bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral monocyte counts predict the clinical outcome for patients with colorectal cancer: a systematic review and meta-analysis
Authors: Wen Shu , Chen Nan , Peng Jin , Ling Wei , Fang Qian , Yin Sai-fu , He Xin , Qiu Meng , Hu Ying
Published: September 2019

Monocytes originating from bone marrow play a key role in the inflammatory response. Divergent findings regarding the prognostic value of inflammatory factors like absolute monocyte count (AMC) in colorectal cancer (CRC) exist in the current literature. Thus, we sought to perform a systemic meta-analysis to comprehensively estimate whether the peripheral AMC affects the clinical outcome of CRC patients. A comprehensive literature search was performed in PubMed, Web of Science and EMBASE last updated to 23 December 2018, to identify studies reporting the prognostic value of AMC in patients with CRC. Hazard ratios and corresponding 95% confidence intervals (CIs) or P values were used as the effect size estimates for clinical outcomes including overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS) and progression-free survival (PFS) with the random-effect inverse variance weighted method. The potential heterogeneity was assessed with Q test and I2 statistics. Subgroup analyses with respect to some clinicopathological parameters were conducted. A total of 16 clinical studies comprising 3826 patients were included for analysis. Pooled analyses revealed that CRC patients with elevated AMC were significantly associated with worse OS (hazard ratio = 1.708, 95% CI: 1.480–1.971, P < 0.001), DFS (hazard ratio = 1.817, 95% CI: 1.289–2.560, P = 0.001), CSS (hazard ratio = 1.551, 95% CI: 1.187–2.027, P = 0.001) and PFS (hazard ratio = 1.487, 95% CI: 1.259–1.756, P < 0.001). In addition, subgroup analyses provided more information and demonstrated the prognostic effect of elevated preoperative AMC in patients with CRC. There were no significant heterogeneity and publication bias. In conclusion, elevated AMC seems to be served as an unfavorable and robust predicative indicator in CRC patients.
A randomized controlled trial of the effects of local tranexamic acid on mortality, rebleeding, and recurrent endoscopy need in patients with upper gastrointestinal hemorrhage
Authors: Karadaş Adnan , Doğan Nurettin Özgür , Pinar Seda Güney , Yeşil Olcay , Pekdemir Murat , Yilmaz Serkan , Yaka Elif
Published: September 2019

Objective

Tranexamic acid (TXA) is an antifibrinolytic agent used to control bleeding in different circumstances. We conducted a randomized controlled trial to assess the efficacy and safety of locally administered TXA in upper gastrointestinal hemorrhage.

Methods

This single-center, double-blind, randomized controlled trial was performed in a tertiary emergency department (ED) in patients presenting with upper gastrointestinal bleeding symptoms between 2016 and 2018. The patients received either 2000 mg of 5% TXA in 100 mL of isotonic saline solution or 100 mL isotonic saline (control group) via the nasogastric route. As a composite outcome, recurrent endoscopy need, rebleeding, surgery need, recurrent admission to the ED, and mortality parameters were evaluated at the end of a one-month period.

Results

During the study period, 78 patients were randomized into the TXA group, and 79 patients were randomized into the isotonic saline group. The majority of the bleedings (61%) were in Forrest class 3, and the most frequent cause was peptic ulcer disease. The composite outcome occurred in 25 of the TXA patients (32.1%) and 23 of the isotonic saline patients (29.1%); no statistically significant difference was found between the groups (P = 0.690). In addition, no statistically significant differences were observed between the TXA and control groups regarding mortality (10.3 vs 12.7%; P = 0.637), recurrent ED admission (17.9 vs 12.7%; P = 0.357), or thromboembolic complications (3.8 vs 1.3%; P = 0.367).

Conclusion

Locally administered TXA confers no additional benefit over standard care in patients with upper gastrointestinal hemorrhage.
Prediction and Comparison of Fentanyl Infusion Pharmacokinetics in Obese and Nonobese Children
Authors: Lim Sin Yin , Woo Sukyung , Miller Jamie L. , Skrepnek Grant H. , Henry Emilie D. , Johnson Peter N.
Published: September 2019

Objectives:

To compare fentanyl infusion pharmacokinetic variables in obese children and nonobese children.

Design:

A pharmacokinetic simulation study.

Setting:

We used a semi-physiologically based pharmacokinetic model to generate fentanyl pharmacokinetic variables.

Subjects:

Simulations of pharmacokinetic variables were based on historical inpatient demographic data in less than 18-year-olds.

Interventions:

Obese children were defined as children less than 2 years with weight-for-length greater than or equal to 97.7th percentile or body mass index-for-age greater than or equal to 95th percentile for greater than or equal to 2–17-year-olds.

