bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel estimator for the equation of state of the IGM by Ly α forest tomography
Authors: Müller Hendrik , Behrens Christoph , Marsh David J E
Published: March 2021

We present a novel procedure to estimate the equation of state of the intergalactic medium in the quasi-linear regime of structure formation based on Ly α forest tomography and apply it to 21 high-quality quasar spectra from the UVES_SQUAD survey at redshift z = 2.5. Our estimation is based on a full tomographic inversion of the line of sight. We invert the data with two different inversion algorithms, the iterative Gauss–Newton method and the regularized probability conservation approach, which depend on different priors and compare the inversion results in flux space and in density space. In this way our method combines fitting of absorption profiles in flux space with an analysis of the recovered density distributions featuring prior knowledge of the matter distribution. Our estimates are more precise than existing estimates, in particular on small redshift bins. In particular, we model the temperature–density relation with a power law and observe for the temperature at mean density $T_0 = 13\,400^{+1700}_{-1300}\, \mathrm{K}$ and for the slope of the power law (polytropic index) γ = 1.42 ± 0.11 for the power-law parameters describing the temperature–density relation. Moreover, we measure an photoionization rate $\Gamma _{-12} = 1.1^{+0.16}_{-0.17}$. An implementation of the inversion techniques used will be made publicly available.
G-Quadruplexes as pathogenic drivers in neurodegenerative disorders
Authors: Wang Ernest , Thombre Ravi , Shah Yajas , Latanich Rachel , Wang Jiou
Published: March 2021

G-quadruplexes (G4s), higher-order DNA and RNA secondary structures featuring guanine-rich nucleic acid sequences with various conformations, are widely distributed in the human genome. These structural motifs are known to participate in basic cellular processes, including transcription, splicing, and translation, and their functions related to health and disease are becoming increasingly recognized. In this review, we summarize the landscape of G4s involved in major neurodegenerative disorders, describing the genes that contain G4-forming sequences and proteins that have high affinity for G4-containing elements. The functions of G4s are diverse, with potentially protective or deleterious effects in the pathogenic cascades of various neurological diseases. While the studies of the functions of G4s in vivo, including those involved in pathophysiology, are still in their early stages, we will nevertheless discuss the evidence pointing to their biological relevance. A better understanding of this unique structural element in the biological context is important for unveiling its potential roles in the pathogenesis of diseases such as neurodegeneration and for designing new diagnostic and therapeutic strategies.
iNetModels 2.0: an interactive visualization and database of multi-omics data
Authors: Arif Muhammad , Zhang Cheng , Li Xiangyu , Güngör Cem , Çakmak Buğra , Arslantürk Metin , Tebani Abdellah , Özcan Berkay , Subaş Oğuzhan , Zhou Wenyu , Piening Brian , Turkez Hasan , Fagerberg Linn , Price Nathan , Hood Leroy , Snyder Michael , Nielsen Jens , Uhlen Mathias , Mardinoglu Adil
Published: March 2021

It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.
Formation and Evolution of a Neoproterozoic Continental Magmatic Arc
Authors: Zhao Jun-Hong , Nebel Oliver , Johnson Tim E
Published: March 2021

Unlike many Archean diorites and granitoids that arguably formed in different geodynamic settings, their post-Archean counterparts are commonly regarded to have formed at convergent margins, although in detail their petrogenesis remains contentious. Here we present new whole-rock data and zircon Hf–O isotope analyses from dioritic (750–730 Ma), granitic (810–790 Ma) and tonalite–trondhjemite–granodiorite (TTG)-like intrusions (800–740 Ma) from the Panxi and Hannan regions, which form part of an extensive Neoproterozoic convergent margin exposed in South China. The dioritic rocks from the Panxi region exhibit high zircon εHf(t) (+10.1 to +13.1) and sub-mantle to mantle-like δ18O (3.1–6.3 ‰) values, whereas those from the Hannan region preserve low εHf(t) (+4.1 to +8.1) and high δ18O values (5.9–6.6 ‰), indicating that the dioritic melts were derived from subduction-modified lithospheric mantle sources and experienced variable degrees of lower crustal contamination. Zircons within granite and TTG from the Panxi region show a narrow range of Hf isotopic compositions generally spanning 2–4 εHf units (+3.1 to +7.9 for most felsic intrusions). By contrast, those from the Hannan region show a much wider range of zircon εHf(t) values spanning almost 10 εHf units (+1.1 to +10.9). Based on their O–Hf–Nd isotopic signatures, we propose that the granite and TTG from both areas were derived through partial melting of hydrated basaltic rocks in the arc root, and that the isotopic variability between the intrusions mirrors spatial and temporal chemical variations in these deep crustal source rocks. In both regions, the granites, along with mantle-derived mafic–ultramafic and intermediate rocks, show a coupled evolution associated with increasing εNd(t) and εHf(t) and decreasing δ18O with decreasing ages, whereas the TTGs formed during late-stage arc magmatism and preserve relatively homogeneous Nd–Hf isotopes and mantle-like δ18O values. Combined, these data record continuous crustal thickening through underplating of juvenile magmas and a progressive increase in the depth of melting, along with a decrease in the degree of interaction between the melts and basement rocks within the arc root. Our results suggest that slab melting was not required to produce post-Archean TTG signatures. Further, we suggest that the variability in the Hf–O–Nd isotopic compositions of metaluminous (I-type) granites mostly does not reflect a heterogeneity in upper mantle signatures, and that there is no conclusive evidence for the involvement of partial melts of subducted sediment based on Hf–O isotope signatures in zircon.
Testing the Utility of Alternative Metrics of Branch Support to Address the Ancient Evolutionary Radiation of Tunas, Stromateoids, and Allies (Teleostei: Pelagiaria)
Authors: Arcila Dahiana , Hughes Lily C , Meléndez-Vazquez Bruce , Baldwin Carole C , White William T , Carpenter Kent E , Williams Jeffrey T , Santos Mudjekeewis D , Pogonoski John J , Miya Masaki , Ortí Guillermo , Betancur-R Ricardo
Published: March 2021

