, 8596 concepts were extracted. Contextual factors (ie, the person and environment), except for physiotherapy, accounted for almost half of each discipline's assessments (range: 49%-58%). Concepts spanned 113 second-level ICF categories, including 73/78 LBP-CS categories. Overall, the findings revealed novel insights into the content of MPC clinical assessments that can be used to improve health care delivery. International Classification of Functioning, Disability and Health–based assessment profiles demonstrated unique contributions from each discipline to chronic low back pain assessment. Finally, users of the LBP-CS can be confident that the tool exhibits sound content validity from the perceptive of MDT assessments of functioning, disability, and health.
Amount and Socio-Ecological Correlates of Exercise in Men and Women at Cardiac Rehabilitation Completion
Authors: Taherzadeh Golnoush , Reid Robert D. , Prince Stephanie A. , Blanchard Chris M. , Chessex Caroline , Harris Jennifer , Pipe Andrew L. , Grace Sherry L.
Published: May 2018

Objective

The aim of the study was to describe (1) the amount of physical activity (PA) in cardiac rehabilitation (CR) graduates by sex, and (2) the correlates of their PA.

Design

Secondary analysis of baseline data from a randomized trial was undertaken. Graduates were recruited from three CR programs. Participants completed a questionnaire, which assessed constructs from the socio-ecological model (i.e., individual-level, social- and physical-environmental levels). Physical activity was measured objectively using an ActiGraph GT3X accelerometer. Multilevel modeling was performed.

Results

Two hundred fifty-five patients consented, of which 200 (78.4%) completed the survey and provided valid accelerometer data. Participants self-reported engaging in a mean ± standard deviation of 184.51 ± 129.10 min of moderate-to-vigorous-intensity PA (MVPA) per week (with men engaging in more than women, P < 0.05). Accelerometer data revealed participants engaged in 169.65 ± 136.49 mins of MVPA per week, with 43 (25.1%) meeting recommendations. In the mixed models, the socio-ecological correlate significantly related to greater self-reported MVPA was self-regulation (P = 0.01); the correlate of accelerometer-derived MVPA was neighborhood aesthetics (P = 0.02).

Conclusions

Approximately one-quarter of CR program completers are achieving MVPA recommendations, although two-thirds perceive they are. The CR programs should exploit accelerometry and promote self-regulation skills, namely, self-monitoring, goal-setting, positive reinforcement, time management, and relapse prevention. Patients should be encouraged to exercise in pleasing locations.
Vertical Spacing of Perforators in Deep Inferior Epigastric Perforator Flap Breast Reconstruction Can Affect the Outcomes
Authors: Lee Kyeong-Tae , Eom Yeseul , Jeon Byung-Joon , Mun Goo-Hyun
Published: May 2018

Background:

The present study aimed to evaluate the influence of vertical location and spacing of perforators within flaps on the outcomes of deep inferior epigastric perforator (DIEP) flap breast reconstruction.

Methods:

Patients who underwent unilateral breast reconstruction with unipedicle DIEP flaps were identified. They were categorized into cohorts based on the entry of perforators in the middle third (cohort 1), upper third (cohort 2), and multiple third parts (cohort 3) of the flaps. Perfusion-related complications including fat necrosis diagnosed with ultrasound and donor-site morbidity were compared between the cohorts.

Results:

A total of 287 patients were analyzed, including 51 in cohort 1, 75 in cohort 2, and 161 in cohort 3. The cohorts were well matched, except for a greater number of perforators and more frequent harvest of both medial and lateral row perforators in cohort 3. Rates of overall perfusion-related complications and fat necrosis differed significantly between cohorts, with the highest rates in cohort 2. Fat necrosis occurred predominantly in the caudal portion of the flap in cohort 2, whereas it was relatively evenly distributed in the cephalic and caudal portions in cohorts 1 and 3. Rates of donor-site complications were similar across the cohorts. Multivariate analyses demonstrated that vertical spacing of perforators had an independent influence on developing perfusion-related complications and fat necrosis, showing that cohort 2 had significantly higher odds compared with cohorts 1 and 3, respectively.