Measurements and Main Results:

Overall, 4,376 patients were included, with 807 (18.4%) classified as obese children. The majority (52.9%) were male, with a median age of 8.1 years (interquartile range, 4.3–13.0 yr). The differences in total clearance (CLS), volume of distribution at steady-state values, weight-normalized CLS, and weight-normalized volume of distribution at steady state were assessed in obese children and nonobese children. Multivariable analyses indicated that obesity was significantly associated with a higher CLSin obese children greater than 6-year-olds (p< 0.0375). However, there was an 11–30% decrease in weight-normalized CLSin obese children versus nonobese children in all age groups (p< 0.05). Both volume of distribution at steady state and weight-normalized volume of distribution at steady state increased significantly in obese children compared with nonobese children (p< 0.05). Fentanyl plasma concentration-time profiles of obese children and nonobese children pairs (ages 4, 9, and 15) receiving 1 µg/kg/hr using total body weight were also compared. Steady-state concentrations of the obese children using similar weight-based dosing increased by 25%, 77%, and 44% in comparison to nonobese children 4-, 9-, and 15-year-olds, respectively. Time to steady state and elimination half-lives were two- to four-fold longer in obese children. An additional simulation was conducted for 15-year-old obese children and nonobese children using a fixed dose of 50 µg/hr and it provided similar pharmacokinetic profiles.

Conclusions:

CLSmay increase less than proportional to weight in obese children greater than 6-year-olds, while volume of distribution at steady state increases more than proportional to weight in all obese children compared with nonobese children. Weight-based dosing in obese children may cause an increase in steady-state concentration while prolonging the time to steady state. Exploring alternative dosing strategies for obese children is warranted.
Multiple Regional Listing Increases Liver Transplant Rates for Those With Model for End-stage Liver Disease Score <15
Authors: Brown Sara , Savva Yulia , Barth Rolf , LaMattina John , Thuluvath Paul J.
Published: September 2019

Background.

Multiple listing (ML) at >1 transplant center is one mechanism to combat the geographic disparities in liver transplantation (LT) rates. The objective of our study was to determine the impact of multiple listing on LT rates.

Methods.

We examined the United Network of Organ Sharing database from 2002 to 2016 after excluding those listed for multiple organs, hepatocellular carcinoma, or living donor LT. The waitlist mortality and LT rates for the ML groups and the single listed (SL) group were compared after stratifying patients by the Model for End-Stage Liver Disease (MELD) with a cutoff at 15 (<15 and ≥15).

Results.

Of the 83 935 listed during the study period, 80 351 were listed in a single center (SL group), and 3584 were listed in >1 center (ML group). Of the ML groups, 2028 (2.4%) were listed at multiple donor service areas but within the same region (ML-SR) and 1556 (1.9%) listed in different regions (ML-DR). The median MELD at LT was 20, 21, and 24 for ML-DR, ML-SR, and SL groups, respectively (P = 0.001). Although the probability of receiving LT was significantly higher for the ML groups relative to the SL group for both MELD groups (<15 and ≥15), the impact was the highest for ML-DR group. At MELD score <15, the probability of LT was 72% for ML-DR, 38% for ML-SR, and 32% for SL groups. At MELD score ≥15, the probability of LT was 79% for ML-DR, 67% for ML-SR, and 61% for SL groups.

Conclusions.

Multiple listing appeared to considerably improve a patient’s chance of receiving LT and survival with the highest benefit for those with low MELD scores (<15) listed at multiple regions.
Cortical and subcortical gray matter alterations in first-episode drug-naïve adolescents with major depressive disorder
Authors: Kim Ji Hyun , Suh Sang-il , Lee Ho-Jun , Lee Jong-ha , Lee Moon-Soo
Published: September 2019

Major depressive disorder is a major mental disorder affecting adolescents. Cortical thickness provides a sensitive measure of age-associated changes. Previous studies using cortical thickness analysis reported inconsistent results on brain structural changes in adolescent major depressive disorder. The neuroanatomical substrates of major depressive disorder in adolescents are not fully understood. We aimed to compare the anatomical structures of the brain in first-onset drug-naïve adolescents with major depressive disorder to normal controls. Twenty-seven first-episode drug-naïve adolescents with major depressive disorder and an equal number of age-matched control subjects were scanned on a 3T MRI scanner. Comparisons between those two groups were performed using surface-based morphometry analysis for cortical thickness and volumetric analysis of subcortical gray matter. The correlations between morphometric indexes and clinical measures (Hamilton depression rating scale score or children’s depression inventory score) were also calculated. We found that the cortical area is thinner in major depressive disorder patients than in controls, specifically in the left occipital area (precuneus and cuneus, cluster-level family-wise corrected P < 0.05). The hippocampus volume was also smaller in major depressive disorder patients than in the control group. No significant correlations were found between morphometric indexes (average cortical thickness extracted from the left precuneus cluster and hippocampal volume) and clinical measures. The left occipital cortical regions may have a role in the pathophysiology of adolescent major depressive disorder, and the involvement of the hippocampus is important for pathogenic changes even in the early stages of major depressive disorder.
The effect of response frequency on cognitive brain activity during an alertness task
Authors: Schouwenaars Irena T. , de Dreu Miek J. , Rutten Geert-Jan M. , Ramsey Nick F. , Jansma Johan M.
Published: September 2019

