bluuebunny/crossref_metadata_2025 huggingface dataset:
ER stress arm XBP1s plays a pivotal role in proteasome inhibition-induced bone formation
Authors: Zhang Dan , De Veirman Kim , Fan Rong , Jian Qiang , Zhang Yuchen , Lei Li , Evans Holly , Wang Yanmeng , Lei Lei , Wang Baiyan , Williamson Ramone A. , Chantry Andrew , He Pengcheng , Li Ang , De Raeve Hendrik , Vanderkerken Karin , He Aili , Hu Jinsong
Published: November 2020

Background

Bone destruction is a hallmark of multiple myeloma (MM). It has been reported that proteasome inhibitors (PIs) can reduce bone resorption and increase bone formation in MM patients, but the underlying mechanisms remain unclear.

Methods

Mesenchymal stem cells (MSCs) were treated with various doses of PIs, and the effects of bortezomib or carfilzomib on endoplasmic reticulum (ER) stress signaling pathways were analyzed by western blotting and real-time PCR. Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were used to determine the osteogenic differentiation in vitro. Specific inhibitors targeting different ER stress signaling and a Tet-on inducible overexpressing system were used to validate the roles of key ER stress components in regulating osteogenic differentiation of MSCs. Chromatin immunoprecipitation (ChIP) assay was used to evaluate transcription factor-promoter interaction. MicroCT was applied to measure the microarchitecture of bone in model mice in vivo.

Results

We found that both PERK-ATF4 and IRE1α-XBP1s ER stress branches are activated during PI-induced osteogenic differentiation. Inhibition of ATF4 or XBP1s signaling can significantly impair PI-induced osteogenic differentiation. Furthermore, we demonstrated that XBP1s can transcriptionally upregulate ATF4 expression and overexpressing XBP1s can induce the expression of ATF4 and other osteogenic differentiation-related genes and therefore drive osteoblast differentiation. MicroCT analysis further demonstrated that inhibition of XBP1s can strikingly abolish bortezomib-induced bone formation in mouse.

Conclusions

These results demonstrated that XBP1s is a master regulator of PI-induced osteoblast differentiation. Activation of IRE1α-XBP1s ER stress signaling can promote osteogenesis, thus providing a novel strategy for the treatment of myeloma bone disease.
The effect of bed-to-nurse ratio on hospital mortality of critically ill children on mechanical ventilation: a nationwide population-based study
Authors: Jung Minyoung , Park Hyejeong , Kang Danbee , Park Esther , Jeon Kyeongman , Chung Chi Ryang , Yang Jeong Hoon , Suh Gee Young , Guallar Eliseo , Cho Juhee , Cho Joongbum
Published: November 2020

Background

Despite the high workload of mechanical ventilation, there has been a lack of studies on the association between nurse workforce and mortality in mechanically ventilated patients. We evaluated the association of the bed-to-nurse ratio with mortality in ventilated pediatric patients admitted to an intensive care unit (ICU).

Methods

We conducted a nationwide retrospective analysis by using the Korean National Health Insurance database, which categorizes the bed-to-nurse ratio into 9 grades according to the number of beds divided by the number of full-time equivalent registered nurses in a unit. Patients of ages between 28 days and 18 years were enrolled. Multiple admissions and transfers from other hospitals were excluded. We evaluated the odds ratios (ORs) of in-hospital mortality using 4 groups (Grade 1: bed-to-nurse < 0.50, Grade 2: < 0.63, Grade 3: < 0.77, Grade 4 or above > 0.77) with adjustment of patient factors, hospital factors, and treatment requirements.

Results

Of the 27,849 patients admitted to ICU, 11,628 (41.8%) were on mechanical ventilation. The overall in-hospital mortality rates in Grade 1, Grade 2, Grade 3, and Grade 4 or above group were 4.5%, 6.8%, 6.9%, and 4.7%, respectively. The adjusted ORs (95% CI) for in-hospital mortality of mechanically ventilated patients in the Grade 2, Grade 3, and Grade 4 or above compared to those in Grade 1 were 2.73 (95% CI 1.51–4.95), 4.02 (95% CI 2.23–7.26), and 7.83 (4.07–15.07), respectively. However, for patients without mechanical ventilation, the adjusted ORs of in-hospital mortality were not statistically significant.

Conclusion

In mechanically ventilated patients, the adjusted mortality rate increased significantly, as the bed-to-nurse ratio of the ICU increased. Policies that limit the number of ventilated patients per nurse should be considered.