Conclusion:

Vertical spacing of perforators might affect the risk of perfusion-related complications in DIEP flap breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Transforming Pain With Prosocial Meaning: A Functional Magnetic Resonance Imaging Study
Authors: López-Solà Marina , Koban Leonie , Wager Tor D.
Published: May 2018

Objective

Contextual factors can transform how we experience pain, particularly if pain is associated with other positive outcomes. Here, we test a novel meaning-based intervention. Participants were given the opportunity to choose to receive pain on behalf of their romantic partners, situating pain experience in a positive, prosocial meaning context. We predicted that the ventromedial prefrontal cortex (vmPFC), a key structure for pain regulation and generation of affective meaning, would mediate the transformation of pain experience by this prosocial interpersonal context.

Methods

We studied fMRI activity and behavioral responses in 29 heterosexual female participants during (1) a baseline pain challenge and (2) a task in which participants decided to accept a self-selected number of additional pain trials to reduce pain in their male romantic partners (“accept-partner-pain” condition).

Results

Enduring extra pain for the benefit of the romantic partner reduced pain-related unpleasantness (t = −2.54, p = .016) but not intensity, and increased positive thoughts (t = 3.60, p = .001) and pleasant feelings (t = 5.39, p < .0005). Greater willingness to accept the pain of one's partner predicted greater unpleasantness reductions (t = 3.94, p = .001) and increases in positive thoughts (r = .457, p = .013). The vmPFC showed significant increases (q < .05 FDR-corrected) in activation during accept-partner-pain, especially for women with greater willingness to relieve their partner's pain (t = 2.63, p = .014). Reductions in brain regions processing pain and aversive emotion significantly mediated reductions in pain unpleasantness (q < .05 FDR-corrected).

Conclusions

The vmPFC has a key role in transforming the meaning of pain, which is associated with a cascade of positive psychological and brain effects, including changes in affective meaning, value, and pain-specific neural circuits.
Exercise is Associated With Increased Small HDL Particle Concentration and Decreased Vascular Stiffness in Rheumatoid Arthritis
Authors: Byram Kevin W. , Oeser Annette M. , Linton MacRae F. , Fazio Sergio , Stein C. Michael , Ormseth Michelle J.
Published: May 2018

Objective

Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA.

Methods

Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex.

Results

Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 min/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all p-values < 0.05) but standard lipid profile and body mass index were not significantly different. Patients who exercised had significantly higher concentrations of HDL particles (p = 0.004) and lower vascular stiffness as measured by pulse wave velocity (p = 0.005).

Conclusions

More self-reported exercise in patients with RA was associated with a protective CV risk factor profile including lower waist-hip ratio, higher HDL particle concentration, lower vascular stiffness, and a lower prevalence of hypertension.
AI-MHC: an allele-integrated deep learning framework for improving Class I & Class II HLA-binding predictions
Authors: Sidhom John-William , Pardoll Drew , Baras Alexander
Published: May 2018

Motivation

The immune system has potential to present a wide variety of peptides to itself as a means of surveillance for pathogenic invaders. This means of surveillances allows the immune system to detect peptides derives from bacterial, viral, and even oncologic sources. However, given the breadth of the epitope repertoire, in order to study immune responses to these epitopes, investigators have relied on in-silico prediction algorithms to help narrow down the list of candidate epitopes, and current methods still have much in the way of improvement.

Results

We present Allele-Integrated MHC (AI-MHC), a deep learning architecture with improved performance over the current state-of-the-art algorithms in human Class I and Class II MHC binding prediction. Our architecture utilizes a convolutional neural network that improves prediction accuracy by 1) allowing one neural network to be trained on all peptides for all alleles of a given class of MHC molecules by making the allele an input to the net and 2) introducing a global max pooling operation with an optimized kernel size that allows the architecture to achieve translational invariance in MHC-peptide binding analysis, making it suitable for sequence analytics where a frame of interest needs to be learned in a longer, variable length sequence. We assess AI-MHC against internal independent test sets and compare against all algorithms in the IEDB automated server benchmarks, demonstrating our algorithm achieves state-of-the-art for both Class I and Class II prediction.