A required response forces the brain to react overtly on a stimulus. This may be a factor that influences cognitive activity during a task, as it could facilitate for instance alertness, especially in tasks that are relatively easy. In the current article, we therefore tested the hypothesis that response frequency affects cognitive brain activity in an alertness task. In this 3T functional MRI study, healthy volunteers performed a continuous performance task with three conditions with increasing response frequency. Only scans during presentation of non-targets were analyzed, to exclude activity related to the change in frequency in response selection and motor responses between conditions. To evaluate changes in cognitive brain activity, a network analysis was performed based on two main networks including regions with task-induced activation and task-induced deactivation. We tested for differences in brain activity as an effect of target frequency. Performance results indicated no effect of target frequency on accuracy or reaction time. During non-targets, we found significant signal changes in TID for all three conditions, whereas TIA showed no significant signal changes in any condition. Target frequency did not have a significant effect on the level of signal change at network level, as well as at individual region level. Our study showed predominantly deactivation during non-responses in all three task conditions. Furthermore, our results indicate that response frequency does not influence brain activity during an alertness task. Our results provide additional information relevant for the understanding of the neurophysiological implementation of cognitive control or alertness.
Detection and Classification of Cardiac Arrhythmias by a Challenge-Best Deep Learning Neural Network Model
Authors: Chen Tsai-Min , Huang Chih-Han , Shih Edward S. C. , Hu Yu-Feng , Hwang Ming-Jing
Published: September 2019

Background

Electrocardiogram (ECG) is widely used to detect cardiac arrhythmia (CA) and heart diseases. The development of deep learning modeling tools and publicly available large ECG data in recent years has made accurate machine diagnosis of CA an attractive task to showcase the power of artificial intelligence (AI) in clinical applications.

Methods and Findings

We have developed a convolution neural network (CNN)-based model to detect and classify nine types of heart rhythms using a large 12-lead ECG dataset (6877 recordings) provided by the China Physiological Signal Challenge (CPSC) 2018. Our model achieved a median overall F1-score of 0.84 for the 9-type classification on CPSC2018’s hidden test set (2954 ECG recordings), which ranked first in this latest AI competition of ECG-based CA diagnosis challenge. Further analysis showed that concurrent CAs observed in the same patient were adequately predicted for the 476 patients diagnosed with multiple CA types in the dataset. Analysis also showed that the performances of using only single lead data were only slightly worse than using the full 12 lead data, with leads aVR and V1 being the most prominent. These results are extensively discussed in the context of their agreement with and relevance to clinical observations.

Conclusions

An AI model for automatic CA diagnosis achieving state-of-the-art accuracy was developed as the result of a community-based AI challenge advocating open-source research. In- depth analysis further reveals the model’s ability for concurrent CA diagnosis and potential use of certain single leads such as aVR in clinical applications.

Abbreviations

CA, cardiac arrhythmia; AF, Atrial fibrillation; I-AVB, first-degree atrioventricular block; LBBB, left bundle branch block; RBBB, right bundle branch block; PAC, premature atrial contraction; PVC, premature ventricular contraction; STD, ST-segment depression; STE, ST-segment elevation.
End-to-End Boundary Aware Networks for Medical Image Segmentation
Authors: Hatamizadeh Ali , Terzopoulos Demetri , Myronenko Andriy
Published: September 2019

Fully convolutional neural networks (CNNs) have proven to be effective at representing and classifying textural information, thus transforming image intensity into output class masks that achieve semantic image segmentation. In medical image analysis, however, expert manual segmentation often relies on the boundaries of anatomical structures of interest. We propose boundary aware CNNs for medical image segmentation. Our networks are designed to account for organ boundary information, both by providing a special network edge branch and edge-aware loss terms, and they are trainable end-to-end. We validate their effectiveness on the task of brain tumor segmentation using the BraTS 2018 dataset. Our experiments reveal that our approach yields more accurate segmentation results, which makes it promising for more extensive application to medical image segmentation.
Integrated Low-Energy and Low Carbon Shortcut Nitrogen removal with Biological Phosphorus Removal for Sustainable Mainstream Wastewater Treatment
Authors: Roots Paul , Sabba Fabrizio , Rosenthal Alex F. , Wang Yubo , Yuan Quan , Rieger Leiv , Yang Fenghua , Kozak Joseph A. , Zhang Heng , Wells George F.
Published: September 2019

