bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Instrument Comparison of Reagents From a US FDA-Approved Assay for the Assessment of Ki-67 in High-Risk Early Breast Cancer
Authors: Komforti Miglena , Downs-Kelly Erinn , Sapunar Francisco , Wijayawardana Sameera R. , Gruver Aaron M. , Badve Sunil S.
Published: July 2022

The objective of this study was to measure concordance of results obtained from the US Food and Drug Administration–approved Ki-67 immunohistochemistry MIB-1 pharmDx assay performed on the Dako Omnis automated staining instrument (Omnis) versus results produced from the assay reagents applied using an optimized protocol on the more widely available Autostainer Link 48 (ASL48) platform. Tissue sections obtained from 40 formalin-fixed paraffin-embedded breast carcinoma samples, with available Oncotype DX Breast Recurrence Score (RS) results, were stained. Three certified pathologists scored slides at 3 timepoints, totaling 360 observations for each instrument (N=720 total) using the approved scoring approach. Using the ≥20% cutoff, agreement was calculated with corresponding 2-sided 95% percentile bootstrap confidence intervals (CIs). Pairwise comparisons (N=360) from the interinstrument evaluation, performed with all observers, resulted in 325 (90.3%) concordant outcomes (244 negative and 81 positive) and 35 (9.7%) discordant outcomes. The overall agreement was 90.3% (95% confidence interval, 85.6% to 94.4%). No significant systematic differences were observed between instruments. Specimens scored from the Omnis were on average <1% higher than ASL48, with high correlation and little bias between the continuous Ki-67 scores (concordance correlation coefficient=0.916). Most specimens with a Ki-67 score ≥20% had a RS >25. This study demonstrated that good concordance can be achieved with the reagents run on the ASL48 instrument when using an optimized protocol and standardized scoring.
Sodium Bicarbonate Use During Pediatric Cardiopulmonary Resuscitation: A Secondary Analysis of the ICU-RESUScitation Project Trial*
Authors: Cashen Katherine , Reeder Ron W. , Ahmed Tageldin , Bell Michael J. , Berg Robert A. , Burns Candice , Carcillo Joseph A. , Carpenter Todd C. , Dean J. Michael , Diddle J. Wesley , Federman Myke , Fink Ericka L. , Frazier Aisha H. , Friess Stuart H. , Graham Kathryn , Hall Mark , Hehir David A. , Horvat Christopher M. , Huard Leanna L. , Maa Tensing , Manga Arushi , McQuillen Patrick S. , Morgan Ryan W. , Mourani Peter M. , Nadkarni Vinay M. , Naim Maryam Y. , Notterman Daniel , Palmer Chella A. , Pollack Murray M. , Schneiter Carleen , Sharron Matthew P. , Srivastava Neeraj , Wessel David , Wolfe Heather A. , Yates Andrew R. , Zuppa Athena F. , Sutton Robert M. , Meert Kathleen L. ,   for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) and National Heart Lung and Blood Institute ICU-RESUScitation Project Investigators
Published: July 2022

Objectives:

To evaluate associations between sodium bicarbonate use and outcomes during pediatric in-hospital cardiac arrest (p-IHCA).

Design:

Prespecified secondary analysis of a prospective, multicenter cluster randomized interventional trial.

Setting:

Eighteen participating ICUs of the ICU-RESUScitation Project (NCT02837497).

Patients:

Children less than or equal to 18 years old and greater than or equal to 37 weeks post conceptual age who received chest compressions of any duration from October 2016 to March 2021.

Interventions:

None.

Measurements and Main Results:

Child and event characteristics, prearrest laboratory values (2–6 hr prior to p-IHCA), pre- and intraarrest hemodynamics, and outcomes were collected. In a propensity score weighted cohort, the relationships between sodium bicarbonate use and outcomes were assessed. The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Of 1,100 index cardiopulmonary resuscitation events, median age was 0.63 years (interquartile range, 0.19–3.81 yr); 528 (48.0%) received sodium bicarbonate; 773 (70.3%) achieved ROSC; 642 (58.4%) survived to hospital discharge; and 596 (54.2%) survived to hospital discharge with favorable neurologic outcome. Among the weighted cohort, sodium bicarbonate use was associated with lower survival to hospital discharge rate (adjusted odds ratio [aOR], 0.7; 95% CI, 0.54–0.92; p = 0.01) and lower survival to hospital discharge with favorable neurologic outcome rate (aOR, 0.69; 95% CI, 0.53–0.91; p = 0.007). Sodium bicarbonate use was not associated with ROSC (aOR, 0.91; 95% CI, 0.62–1.34; p = 0.621).