Availability and Implementation

AI-MHC can be used via web interface at baras.pathology.jhu.edu/AI-MHC

Contact

jsidhom1@jhmi.edu
Epigenetic selection and the DNA methylation signatures of adverse prenatal environments
Authors: Tobi Elmar W , van den Heuvel Joost , Zwaan Bas J. , Lumey L.H. , Heijmans Bastiaan T. , Uller Tobias
Published: May 2018

Maternal adversity is associated with long-term physiological changes in offspring. These are believed to be mediated through epigenetic mechanisms, including DNA methylation (DNAm). Changes in DNAm are often interpreted as damage or as part of plastic responses of the embryo. We propose that selection on stochastic DNAm differences generated during epigenetic reprogramming after fertilization contributes to the effects of maternal adversity on DNAm. Using a mathematical model of epigenetic reprogramming in the early embryo we predict that this “epigenetic selection” will generate a characteristic reduction in variance of DNAm at selected loci in populations exposed to maternal adversity. We tested this prediction using DNAm data from a human cohort prenatally exposed to the Dutch Famine and confirmed the reduction in DNAm variance, suggesting that epigenetic selection may have occurred. Epigenetic selection should be considered as a possible mechanism linking adversity in pregnancy to offspring health and may have implications for the likely effectiveness of intervention strategies.
Relevance of coral geometry in the outcomes of the coral-algal benthic war
Authors: George Emma E. , Mullinix James , Meng Fanwei , Bailey Barbara , Edwards Clinton , Felts Ben , Haas Andreas , Hartmann Aaron C. , Mueller Benjamin , Nulton Jim , Roach Ty N.F. , Salamon Peter , Silveira Cynthia B. , Vermeij Mark J.A. , Rohwer Forest L. , Luque Antoni
Published: May 2018

Corals have built reefs on the benthos for millennia, becoming an essential element in marine ecosystems. Climate change and human impact, however, are favoring the invasion of non-calcifying benthic algae and reducing coral coverage. Corals rely on energy derived from photosynthesis and heterotrophic feeding, which depends on their surface area, to defend their outer perimeter. But the relation between geometric properties of corals and the outcome of competitive coral-algal interactions is not well known. To address this, 50 coral colonies interacting with algae were sampled in the Caribbean island of Curaçao. 3D and 2D digital models of corals were reconstructed to measure their surface area, perimeter, and polyp sizes. A box counting algorithm was applied to calculate their fractal dimension. The perimeter and surface dimensions were statistically non-fractal, but differences in the mean surface fractal dimension captured relevant features in the structure of corals. The mean fractal dimension and surface area were negatively correlated with the percentage of losing perimeter and positively correlated with the percentage of winning perimeter. The combination of coral perimeter, mean surface fractal dimension, and coral species explained 19% of the variability of losing regions, while the surface area, perimeter, and perimeter-to-surface area ratio explained 27% of the variability of winning regions. Corals with surface fractal dimensions smaller than two and small perimeters displayed the highest percentage of losing perimeter, while corals with large surface areas and low perimeter-to-surface ratios displayed the largest percentage of winning perimeter. This study confirms the importance of fractal surface dimension, surface area, and perimeter of corals in coral-algal interactions. In combination with non-geometrical measurements such as microbial composition, this approach could facilitate environmental conservation and restoration efforts on coral reefs.
An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease
Authors: Mäkeläinen Suvi , Gòdia Marta , Hellsand Minas , Viluma Agnese , Hahn Daniela , Makdoumi Karim , Zeiss Caroline J , Mellersh Cathryn , Ricketts Sally L , Narfström Kristina , Hallböök Finn , Ekesten Björn , Andersson Göran , Bergström Tomas F
Published: May 2018

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.
GaKCo: a Fast Gappedk-mer string Kernel using Counting
Authors: Singh Ritambhara , Sekhon Arshdeep , Lanchantin Jack , Kowsari Kamran , Wang Beilun , Qi Yanjun
Published: May 2018

String Kernel (SK) techniques, especially those using gappedk-mers as features (gk), have obtained great success in classifying sequences like DNA, protein, and text. However, the state-of-the-art gk-SK runs extremely slow when we increase the dictionary size (Σ) or allow more mismatches (M). This is because current gk-SK uses a trie-based algorithm to calculate co-occurrence of mismatched substrings resulting in a time cost proportional toO(ΣM). We propose afastalgorithm for calculatingGappedk-merKernel usingCounting (GaKCo). GaKCo uses associative arrays to calculate the co-occurrence of substrings using cumulative counting. This algorithm is fast, scalable to largerΣandM, and naturally parallelizable. We provide a rigorous asymptotic analysis that compares GaKCo with the state-of-the-art gk-SK. Theoretically, the time cost of GaKCo is independent of theΣMterm that slows down the trie-based approach. Experimentally, we observe that GaKCo achieves the same accuracy as the state-of-the-art and outperforms its speed by factors of 2, 100, and 4, on classifying sequences of DNA (5 datasets), protein (12 datasets), and character-based English text (2 datasets).1
Magnetic resonance imaging of the regenerating neonatal mouse heart
Authors: Gunadasa-Rohling Mala , Masters Megan , Maguire Mahon L. , Smart Sean C. , Schneider Jürgen E. , Riley Paul R.
Published: May 2018

