bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effectiveness of guselkumab in psoriatic arthritis: results from systematic literature review and network meta-analysis
Authors: Mease Philip J , McInnes Iain B , Tam Lai-Shan , Eaton Kiefer , Peterson Steve , Schubert Agata , Chakravarty Soumya D , Parackal Anna , Karyekar Chetan S , Nair Sandhya , Boehncke Wolf-Henning , Ritchlin Christopher
Published: February 2021

Objective

The efficacy of the novel interleukin (IL)-23p19 inhibitor guselkumab for psoriatic arthritis (PsA) has recently been demonstrated in two phase 3 trials (DISCOVER-1 & -2) but has not been evaluated vs other targeted therapies for PsA. The objective was to compare guselkumab to targeted therapies for PsA for safety and joint and skin efficacy through network meta-analysis (NMA).

Methods

A systematic literature review was conducted in January 2020 to identify randomized controlled trials. Bayesian NMAs were performed to compare treatments on American College of Rheumatology (ACR) 20/50/70 response, mean change from baseline in van der Heijde-Sharp (vdH-S) score, Psoriasis Area Severity Index (PASI) 75/90/100 response, adverse events (AEs) and serious adverse events (SAEs).

Results

Twenty-six phase 3 studies evaluating 13 targeted therapies for PsA were included. For ACR 20 response, guselkumab 100 mg every 8 weeks (Q8W) was comparable to IL-17A inhibitors and subcutaneous tumor necrosis factor (TNF) inhibitors. Similar findings were observed for ACR 50 and 70. For vdH-S score, guselkumab Q8W was comparable to other agents except intravenous TNF therapies. Results for PASI 75 and PASI 90 response suggested guselkumab Q8W was better than most other agents. For PASI 100, guselkumab Q8W was comparable to other active agents. For AEs and SAEs, guselkumab Q8W ranked highly but comparative conclusions were uncertain. Similar results were observed for all outcomes for guselkumab 100 mg every four weeks.

Conclusions

In this NMA, guselkumab demonstrated favorable arthritis efficacy comparable to IL-17A and subcutaneous TNF inhibitors while offering better PASI response relative to many other treatments.
Patients with psychiatric diagnoses have lower quality of life than other patients with juvenile rheumatic disease: a prospective study
Authors: Kosola Silja , Relas Heikki
Published: February 2021

Objectives

Transition of adolescents with chronic diseases from paediatric healthcare to adult care requires attention to maintain optimal treatment results. We examined changes in health-related quality of life (HRQoL) and disease activity among JIA patients with or without concomitant psychiatric diagnoses after transfer to an adult clinic.

Methods

We prospectively followed 106 consecutive patients who were transferred from the New Children’s Hospital to the Helsinki University Hospital Rheumatology outpatient clinic between April 2015 and August 2019 and who had at least one follow-up visit. HRQoL was measured using 15D, a generic instrument.

Results

The patients’ median age at transfer was 16 years and disease duration 4.0 years. Patients were followed for a median of 1.8 years. Disease activity and overall HRQoL remained stable, but distress (dimension 13 of 15D) increased during follow up (P=0.03). At baseline, patients with at least one psychiatric diagnosis had lower overall 15D scores [mean 0.89 (s.d. 0.14) vs 0.95 (s.d. 0.05), P <0.01] and higher disease activity [DAS28mean 1.88 (s.d. 0.66) vs 1.61 (s.d. 0.31), P = 0.01] than patients without psychiatric diagnoses. The difference in overall 15D persisted over the study period.

Conclusion

Transition-phase JIA patients with psychiatric diagnoses had lower HRQoL than other JIA patients. Despite reduced disease activity and pain, HRQoL of patients with psychiatric diagnoses remained suboptimal at the end of follow-up. Our results highlight the necessity of comprehensive care and support for transition-phase JIA patients.
Relationship of serum vitamin D levels with diabetic microvascular complications in patients with type 2 diabetes mellitus
Authors: Zhao Wei-Jing , Xia Xin-Yi , Yin Jun
Published: February 2021

Background:

Vitamin D deficiency has been reported to be associated with diabetic microvascular complications, but previous studies have only focused on the relationship between vitamin D and specific complications. Therefore, we aimed to explore the relationship between vitamin D level and diabetic microvascular complications in general, including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN).

Methods:

This was a cross-sectional study of 815 patients with type 2 diabetes mellitus (T2DM). Clinical information and laboratory results were collected from the medical records. The relationship between vitamin D and the three diabetic microvascular complications was investigated.

Results:

The serum 25-hydroxyvitamin D (25 [OH] D) level of patients with DPN and/or DN was significantly lower than that of T2DM patients without any microvascular complications (P < 0.01). Univariate analysis showed that the 25 (OH) D level was related to DPN and DN, but not DR. After adjustment, the 25 (OH) D level was confirmed to be an independent protective factor for DPN (odds ratio [OR]: 0.968, P = 0.004]) and DN (OR: 0.962, P = 0.006). The prevalence of DPN and DN increased significantly as the serum 25 (OH) D levels decreased. Furthermore, patients with both DPN and DN had the lowest concentration of serum 25 (OH) D (P < 0.001), and the prevalence of macroalbuminuria increased more abruptly than that of microalbuminuria across the 25 (OH) D tertiles. Among the patients with vitamin D insufficiency, those with DPN presented more comorbid macroalbuminuria than those without DPN (15.32% vs. 4.91%; P = 0.001).