Trial registrationretrospectively registered
Trends in deaths from road injuries during the COVID-19 pandemic in Japan, January to September 2020
Authors: Nomura Shuhei , Kawashima Takayuki , Yoneoka Daisuke , Tanoue Yuta , Eguchi Akifumi , Gilmour Stuart , Hashizume Masahiro
Published: November 2020

Background

In Japan, the latest estimates of excess all-cause deaths through January to July 2020 showed that the overall (direct and indirect) mortality burden from the Coronavirus Disease 2019 (COVID-19) in Japan was relatively low compared to Europe and the United States. However, consistency between the reported number of COVID-19 deaths and excess all-cause deaths was limited across prefectures, suggesting the necessity of distinguishing the direct and indirect consequences of COVID-19 by cause-specific analysis. To examine whether deaths from road injuries decreased during the COVID-19 pandemic in Japan, consistent with a possible reduction of road transport activity connected to Japan’s state of emergency declaration, we estimated the exiguous deaths from road injuries in each week from January to September 2020 by 47 prefectures.

Methods

To estimate the expected weekly number of deaths from road injuries, a quasi-Poisson regression was applied to daily traffic fatalities data obtained from Traffic Accident Research and Data Analysis, Japan. We set two thresholds, point estimate and lower bound of the two-sided 95% prediction interval, for exiguous deaths, and report the range of differences between the observed number of deaths and each of these thresholds as exiguous deaths.

Results

Since January 2020, in a few weeks the observed deaths from road injuries fell below the 95% lower bound, such as April 6–12 (exiguous deaths 5–21, percent deficit 2.82–38.14), May 4–10 (8–23, 21.05–43.01), July 20–26 (12–29, 30.77–51.53), and August 3–9 (3–20, 7.32–34.41). However, those less than the 95% lower bound were also observed in weeks in the previous years.

Conclusions

The number of road traffic fatalities during the COVID-19 pandemic in Japan has decreased slightly, but not significantly, in several weeks compared with the average year. This suggests that the relatively small changes in excess all-cause mortality observed in Japan during the COVID-19 pandemic could not be explained simply by an offsetting reduction in traffic deaths. Considering a variety of other indirect effects, evaluating an independent, unbiased measure of COVID-19-related mortality burden could provide insight into the design of future broad-based infectious disease counter-measures and offer lessons to other countries.
Comparing quality of reporting between preprints and peer-reviewed articles in the biomedical literature
Authors: Carneiro Clarissa F. D. , Queiroz Victor G. S. , Moulin Thiago C. , Carvalho Carlos A. M. , Haas Clarissa B. , Rayêe Danielle , Henshall David E. , De-Souza Evandro A. , Amorim Felippe E. , Boos Flávia Z. , Guercio Gerson D. , Costa Igor R. , Hajdu Karina L. , van Egmond Lieve , Modrák Martin , Tan Pedro B. , Abdill Richard J. , Burgess Steven J. , Guerra Sylvia F. S. , Bortoluzzi Vanessa T. , Amaral Olavo B.
Published: November 2020

Background

Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader’s ability to independently interpret data and reproduce findings.

Methods

In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals.

Results

Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication.

Conclusions

Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.
Natural bioactive substances for the control of food-borne viruses and contaminants in food
Authors: Pan Yao , Deng Zeyuan , Shahidi Fereidoon
Published: November 2020

Food-borne viruses and contaminants, as an important global food safety problem, are caused by chemical, microbiological, zoonotic, and other risk factors that represent a health hazard. Natural bioactive substances, originating from plants, animals, or microorganisms, might offer the possibility of preventing and controlling food-borne diseases. In this contribution, the common bioactive substances such as polyphenols, essential oils, proteins, and polysaccharides which are effective in the prevention and treatment of food-borne viruses and contaminants are discussed. Meanwhile, the preventive effects of natural bioactive substances and the possible mechanisms involved in food protection are discussed and detailed. The application and potential effects of natural bioactive substances in the adjuvant treatment for food-borne diseases is also described.

Graphical abstract
Urinary schistosomiasis and the associated bladder cancer: update
Authors: Zaghloul Mohamed S. , Zaghloul Tarek M. , Bishr Mai K. , Baumann Brian C.
Published: November 2020

Background

Urinary schistosomiasis and its severe complications, mainly bladder cancer, are scarce in non-endemic areas. The deficiency in knowledge and clinical experience of schistosomiasis may lead to inadequate management. Highlighting these topics may be of value, especially with the increased immigration from endemic low-/middle-income countries (LMIC) to non-endemic high-income countries (HIC). Schistosomiasis is a parasitic infection endemic in many low- and middle-income countries. It can affect various systems but is best known for its effect on the urinary system.

Main Body

PubMed, Scopus, Google Scholar, and the Cochrane Library databases were searched for urinary schistosomiasis and its related bladder cancer published from 1980 till 2020.