We present longitudinal magnetic resonance imaging (MRI) of neonatal mouse hearts during the first three weeks following coronary artery ligation to mimic heart attack. We confirm heart regeneration in individual animals injured on post-natal day 1 (P1) while those injured on P7 show the adult response of fibrosis, scarring and impaired heart performance. We document heart growth and development of the principal functional cardiac parameters, and also remodeling during tissue regeneration as compared to fibrosis when imaging repeatedly up to 21 days after myocardial infarction (MI). We reveal compensatory changes in cardiac function with the restoration of tissue and resolution of injury for the P1 cohort and sustained injury responses for the P7 cohort. This study resolves the controversy surrounding neonatal mouse heart regeneration and establishes a functional platform for live capture of the regenerative process and for the future testing of genetic or therapeutic interventions.
The Charlson Index is insufficient to control for comorbidities in a national trauma registry
Authors: Renson Audrey , Bjurlin Marc A.
Published: May 2018

Background

The Charlson Comorbidity Index (CCI) is frequently used to control for confounding by comorbidities in observational studies, but its performance as such has not been studied. We evaluated the performance of CCI and an alternative summary method, logistic principal component analysis (LPCA), to adjust for comorbidities, using as an example the association between insurance and mortality.

Materials and Methods

Using all admissions in the National Trauma Data Bank 2010-2015, we extracted mortality, payment method, and 36 ICD-9-derived comorbidities. We estimated ORs for the association between uninsured status and mortality before and after adjusting for CCI, LPCA, and separate covariates. We also calculated standardized mean differences (SMDs) of comorbidity variables before and after weighting the sample using inverse probability of treatment weights (IPTW) for CCI, LPCA, and separate covariates.

Results

In 4,936,880 admissions, most (68.3%) had at least one comorbidity. Considerable imbalance was observed in the unweighted sample (mean SMD=0.086, OR=1.17), which was almost entirely eliminated by IPTW on separate covariates (mean SMD=0.012, OR=1.36). The CCI performed similarly to the unweighted sample (mean SMD=0.080, OR=1.25), while 2 LPCA axes were better able to control for confounding (mean SMD=0.04, OR=1.31). Using covariate adjustment, the CCI accounted for 56.1% of observed confounding, whereas 2 LPCA axes accounted for 91.3%.

Conclusions

The use of the CCI to adjust for confounding may result in residual confounding, and alternative strategies should be considered. LPCA may be a viable alternative to adjusting for each comorbidity when samples are small or positivity assumptions are violated.
Controlling for contaminants in low biomass 16S rRNA gene sequencing experiments
Authors: Karstens Lisa , Asquith Mark , Davin Sean , Fair Damien , Gregory W. Thomas , Wolfe Alan J. , Braun Jonathan , McWeeney Shannon
Published: May 2018

Background

Microbial communities are commonly studied using culture-independent methods such as 16S rRNA gene sequencing. However, one challenge in accurately characterizing microbial communities is exogenous bacterial DNA contamination. This is particularly problematic for sites of low microbial biomass such as the urinary tract, placenta, and lower airway. Computational approaches have been proposed as a post-processing step to identify and remove potential contaminants, but their performance has not been independently evaluated.

To identify the impact of decreasing microbial biomass on polymicrobial 16S rRNA gene sequencing experiments, we used a serial dilution of a mock microbial community. We evaluated two computational approaches to identify and remove contaminants: 1) identifying sequences that have an inverse correlation with DNA concentration implemented in Decontam and 2) predicting the proportion of experimental sample arising from defined contaminant sources implemented in SourceTracker.