While enhanced biological phosphorus removal (EBPR) is widely utilized for phosphorus (P) removal from wastewater, understanding of efficient process alternatives that allow combined biological P removal and shortcut nitrogen (N) removal, such as nitritation-denitritation, is limited. Here, we demonstrate efficient and reliable combined total N, P, and chemical oxygen demand removal (70%, 83%, and 81%, respectively) in a sequencing batch reactor (SBR) treating real mainstream wastewater (primary effluent) at 20°C. Anaerobic – aerobic cycling (with intermittent oxic/anoxic periods during aeration) was used to achieve consistent removal rates, nitrite oxidizing organism (NOO) suppression, and high effluent quality. Importantly, high resolution process monitoring coupled toex situbatch activity assays demonstrated that robust biological P removal was coupled to energy and carbon efficient nitritation-denitritation, not simultaneous nitrification-denitrification, for the last >400 days of 531 total days of operation. Nitrous oxide emissions of 2.2% relative to the influent TKN (or 5.2% relative to total inorganic nitrogen removal) were similar to those measured in other shortcut N bioprocesses. No exogenous chemicals were needed to achieve consistent process stability and high removal rates in the face of frequent wet weather flows and highly variable influent concentrations. Process modeling reproduced the performance observed in the SBR and confirmed that nitrite drawdown via denitritation contributed to suppression of NOO activity.
Neural Correlates of Task-related Refixation Behaviour
Authors: Meghanathan Radha Nila , van Leeuwen Cees , Giannini Marcello , Nikolaev Andrey R.
Published: September 2019

Information uptake during scene viewing under free viewing conditions is crucially determined by the scanning plan. This plan is determined both by top-down and bottom-up factors. To capture top-down factors affecting saccade planning, we compared EEG between first fixations and refixations on items varying in task-relevance. First fixations and refixations impose different working memory costs because first fixations involve encoding of new items whereas refixations involve rehearsal of existing items in working memory. These memory requirements also differ with the task-relevance of the item being encoded. Together, these two factors of task-relevance and memory processes related to refixation behavior would affect saccade planning. In a visual task involving search and memorization of multiple targets, we compared saccade-related potentials (SRPs) between first fixations and refixations for task-relevant (target) and task-irrelevant (distractor) items. We assessed the interval preceding a saccade away from the fixation of interest. Studying this presaccadic interval revealed how mechanisms related to saccade preparation are affected by task-relevance and refixation behavior. We found higher SRP amplitudes for first fixations than refixations over the occipital region for task-relevant items only. Our findings indicate that saccade planning is modulated by both task-relevance of an item and working memory load.
A system for tracking whisker kinematics and whisker shape in three dimensions
Authors: Petersen Rasmus S. , Rodriguez Andrea Colins , Evans Mathew Hywel , Campagner Dario , Loft Michaela S. E.
Published: September 2019

Quantification of behaviour is essential for systems neuroscience. Since the whisker system is a major model system for investigating the neural basis of behaviour, it is important to have methods for measuring whisker movements from behaving animals. Here, we developed a high-speed imaging system that measures whisker movements simultaneously from two vantage points. We developed an algorithm that uses the ‘stereo’ video data to track multiple whiskers by fitting 3D curves to the basal section of each target whisker. By using temporal information to constrain the fits, the algorithm is able to track multiple whiskers in parallel with low error rate. We used the output of the tracker to produce a 3D description of each tracked whisker, including its 3D orientation and 3D shape, as well as bending-related mechanical force. In conclusion, we present an automatic system to track whiskers in 3D from high-speed video, creating the opportunity for comprehensive 3D analysis of sensorimotor behaviour and its neural basis.

Author summary

The great ethologist Niko Tinbergen described a crucial challenge in biology to measure the “total movements made by the intact animal”. Advances in high-speed video and machine analysis of such data have made it possible to make profound advances. Here, we target the whisker system. The whisker system is a major experimental model in neurobiology and, since the whiskers are readily imageable, the system is ideally suited to machine vision. Rats and mice explore their environment by sweeping their whiskers to and fro. It is important to measure whisker movements in 3D, since whiskers move in 3D and since the mechanical forces that act on them are 3D. However, the problem of automatically tracking whiskers in 3D from video has generally been regarded as prohibitively difficult. Our innovation here is to extract 3D information about whiskers using a two-camera, high-speed imaging system and to develop computational methods to infer 3D whisker state from the imaging data. Our hope is that this study will facilitate comprehensive, 3D analysis of whisker behaviour and, more generally, contribute new insight into brain mechanisms of perception and behaviour.
C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus
Authors: Kim Eun Seon , Chung Chang Geon , Kim Yoon Ha , Cha In Jun , Park Jeong Hyang , Kim Jaekwang , Ha Chang Man , Kim Hyung-Jun , Lee Sung Bae
Published: September 2019

Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential toxic cellular consequences remain largely undefined. RNA accumulated in the nucleus may interact with and increase nuclear localization of RNA-binding proteins (RBPs). Here, we show in C9-ALS/FTD Drosophila melanogaster model that Staufen, a double-stranded RBP normally localized in cytoplasm, accumulates in the nucleus, which is in contrast to many nuclear-localized RBPs, such as TDP-43 and FUS, whose cytoplasmic accumulation is thought to be a pathological hallmark of ALS/FTD. We found that in Drosophila neurons expressing arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in an RNA-dependent manner. In the nucleus, Staufen localized closely to, and potentially interacts with, heterochromatin and nucleolus in Drosophila C4 da neurons expressing poly(PR), a proline-arginine (PR) DPR. PR toxicity in C4 da neurons increased Fibrillarin staining in the nucleolus, which was enhanced by stau heterozygous mutation. Furthermore, knockdown of fib exacerbated retinal degeneration mediated by PR toxicity, which suggests that increased amount of Fibrillarin by stau heterozygous mutation is protective. Heterozygotic mutation of stau could also mitigate retinal degeneration and rescue viability of flies exhibiting PR toxicity. Taken together, our data show that nuclear accumulation of cytoplasmic protein, such as Staufen, may also be an important pathological feature of C9-ALS/FTD.

Author summary

Cytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity and further augmented by reduction in stau dosage, the gene encoding Staufen. When we knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their retinal degeneration and viability were largely rescued. Based on these data, we suggest that nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that reducing stau dosage is a promising therapeutic target.
Disentangling sound from syntax: electrophysiological analysis of linguistics expressions
Authors: Artoni Fiorenzo , d’Orio Piergiorgio , Catricalà Eleonora , Conca Francesca , Bottoni Franco , Pelliccia Veronica , Sartori Ivana , Russo Giorgio Lo , Cappa Stefano F. , Micera Silvestro , Moro Andrea
Published: September 2019

Syntax is a species-specific component of human language combining a finite set of words in a potentially infinite number of sentences. Since words are by definition expressed by sound, factoring out syntactic information is normally impossible. Here, we circumvented this problem in a novel way by designing phrases with exactly the same acoustic content but different syntactic structures depending on the other words they occur with. By performing stereo- electroencephalographic (SEEG) recordings in epileptic patients we measured a different electrophysiological correlate of verb phrases vs. noun phrases by analyzing the high gamma band activity (150-300Hz frequency), in multiple cortical areas in both hemispheres, including language areas and their homologous in the non-dominant hemisphere. Our findings contribute to the ultimate goal of a complete neural decoding of linguistic structures from the brain.
Imaging plant germline differentiation within Arabidopsis flower by light sheet microscopy
Authors: Valuchova Sona , Mikulkova Pavlina , Pecinkova Jana , Klimova Jana , Krumnikl Michal , Bainar Petr , Heckmann Stefan , Tomancak Pavel , Riha Karel
Published: September 2019

In higher plants, germline differentiation occurs during a relatively short period within developing flowers. Understanding of the mechanisms that govern germline differentiation lags behind other plant developmental processes. This is largely because the germline is restricted to relatively few cells buried deep within floral tissues, which makes them difficult to study. To overcome this limitation, we have developed a methodology for live imaging of the germ cell lineage within floral organs of Arabidopsis using light sheet fluorescence microscopy. We have established reporter lines, cultivation conditions, and imaging protocols for high-resolution microscopy of developing flowers continuously for up to several days. We used multiview imagining to reconstruct a three-dimensional model of a flower at subcellular resolution. We demonstrate the power of this approach by capturing male and female meiosis, asymmetric pollen division, movement of meiotic chromosomes, and unusual restitution mitosis in tapetum cells. This method will enable new avenues of research into plant sexual reproduction.
Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure
Authors: Fan Jason , Du Wen , Kim-Muller Ja Young , Son Jinsook , Kuo Taiyi , Larrea Delfina , Garcia Christian , Kitamoto Takumi , Kraakman Michael J. , Owusu-Ansah Edward , Cirulli Vincenzo , Accili Domenico
Published: September 2019

Objective

Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β-cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell’s response to an adverse metabolic environment with impaired mitochondrial function remains unclear.

Methods

Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and NAD/NADH ratios.

Results

Expression of Cyb5r3 is decreased in FoxO1-deficient β-cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β-cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β-cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability.