The use of high-throughput sequencing technologies to produce genome-scale data sets was expected to settle some long-standing controversies across the Tree of Life, particularly in areas where short branches occur at deep timescales. Instead, these data sets have often yielded many well-supported but conflicting topologies, and highly variable gene-tree distributions. A variety of branch-support metrics beyond the nonparametric bootstrap are now available to assess how robust a phylogenetic hypothesis may be, as well as new methods to quantify gene-tree discordance. We applied multiple branch-support metrics to a study of an ancient group of marine fishes (Teleostei: Pelagiaria) whose interfamilial relationships have proven difficult to resolve due to a rapid accumulation of lineages very early in its history. We analyzed hundreds of loci including published ultraconserved elements and newly generated exonic data along with their flanking regions to represent all 16 extant families for more than 150 out of 284 valid species in the group. Branch support was typically lower at inter- than intra-familial relationships regardless of the type of marker used. Several nodes that were highly supported with bootstrap had a very low site and gene-tree concordance, revealing underlying conflict. Despite this conflict, we were able to identify four consistent interfamilial clades, each comprised of two or three families. Combining exons with their flanking regions also produced increased branch lengths at the deep branches of the pelagiarian tree. Our results demonstrate the limitations of employing current metrics of branch support and species-tree estimation when assessing the confidence of ancient evolutionary radiations and emphasize the necessity to embrace alternative measurements to explore phylogenetic uncertainty and discordance in phylogenomic data sets.[Concatenation; exons; introns; phylogenomics; species-tree methods; target capture.]
Mackay v Wesley: mistaken trusteeships and sufficiently distinct mistakes
Authors: Gunson Hugh , Watts Thomas
Published: March 2021

In Mackay v Wesley the High Court, on appeal, ordered that a claimant’s acceptance of her appointment as trustee of an offshore trust should be rescinded and set aside on the ground of undue influence. The claimant (Mrs Mackay), for whom the authors acted at first instance and on appeal, brought a claim on the grounds of undue influence, mistake, non est factum, and lack of capacity. The claim was dismissed at first instance but succeeded on appeal. The first-instance decision, of Deputy Master Henderson, contains a number of significant developments to, and arguably departures from, the doctrine of mistake as set out in Pitt v Holt [2013] 2 A.C. 108; [2013] UKSC 26, as well as to trusts law and the nature of appointments of trustees. As the appeal was allowed on the ground of undue influence only (without comment on mistake, the other ground advanced on appeal), the first instance decision remains unchallenged and potentially has important implications for mistake claims in the future.
Electrographic Features of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling
Authors: Liu Haiyu , Tufa Uilki , Zahra Anya , Chow Jonathan , Sivanenthiran Nila , Cheng Chloe , Liu Yapg , Cheung Phinehas , Lim Stellar , Jin Yaozhong , Mao Min , Sun Yuqing , Wu Chiping , Wennberg Richard , Bardakjian Berj , Carlen Peter L , Eubanks James H , Song Hongmei , Zhang Liang
Published: March 2021