Conclusions:

In this propensity weighted multicenter cohort study of p-IHCA, sodium bicarbonate use was common and associated with lower rates of survival to hospital discharge.
Vertigo-Associated Vomiting: Acute Presentation of Thiamine Deficiency in Intestinal Failure
Authors: Zhang Xiaoyi , Arnone Vincent , Ackerman Kimberly , Al-issa Feras
Published: July 2022

Thiamine deficiency can manifest as Wernicke encephalopathy, with the classic clinical triad of altered mental status, nystagmus, and ataxia. Although a rare diagnosis in pediatric patients within developed countries, gastrointestinal disorders that impair nutritional intake and absorption can place patients at higher risk. Rapid diagnosis and early empiric treatment of Wernicke encephalopathy is paramount due to high risk of mortality and long-term morbidity. We present a patient with intestinal failure who developed thiamine deficiency following weaning off parenteral nutrition with acute onset of vertigo-associated vomiting. In the absence of consensus guidelines for treatment dosing and duration, in both adult and pediatric populations, we review prior pediatric cases and propose a strategy for dosing with symptom-guided step-up approach to maximize treatment efficacy in a time-conscious manner.
A Case of Red Retching?
Authors: Karim Sabrina A. , Holmes Tao Tao , Wu Allison J. , Kamin Daniel
Published: July 2022

This piece features a 14-year-old young man who presented with epigastric pain and bright red emesis. His father brought both a photo and sample of the vomitus, which guided initial management in one direction, and then on closer inspection, diverted his diagnostic trajectory. Through a traditional case report and accompanied image and prose, we explore how we process and reinterpret visual data to help guide our management of hematemesis.
COVID-19 Presenting With Acute Anicteric Hepatitis in Pediatric Patient: A Case Report
Authors: Greenberg Gillian M. , Salman Salman S.
Published: July 2022

The impact that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has on the hepatobiliary system is poorly described in the pediatric population compared with the adult population. In adults, gastrointestinal symptoms and marked elevation in liver enzymes in the setting of coronavirus disease 2019 (COVID-19) has been directly correlated with disease severity. This case is a unique presentation of a pediatric patient with a relatively mild disease course despite the presence of gastrointestinal symptoms and marked elevation in transaminases, suggesting that SARS-CoV-2 virus may cause isolated acute hepatitis in pediatric patients.
Clinical Application of Digital Joint Guide in the Fracture of the Condyle Neck
Authors: Gao Tingyi , Wang Dong , Han Rui , Du Yue , Luo Bing , Zhang Kai
Published: July 2022

Purpose:

The purpose of this study is to use a digital guide plate for joint positioning to assist the reduction of condylar neck fractures and evaluate the accuracy of the reduction after surgery.

Materials and Methods:

In this study, 20 patients were selected from January 2016 to October 2020, and the reduction of the mandibular condyle neck fracture was designed virtual and digital based on the computed tomography data of the patients, based on the position of the condyle in the articular socket, the height of the ascending mandibular ramus, and the joints. The average value of the anterior space and the posterior space of the joint is these indicators, the position of the condyle is reconstructed, and the fracture reduction finger guide plate is designed. During the operation, the digital guide plate is used to assist the reduction of the condyle neck fracture. The postoperative follow-up was 4 to 12 months to check the accuracy of the reduction.

Results:

A total of 20 patients, all fractures achieved complete bone healing, the patients’ mouth opening was normal, no obvious complications were found, and none of the patients had facial paralysis. In the postoperative evaluation and preoperative virtual design plan, the chromatographic error was within 2 mm, and the magnetic resonance of the temporomandibular joint showed no displacement of the articular disc.

Conclusion:

The digital joint guide can reduce the fracture of the condyle neck while ensuring the position of the condyle in the joint socket, which is beneficial to reduce the occurrence of subsequent temporomandibular joint complications.
A New Laparoscopic Entry Point in Patients With Previous Laparotomy: A Prospective Comparative Study
Authors: Elbanna Mohey R. , Helmy Ramy F. , Sabry Ahmed M. , El Zemeity Ahmed O.
Published: July 2022

Introduction:

Intraperitoneal access and establishing pneumoperitoneum for laparoscopy is a critical step especially in patients who underwent previous laparotomy due to the higher risk of visceral or vascular injuries. In this study, we propose a new entry point for safe laparoscopic access in cases having previous laparotomy.

Materials and Methods:

This is a prospective controlled randomized trial conducted between January 2016 and January 2022 in Ain Shams University Hospitals. It included 232 patients who underwent laparoscopic procedures after previous laparotomy. They were randomly divided into 2 equal groups. In group 1, laparoscopic access was carried out by an optical trocar through the new point situated in the subxiphoid region 1 cm below the costal margin and centered 2.5 cm from the midline on either side. In group 2, laparoscopic access was performed by an optical subumbilical trocar after Verres needle insufflation in Palmer point. The primary end points were success and safety of entry, measured by the number of entry attempts and the incidence of bowel and vascular injuries. The secondary end point was the entry time.

Results:

In group 1, safe entry into the abdomen was achieved without visceral or vascular injury. In the 3 cases, minor liver injuries occurred. In group 2, 2 major vascular injuries and 5 bowel injuries occurred. There was a significant difference in procedure time (55±7.2 s in group 1 vs. 192±11.6 s in group 2).