Conclusions

The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.
Adaptive Tuning Curve Widths Improve Sample Efficient Learning
Authors: Meier Florian , Dang-Nhu Raphaël , Steger Angelika
Published: September 2019

Natural brains perform miraculously well in learning new tasks from a small number of samples, whereas sample efficient learning is still a major open problem in the field of machine learning. Here, we raise the question, how the neural coding scheme affects sample efficiency, and make first progress on this question by proposing and analyzing a learning algorithm that uses a simple reinforce-type plasticity mechanism and does not require any gradients to learn low dimensional mappings. It harnesses three bio-plausible mechanisms, namely, population codes with bell shaped tuning curves, continous attractor mechanisms and probabilistic synapses, to achieve sample efficient learning. We show both theoretically and by simulations that population codes with broadly tuned neurons lead to high sample efficiency, whereas codes with sharply tuned neurons account for high final precision. Moreover, a dynamic adaptation of the tuning width during learning gives rise to both, high sample efficiency and high final precision. We prove a sample efficiency guarantee for our algorithm that lies within a logarithmic factor from the information theoretical optimum. Our simulations show that for low dimensional mappings, our learning algorithm achieves comparable sample efficiency to multi-layer perceptrons trained by gradient descent, although it does not use any gradients. Furthermore, it achieves competitive sample efficiency in low dimensional reinforcement learning tasks. From a machine learning perspective, these findings may inspire novel approaches to improve sample efficiency. From a neuroscience perspective, these findings suggest sample efficiency as a yet unstudied functional role of adaptive tuning curve width.
Probing glioblastoma and its microenvironment using single-nucleus and single-cell sequencing
Authors: Peng Sen , Rath Sanhita , Vuong Connor , Bollam Saumya , Eschbacher Jenny , Dong Xishuang , Mehta Shwetal , Sanai Nader , Berens Michael , Kim Seungchan , Dhruv Harshil
Published: September 2019

Single-cell (scSeq) and single-nucleus sequencing (snSeq) are powerful tools to investigate cancer genomics at single cell resolution. Multiple studies have recently illuminated intratumoral heterogeneity in glioblastoma, however, the majority focused on molecular complexity of tumor cells, without considering unexplored host cell types that contribute to the microenvironment around tumor. To address the glioblastoma microenvironment composition and potential tumor-host interactions, we performed deep coverage sequencing of freshly resected primary GBM patient tissue without implementing any tumor enrichment strategies. The sequencing resulted in 902 cells and 1186 nuclei, respectively, passing quality control and with low mitochondrial gene percentage. We customized reference transcriptome by listing gene transcript loci as exons to take into account immature RNA, which greatly improved the alignment rate for single-nucleus data. We applied Cell Ranger pipelines (Version 3.0.2) and Seurat package (Version 2.3.1) and discovered 10 clusters in both scSeq and snSeq. Pathway analysis of each cluster signature in scSeq data along with known GBM microenvironment cell signatures revealed glioma tumor population along with surrounding microglia/macrophages, astrocytes, pericytes, oligodendrocytes, T cells and endothelial cells. The analysis of snSeq was able to capture the majority of cell types from patient tissues (tumor and microenvironment cells), but interestingly presented different cell type composition in microenvironment cell types such as microglia/macrophages. Integrating single-cell and single-nucleus transcriptomic data using canonical correlation analysis facilitated a comparison of snSeq and scSeq, contrasting depiction for certain cell types (e.g. NKX6-2 gene in Oligodendrocytes). Differential analysis of pathways between tumor and microenvironment cells unveiled potentially rewired pathways such as double strand break repair pathway. Our results demonstrate the cellular diversity of brain tumor microenvironment and lay a foundation to further investigate the individual tumor and host cell transcriptomes that are influenced not only by their cell identity but also by their interaction with surrounding microenvironment.
FANCY: Fast Estimation of Privacy Risk in Functional Genomics Data
Authors: Gürsoy Gamze , Brannon Charlotte M. , Navarro Fabio C.P. , Gerstein Mark
Published: September 2019