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures (SRS) and comorbidities. Kindling through repetitive brief stimulation of a limbic structure is a commonly used model of temporal lobe epilepsy. Particularly, extended kindling over a period up to a few months can induce SRS, which may simulate slowly evolving epileptogenesis of temporal lobe epilepsy. Currently, electroencephalographic (EEG) features of SRS in rodent models of extended kindling remain to be detailed. We explored this using a mouse model of extended hippocampal kindling. Intracranial EEG recordings were made from the kindled hippocampus and unstimulated hippocampal, neocortical, piriform, entorhinal, or thalamic area in individual mice. Spontaneous EEG discharges with concurrent low-voltage fast onsets were observed from the two corresponding areas in nearly all SRS detected, irrespective of associated motor seizures. Examined in brain slices, epileptiform discharges were induced by alkaline artificial cerebrospinal fluid in the hippocampal CA3, piriform and entorhinal cortical areas of extended kindled mice but not control mice. Together, these in vivo and in vitro observations suggest that the epileptic activity involving a macroscopic network may generate concurrent discharges in forebrain areas and initiate SRS in hippocampally kindled mice.
Assessment of Quinone Outside Inhibitor Sensitivity and Frogeye Leaf Spot Race of Cercospora sojina in Georgia Soybean
Authors: Harrelson Bennett C. , Kemerait Robert C. , Culbreath Albert K. , Ghimire Bikash , Li Zenglu , Severns Paul M. , Buck James W.
Published: March 2021

Frogeye leaf spot (FLS), caused by the fungal pathogen Cercospora sojina K. Hara, is a foliar disease of soybean (Glycine max L. [Merr.]) responsible for yield reductions throughout the major soybean-producing regions of the world. In the United States, management of FLS relies heavily on the use of resistant cultivars and in-season fungicide applications, specifically within the class of quinone outside inhibitors (QoIs), which has resulted in the development of fungicide resistance in many states. In 2018 and 2019, 80 isolates of C. sojina were collected from six counties in Georgia and screened for QoI fungicide resistance using molecular and in vitro assays, with resistant isolates being confirmed from three counties. Additionally, 50 isolates, including a “baseline isolate” with no prior fungicide exposure, were used to determine the percent reduction of mycelial growth to two fungicides, azoxystrobin and pyraclostrobin, at six concentrations: 0.0001, 0.001, 0.01, 0.1, 1, and 10 μg ml−1. Mycelial growth observed for resistant isolates varied significantly from both sensitive isolates and baseline isolate for azoxystrobin concentrations of 10, 1, 0.1, and 0.01 μg ml−1 and for pyraclostrobin concentrations of 10, 1, 0.1, 0.01, and 0.001 μg ml−1. Moreover, 40 isolates were used to evaluate pathogen race on six soybean differential cultivars by assessing susceptible or resistant reactions. Isolate reactions suggested 12 races of C. sojina present in Georgia, 4 of which have not been previously described. Species richness indicators (rarefaction and abundance-based coverage estimators) indicated that within-county C. sojina race numbers were undersampled in this study, suggesting the potential for the presence of either additional undescribed races or known but unaccounted for races in Georgia. However, no isolates were pathogenic on ‘Davis’, a differential cultivar carrying the Rcs3 resistance allele, suggesting that the gene is still an effective source of resistance in Georgia.
Dieback and Leaf Spot in Box Elder (Acer negundo) Caused by Exserohilum rostratum
Authors: Liu Cheng-long , Zheng Xiang-rong , Chen Feng-mao
Published: March 2021

Leaf spot and dieback were observed on box elder (Acer negundo) grown in a nursery in Tai’an city, Shandong Province, China, in 2019, with a disease incidence of 86%. The incidences of Exserohilum rostratum isolation were 75% from the shoots and 66.6% from the leaves of field-infected plants. Isolates were identified at the species level on the basis of morphological characteristics and through phylogenetic analysis of concatenated partial sequences of the internal transcribed spacer (ITS) region and cam, gapdh, tef1, rpb2, tub2, and his genes from the Exserohilum isolates. The effects of temperature on the mycelial growth of the Exserohilum rostratum isolates were also characterized. In greenhouse tests, seedlings inoculated with the pathogen exhibited systemic symptoms similar to those observed in the field. In pathogenicity experiments on shoots, wounded seedlings were observed to be blighted, suggesting that leaf spot and dieback may develop into more severe blight or dieback when high winds, sudden temperature decreases, or insect infestations occur. To our knowledge, this is the first report of dieback and leaf spot caused by E. rostratum on a species of A. negundo.
Hybrid Rice Outperforms Inbred Rice in Resistance to Sheath Blight and Narrow Brown Leaf Spot
Authors: Shi Jun , Zhou Xin-Gen , Yan Zongbu , Tabien Rodante E. , Wilson Lloyd T. , Wang Li
Published: March 2021