Results

As expected, the proportion of contaminant bacterial DNA increased with decreasing starting microbial biomass, with 79.12% of the most dilute sample arising from contaminant sequences. Inclusion of contaminant sequences in analyses leads to overinflated diversity estimates (up to 12 times greater than the expected values) and distorts microbiome composition. SourceTracker successfully removed over 98% of contaminants when the experimental environments are well defined. However, SourceTracker performed poorly when the experimental environment is unknown, failing to remove the majority of contaminants. Decontam successfully removed 74-91% of contaminants regardless of prior knowledge of the experimental environment.

Conclusions

Our study indicates that computational methods can reduce the amount of contaminants in 16S rRNA gene sequencing experiments. The appropriate computational approach for removing contaminant sequences from an experiment depends on the prior knowledge about the microbial environment under investigation and can be evaluated with a dilution series of a mock microbial community.
Targeting ion channel TRPM7 promotes thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation
Authors: Mendu Suresh K. , Schappe Michael S. , Moser Emily K. , Krupa Julia K. , Rogers Jason S. , Stipes Eric J. , Parker Clare A. , Braciale Thomas J. , Desai Bimal N.
Published: May 2018

In Brief

Genetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2Rα and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.

HIGHLIGHTS

Ion channel TRPM7 controls Treg development

The deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the periphery

TRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activation

Inhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cells

The thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2Rα expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.
Tau local structure shields amyloid motif and controls aggregation propensity
Authors: Chen Dailu , Drombosky Kenneth W. , Hou Zhiqiang , Sari Levent , Kashmer Omar M. , Ryder Bryan D. , Perez Valerie A. , Woodard DaNae R. , Lin Milo M. , Diamond Marc I. , Joachimiak Lukasz A.
Published: May 2018

Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau’s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. Using cross-linking mass spectrometry, intramolecular FRET, recombinant protein and synthetic peptide systems, in silico modeling, and cell models, we conclude that the aggregation prone 306VQIVYK311 motif forms metastable compact structures with the upstream sequence that modulates aggregation propensity. Disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.
Coral: Clear and customizable visualization of human kinome data
Authors: Metz Kathleen S. , Deoudes Erika M. , Berginski Matthew E. , Jimenez-Ruiz Ivan , Aksoy Bulent Arman , Hammerbacher Jeff , Gomez Shawn M. , Phanstiel Douglas H.
Published: May 2018

Protein kinases represent one ofthe largest gene families in eukaryotes and play roles in a wide range of cell signaling processes and human diseases, making them attractive targets for drug development. The human kinome is extensively featured inhigh-throughput studiesgenerating genomic, proteomic, and kinase profiling data. Current tools for visualizing kinase data in the context of the human kinome superfamily are limited to encoding data through the addition of nodes to a low-resolution image of the kinome tree. We present Coral, a user-friendly interactive webapplication for visualizing both quantitative and qualitative data. Unlike previous tools, Coral can encode data in three features (node color, node size, and branchcolor), allowsthreemodesofkinomevisualization (the traditional kinome tree as well as radial and dynamic-force networks) and generates high-resolution scalable vector graphic files suitable for publication without the need for refinement in graphic editing software. Due to its user-friendly, interactive, and highly customizable design, Coral is broadly applicable to high-throughput studies of the human kinome. The source code and web application are available at github.com/dphansti/Coral. html and phanstiel-lab.med.unc.edu/Coral respectively.
Assessing sustainability in North America’s ecosystems using criticality and information theory
Authors: Ramírez-Carrillo Elvia , López-Corona Oliver , Toledo-Roy Juan C. , Lovett Jon C. , de León-González Fernando , Osorio-Olvera Luis , Equihua Julian , Robredo Everardo , Frank Alejandro , Dirzo Rodolfo , Perez-Cirera Vanessa
Published: May 2018

Sustainability is a key concept in economic and policy debates. Nevertheless, it is usually treated only in a qualitative way and has eluded quantitative analysis. Here, we propose a sustainability index based on the premise that sustainable systems do not lose or gain Fisher Information over time. We test this approach using time series data from the AmeriFlux network that measures ecosystem respiration, water and energy fluxes in order to elucidate two key sustainability features: ecosystem health and stability. A novel definition of ecosystem health is developed based on the concept of criticality, which implies that if a system’s fluctuations are scale invariant then the system is in a balance between robustness and adaptability. We define ecosystem stability by taking an information theory approach that measures its entropy and Fisher information. Analysis of the Ameriflux consortium big data set of ecosystem respiration time series is contrasted with land condition data. In general we find a good agreement between the sustainability index and land condition data. However, we acknowledge that the results are a preliminary test of the approach and further verification will require a multi-signal analysis. For example, high values of the sustainability index for some croplands are counter-intuitive and we interpret these results as ecosystems maintained in artificial health due to continuous human-induced inflows of matter and energy in the form of soil nutrients and control of competition, pests and disease.
Solving scaffolding problem with repeats
Authors: Mandric Igor , Zelikovsky Alex
Published: May 2018