Schistosoma haematobium (SH) infecting the urinary bladder was considered by the IARC as group 1 definitive biological carcinogenic agent. Several carcinogenic pathways have been postulated but the exact mechanism(s) are not defined yet. A more thorough understanding of the parasite life cycle was explored to help eradicate the infection especially for the immigrants from endemic areas. This may prevent or slow down the process of carcinogenesis that leads to Schistosoma-associated bladder cancer (SA-BC), which is usually, but not conclusively, squamous cell carcinoma. Treatment of SA-BC generally follows the same guidelines as urothelial Schistosoma-non-associated bladder cancer (SNA-BC) management; however, prospective trials to confirm and refine the treatment approach for SA-BC have been relatively limited.

Conclusion

The available data showed that despite some etiologic and carcinogenic differences, the oncologic outcomes are generally comparable for SA-BC and NSA-BC when adjusting for stage, risk status, and comorbidities.
Missing Events in Event Studies: Identifying the Effects of Partially Measured News Surprises
Authors: Gürkaynak Refet S. , Kısacıkoğlu Burçin , Wright Jonathan H.
Published: November 2020

Macroeconomic news announcements are elaborate and multidimensional. We consider a framework in which jumps in asset prices around announcements reflect both the response to observed surprises in headline numbers and to latent factors, reflecting other news in the release. Non-headline news, for which there are no expectations surveys, is unobservable to the econometrician but nonetheless elicits a market response. We estimate the model by the Kalman filter, which efficiently combines OLS and heteroskedasticity-based event study estimators in one step. With the inclusion of a single latent surprise factor, essentially all yield curve variance in event windows are explained by news. (JEL C51, E43, E52, G12, G14)
A Model of Competing Narratives
Authors: Eliaz Kfir , Spiegler Ran
Published: November 2020

We formalize the argument that political disagreements can be traced to a “clash of narratives.” Drawing on the “Bayesian Networks” literature, we represent a narrative by a causal model that maps actions into consequences, weaving a selection of other random variables into the story. Narratives generate beliefs by interpreting long-run correlations between these variables. An equilibrium is defined as a probability distribution over narrative-policy pairs that maximize a representative agent's anticipatory utility, capturing the idea that people are drawn to hopeful narratives. Our equilibrium analysis sheds light on the structure of prevailing narratives, the variables they involve, the policies they sustain, and their contribution to political polarization. (JEL D72, D83, D85, F52)
A Few Bad Apples Spoil the Barrel: An Anti-Folk Theorem for Anonymous Repeated Games with Incomplete Information
Authors: Sugaya Takuo , Wolitzky Alexander
Published: November 2020

We study anonymous repeated games where players may be “commitment types” who always take the same action. We establish a stark anti-folk theorem: if the distribution of the number of commitment types satisfies a smoothness condition and the game has a “pairwise dominant” action, this action is almost always taken. This implies that cooperation is impossible in the repeated prisoner's dilemma with anonymous random matching. We also bound equilibrium payoffs for general games. Our bound implies that industry profits converge to zero in linear-demand Cournot oligopoly as the number of firms increases. (JEL C72, C73, D83)
Πλατωνικοί και Πληθωνικοί φύλακες
Authors: Τσούχλος Θεόδωρος
Published: November 2020

Δεν διατίθεται περίληψη
The effect of femoral stem collar on implant migration and clinical outcomes following direct anterior approach total hip arthroplasty
Authors: Perelgut Maxwell E. , Polus Jennifer S. , Lanting Brent A. , Teeter Matthew G.
Published: November 2020

Aims

The direct anterior (DA) approach has been associated with rapid patient recovery after total hip arthroplasty (THA) but may be associated with more frequent femoral complications including implant loosening. The objective of this study was to determine whether the addition of a collar to the femoral stem affects implant migration, patient activity, and patient function following primary THA using the DA approach.

Methods

Patients were randomized to either a collared (n = 23) or collarless (n = 26) cementless femoral stem implanted using the DA approach. Canal fill ratio (CFR) was measured on the first postoperative radiographs. Patients underwent a supine radiostereometric analysis (RSA) exam postoperatively on the day of surgery and at two, four, six, 12, 26, and 52 weeks postoperatively. Patient-reported outcome measures (Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, the 12-item Short Form Health Survey Mental and Physical Score, and University of California, Los Angeles (UCLA) Activity Score) were measured preoperatively and at each post-surgery clinic visit. Activity and function were also measured as the weekly average step count recorded by an activity tracker, and an instrumented timed up-and-go (TUG) test in clinic, respectively.