Sheath blight (ShB; caused by Rhizoctonia solani AG1-1A) and narrow brown leaf spot (NBLS; Cercospora janseana) are among the most important diseases affecting rice production in Texas and other southern parts of the United States. Because of the high yield potential, hybrid rice acreage is continually increasing. Understanding the relative levels of resistance to ShB and NBLS in hybrids compared to those of inbreds is important for effective disease management; however, this information remains largely unknown. A comparison of the performance of hybrid rice and inbred rice was performed involving 173 hybrid and 155 inbred genotypes (cultivars and elite breeding lines) over the course of five crop seasons (2016 to 2020) and two locations in Texas. The results showed that genotype, cultivar type (hybrid or inbred), location, and their interactions had significant effects on the severity of ShB and NBLS. The ShB severity in hybrid genotypes was significantly lower than that in inbred genotypes, with an average reduction of 27% in disease severity during the 5-year, two-location evaluation. Most (53%) of the hybrid genotypes were rated moderately resistant, whereas almost all (97%) of the inbred genotypes ranged from very susceptible to moderately susceptible. Similarly, NBLS severity in hybrid genotypes is significantly lower than that in inbred genotypes. All but four hybrid genotypes exhibit immune reactions to NBLS. In contrast, 77% of inbred genotypes exhibit NBLS symptoms, with disease resistance reactions ranging from susceptible to resistant. The results demonstrate that hybrid rice is generally less susceptible to sheath blight and has a higher level of resistance against NBLS compared with inbred rice.
Nutrition in Caring for Pregnant Women During the COVID-19 Pandemic in Low-Income Countries
Authors: Amini Shirin , Mohseni Houra , Kalantar Mojtaba , Amani Reza
Published: March 2021

In recent months, the greatest health challenge worldwide has been the outbreak of the novel coronavirus, COVID-19. During pregnancy, women are especially vulnerable perhaps in part because of fluctuations in levels of hormones that are involved in the immune response, and therefore, they need to take special preventive measures. In addition to measures to avoid the spread of the virus, such as handwashing, masks, and social distancing, it is important to ensure that food intakes are healthy, adequate, and high in both nutritional quality and food safety. Supportive nutrition through the provision of food baskets adequate in energy, protein, calcium, iron, folic acid, choline, omega-3 fatty acids, and vitamin D at levels sufficient for pregnancy is likely to be needed for many pregnant women in low-income families or families where spouses, jobs, and income have been lost because of COVID-19.
Assessing the Relationship Between Individual Diet Quality and Food Waste
Authors: O'Regan Alisha , Wolfe Kara
Published: March 2021

This pilot study of 21 university students tested a novel food intake and waste diary and assessed it for the relationship between diet quality and food wasted. The study demonstrated the novel diary's potential to accurately record both individual food intake and waste, and correlations were found between certain food groups consumed and levels of waste. Knowledge from this study and future studies using the novel diary can provide information on food waste practices and help tailor education on food waste reduction.
Update on Liposuction: What All Plastic Surgeons Should Know
Authors: Beidas Omar E. , Gusenoff Jeffrey A.
Published: March 2021

Learning Objectives:

After studying this article, the participant should be able to: 1. Understand the types of tumescence available for liposuction. 2. Explain the various modalities available for liposuction. 3. Describe the patient selection, staging, and complications associated with debulking liposuction. 4. Describe ways to optimize outpatient liposuction.

Liposuction is one of the most common procedures performed by board-certified plastic surgeons and is likely greatly underestimated, given underreporting of office procedures and the number of non–plastic surgeons performing these operations. With the ever-increasing popularity of liposuction, various methodologies and technology have been designed to make this task simpler and faster for the surgeon and hasten the recovery for the patient. In the past 10 years, over 50 devices or techniques have been released to assist, refine, or altogether replace liposuction. With the advent of these newer tools, a thorough Continuing Medical Education study was performed to review the available literature.
Conformity of the Virtual Surgical Plan to the Actual Result Comparing Five Craniofacial Procedure Types
Authors: Maniskas Seija , Pourtaheri Navid , Chandler Ludmila , Lu Xiaona , Bruckman Karl C. , Steinbacher Derek M.
Published: March 2021

Background:

The “accuracy” of virtual surgical planning across multiple procedure types is not known. The authors aimed to compare the planned outcome from virtual surgical planning to the actual postoperative outcome for five craniofacial procedure types performed by a single surgeon: implant cranioplasty, cranial vault remodeling, orthognathic surgery, mandible reconstruction, and mandibular distraction.

Methods:

Stereolithography formats were obtained from virtual surgical planning and compared to postoperative computed tomographic scans for consecutive patients who underwent one of the five procedure types. Volumetric renderings of the operated bony region of interest were overlaid and compared using a Boolean operation to compute conformity (as a percentage of the region of interest). Conformity across procedure type was analyzed using analysis of variance and post hoc Bonferroni analysis, where appropriate.

Results:

One hundred thirty patients were included (51.5 percent male and 49.5 percent female; mean age, 27 years; 59 orthognathic surgery, 32 cranial vault remodeling, 16 mandible reconstruction, 12 mandibular distraction, and 11 implant cranioplasty patients). The highest tier of conformity was obtained for implant cranioplasty (median, 76.8 ± 10.3 percent) and mandible reconstruction (mean, 69.4 ± 11.2 percent), followed by orthognathic surgery (mean, 55.0 ± 7.3 percent) and mandibular distraction (median, 41.9 ± 20.3 percent), followed by cranial vault remodeling (mean, 22.2 ± 12.1 percent) (p < 0.001 between tiers and p > 0.05 among tiers).