Functional genomics data is becoming clinically actionable, raising privacy concerns. However, quantifying the privacy leakage by genotyping is difficult due to the heterogeneous nature of sequencing techniques. Thus, we present FANCY, a tool that rapidly estimates number of leaking variants from raw RNA-Seq, ATAC-Seq and ChIP-Seq reads, without explicit genotyping. FANCY employs supervised regression using overall sequencing statistics as features and provides an estimate of the overall privacy risk before data release. FANCY can predict the cumulative number of leaking SNVs with a 0.95 average R2 for all independent test sets. We acknowledged the importance of accurate prediction even when the number of leaked variants is low, so we developed a special version of model, which can make predictions with higher accuracy for only a few leaking variants. A python and MATLAB implementation of FANCY, as well as custom scripts to generate the features can be found at https://github.com/gersteinlab/FANCY. We also provide jupyter notebooks so that users can optimize the parameters in the regression model based on their own data. An easy-to-use webserver that takes inputs and displays results can be found at fancy.gersteinlab.org.
A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques
Authors: Su Jonathan T. , Simpson Solange M , Sung Samuel , Tfaily Ewa Bryndza , Veazey Ronald , Marzinke Mark , Qiu Jiang , Watrous David , Widanapathirana Lakmini , Pearson Elizabeth , Peet M. Melissa , Karunakaran Dipu , Grasperge Brooke , Dobek Georgina , Cain Charlette M. , Hope Thomas , Kiser Patrick F.
Published: September 2019

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbits and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a dose of 10 µg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. Inflammation in the primates was markedly lower in the placebo group than the active implant. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve sustained target dose we observed unacceptable inflammatory response locally at the implant tissue interface.
Reduced frontal white matter microstructure in healthy older adults with low tactile recognition performance
Authors: Higgen Focko L. , Braaß Hanna , Schulz Robert , Xue Gui , Gerloff Christian
Published: September 2019

Aging leads to a reduction of connectivity in large-scale structural brain networks. Sensory processing and other cognitive processes rely on information flow between distant brain areas. However, data linking age-related structural brain alterations to cognitive functioning, especially sensory processing, is sparse.

Aiming to determine group differences in sensory processing between older and younger participants, we implemented a complex tactile recognition task and investigated to what extent changes in microstructural white matter integrity of large-scale brain networks might reflect success in task performance. Structural brain integrity was accessed by means of diffusion-weighted imaging and fractional anisotrophy.

The data revealed that poor performance in complex tactile recognition in older, neurologically healthy individuals is related to decreased structural integrity pronounced in the anterior corpus callosum. This region was strongly connected to the prefrontal cortex. Our data suggests decreased fractional anisotrophy in the anterior corpus callosum as a surrogate marker for progressed brain aging, leading to disturbances in networks relevant for higher-order cognitive processing. Complex tactile recognition might be a sensitive marker for identifying these starting cognitive impairments in older adults.
Spatio-temporal control of DNA replication by the pneumococcal cell cycle regulator CcrZ
Authors: Gallay Clement , Sanselicio Stefano , Anderson Mary E. , Soh Young Min , Liu Xue , Stamsås Gro A. , Pelliciari Simone , van Raaphorst Renske , Dénéréaz Julien , Kjos Morten , Murray Heath , Gruber Stephan , Grossman Alan D. , Veening Jan-Willem
Published: September 2019

Most bacteria replicate and segregate their DNA concomitantly while growing, before cell division takes place. How bacteria synchronize these different cell cycle events to ensure faithful chromosome inheritance is poorly understood. Here, we identified a conserved and essential protein in pneumococci and related Firmicutes named CcrZ (for Cell Cycle Regulator protein interacting with FtsZ) that couples cell division with DNA replication by controlling the activity of the master initiator of DNA replication, DnaA. The absence of CcrZ causes mis-timed and reduced initiation of DNA replication, which subsequently results in aberrant cell division. We show that CcrZ from Streptococcus pneumoniae directly interacts with the cytoskeleton protein FtsZ to place it in the middle of the newborn cell where the DnaA-bound origin is positioned. Together, this work uncovers a new mechanism for the control of the bacterial cell cycle in which CcrZ controls DnaA activity to ensure that the chromosome is replicated at the right time during the cell cycle.
Interactions ofPlasmodium falciparumETRAMP14.1 with PfEMP1, translocon components and other ETRAMP members at the interface of host-parasite
Authors: Sindhe Kirthana Mysore Vasudevarao , Ray Ananya , Kumar Sanjeev , Surolia Namita
Published: September 2019

The Early Transcribed Membrane Proteins (ETRAMPs) belong to a multigene family which are conserved, are specific toPlasmodiumspecies, and abundantly present in parasitophorous vacuolar membrane (PVM). The functions of the members of this family are poorly understood.PfETRAMP14.1 (PF3D7_1401400) is a member of this family, present only inPlasmodium falciparum. In this study, we report the potential interacting partners ofPfETRAMP14.1 by using immunoprecipitation (IP) LC-MS/MS as well as protein-interaction network reconstructed onin vivoarray analyses of severe malaria inflicted patients from malaria endemic Indian regions. We findPfETRAMP14.1 to be the most highly transcribed gene in severe infection. Our studies with western blot analysis and Immuno-flurorescence show thatPfETRAMP14.1 is expressed at PVM during all the intraerythrocytic stages ofP.falciparumwith maximum expression at early trophozoite stage. Further, our results reveal interactions of ETRAMP14.1 withPlasmodium falciparumerythrocyte membrane protein 1(PfEMP1), thioredoxin (TRX2), export protein 2 (EXP2), heat shock protein 70-1 (Hsp70-1) and some of the ETRAMP family members. We propose that ETRAMP14.1 helps trafficking of PfEMP1 to the host RBC surface in conjunction with translocon machinery and the chaperone HSP 70-1.
Coexistence withPseudomonas aeruginosaaltersStaphylococcus aureustranscriptome, antibiotic resistance and internalization into epithelial cells
Authors: Briaud Paul , Camus Laura , Bastien Sylvère , Doléans-Jordheim Anne , Vandenesch François , Moreau Karen
Published: September 2019