Results

Comparing the RSA between the day of surgery baseline exam to two weeks postoperatively, subsidence was significantly lower (mean difference 2.23 mm (SD 0.71), p = 0.023) with collared stems, though these patients had a greater CFR (p = 0.048). There was no difference (p = 0.426) in subsidence between stems from a two-week baseline through to one year postoperatively. There were no clinically relevant differences in PROMs; and there was no difference in the change in activity (p = 0.078) or the change in functional capacity (p = 0.664) between the collared stem group and the collarless stem group at any timepoint.

Conclusion

Presence of a collar on the femoral stem resulted in reduced subsidence during the first two postoperative weeks following primary THA using the DA approach. However, the clinical implications are unclear, and larger studies examining patient activity and outcomes are required. Cite this article: Bone Joint J 2020;102-B(12):1654–1661.
The neck-shaft angle is the key factor for the positioning of calcar screw when treating proximal humeral fractures with a locking plate
Authors: Wang Qiuke , Sheng Ning , Rui Biyu , Chen Yunfeng
Published: November 2020

Aims

The aim of this study was to explore why some calcar screws are malpositioned when a proximal humeral fracture is treated by internal fixation with a locking plate, and to identify risk factors for this phenomenon. Some suggestions can be made of ways to avoid this error.

Methods

We retrospectively identified all proximal humeral fractures treated in our institution between October 2016 and October 2018 using the hospital information system. The patients’ medical and radiological data were collected, and we divided potential risk factors into two groups: preoperative factors and intraoperative factors. Preoperative factors included age, sex, height, weight, body mass index, proximal humeral bone mineral density, type of fracture, the condition of the medial hinge, and medial metaphyseal head extension. Intraoperative factors included the grade of surgeon, neck-shaft angle after reduction, humeral head height, restoration of medial support, and quality of reduction. Adjusted binary logistic regression and multivariate logistic regression models were used to identify pre- and intraoperative risk factors. Area under the curve (AUC) analysis was used to evaluate the discriminative ability of the multivariable model.

Results

Data from 203 patients (63 males and 140 females) with a mean age of 62 years (22 to 89) were analyzed. In 49 fractures, the calcar screw was considered to be malpositioned; in 154 it was in the optimal position. The rate of malpositioning was therefore 24% (49/203). No preoperative risk factor was found for malpositioning of the calcar screws. Only the neck-shaft angle was found to be related to the risk of screw malpositioning in a multivariate model (with an AUC of 0.72). For the fractures in which the neck-shaft angle was reduced to between 130° and 150°, 91% (133/46) of calcar screws were in the optimal position.

Conclusion

The neck-shaft angle is the key factor for the appropriate positioning of calcar screws when treating a proximal humeral fracture with a locking plate. We recommend reducing the angle to between 130° and 150°. Cite this article: Bone Joint J 2020;102-B(12):1629–1635.
Recurrent posterior shoulder instability starting in childhood and adolescence
Authors: Langlais Tristan , Hardy Marie B. , Lavoue Vincent , Barret Hugo , Wilson Adam , Boileau Pascal
Published: November 2020

Aims

We aimed to address the question on whether there is a place for shoulder stabilization surgery in patients who had voluntary posterior instability starting in childhood and adolescence, and later becoming involuntary and uncontrollable.

Methods

Consecutive patients who had an operation for recurrent posterior instability before the age of 18 years were studied retrospectively. All patients had failed conservative treatment for at least six months prior to surgery; and no patients had psychiatric disorders. Two groups were identified and compared: voluntary posterior instability starting in childhood which became uncontrollable and involuntary (group VBI); and involuntary posterior instability (group I). Patients were reviewed and assessed at least two years after surgery by two examiners.

Results

In all 38 patients (40 shoulders) were included: group I (20 shoulders), with involuntary posterior instability (onset at 14 years of age (SD 2.3), and group VBI (20 shoulders), with initially voluntary posterior instability (onset at 9 years of age (SD 2.6) later becoming involuntary (16 years of age (SD 3.5). Mean age at surgery was 20 years (SD 4.6 years; 12 to 35). A posterior bone block was performed in 18 patients and a posterior capsular shift in 22. The mean follow-up was 7.7 years (2 to 18). Recurrence of posterior instability was seen in nine patients, 30% in group VBI (6/20 shoulders) and 15% in group I (3/20 shoulders) (p > 0.050). At final follow-up, the shoulder's of two patients in each group had been revised. No differences between either group were found for functional outcomes, return to sport, subjective, and radiological results.