Conclusions:

Virtual surgical planning resulting in custom permanent implants and intraoperative guides provides more predictable results compared to virtual surgical planning used for procedures involving higher degrees of skeletal repositioning and postoperative movement (i.e., mandibular distraction and nonrigid cranial vault remodeling). In cases with expectedly lower conformity, excellent outcomes can be achieved with sound intraoperative judgment.
The Medial Femoral Condyle Flap in the Pediatric Patient
Authors: Colen David L. , Kania Katarzyna E. , Othman Sammy , Levin L. Scott , Reece Edward M. , Pederson William C. , Innocenti Marco , Kovach Stephen J.
Published: March 2021

Background:

The use of free flaps from the medial femoral condyle has grown in popularity and is now a workhorse in the reconstruction of skeletal defects. The utility of this technique has not yet been described for the pediatric patient population. The authors present their series of pediatric patients who underwent surgery using a medial femoral condyle free flap or a variant thereof in skeletal reconstruction and demonstrate the efficacy of this technique in this population.

Methods:

A multi-institutional retrospective review of patients aged 18 years or younger who required a medial femoral condyle flap for skeletal reconstruction was undertaken. Operative technique, radiographs, and clinical outcomes were recorded. A novel technique (Innocenti) was used to avoid the distal femoral physis in which a Kirschner wire was placed under fluoroscopic guidance just proximal to the growth plate.

Results:

Thirteen patients met inclusion criteria, with an average age of 14.7 years (range, 7 to 18 years) and mean follow-up of 28 months (range, 3 to 120 months). Six were skeletally immature at the time of medial femoral condyle harvest, with the last patient having organic bone disease, putting her at risk for pathologic fracture. All 13 patients achieved bony union, and no patients suffered pathologic fractures or physeal injuries; no patients developed length discrepancies.

Conclusions:

The authors present the first series of corticocancellous medial femoral condyle free flaps in the pediatric population along with a novel technique to avoid injury to the physis in skeletally immature patients. This technique is effective for a variety of skeletal defects or nonunions and is safe for growing patients without causing physeal arrest or growth disturbance.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Not All Breast Explants Are Equal: Contemporary Strategies in Breast Explantation Surgery
Authors: Tanna Neil , Calobrace M. Bradley , Clemens Mark W. , Hammond Dennis C. , Nahabedian Maurice Y. , Rohrich Rod J. , Zhang Ben H. , Bregman Dana , Perry Adam D.
Published: March 2021

Breast implant removal and replacement has been a common secondary breast procedure in the long-term maintenance of breast augmentation, but more recently growing concerns about silicone-related systemic illness, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), and changing perceptions of aesthetic beauty have seen breast implant removal without replacement become increasingly requested by patients. Explantation can be challenging, especially when performed with a total capsulectomy. Currently, there is no evidence regarding whether a partial or total capsulectomy has any effect on BIA-ALCL risk mitigation in patients that have textured implants without disease. Total capsulectomy with incomplete resection of a mass can contribute to hyperprogression of BIA-ALCL and death. There have also been cases of BIA-ALCL diagnosed years after removal of the textured device and “total capsulectomy.” Therefore, the common practice of simple prophylactic capsulectomy in a textured implant to mitigate future disease has not been established and at the current time should be discouraged. In addition, aesthetic outcomes can be quite variable, and patients should have appropriate preoperative counseling regarding the indications and contraindications for explantation, associated risks, financial implications, and postoperative appearance. The authors review salient aspects related to the planning and management of breast implant removal.
Towards validated multiscale simulations for fusion
Authors: Luk O. O. , Lakhlili J. , Hoenen O. , von Toussaint U. , Scott B. D. , Coster D. P.
Published: March 2021

Harnessing energy produced by thermonuclear fusion reactions has the potential to provide a clean and inexpensive source of energy to Earth. However, throughout the past seven decades, physicists learned that creating our very own fusion energy source is very difficult to achieve. We constructed a component-based, multiscale fusion workflow to model fusion plasma inside the core of a tokamak device. To ensure the simulation results agree with experimental values, the model needs to undergo the process of verification, validation and uncertainty quantification (VVUQ). This paper will go over the VVUQ work carried out in the multiscale fusion workflow (MFW), with the help of the EasyVVUQ software library developed by the VECMA project. In particular, similarity of distributions from simulation and experiment is explored as a validation metric. Such initial validation measures provide insights into the accuracy of the simulation results.