One of the most important steps in genome assembly is scaffolding. Increasing the length of sequencing reads allows assembling short genomes but assembly of long repeat-rich genomes remains one of the most interesting and challenging problems in bioinformatics. There is a high demand in developing computational approaches for repeat aware scaffolding. In this paper, we propose a novel repeat-aware scaffolder BATISCAF based on the optimization formulation for filtering out repeated and short contigs. Our experiments with five benchmarking datasets show that the proposed tool BATISCAF outperforms state-of-the-art tools. BATISCAF is freely available on GitHub: https://github.com/mandricigor/batiscaf.
REVA: a rank-based multi-dimensional measure of correlation
Authors: Afsari Bahman , Favorov Alexander , Fertig Elana J. , Cope Leslie
Published: May 2018

The neighbors principle implicit in any machine learning algorithm says that samples with similar labels should be close to one another in feature space as well. For example, while tumors are heterogeneous, tumors that have similar genomics profiles can also be expected to have similar responses to a specific therapy. Simple correlation coefficients provide an effective way to determine whether this principle holds when features and labels are both scalar, but not when either is multivariate. A new class of generalized correlation coefficients based on inter-point distances addresses this need and is called “distance correlation”. There is only one rank-based distance correlation test available to date, and it is asymmetric in the samples, requiring that one sample be distinguished as a fixed point of reference. Therefore, we introduce a novel, nonparametric statistic, REVA, inspired by the Kendall rank correlation coefficient. We use U-statistic theory to derive the asymptotic distribution of the new correlation coefficient, developing additional large and finite sample properties along the way. To establish the admissibility of the REVA statistic, and explore the utility and limitations of our model, we compared it to the most widely used distance based correlation coefficient in a range of simulated conditions, demonstrating that REVA does not depend on an assumption of linearity, and is robust to high levels of noise, high dimensions, and the presence of outliers. We also present an application to real data, applying REVA to determine whether cancer cells with similar genetic profiles also respond similarly to a targeted therapeutic.

Author summary

Sometimes a simple question arises: how does the distance between two samples in multivariate space compare to another scalar value associated with each sample. Here, we propose theory for a nonparametric test to statistically test this association. This test is independent of the scale of the scalar data, and thus generalizable to any comparison of samples with both high-dimensional data and a scalar. We apply the resulting statistic, REVA, to problems in cancer biology motivated by the model that cancer cells with more similar gene expression profiles to one another can be expected to have a more similar response to therapy.
General Functional Connectivity: shared features of resting-state and task fMRI drive reliable and heritable individual differences in functional brain networks
Authors: Elliott Maxwell L. , Knodt Annchen R. , Cooke Megan , Kim M. Justin , Melzer Tracy R. , Keenan Ross , Ireland David , Ramrakha Sandhya , Poulton Richie , Caspi Avshalom , Moffitt Terrie E. , Hariri Ahmad R.
Published: May 2018

Intrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations, many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data alone. Furthermore, at equivalent scan lengths, GFC displays higher heritability on average than resting-state functional connectivity. We also show that predictions of cognitive ability from GFC generalize across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.
Learning Nonlinear Brain Dynamics: van der Pol Meets LSTM
Authors: Abrevaya Germán , Aravkin Aleksandr , Cecchi Guillermo , Rish Irina , Polosecki Pablo , Zheng Peng , Dawson Silvina Ponce
Published: May 2018