Conclusion:

The suggested entry point is fast, safe, and reliable in patients having previous laparotomy.
Pigmented Long-Evans rats demonstrate better visual ability than albino Wistar rats in slow angles-descent forepaw grasping test
Authors: Li Shuiyu , Li Hangqi , Takahata Toru
Published: July 2022

Albino people are known to have vision deficit. Albino animals are shown to have abnormal connectivity and malformation of the visual system. However, not many studies have revealed visual impairment of albino animals in the level of perception. To link anatomical abnormality and perceptual visual impairment of albinism, we compared the perceptual vision between the pigmented Long-Evans and the albino Wistar rats. We used the slow angled-descent forepaw grasping (SLAG) test. We hanged the rats in the air by their tails and slowly moved them around a safety bar so that they could see it. When the rats recognized the bar and try to grab it to escape, we counted the trial as ‘positive’, and we measured positive rates. We also measured the distance between the bar and their whiskers during the rats’ initial grasping action, and evaluated type of action at the first contact to the bar. The positive-action rate in the Long-Evans rat group showed significantly higher than the Wistar rat group (0.85 ± 0.047, n = 10, vs. 0.29 ± 0.043, n = 10; P < 0.0001). Besides, when the action was positive, the distance between the bar and their whiskers was longer in the Long-Evans rat group than that in the Wistar rat group (117 ± 5.3 mm vs. 58.8 ± 4.6 mm; P < 0.0001). The Long-Evans rats grasped the bar more precisely than the Wistar rats. The pigmented Long-Evans rats have much better visual perception than the albino Wistar rats.
SARS-CoV-2 omicron variants succumbin vitrotoArtemisia annuahot water extracts
Authors: Nair M.S. , Huang Y. , Weathers P.J.
Published: July 2022

The SARS-CoV-2 (COVID-19) global pandemic continuous to infect and kill millions while rapidly evolving new variants that are more transmissible and evading vaccine-elicited antibodies.Artemisia annuaL. extracts have shown potency against all previously tested variants. Here we further queried extract efficacy against omicron and its recent subvariants. Using Vero E6 cells, we measured thein vitroefficacy (IC50) of stored (frozen) dried-leaf hot-waterA. annuaL. extracts of four cultivars (A3, BUR, MED, and SAM) against SARS-CoV-2 variants: original WA1 (WT), BA.1.1.529+R346K (omicron), BA.2, BA.2.12.1, and BA.4. IC50values normalized to the extract artemisinin (ART) content ranged from 0.5-16.5 µM ART. When normalized to dry mass of the extractedA. annualeaves, values ranged from 20-106 µg. Although IC50values for these new variants are slightly higher than those reported for previously tested variants, they were within limits of assay variation. There was no measurable loss of cell viability at leaf dry weights ≤50 µg of any cultivar extract. Results continue to indicate that oral consumption ofA. annuahot-water extracts (tea infusions) could potentially provide a cost-effective approach to help stave off this pandemic virus and its rapidly evolving variants.
Convolutional neural networks for quantitative smartphone video nystagmography: ConVNG
Authors: Friedrich M. , Schneider E. , Buerklein M. , Taeger J. , Hartig J. , Volkmann J. , Peach R. , Zeller D.
Published: July 2022

Background

Eye movement abnormalities are paramount in neurological disorders. However, unaided eye movement assessments lack granularity. Although videooculography (VOG) improves diagnostic accuracy, resource intensiveness preclude its broad use. To bridge this care gap, we here validate a framework for smartphone video-based nystagmography capitalizing on recent computer vision advances.

Methods

A recurrent convolutional network was fine-tuned for pupil tracking using >550 annotated frames: ConVNG. Slow phase velocity of optokinetic nystagmus was calculated in 10 subjects using both ConVNG and VOG. Equivalence of accuracy and precision was assessed using the “two one-sample t-test” (TOST) and Bayesian interval-null approaches.

Results

ConVNG tracking accuracy reached 9-15% of an average pupil diameter. SPV measurement accuracy was equivalent to VOG (p< .017; Bayes factors (BF) > 24). Average precision was 0.30° for ConVNG and 0.12° for VOG.

Conclusions

ConVNG enables smartphone video nystagmography with an accuracy comparable to VOG and precision approximately one order of magnitude higher than comparable ARKit applications. This serves as a blueprint for highly accessible tools with potential to accelerate progress toward precise and personalized Medicine.
Highlighting the importance of semantics in COVID-19 fake news detection using a CNN hashmap color-based method
Authors: El Azhari Maryam
Published: July 2022

With the exponential development and exploitation of social media sites and platforms such as facebook, twitter and instagram, a diversity type of news are reached to the users,resulting in a major influence on human health and safety.Spreading misinformation and disinformation during the Covid-19 pandemic has become increasingly significant. Although it is usually not a criminal act, it can cause serious endangerment to public health. Such infodemic movement is often lead to advance geopolitical interests by the states, to achieve some sort of profit by some opportunists and individuals or discredit official sources. Hence,it has become crucial to automate the detection of fake news in order to shield people from any harmful repercussions. In this paper, the importance of semantics in Covid-19 fake news detection is highlighted based on a convolutional neural network classifier and a hashmap color-based technique. The experiments are performed with CoAID(Covid-19 heAlthcare mIsinformation Dataset),and the results prove that the loss of semantics yields to a poor performance of the classifier. This implicates additional constraints to the training images,with focus on creating a CNN-based color hashmap classifier that includes anterior and posterior neighbors.
Can MRI-based multivariate gray matter volumetric distance predict motor progression and classify slow versus fast progressors in Parkinson’s disease?
Authors: Vijayakumari Anupa A , Fernandez Hubert H , Walter Benjamin L
Published: July 2022