This article is part of the theme issue ‘Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification
in silico
’.
Uncertainty quantification of dynamic earthquake rupture simulations
Authors: Daub Eric G. , Arabnejad Hamid , Mahmood Imran , Groen Derek
Published: March 2021

We present a tutorial demonstration using a surrogate-model based uncertainty quantification (UQ) approach to study dynamic earthquake rupture on a rough fault surface. The UQ approach performs model calibration where we choose simulation points, fit and validate an approximate surrogate model or emulator, and then examine the input space to see which inputs can be ruled out from the data. Our approach relies on themogp_emulatorpackage to perform model calibration, and the FabSim3 component from the VECMA toolkit to streamline the workflow, enabling users to manage the workflow using the command line to curate reproducible simulations on local and remote resources. The tools in this tutorial provide an example template that allows domain researchers that are not necessarily experts in the underlying methods to apply them to complex problems. We illustrate the use of the package by applying the methods to dynamic earthquake rupture, which solves the elastic wave equation for the size of an earthquake and the resulting ground shaking based on the stress tensor in the Earth. We show through the tutorial results that the method is able to rule out large portions of the input parameter space, which could lead to new ways to constrain the stress tensor in the Earth based on earthquake observations.

This article is part of the theme issue ‘Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantificationin silico’.
The case for free and open source software in research and scholarship
Authors: Fortunato Laura , Galassi Mark
Published: March 2021

Free and open source software (FOSS) is any computer program released under a licence that grants users rights to run the program for any purpose, to study it, to modify it, and to redistribute it in original or modified form. Our aim is to explore the intersection between FOSS and computational reproducibility. We begin by situating FOSS in relation to other ‘open’ initiatives, and specifically open science, open research, and open scholarship. In this context, we argue that anyone who actively contributes to the research process today is a computational researcher, in that they use computers to manage and store information. We then provide a primer to FOSS suitable for anyone concerned with research quality and sustainability—including researchers in any field, as well as support staff, administrators, publishers, funders, and so on. Next, we illustrate how the notions introduced in the primer apply to resources for scientific computing, with reference to the GNU Scientific Library as a case study. We conclude by discussing why the common interpretation of ‘open source’ as ‘open code’ is misplaced, and we use this example to articulate the role of FOSS in research and scholarship today.

This article is part of the theme issue ‘Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantificationin silico’.
Multifocal vascular affection in a patient with angina pectoris - rationale and design of a clinical study
Authors: Pintova M. , Simova I. , Dimitrov N. , Krasnaliev J. , Kornovski V. , Vekov T.
Published: March 2021

Atherosclerosis is a disease of the large and middle arteries and is characterized mainly by endothelial dysfunction, inflammation of the vascular wall and the accumulation of lipids, cholesterol, calcium and cell debris in the intima of the vascular wall. This accumulation leads to plaque formation, vascular remodeling, acute and chronic obstruction of the vessel lumen, blood flow abnormalities, and reduced oxygen supply to target organs. As a result, blood vessels become harder and their lumen shrinks, which increases the risk of obstruction and thrombosis. Depending on the affected area, the corresponding symptoms appear - angina or myocardial infarction when affecting the coronary circulation; transient ischemic attack (TIA) or stroke affecting cerebral circulation; claudication or gangrene when affecting the limbs; aneurysm or dissection affecting the aorta. Various risk factors are known to affect the onset of the disease. They are divided into adjustable (dyslipoproteinemia, hypertension, diabetes mellitus, smoking, obesity, inactivity, emotional stress, etc.) and unadjustable (gender, age, family predisposition). The risk of developing atherosclerosis increases significantly in the presence of several risk factors. For example, the presence of 2 risk factors increases the risk of developing atherosclerosis 4 times.

The atherosclerotic process is multifocal - it develops everywhere in the body - affecting the cardiac, cerebral and peripheral arteries almost simultaneously or sequentially. Its isolated manifestations in only one area are an exception.
The recombinant Link module of human TSG-6 suppresses cartilage damage in models of osteoarthritis: a potential disease-modifying OA drug
Authors: Drummond Sheona P , Bartnik Eckart , Kouvatsos Nikolaos , Scott Jenny L , Dyer Douglas P , Thomson Jennifer M , Price Andrew J , Anand Sanjay , Biant Leela C , Leeuw Thomas , Herrmann Matthias , Milner Caroline M , Day Anthony J
Published: March 2021

Objectives

To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.

Methods

Knee articular cartilages from OA patients were analysed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module domain (Link_TSG6) on cytokine-induced glycosaminoglycan loss in OA cartilage explants were compared. Mesenchymal stem/stromal cell (MSC)-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β- or TNF-stimulated ADAMTS4, ADAMTS5 and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model and cartilage damage and tactile allodynia were assayed.

Results

TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage and its expression is negatively correlated with MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at dose-dependently inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants; about 50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Similarly, Link_TSG6 displayed more potent effects in 3D pellet cultures, suppressing aggrecanase and collagenase gene expression. Link_TSG6 treatment reduced touch-evoked pain and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.

Conclusions

Native TSG-6 is associated with a low catabolic chondrocyte phenotype in OA cartilage. Link_TSG6, which has enhanced chondroprotective activity compared to the full-length TSG-6 protein, demonstrates potential as a disease modifying OA drug (DMOAD) and warrants further investigation and development.