Many real-world data sets, especially in biology, are produced by highly multivariate and nonlinear complex dynamical systems. In this paper, we focus on brain imaging data, including both calcium imaging and functional MRI data. Standard vector-autoregressive models are limited by their linearity assumptions, while nonlinear general-purpose, large-scale temporal models, such as LSTM networks, typically require large amounts of training data, not always readily available in biological applications; furthermore, such models have limited interpretability. We introduce here a novel approach for learning a nonlinear differential equation model aimed at capturing brain dynamics. Specifically, we propose a variable-projection optimization approach to estimate the parameters of the multivariate (coupled) van der Pol oscillator, and demonstrate that such a model can accurately represent nonlinear dynamics of the brain data. Furthermore, in order to improve the predictive accuracy when forecasting future brain-activity time series, we use this analytical model as an unlimited source of simulated data for pretraining LSTM; such model-specific data augmentation approach consistently improves LSTM performance on both calcium and fMRI imaging data.
Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription
Authors: Hocquet Clémence , Robellet Xavier , Modolo Laurent , Sun Xi-Ming , Burny Claire , Cuylen-Haering Sara , Toselli Esther , Clauder-Münster Sandra , Steinmetz Lars M. , Haering Christian H. , Marguerat Samuel , Bernard Pascal
Published: May 2018

Condensins are genome organisers that shape chromosomes and promote their accurate transmission. Several studies have also implicated condensins in gene expression, although the mechanisms have remained enigmatic. Here, we report on the role of condensin in gene expression in fission and budding yeasts. In contrast to previous studies, we provide compelling evidence that condensin plays no direct role in the maintenance of the transcriptome, neither during interphase nor during mitosis. We further show that the changes in gene expression in post-mitotic fission yeast cells that result from condensin inactivation are largely a consequence of chromosome missegregation during anaphase, which notably depletes the RNA-exosome from daughter cells. Crucially, preventing karyotype abnormalities in daughter cells restores a normal transcriptome despite condensin inactivation. Thus, chromosome instability, rather than a direct role of condensin in the transcription process, changes gene expression. This knowledge challenges the concept of gene regulation by canonical condensin complexes.
Transparent Titanium Dioxide Nanotubes: Processing, Characterization, and Application in Establishing Cellular Response Mechanisms
Authors: Meyerink Jevin G. , Kota Divya , Wood Scott T. , Crawford Grant A.
Published: May 2018

The therapeutic applications of titanium dioxide nanotubes (TiO2 NTs) as osteogenic surface treatments for titanium (Ti)-based implants are largely due to the finely tunable physical characteristics of these nanostructures. As these characteristics change, so does the cellular response, yet the exact mechanisms for this relationship remains largely undefined. We present a novel TiO2 NT imaging platform that is suitable for use with live-cell imaging techniques, thereby enabling, for the first time, dynamic investigation of those mechanisms. In this work, fabrication methods for producing transparent TiO2 NTs with diameters of 56 ± 6 nm, 75 ± 7 nm, 92 ± 9 nm, and 116 ± 10 nm are described. To demonstrate the diagnostic potential of these TiO2 NT imaging platforms, the focal adhesion protein vinculin and actin cytoskeletal filaments were fluorescently tagged in osteoblasts and real-time, high-resolution fluorescent microscopy of live-cell interactions with TiO2 NT substrates were observed. The scope of such a platform is expected to extend far beyond the current proof-of-concept, with great potential for addressing the dynamic response of cells interacting with nanostructured substrates.
Age-specific differences in the dynamics of protective immunity to influenza
Authors: Ranjeva Sylvia , Subramanian Rahul , Fang Vicky J. , Leung Gabriel M. , Ip Dennis K. M. , Perera Ranawaka A. P. M. , Peiris J. S. Malik , Cowling Benjamin J. , Cobey Sarah
Published: May 2018

Influenza A viruses evolve rapidly to escape host immunity, such that individuals can be infected multiple times with the same subtype. The form and duration of protective immunity after each influenza infection are poorly understood. Here, we quantify the dynamics of protective immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology from children and adults in a household cohort study. We find that most protection in children is explained by antibody titers measured by the hemagglutination inhibition (HI) assay. In contrast, in adults, HI antibody titers explain a smaller fraction of protection. Protection against circulating strains wanes to approximately 50% of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that the focus of influenza antibody responses changes over time from the highly mutable hemagglutinin head to other epitopes, consistent with the immunological theory of original antigenic sin, and that this change of focus might affect protection. Additionally, we estimate that imprinting, or primary infection with a subtype of one phylogenetic group, has little to no effect on the risk of non-medically attended influenza infections in adults. We also find no evidence of long-term cross-protection between subtypes. This work underscores the need for longitudinal data on multiple components of the immune response to better understand the development of immunity and differences in susceptibility within populations.