Introduction

While Parkinson’s disease (PD) related neurodegeneration is associated with structural changes in the brain, magnetic resonance imaging (MRI) has not been helpful in diagnosing PD or predicting the progression of motor symptoms. In this study, we aimed to develop a structural MRI-based biomarker to predict the rate of progression of motor symptoms and to classify patients based on the symptom severity (i.e. slow vs. fast progressors) in the early stages of PD.

Methods

The study included 59 patients with PD (n=40 for the primary analysis, 19 for the validation analysis), and 55 healthy controls with structural MRI from the Parkinson’s Progression Markers Initiative (PPMI) database. We developed a patient-specific multivariate gray matter volumetric distance using Mahalanobis distance (MGMV) to investigate the changes in MGMVover time using longitudinal linear mixed-effect model, its potential as a biomarker to predict the rate of progression of motor function (MDS-UPDRS-part III) using multiple linear regression model, and classification of patients based on symptom severity using machine learning (ML).

Results

MGMVat BL significantly predicted changes in motor severity (p<0.05) and a trend level increase in MGMVover time (p = 0.09) were noted. We obtained 85% accuracy in discriminating patients according to their symptom severity, and on an independent test cohort, an accuracy of 90% was achieved.

Conclusions

We identified a promising structural MRI-based biomarker for predicting the rate of progression of motor symptoms and classification of patients based on motor symptom severity.
Cost-effectiveness analysis of a maternal pneumococcal vaccine in low-income, high-burden settings such as Sierra Leone
Authors: Bilgin Gizem M. , Munira Syarifah Liza , Lokuge Kamalini , Glass Kathryn
Published: July 2022

Maternal pneumococcal vaccines have been proposed as a method of protecting infants in the first few months of life. In this paper, we assess the cost-effectiveness of a maternal pneumococcal polysaccharide vaccine using a health sector perspective. We estimate the costs of delivering a maternal pneumococcal polysaccharide vaccine, and the healthcare costs averted through the prevention of severe pneumococcal outcomes such as pneumonia and meningitis, with estimates of vaccine effectiveness based on previous research. Our model estimates that a maternal pneumococcal program would cost $570 per DALY averted (2020 USD, range $558-582), and hence not be cost-effective in our study setting of Sierra Leone using the nation’s GDP per capita of $527 as a benchmark. However, the choice of discounting rates for health outcomes determines whether the maternal pneumococcal vaccine was deemed cost-effective. Without discounting, the cost per DALY averted would be $277 (53% of Sierra Leone’s GDP per capita). Further, the cost per DALY averted would be $128 (24% GDP per capita) if PPV could be procured at the same cost relative to PCV in Sierra Leone as on the PAHO reference price list. Overall, our paper demonstrates that maternal pneumococcal vaccines have the potential to be cost-effective in low-income settings; however, their cost-effectiveness depends on the choice of discounting rates determined by social values, and negotiations with vaccine providers on vaccine price. Vaccine price is the largest cost driving the cost-effectiveness of a future maternal pneumococcal vaccine.
Transfer learning for Covid-19 detection in medical images
Authors: Azhari Maryam El
Published: July 2022

As of late, the Covid infection 2019 (COVID-19) has caused a pandemic sickness in more than 200 nations, therefore impacting billions of people. To control the spread of the coronavirus, it is crucial to detect infected individuals and ensure their complete isolation to prevent further infection. Chest X-rays and CT-scans have been proven to be very promising as signals of the infection can be clearly shown in lung areas. Transfer learning from ImageNet dataset has become the latent trend in medical imaging applications. However, there are major differences between ImageNet and medical imaging datasets. Therefore, the feasibility of transfer learning in medical applications remains questionable. This paper investigates the performance of five fine-tuned pre-trained models for chest x-rays and CT-scans classification in contrast with a deep CNN model built from scratch. DenseNet121, Resnet-50, Inception v2, Resnet101-V2 and VGG16 are selected and initialized with either random or pre-trained weights to classify augmented images into two classes: Covid and non-Covid. The performance evaluation proves the minuscule impact of training transfer learning models for good quality results, as all CNN models contribute almost equally to the classification and achieve considerable results in terms of precision, accuracy, recall and F1 score.
Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer and coronary disease pathways
Authors: Wang Lihua , Western Dan , Timsina Jigyasha , Repaci Charlie , Song Won-Min , Norton Joanne , Kohlfeld Pat , Budde John , Climer Sharlee , Butt Omar H. , Jacobson Daniel , Garvin Michael , Templeton Alan R , Campagna Shawn , O’Halloran Jane , Presti Rachel , Goss Charles W. , Mudd Philip A. , Ances Beau M. , Zhang Bin , Sung Yun Ju , Cruchaga Carlos
Published: July 2022