KEY MESSAGES

What is already known about this subject?

TSG-6, a protein with anti-inflammatory and protective effects in other tissues, is expressed in joints affected by osteoarthritis – a condition for which there are no disease-modifying drugs.

What does this study add?

A novel protective mechanism has been identified, whereby TSG-6 inhibits inflammatory cytokine-induced catabolic pathways in cartilage.

The Link module of TSG-6 (Link_TSG6) has been shown to have greater potency than TSG-6 as an inhibitor of cartilage damage and is efficacious in a rat model of osteoarthritis.

Data from cartilage explants indicate that OA patients can be stratified for Link_TSG6 responsiveness.

How might this impact on clinical practice or future developments?

Link_TSG6 has been identified as potential disease-modifying OA drug that mimics an intrinsic protective process.
Emergence and spread of SARS-CoV-2 lineages B.1.1.7 and P.1 in Italy
Authors: Di Giallonardo Francesca , Puglia Ilaria , Curini Valentina , Cammà Cesare , Mangone Iolanda , Calistri Paolo , Cobbin Joanna C.A. , Holmes Edward C. , Lorusso Alessio
Published: March 2021

Italy’s second wave of SARS-CoV-2 has hit hard, with more than 3 million cases and over 100,000 deaths, representing an almost ten-fold increase on the numbers reported by August 2020. Herein, we present the analysis of 6,515 SARS-CoV-2 sequences sampled in Italy between 29th January 2020 and 1st March 2021 and show how different lineages emerged multiple times independently despite lockdown restrictions. Virus lineage B.1.177 became the dominant variant in November 2020, when cases peaked at 40,000 a day, but since January 2021 this is being replaced by the B.1.1.7 ‘variant of concern’. In addition, we report a sudden increase in another documented variant of concern – lineage P.1 – from December 2020 onwards, most likely caused by a single introduction into Italy. We again highlight how international importations drive the emergence of new lineages and that genome sequencing should remain a top priority for ongoing surveillance in Italy.
Logistic Formula in Biology and Its Application to COVID-19 in Japan
Authors: Kokado Akira , Saito Takesi
Published: March 2021

A logistic formula in biology is applied, as the first principle, to analyze the second and third waves of COVID-19 in Japan.
De novo Powered Air-Purifying Respirator Design and Fabrication for Pandemic Response
Authors: Kothakonda Akshay , Atta Lyla , Plana Deborah , Ward Ferrous , Davis Chris , Cramer Avilash , Moran Robert , Freake Jacob , Tian Enze , Mazor Ofer , Gorelik Pavel , Van Christopher , Hansen Christopher , Yang Helen , Sinha Michael S. , Li Ju , Yu Sherry H. , LeBoeuf Nicole R. , Sorger Peter K.
Published: March 2021

The rapid spread of COVID-19 and disruption of normal supply chains resulted in severe shortages of personal protective equipment (PPE), particularly devices with few suppliers such as powered air-purifying respirators (PAPRs). A scarcity of information describing design and performance criteria represents a substantial barrier to new approaches to address these shortages. We sought to apply open-source product development to PAPRs to enable alternative sources of supply and further innovation. We describe the design, prototyping, validation, and user testing of locally manufactured, modular, PAPR components, including filter cartridges and blower units, developed by the Greater Boston Pandemic Fabrication Team (PanFab). Two designs, one with a fully custom-made filter and blower unit housing, and the other with commercially available variants (the “Custom” and “Commercial” designs respectively) were developed. Engineering performance of the prototypes was measured and safety validated using NIOSH-equivalent tests on apparatus available under pandemic conditions, at university laboratories. Feedback on designs was obtained from four individuals, including two clinicians working in an ambulatory clinical setting and two research technical staff for whom PAPR use is a standard part of occupational PPE. Respondents rated the PanFab Custom PAPR a 4 to 5 on a 5 Likert-scale 1) as compared to current PPE options, 2) for the sense of security with use in a clinical setting, and 3) for comfort. The three other versions of the designs (with a commercial blower unit, filter, or both) performed favorably, with survey responses consisting of scores ranging from 3-5. Engineering testing and clinical feedback demonstrate that the PanFab designs represents favorable alternative PAPRs in terms of user comfort, mobility, and sense of security. A nonrestrictive license promotes innovation in respiratory protection for current and future medical emergencies.
Plasma lipids and growth faltering: a longitudinal cohort study in rural Gambian children
Authors: Gonzales Gerard Bryan , Brals Daniella , Sonko Bakary , Sosseh Fatou , Darboe Momodou , Prentice Andrew M. , Moore Sophie E. , Koulman Albert
Published: March 2021

Growth faltering in children arises from metabolic and endocrine dysfunction driven by complex interactions between poor diet, persistent infections and immunopathology. Here, we determined the progression of the plasma lipidome among Gambian children and assessed its influence on growth faltering over the first 2 years of life using panel vector autoregression modelling. We further investigated temporal associations among lipid clusters. We observed that measures of stunting, wasting and underweight significantly influence each other, and that lipid groups containing PUFA and phosphatidylcholines significantly influence growth outcomes. Linear growth was influenced by the majority of lipids, indicating a higher nutritional demand to improve height compared to weight among growth-restricted children. Our results indicate a critical role for PUFAs and choline in early life dietary interventions to combat the child growth faltering still so prevalent in low-income settings.