Conclusion

Although achieving stability in patients with so-called voluntary instability, which evolves into an involuntary condition, is difficult, shoulder stabilization may be undertaken with similar outcomes to those patients treated surgically for involuntary instability. Cite this article: Bone Joint J 2020;102-B(12):1760–1766.
The Linear and Nonlinear Bending Analyses of Functionally Graded Carbon Nanotube-Reinforced Composite Plates Based on the Novel Four-Node Quadrilateral Element
Authors: Ton-That Hoang Lan
Published: November 2020

This paper presents the linear and nonlinear analyses of functionally graded carbon nanotube- reinforced composite (FG-CNTRC) plates using a four-node quadrilateral element based on the C0-type of Shi’s third-order shear deformation theory (C0-STSDT). Shi’s theory is taking the advantages and desirable properties of the third-order shear deformation theory. Besides, material properties of FG-CNTRC plates are changed from the bottom to top surface and based on the rule of mixture. Numerical results and comparison with other reference solutions suggest that the advantages of present element are accuracy and efficiency in analysis of FG-CNTRC plates. Some nonlinear numerical results of FG-CNTRC plates are also given in this paper and this contributes to providing additional data for future research work.
Classification of laser modality for a self-mixing interferometric sensor
Authors: Usman Muhammad , Zabit Usman , Asad Alam Syed
Published: November 2020

Robust detection and classification of multimodal self-mixing (SM) signals emanating from the optical feedback-based SM interferometric laser sensor are necessary for accurate retrieval of sensing information. An abrupt shift in the modality of SM signals can occur due to different operating conditions; consequently, an unidentified modality shift can cause severe measurement errors. Therefore, it is necessary to detect and identify the type of multimodality so that relevant adjustments could then be made, either in the SM sensor setup or in the relevant signal processing, to avoid the errors caused by the shift in modality. In this work, SM modality identification and classification techniques based on the machine learning classifier algorithms of linear regression, XGB regressor, and decision tree regressor are proposed. The distinguishing feature values, which are used to train and test the classifiers, are extracted from the given SM signal by applying techniques such as principal component analysis, peak width, and linear discriminant analysis. Proposed methods are tested on an SM signal dataset containing a total of 45 unseen SM signals, acquired experimentally from the SM sensor. The identification and classification accuracy of the three classifiers of linear regression, XGB regressor, and decision tree regressor is 76%, 96%, and 100%, respectively.
Combined total internal reflection AF spectral-imaging and Raman spectroscopy for fast assessment of surgical margins during breast cancer surgery
Authors: Lizio Maria Giovanna , Liao Zhiyu , Shipp Dustin W. , Boitor Radu , Mihai Raluca , Sharp James S. , Russell Matthew , Khout Hazem , Rakha Emad A. , Notingher Ioan
Published: November 2020

The standard treatment for breast cancer is surgical removal mainly through breast-conserving surgery (BCS). We developed a new technique based on auto-fluorescence (AF) spectral imaging and Raman spectroscopy for fast intraoperative assessment of excision margins in BCS. A new wide-field AF imaging unit based on total internal reflection (TIR) was combined with a Raman spectroscopy microscope equipped with a 785 nm laser. The wavelength of the AF excitation was optimized to 365 nm in order to maximize the discrimination of adipose tissue. This approach allows for the non-adipose regions of tissue, which are at a higher risk of containing a tumor, to be targeted more efficiently by the Raman spectroscopy measurements. The integrated TIR-AF-Raman was tested on small tissue samples as well as fresh wide local excisions, delivering the analysis of the entire cruciate surface of BCS specimens (5.1 × 7.6 cm2) in less than 45 minutes and also providing information regarding the location of the tumor in the specimen. Full automation of the instrument and selection of a faster translation stage would allow for the measurement of BCS specimens within an intraoperative time scale (20 minutes). This study demonstrates that the TIR-AF Raman microscope represents a feasible step towards the development of a technique for intraoperative assessment of large WLE within intraoperative timescales.
Analysis of angular dispersion induced by wavefront rotation in nanosecond optical parametric chirped pulse amplification
Authors: Kim Yeong Gyu , Lee Hwang Woon , Im Han Bum , Kim Ji In , Sung Jae Hee , Yoon Jin Woo , Lee Seong Ku , Nam Chang Hee
Published: November 2020

Angular dispersion observed in a nanosecond optical parametric chirped-pulse amplification (ns-OPCPA) amplifier adopted in the frontend of a multi-PW laser was analyzed. The theory on the angular dispersion, extended by including the wavefront rotation and the pulse front tilt of a strongly chirped laser pulse, revealed that the wavefront rotation is a major contributor to the angular dispersion, as compared to the pulse front tilt, in a ns-OPCPA amplifier. It was also shown that the wavefront rotation could be introduced by the phase mismatch and the noncollinear propagation angle in the noncollinear ns-OPCPA amplifier. The theoretical prediction was experimentally verified by measuring the angular dispersion of the ns-OPCPA frontend installed in the 20-fs, 4-PW Ti:Sapphire laser. We emphasize the importance of the proper characterization and control of the angular dispersion in the ns-OPCPA amplifier since the focus intensity of an ultrahigh power laser could be significantly reduced due to the spatiotemporal effect even for small induced angular dispersion.
We need to keep a reproducible trace of facts, predictions, and hypotheses from gene to function in the era of big data
Authors: Kasif Simon , Roberts Richard J.
Published: November 2020