Identification of the plasma proteomic changes of Coronavirus disease 2019 (COVID-19) is essential to understanding the pathophysiology of the disease and developing predictive models and novel therapeutics. We performed plasma deep proteomic profiling from 332 COVID-19 patients and 150 controls and pursued replication in an independent cohort (297 cases and 76 controls) to find potential biomarkers and causal proteins for three COVID-19 outcomes (infection, ventilation, and death). We identified and replicated 1,449 proteins associated with any of the three outcomes (841 for infection, 833 for ventilation, and 253 for death) that can be query on a web portal (https://covid.proteomics.wustl.edu/). Using those proteins and machine learning approached we created and validated specific prediction models for ventilation (AUC>0.91), death (AUC>0.95) and either outcome (AUC>0.80). These proteins were also enriched in specific biological processes, including immune and cytokine signaling (FDR ≤ 3.72×10-14), Alzheimer’s disease (FDR ≤ 5.46×10-10) and coronary artery disease (FDR ≤ 4.64×10-2). Mendelian randomization using pQTL as instrumental variants nominated BCAT2 and GOLM1 as a causal proteins for COVID-19. Causal gene network analyses identified 141 highly connected key proteins, of which 35 have known drug targets with FDA-approved compounds. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes (ventilation and death), reveal their relationship to Alzheimer’s disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes.
Female investment in terminal reproduction or somatic maintenance depends on infection dose
Authors: Schulz Nora K. E. , Stewart Carly M. , Tate Ann T.
Published: July 2022

Immune responses are energetically costly to produce and often trade off with investment in reproduction and offspring provisioning. We predicted that hosts can interpret the magnitude of the infection threat from cues like initial bacterial load to adjust reproductive investment into offspring quantity and quality. To test this prediction, we exposed female flour beetles (Tribolium castaneum) to naïve or sterile media controls or one of three increasing doses of heat-killed Bacillus thuringiensis (Bt). To estimate offspring quantity, we measured the number of eggs and hatched larvae from each maternal treatment group. To estimate offspring quality, we measured egg protein content, development to pupation, pupal weight, and offspring survival against Bt infection. Compared to naïve controls, low and intermediate bacterial doses resulted in lower female fecundity, suggesting a shift to a somatic maintenance strategy. Meanwhile, in the highest-dose group, fecundity was negatively correlated with egg protein content, suggesting a trade-off between offspring quality and quantity that could mask terminal investment based on metrics of quantity alone. Our results underscore the need to account for the magnitude of environmental cue when quantifying plasticity and trade-offs among life history traits, and provide new insight into the trans-generational effects of immune responses.
Zinc transporter somatic gene mutations cause primary aldosteronism
Authors: Rege Juilee , Nanba Kazutaka , Bandulik Sascha , Kosmann Carla , Blinder Amy R. , Vats Pankaj , Kumar-Sinha Chandan , Lerario Antonio M. , Else Tobias , Yamazaki Yuto , Satoh Fumitoshi , Sasano Hironobu , Giordano Thomas J. , Williams Tracy Ann , Reincke Martin , Turcu Adina F. , Udager Aaron M. , Warth Richard , Rainey William E.
Published: July 2022

Primary aldosteronism (PA) is the most common form of endocrine hypertension and effects one in 50 adults. PA is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Using next-generation sequencing, we identified recurrent in-frame deletions inSLC30A1in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2).SLC30A1encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identifiedSLC30A1variants are situated in close proximity of the zincbinding site (H43 and D47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the uniqueSLC30A1mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57delvariant in a doxycycline-inducible adrenal cell system revealed abnormal Na+conductivity caused by the mutant, which in turn led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca2+activity, which stimulatedCYP11B2mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.
Integration ofCandida albicans-induced single-cell gene expression data and circulatory protein concentrations reveal genetic regulators of inflammation
Authors: Boahen Collins K. , Oelen Roy , Le Kieu T.T , Netea Mihai G. , Franke Lude , van der Wijst Monique G.P. , Kumar Vinod
Published: July 2022

Both gene expression and protein concentrations are regulated by genetic variants. Exploring the regulation of both eQTLs and pQTLs simultaneously in a context- and cell-type dependent manner may help to unravel mechanistic basis for genetic regulation of pQTLs. Here, we performed meta-analysis ofCandida albicans-induced pQTLs from two population-based cohorts and intersected the results withCandida-induced cell-type specific expression association data (eQTL). This revealed systematic differences between the pQTLs and eQTL, with only 35% of common genetic variants modulating both intermediate molecular phenotypes. By taking advantage of the tightly co-regulated pattern of the proteins, we also identified SNPs affecting protein network uponCandidastimulations. Colocalization of pQTLs and eQTLs signals implicated several genomic loci including MMP-1 and AMZ1. Analysis ofCandida-induced single cell gene expression data implicated specific cell types that exhibit significant expression QTLs upon stimulation. By highlighting the role of trans-regulatory networks in determining the abundance of proteins in blood, our study serve as a framework to gain insights into the mechanisms of genetic regulation of protein levels in a context-dependent manner.
Robust probabilistic modeling for single-cell multimodal mosaic integration and imputation via scVAEIT
Authors: Du Jin-Hong , Cai Zhanrui , Roeder Kathryn
Published: July 2022