Abstract Figure
Early experiences of rehabilitation for patients post-COVID to improve fatigue, breathlessness exercise capacity and cognition
Authors: Daynes E , Gerlis C , Chaplin E , Gardiner N , Singh S
Published: March 2021

Patients with lasting symptoms of COVID-19 should be offered a comprehensive recovery programme. Patients that completed a six week, twice supervised adapted pulmonary rehabilitation programme demonstrated statistically significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition. Participants improved by 112m on the Incremental Shuttle Walking Test and 544 seconds on the Endurance Shuttle Walking Test. There were no serious adverse events recorded, and there were no dropouts related to symptom worsening. COVID-19 rehabilitation appears feasible and significantly improves clinical outcomes.
Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes
Authors: Caron Barthelemy , Patin Etienne , Rotival Maxime , Charbit Bruno , Albert Matthew L , Quintana-Murci Lluis , Duffy Darragh , Rausell Antonio ,   Milieu Intérieur Consortium†
Published: March 2021

Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system and the acute-phase response. Recent large-scale studies have reported genetic (i.e. quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood cell composition to plasma protein heterogeneity has not been fully characterized and may act as a confounding factor in association studies. Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Intérieur cohort. We quantified 297 proteins by Luminex in a clinically certified laboratory and their levels of variation were analysed together with 5.2M single-nucleotide polymorphisms. With respect to non-genetic variables, we included more than 700 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry. Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 30 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood cell fractions, including leukocytes, lymphocytes and three types of polymorphonuclear cells, had a larger contribution to inter-individual variability than age and sex, and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of eight monogenic Mendelian disease genes including three primary immunodeficiency genes (Ficolin-3, Interleukine-2 Receptor alpha and FAS). Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.
Recent trends in postoperative mortality after liver resection- A systemic review and metanalysis of studies published in last 5 years and metaregression of various factors affecting 90 days mortality
Authors: Vasavada Bhavin , Patel Hardik
Published: March 2021

Aim

The aim of this systemic review and meta-analysis was to analyse 90 days mortality after liver resection, and also study various factors associated with mortality via univariate and multivariate metaregression.

Methods

PubMed, Cochrane library, Embase, google scholar, web of science with keywords like ‘liver resection”; “mortality”;” hepatectomy”. Weighted percentage 90 days mortalities were analysed. univariate metaregression was done by DerSimonian-Liard methods. Major hepatectomy, open surgery, cirrhotic livers, blood loss, hepatectomy for hepatocellular carcinoma, hepatectomy for colorectal liver metastasis were taken as moderators in metaregression analysis. We decided to enter all co-variants in multivariate model to look for mixed effects. Heterogeneity was assessed using the Higgins I2 test, with values of 25%, 50% and 75% indicating low, moderate and high degrees of heterogeneity. Cohort studies were assessed for bias using the Newcastle-Ottawa Scale to assess for the risk of bias. Publication bias was assessed using funnel plot. Funnel plot asymmetry was evaluated by Egger’s test.

Results

Total 29931 patients’ data who underwent liver resections for various etiologies were pooled from 41 studied included1257 patients died within 90 days post operatively. Weighted 90 days mortality was 3.6% (95% C.I 2.8% −4.4%). However, heterogeneity of the analysis was high with I2 94.625%.(p<0.001). We analysed various covariates like major hepatectomy, Age of the patient, blood loss, open surgery, liver resections done for hepatocellular carcinoma or colorectal liver metastasis and cirrhotic liver to check for their association with heterogeneity in the analysis and hence 90 days mortality. On univariate metaregression analysis major hepatectomy (p<0.001), Open hepatectomy (p<0.001), blood loss (p=0.002) was associated with heterogeneity in the analysis and 90 days mortality. On multivariate metaregression Major hepatectomy(p=0.003) and Open surgery (p=0.012) was independently associated with higher 90 days mortality, and liver resection for colorectal liver metastasis was independently associated with lesser 90 days mortality (z= −4.11,p<0.01). Residual heterogeneity after all factor multivariate metaregression model was none (I2=0,Tau2=0, H2=1) and nonsignificant (p=0.49).

Conclusion

Major hepatectomy, open hepatectomy, and cirrhotic background is associated with higher mortality rates and colorectal liver metastasis is associated with lower peri operative mortality rates.