How do we scale biological science to the demand of next generation biology and medicine to keep track of the facts, predictions, and hypotheses? These days, enormous amounts of DNA sequence and other omics data are generated. Since these data contain the blueprint for life, it is imperative that we interpret it accurately. The abundance of DNA is only one part of the challenge. Artificial Intelligence (AI) and network methods routinely build on large screens, single cell technologies, proteomics, and other modalities to infer or predict biological functions and phenotypes associated with proteins, pathways, and organisms. As a first step, how do we systematically trace the provenance of knowledge from experimental ground truth to gene function predictions and annotations? Here, we review the main challenges in tracking the evolution of biological knowledge and propose several specific solutions to provenance and computational tracing of evidence in functional linkage networks.
Biological network growth in complex environments: A computational framework
Authors: Paul Torsten Johann , Kollmannsberger Philip
Published: November 2020

Spatial biological networks are abundant on all scales of life, from single cells to ecosystems, and perform various important functions including signal transmission and nutrient transport. These biological functions depend on the architecture of the network, which emerges as the result of a dynamic, feedback-driven developmental process. While cell behavior during growth can be genetically encoded, the resulting network structure depends on spatial constraints and tissue architecture. Since network growth is often difficult to observe experimentally, computer simulations can help to understand how local cell behavior determines the resulting network architecture. We present here a computational framework based on directional statistics to model network formation in space and time under arbitrary spatial constraints. Growth is described as a biased correlated random walk where direction and branching depend on the local environmental conditions and constraints, which are presented as 3D multilayer grid. To demonstrate the application of our tool, we perform growth simulations of a dense network between cells and compare the results to experimental data from osteocyte networks in bone. Our generic framework might help to better understand how network patterns depend on spatial constraints, or to identify the biological cause of deviations from healthy network function.
Brain Modeling ToolKit: An open source software suite for multiscale modeling of brain circuits
Authors: Dai Kael , Gratiy Sergey L. , Billeh Yazan N. , Xu Richard , Cai Binghuang , Cain Nicholas , Rimehaug Atle E. , Stasik Alexander J. , Einevoll Gaute T. , Mihalas Stefan , Koch Christof , Arkhipov Anton
Published: November 2020

Experimental studies in neuroscience are producing data at a rapidly increasing rate, providing exciting opportunities and formidable challenges to existing theoretical and modeling approaches. To turn massive datasets into predictive quantitative frameworks, the field needs software solutions for systematic integration of data into realistic, multiscale models. Here we describe the Brain Modeling ToolKit (BMTK), a software suite for building models and performing simulations at multiple levels of resolution, from biophysically detailed multi-compartmental, to point-neuron, to population-statistical approaches. Leveraging the SONATA file format and existing software such as NEURON, NEST, and others, BMTK offers a consistent user experience across multiple levels of resolution. It permits highly sophisticated simulations to be set up with little coding required, thus lowering entry barriers to new users. We illustrate successful applications of BMTK to large-scale simulations of a cortical area. BMTK is an open-source package provided as a resource supporting modeling-based discovery in the community.
Dopamine release, diffusion and uptake: A computational model for synaptic and volume transmission
Authors: Wiencke Kathleen , Horstmann Annette , Mathar David , Villringer Arno , Neumann Jane
Published: November 2020

Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission.
Phenomic screen identifies a role for the yeast lysine acetyltransferase NuA4 in the control of Bcy1 subcellular localization, glycogen biosynthesis, and mitochondrial morphology
Authors: Walden Elizabeth A. , Fong Roger Y. , Pham Trang T. , Knill Hana , Laframboise Sarah Jane , Huard Sylvain , Harper Mary-Ellen , Baetz Kristin
Published: November 2020