Recent advances in single-cell technologies enable joint profiling of multiple omics. These profiles can reveal the complex interplay of different regulatory layers in single cells; still, new challenges arise when integrating datasets with some features shared across experiments and others exclusive to a single source; combining information across these sources is called mosaic integration. The difficulties lie in imputing missing molecular layers to build a self-consistent atlas, finding a common latent space, and transferring learning to new data sources robustly. Existing mosaic integration approaches based on matrix factorization cannot efficiently adapt to nonlinear embeddings for the latent cell space and are not designed for accurate imputation of missing molecular layers. By contrast, we propose a probabilistic variational autoencoder model, scVAEIT, to integrate and impute multimodal datasets with mosaic measurements. A key advance is the use of a missing mask for learning the conditional distribution of unobserved modalities and features, which makes scVAEIT flexible to combine different panels of measurements from multimodal datasets accurately and in an end-to-end manner. Imputing the masked features serves as a supervised learning procedure while preventing overfitting by regularization. Focusing on gene expression, protein abundance, and chromatin accessibility, we validate that scVAEIT robustly imputes the missing modalities and features of cells biologically different from the training data. scVAEIT also adjusts for batch effects while maintaining the biological variation, which provides better latent representations for the integrated datasets. We demonstrate that scVAEIT significantly improves integration and imputation across unseen cell types, different technologies, and different tissues.

Significance Statement

Single-cell multimodal assays provide an unprecedented opportunity for investigating heterogeneity of cell types and novel associations with disease and development. Although analyses of such multimodal datasets have the potential to provide new insights that cannot be inferred with a single modality, access typically requires the integration of multiple data sources. We propose a probabilistic variational autoencoder model for mosaic integration, which involves merging data sources that include features shared across datasets and features exclusive to a single data source. Our model is designed to provide a lower dimensional representation of the cells for visualization, clustering, and other downstream tasks; accurate imputation of missing features and observations; and transfer learning for robustly imputing new datasets when only partial measurements are available.
Single Cell Epigenetics Reveal Cell-Cell Communication Networks in Normal and Abnormal Cardiac Morphogenesis
Authors: Ranade Sanjeev S. , Whalen Sean , Zlatanova Ivana , Nishino Tomohiro , van Soldt Benjamin , Ye Lin , Pelonero Angelo , Wallace Langley Grace , Huang Yu , Alexanian Michael , Padmanabhan Arun , Gonzalez-Teran Barbara , Przytycki Pawel , Costa Mauro W. , Gifford Casey A. , Black Brian L. , Pollard Katherine S. , Srivastava Deepak
Published: July 2022

Communication between myriad cell types during organ formation underlies proper morphogenesis1. In cardiac development, reciprocal signaling between mesoderm progenitors and neural crest cells is essential, and its disruption leads to congenital heart malformations, the most common human birth defect. However, mechanistic interrogation of temporal gene networks andcisregulatory elements in this crosstalk is limited2,3. Here, we integrated single cell chromatin accessibility and transcriptomics to establish an unbiased and temporal epigenomic map of the embryonic mouse heart over multiple stages and developed machine learning models to predict enhancers for heart and neural crest. We leveraged these advances to determine the consequences of dysregulated signaling at single cell resolution caused by deletion of TBX1, a transcription factor that causes morphogenetic defects of the cardiac outflow tract in humans and functions non-cell autonomously in cardiac mesodermal progenitors to direct pharyngeal neural crest differentiation4–6. Loss of Tbx1 in mice led to broad closure of chromatin regions enriched in cardiac progenitor transcription factor motifs within a narrow subset of cardiac mesodermal progenitors and correlated with diminished expression of numerous members of the fibroblast growth factor, retinoic acid, Notch and Semaphorin pathways. In affected progenitors, ectopic accessibility and expression of posterior heart field factors in the anterior heart field suggested impaired axial patterning. In response, a subset of cardiac neural crest cells displayed epigenomic and transcriptional defects, indicating a failure of differentiation corresponding to dysregulation of the anterior-posterior gradient of pharyngeal Hox gene expression. This study demonstrates that single-cell genomics and machine learning can generate a mechanistic model for how disruptions in cell communication selectively affect spatiotemporally dynamic regulatory networks in cardiogenesis.
Faster responses of photosynthesis to light transitions increase biomass and grain yield in transgenicSorghum bicoloroverexpressing Rieske FeS
Authors: Ermakova Maria , Woodford Russell , Taylor Zachary , Furbank Robert T. , Belide Srinivas , von Caemmerer Susanne
Published: July 2022