Cystic fibrosis (CF) is the most common life-threatening genetic disease among Caucasians. CF patients suffer from chronic lung infections due to the presence of thick mucus, caused bycftrgene dysfunction. The two most commonly found bacteria in the mucus of CF patients areStaphylococcus aureusandPseudomonas aeruginosa. It is well known that early-infectingP. aeruginosastrains produce anti-staphylococcal compounds and inhibitS. aureusgrowth. More recently, it has been shown that late-infectingP. aeruginosastrains develop commensal-like/coexistence interaction withS. aureus. The aim of this study was to decipher the impact ofP. aeruginosastrains onS. aureus. RNA sequencing analysis showed 77 genes were specifically dysregulated in the context of competition and 140 genes in the context of coexistence in the presence ofP. aeruginosa. In coexistence, genes encoding virulence factors and proteins involved in carbohydrates, lipids, nucleotides and amino acids metabolism were downregulated. On the contrary, several transporter family encoding genes were upregulated. In particular, several antibiotic pumps belonging to the Nor family were upregulated:tet38,norAandnorC, leading to an increase in antibiotic resistance ofS. aureuswhen exposed to tetracycline and ciprofloxacin and an enhanced internalization rate within epithelial pulmonary cells. This study shows that coexistence withP. aeruginosaaffects theS. aureustranscriptome and virulence.
A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasitePlasmodium falciparum
Authors: Chan Amanda , Dziedziech Alexis , Kirkman Laura A , Deitsch Kirk W , Ankarklev Johan
Published: September 2019

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencingclag3gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in bothclag3gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance inP. falciparum.

Importance

Drug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.
Chagas disease awareness and socioeconomic characteristics of Bolivian immigrants living in São Paulo, Brazil
Authors: da Silva Rubens Antonio , Wanderley Dalva Marli Valério , Forsyth Colin , Leite Ruth Moreira , de Albuquerque Luna Expedito José , Júnior Nivaldo Carneiro , Shikanai-Yasuda Maria Aparecida ,   Grupo de Pesquisa em Doença de Chagas: atenção primária e imigração (Chagas Disease Research Group: Primary Care and Immigration)
Published: September 2019

In this study, part of a research project on Chagas disease among residents of Bolivia in São Paulo, we describe socioeconomic characteristics, knowledge about the disease and access to health services. A structured questionnaire was applied to a sample of 472 Bolivian adults (> 18 years) living in São Paulo enrolled in the Barra Funda School Health Center. The median age of participants was 28.5 years, 75.0% from the Bolivian department of La Paz, who were living in São Paulo for an average of 5.8 years. Regarding knowledge about the disease and exposure to certain risk factors, 47.7% indicated familiarity with the vector, 23.9% had seen vinchuca in their homes in Bolivia and 6.4% reported having been bitten by a triatomine. The conditions of living in rural areas in Bolivia or in other department than La Paz, have a relative with illness, high school graduation and have seen or been bitten by a vinchuca were significantly associated with the knowledge of the vector. This study provides a view on migration that has important implications for the distribution of Chagas’ disease and access to health care by providing subsidies for proposing public health policies.

Author summary

This article expresses part of the results of a research project called “Chagas disease in a population of Bolivian immigrants in São Paulo: an analysis of the prevalence ofTrypanosoma cruziinfection and morbidity of Chagas disease, knowledge of the population about the disease and access to different levels of health care”. The problem of chronic Chagas disease occurs in many countries, including those not considered endemic, as a result of population movements, mainly by immigration due to urbanization which has led to its globalization. It is now considered an emerging disease with significant potential for transmission via blood transfusions, organ transplants and congenital via, in the absence of appropriate strategies in terms of public health, as well as reactivation of chronic disease in urban centers. It’s no different this phenomenon to the city of Sao Paulo. This study analyzed the sociodemographic inserts, labor, migration and knowledge about Chagas disease and its impact on personal, family and professional life of Bolivian immigrants living in São Paulo.