Cellular metabolism is tightly regulated by many signaling pathways and processes, including lysine acetylation of proteins. While lysine acetylation of metabolic enzymes can directly influence enzyme activity, there is growing evidence that lysine acetylation can also impact protein localization. As theSaccharomyces cerevisiaelysine acetyltransferase complex NuA4 has been implicated in a variety of metabolic processes, we have explored whether NuA4 controls the localization and/or protein levels of metabolic proteins. We performed a high-throughput microscopy screen of over 360 GFP-tagged metabolic proteins and identified 23 proteins whose localization and/or abundance changed upon deletion of the NuA4 scaffolding subunit,EAF1. Within this, three proteins were required for glycogen synthesis and 14 proteins were associated with the mitochondria. We determined that ineaf1Δ cells the transcription of glycogen biosynthesis genes is upregulated resulting in increased proteins and glycogen production. Further, in the absence ofEAF1, mitochondria are highly fused, increasing in volume approximately 3-fold, and are chaotically distributed but remain functional. Both the increased glycogen synthesis and mitochondrial elongation ineaf1Δ cells are dependent on Bcy1, the yeast regulatory subunit of PKA. Surprisingly, in the absence ofEAF1, Bcy1 localization changes from being nuclear to cytoplasmic and PKA activity is altered. We found that NuA4-dependent localization of Bcy1 is dependent on a lysine residue at position 313 of Bcy1. However, the glycogen accumulation and mitochondrial elongation phenotypes ofeaf1Δ, while dependent on Bcy1, were not fully dependent on Bcy1-K313 acetylation state and subcellular localization of Bcy1. As NuA4 is highly conserved with the human Tip60 complex, our work may inform human disease biology, revealing new avenues to investigate the role of Tip60 in metabolic diseases.
Epilepsy surveillance in normocephalic children with and without prenatal Zika virus exposure
Authors: Blackmon Karen , Waechter Randall , Landon Barbara , Noël Trevor , Macpherson Calum , Donald Tyhiesia , Cudjoe Nikita , Evans Roberta , Burgen Kemi S. , Jayatilake Piumi , Oyegunle Vivian , Pedraza Otto , Abdel Baki Samah , Thesen Thomas , Dlugos Dennis , Chari Geetha , Patel Archana A. , Grossi-Soyster Elysse N. , Krystosik Amy R. , LaBeaud A. Desiree
Published: November 2020

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003–0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.
Stereotactic body radiation therapy mitigates radiation induced lymphopenia in early stage non-small cell lung cancer
Authors: McLaughlin Mark F. , Alam Morshed , Smith Lynnette , Ryckman Jeffrey , Lin Chi , Baine Michael J.
Published: November 2020

Introduction

Radiation-induced lymphopenia (RIL) occurs during treatment with conventional radiation in multiple organ sites. Development of RIL portends poor prognosis. Stereotactic body radiation therapy (SBRT) spares RIL in pancreatic cancer, but has not been examined in other sites commonly treated with SBRT. This work examines if SBRT similarly spares RIL in patients with non-small cell lung cancer (NSCLC).

Materials and methods

Retrospective analysis was done at a single institution on 40 distinct cases of SBRT for early stage NSCLC from 2006–2017. Incidentally collected lymphocyte counts collected within 6 months of SBRT treatment were analyzed to determine if RIL occurred. The presence of RIL was correlated with location of initial failure and survival endpoints. Kaplan-Meier curves were constructed with significance defined at the level p < 0.05.

Results

RIL was observed in 35% of the analyzed patients. Patterns of failure and survival data were comparable to prior SBRT literature. There was no observed association in two year local, nodal, or distant failure, progression free survival, or overall survival based on the presence of RIL.

Discussion

SBRT spares RIL in NSCLC compared to historical rates observed with conventionally fractionated radiation. As understanding of the role of the immune system in cancer control continues to evolve, the importance of RIL sparing techniques take on increasing importance. This study represents further analysis of RIL sparing in SBRT in an early stage NSCLC cohort without the confounding influence of chemotherapy.
Chemical profiling and anti-psoriatic activity of marine sponge (Dysidea avara) in induced imiquimod-psoriasis-skin model
Authors: Khaledi Mostafa , Sharif Makhmal Zadeh Behzad , Rezaie Annahita , Nazemi Melika , Safdarian Mehdi , Nabavi Mohammad Bagher
Published: November 2020

Since Marine sponge Dysidea avara is regarded as a source of anti-inflammatory compounds, we decided to evaluate its potential anti-psoriatic activity in a psoriasis Imiquimod-induced in the mouse model. Psoriatic mice were treated with three different methanolic extracts of Dysidea avara compared with betamethasone-treated mice in in- vivo studies. Clinical skin severity was assessed with the psoriasis area index (PASI), whilst ELISA detected the expression of TNF-α, IL-17A, and IL-22. Dysidea avara activity was studied by employing GC-MS (to distinguish compounds), HPTLC (for skin permeation and accumulation), and SEA DOCK to predict single compound potential anti-inflammatory activity. After 7 days of treatment, mice treated with Dysidea avara displayed a dose-dependent, statistically significant improvement compared to controls (p< 0.001). In line with the clinical results, ELISA revealed a statistically significant decrease in IL-22, IL-17A, and TNF-α after treatment; the same SEA DOCK analysis suggests a possible anti-psoriatic activity of the extracts.
The impact of angiotensin-converting-enzyme inhibitors versus angiotensin receptor blockers on 3-year clinical outcomes in patients with acute myocardial infarction without hypertension
Authors: Her Ae-Young , Choi Byoung Geol , Rha Seung-Woon , Kim Yong Hoon , Choi Cheol Ung , Jeong Myung Ho
Published: November 2020