Sorghum is one of the most important crops providing food and feed in many of the world’s harsher environments. Sorghum utilises the C4pathway of photosynthesis in which a biochemical carbon concentrating mechanism results in high CO2assimilation rates. Overexpressing the Rieske subunit of the Cytochromeb6fcomplex was previously shown to increase the rate of photosynthetic electron transport and stimulate CO2assimilation in the model C4plantSetaria viridis. To test whether productivity of C4crops could be improved by Rieske overexpression, we created transgenicSorghum bicolorplants with increased Rieske content. The transgenic plants showed no marked changes in abundance of other photosynthetic proteins or chlorophyll content. Increases in yield of Photosystem II and CO2assimilation rate as well as faster responses of non-photochemical quenching during transient photosynthetic responses were observed as a result of an elevatedin vivoCytochromeb6factivity in plants overexpressing Rieske. The steady-state rates of electron transport and CO2assimilation did not differ between transgenic and control plants, suggesting that Cytochromeb6fis not the only factor limiting electron transport in sorghum at high light and high CO2. Nevertheless, more agile responses of photosynthesis to light transitions led to increases in biomass and grain yield in plants overexpressing Rieske. Our results indicate that increasing Rieske content could boost productivity of C4crops by improving the efficiency of light utilisation and conversion to biomass.
Single-molecule tracking reveals two low-mobility states for chromatin and transcriptional regulators within the nucleus
Authors: Wagh Kaustubh , Stavreva Diana A , Jensen Rikke AM , Paakinaho Ville , Fettweis Gregory , Schiltz R Louis , Wüstner Daniel , Mandrup Susanne , Presman Diego M , Upadhyaya Arpita , Hager Gordon L
Published: July 2022

How transcription factors (TFs) navigate the complex nuclear environment to assemble the transcriptional machinery at specific genomic loci remains elusive. Using single-molecule tracking, coupled with machine learning, we examined the mobility of multiple transcriptional regulators. We show that H2B and ten different transcriptional regulators display two distinct low-mobility states. Our results indicate that both states represent dynamic interactions with chromatin. Ligand activation results in a dramatic increase in the proportion of steroid receptors in the lowest mobility state. Mutational analysis revealed that only chromatin interactions in the lowest mobility state require an intact DNA-binding domain as well as oligomerization domains. Importantly, these states are not spatially separated as previously believed but in fact, individual H2B and TF molecules can dynamically switch between them. Together, our results identify two unique and distinct low-mobility states of transcriptional regulators that appear to represent common pathways for transcription activation in mammalian cells.
Goal-directed action is transiently impaired in an hAPP-J20 mouse model of Alzheimer’s disease, and in aging male mice regardless of genotype
Authors: Dhungana Amolika , Becchi Serena , Leake Jessica , Morris Gary , Avgan Nesli , Balleine Bernard W. , Vissel Bryce , Bradfield Laura A.
Published: July 2022

Cognitive-behavioural testing in preclinical models of Alzheimer’s disease has typically been limited to visuo-spatial memory tests and has failed to capture the broad scope of deficits patients also display in goal-directed action control. The current study addresses this gap by providing the first comprehensive investigation of how goal-directed actions are affected in a transgenic mouse model of Alzheimer’s disease. Specifically, we tested outcome devaluation performance – a popular test of goal-directed action – in male and female human amyloid precursor protein (hAPP)-J20 mice. Mice were first trained to press a left and right lever for unique pellet and sucrose outcomes respectively (counterbalanced) over four days. On test, mice were fed one of the two outcomes to reduce its value via sensory specific satiety and subsequently given a choice between levers. Goal-directed action was intact for 36-week-old wildtype mice of both sexes, because they responded more on the lever associated with the still-valued outcome than that associated with the devalued outcome (i.e. Valued > Devalued). Goal-directed action was impaired (Valued = Devalued) for J20 mice of both sexes, and for 52-week-old male mice regardless of genotype. Following an additional 4 days of lever press training (i.e., 8 days lever pressing in total), outcome devaluation was intact for all mice regardless of age or genotype. Immunohistochemical analysis revealed that increased microglial expression in the dorsal CA1 region of the hippocampus was associated with poorer outcome devaluation performance on initial tests, but not with tests performed after 8 days of lever pressing. Together, these data demonstrate that goal-directed action is transiently impaired in J20 mice of both sexes and in aging male mice regardless of genotype, and that this impairment is related to neuroinflammation in the dorsal CA1 region of the hippocampus.
Constraints to formal small business performance in the service sector in Cameroon
Authors: Kabange Martin Mulunda , Simatele Munacinga
Published: July 2022

Purpose

This study aims to investigate whether social capital mediates the impact of financial capital on business performance in Cameroon.

Design/methodology/approach

The study uses quantitative data collected from 370 small businesses in Yaoundé and Douala in Cameroon. All businesses in the sample are formally registered and are in the services sector. A structural equation modelling (SEM) approach is used for the analysis.

Findings

Structural and relational capital constraints are significant mediators of formal and informal finance. The magnitude effects of relational capital are the largest, underlining information's importance in resolving small and medium enterprises’ (SMEs') financial constraints. In addition, the effect of informal finance constraints on business performance is larger in magnitude, confirming the substantial impact of informal finance on SME operations.

Research limitations/implications

The paper confirms that relational and structural social capital are vital in business. However, the study did not investigate the disaggregated effects of these dimensions of social capital. Furthermore, how SMEs transition between formal and informal finance could provide further understanding of the role of social capital. A disaggregated and panel data set would help to provide additional insights.