This study aimed to investigate the impact of angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on 3-year clinical outcomes in acute myocardial infarction (AMI) patients without a history of hypertension who underwent successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES). A total of 13,104 AMI patients who were registered in the Korea AMI registry (KAMIR)-National Institutes of Health (NIH) were included in the study. The primary endpoint was 3-year major adverse cardiac events (MACE), which was defined as the composite of all-cause death, recurrent myocardial infarction (MI), and any repeat revascularization. To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed. The patients were divided into two groups: the ACEI group, n = 4,053 patients and the ARB group, n = 4,107 patients. During the 3-year clinical follow-up, the cumulative incidences of MACE (hazard ratio [HR], 0.843; 95% confidence interval [CI], 0.740–0.960; p = 0.010), any repeat revascularization (HR, 0.856; 95% CI, 0.736–0.995; p = 0.044), stroke (HR, 0.613; 95% CI, 0.417–0.901; p = 0.013), and re-hospitalization due to heart failure (HF) (HR, 0.399; 95% CI, 0.294–0.541; p <0.001) in the ACEI group were significantly lower than in the ARB group. In Korean patients with AMI without a history of hypertension, the use of ACEI was significantly associated with reduced incidences of MACE, any repeat revascularization, stroke, and re-hospitalization due to HF than those with the use of ARB.
Eating self-efficacy changes in individuals with type 2 diabetes following a structured lifestyle intervention based on the transcultural Diabetes Nutrition Algorithm (tDNA): A secondary analysis of a randomized controlled trial
Authors: Gilcharan Singh Harvinder Kaur , Chee Winnie Siew Swee , Hamdy Osama , Mechanick Jeffrey Ian , Lee Verna Kar Mun , Barua Ankur , Mohd Ali Siti Zubaidah , Hussein Zanariah
Published: November 2020

Objective

Eating self-efficacy behavior is an important predictor of successful lifestyle intervention. This secondary analysis evaluated the changes in eating self-efficacy behavior in patients with type 2 diabetes (T2D) and overweight/obesity following structured lifestyle intervention based on the Malaysian customized transcultural Diabetes Nutrition Algorithm (tDNA).

Methods

Patients with T2D and overweight/obesity (n = 230) were randomized either into the tDNA group which included a structured low-calorie meal plan using normal foods, incorporation of diabetes-specific meal replacements, and an exercise prescription or usual T2D care (UC) for 6 months. Patients in the tDNA group also received either counseling with motivational interviewing (tDNA-MI) or conventional counseling (tDNA-CC). The UC group received standard dietary and exercise advice using conventional counseling. Eating self-efficacy was assessed using a locally validated Weight Efficacy Lifestyle (WEL) questionnaire. All patients were followed up for additional 6 months’ post-intervention.

Results

There was a significant change in WEL scores with intervention over one-year [Group X Time effect: F = 51.4, df = (3.4, 318.7), p<0.001]. Compared to baseline, WEL scores improved in both the tDNA groups with significantly higher improvement in the tDNA-MI group compared to the tDNA-CC and UC groups at 6 months (tDNA-MI: 25.4±2.1 vs. tDNA-CC: 12.9±2.8 vs. UC: -6.9±1.9, p<0.001). At 12 months’ follow-up, both the tDNA groups maintained improvement in the WEL scores, with significantly higher scores in the tDNA-MI group than tDNA-CC group, and the UC group had decreased WEL scores (tDNA-MI: 28.9±3.1 vs. tDNA-CC: 11.6±3.6 vs. UC: -13.2±2.1, p<0.001). Patients in the tDNA-MI group with greater weight loss and hemoglobin A1C reduction also had a higher eating self-efficacy, with a similar trend observed in comparative groups.

Conclusion

Eating self-efficacy improved in patients with T2D and overweight/obesity who maintained their weight loss and glycemic control following a structured lifestyle intervention based on the Malaysian customized tDNA and the improvement was further enhanced with motivational interviewing.

Clinical trial

This randomized clinical trial was registered under National Medical Research Registry, Ministry of Health Malaysia with registration number: NMRR-14-1042-19455 and also under ClinicalTrials.gov with registration number: NCT03881540.