Practical implications

Social capital emerges as a pivotal factor in enhancing SME access to finance. The results, therefore, confirm the relevance of a holistic approach to easing financial capital constraints for SMEs and enabling small businesses to connect more to various stakeholders to amplify business performance. In addition, the findings identified some intervention points for the governments in Cameroon as it seeks to use SMEs as its pivot for development and to catapult itself to emerging economy status in its Cameroon 2035 vision.

Originality/value

The value of the study lies in assessing the mediating effect of cognitive, relational and structural social capital constraints on business performance and comparing the effect of formal and informal financial constraints on business performance.
OFDI activity and urban-regional development cycles: a co-evolutionary perspective
Authors: Bathelt Harald , Buchholz Maximilian , Cantwell John A.
Published: July 2022

Purpose

While conventional views of foreign investment activity primarily relate to efficiency-seeking investments, the authors argue that most other outward foreign direct investments (OFDIs) likely have positive effects on income development in the home region. Data on the US urban system not only illustrates this but also shows that this impact is not equal in all city-regions. The purpose of this paper is to develop an explanation as to why high- and low-income cities are associated with self-reinforcing cycles of OFDI activity that have different home-region impacts.

Design/methodology/approach

Conventional views assume that inward foreign direct investments (IFDIs) have a positive impact on target regions, while OFDIs are often treated as the flip side of this story, being seen as having negative effects by shifting jobs and income abroad. This paper counters this logic by developing a conceptual argument that systematically distinguishes different types of OFDIs and relates them to economic development effects in the home (investing) region.

Findings

Using a co-evolutionary conceptualization, this paper suggests that many high-income cities are characterized by a virtuous cycle of development where high, successful OFDI activity generates both positive income effects as well as incentives to engage in further OFDIs in the future, thus leading to additional income increases. In contrast, it is suggested that low-income cities are characterized by what we refer to as vicious cycles of development with low OFDI activity, few development impulses and a lack of incentives and capabilities for future investments.

Originality/value

This paper develops a counter-perspective to conventional views of OFDI activity, arguing that these investments have a positive impact on regional income levels. The authors develop a spatially sensitive explanation which acknowledges that OFDIs do not trigger a linear process but are associated with diverging inter-urban development paths and may contribute to higher levels of intra-urban inequality. From these findings, the authors derive conclusions for future research and public policy.
Computational fluid dynamics (CFD) based propeller design improvement for high altitude long endurance (HALE) UAV
Authors: Maulana Fatwa Azam , Amalia Ema , Moelyadi Mochammad Agoes
Published: July 2022

Purpose

High Altitude Long Endurance Unmanned Aerial Vehicle (HALE UAV) driven by a hybrid power between battery and solar panel have attracted many researchers. The HALE UAV which develops at Bandung Institute of Technology has design requirements of a 63 kg MTOW with a cruise velocity of 22.1 m/s at an altitude of 60,000 ft propelled by two propellers. The main problems that arise with the propellers gained from the market are these propellers cannot operate properly at the cruise phase due to inadequate thrust and high drag value. This paper aims to design a propeller that solves those problems.

Design/methodology/approach

The Larrabee method is used to design this propeller geometry with an output in the form of a chord and twist distribution. The CFD approach method is used to improve the design resulting from the Larrabee method.

Findings

This study shows that the inputted thrust value of the propeller designed using the Larrabee method is always higher than the thrust value resulting from the CFD simulation with a difference of around 20% so a design improvement process using CFD is required.

Originality/value

The analysis of propeller implementation in various mission profiles shows that this propeller can operate fully from climbing at sea level to cruising flight at an altitude of 60,000 ft. The same procedure can be applied in other HALE UAV cases to generate a propeller design with different objectives.
Effect of graphitization percentage on fade and recovery performance of copper-free non-asbestos organic brake pads
Authors: G. Saikrishnan , L.S. Jayakumari , R. Vijay
Published: July 2022

Purpose

The purpose of this paper is to deal with the tribological study on the brake pads developed using various purity-based graphitized graphite.

Design/methodology/approach

This paper deals with developing copper-free brake pads by using graphite as a key lubricant produced using a graphitization process with purity percentages (85, 90 and 95%). The brake pads were developed using traditional manufacturing processes and evaluated for their physical, chemical, thermal and mechanical properties as per industrial standards. Fade and recovery characteristics were analyzed using a full-scale inertia brake dynamometer as per JASO-C-406. The scanning electron microscope was used to analyze the worn surfaces of the brake pads.

Findings

The testing findings reveal that the brake pads with 95% graphitized graphite showed better shear strength with good adhesion levels and lesser density, hardness, acetone extract value, loss on ignition and higher porosity. Effectiveness studies of brake pads with graphite (95% graphitized) showed better results at higher pressure speed conditions than others because of better plateau formation and adequate lubrication.

Originality/value

This paper discusses graphitized graphite of different purity influences brake pad's tribological performance by modifying tribo-films and reducing friction undulations.