Conclusions:

Vitamin D deficiency is independently associated with higher risk of DPN and DN, but not DR, in T2DM patients. Further, it may be a potential predictor for both the occurrence and severity of DPN and DN.
Safety of Endoscopic Snare Ampullectomy for Adenomatous Ampullary Lesions: Focus on Pancreatic Stent Placement to Prevent Pancreatitis
Authors: Gambitta Pietro , Aseni Paolo , Villa Federica , Fontana Paola , Armellino Antonio , Vertemati Maurizio
Published: February 2021

Background:

Ampullary tumors, although relatively uncommon, are increasingly diagnosed due to ongoing progress in imaging technology and the diagnostic accuracy of endoscopic ultrasound and magnetic resonance cholangiopancreatography. Endoscopic ampullectomy (EA) has become the preferred treatment option over surgery due to its lower morbidity for benign ampullary adenomas. This study aims to evaluate the efficacy, safety, and outcome of EA in 30 patients with benign-appearing ampullary lesions with particular emphasis on the accuracy of preampullectomy histology and technical details of the pancreatic duct drainage to prevent postprocedural pancreatitis.

Materials and Methods:

Data from a cohort of 30 patients who underwent EA were retrospectively analyzed. Histologic characteristics of the ampullomas, accuracy of histology of pre-EA biopsy specimen, safety of the procedure, recurrence rate, as well as the clinical outcome of all patients, are analyzed and discussed.

Results:

Endoscopic resection was successful as a definitive treatment in 25 patients (83.3%). Five patients required additional surgery. In 8 patients, a definitive histologic specimen revealed an adenocarcinoma (3 in situ and 5 invasive). The diagnostic accuracy obtained by preresection biopsy specimen was low (0.70). Pancreatic duct stent placement after snare resection was unsuccessful in 9 patients, and 3 of them developed pancreatitis after EA.

Conclusions:

EA appears to be a relatively safe alternative to surgery as the first therapeutic option for selected patients with benign-appearing ampullary adenomas. A correct preoperative evaluation by endoscopic ultrasound and magnetic resonance cholangiopancreatography can help to define the anatomy of the pancreatic duct to improve the success rate of pancreatic stent placement which seems to offer a protective role in the prevention of postprocedural pancreatitis.
Data-driven cardiovascular flow modelling: examples and opportunities
Authors: Arzani Amirhossein , Dawson Scott T. M.
Published: February 2021

High-fidelity blood flow modelling is crucial for enhancing our understanding of cardiovascular disease. Despite significant advances in computational and experimental characterization of blood flow, the knowledge that we can acquire from such investigations remains limited by the presence of uncertainty in parameters, low resolution, and measurement noise. Additionally, extracting useful information from these datasets is challenging. Data-driven modelling techniques have the potential to overcome these challenges and transform cardiovascular flow modelling. Here, we review several data-driven modelling techniques, highlight the common ideas and principles that emerge across numerous such techniques, and provide illustrative examples of how they could be used in the context of cardiovascular fluid mechanics. In particular, we discuss principal component analysis (PCA), robust PCA, compressed sensing, the Kalman filter for data assimilation, low-rank data recovery, and several additional methods for reduced-order modelling of cardiovascular flows, including the dynamic mode decomposition and the sparse identification of nonlinear dynamics. All techniques are presented in the context of cardiovascular flows with simple examples. These data-driven modelling techniques have the potential to transform computational and experimental cardiovascular research, and we discuss challenges and opportunities in applying these techniques in the field, looking ultimately towards data-driven patient-specific blood flow modelling.
Py
3
-FITC: a new fluorescent probe for live cell imaging of collagen-rich tissues and ionocytes
Authors: Wang Zhaotong , Mizoguchi Takamasa , Kuribara Takahito , Nakajima Masaya , Iwata Mayuu , Sakamoto Yuka , Nakamura Hiroyuki , Murayama Toshihiko , Nemoto Tetsuhiro , Itoh Motoyuki
Published: February 2021

Polypyrrole-based polyamides are used as sequence-specific DNA probes. However, their cellular uptake and distribution are affected by several factors and have not been extensively studied
in vivo
. Here, we generated a series of fluorescence-conjugated polypyrrole compounds and examined their cellular distribution using live zebrafish and cultured human cells. Among the evaluated compounds, Py
3
-FITC was able to visualize collagen-rich tissues, such as the jaw cartilage, opercle and bulbus arteriosus, in early-stage living zebrafish embryos. Then, we stained cultured human cells with Py
3
-FITC and found that the staining became more intense as the amount of collagen was increased. In addition, Py
3
-FITC-stained HR cells, which represent a type of ionocyte on the body surface of living zebrafish embryos. Py
3
-FITC has low toxicity, and collagen-rich tissues and ionocytes can be visualized when soaked in Py
3
-FITC solution. Therefore, Py
3
-FITC may be a useful live imaging tool for detecting changes in collagen-rich tissue and ionocytes, including their mammalian analogues, during both normal development and disease progression.
Flavihalobacter algicola gen. nov. sp. nov., a member of the family Flavobacteriaceae with alginate-degradation activity, isolated from marine alga Saccharina japonica
Authors: Yin Rui , Yi Yan-Jun , Chen Zhuo , Chen Guan-Jun , Zhou Yan-Xia , Du Zong-Jun
Published: February 2021

A Gram-stain-negative, aerobic, yellow, non-motile, rod-shaped and alginate-degrading bacterium, designated Dm15T, was isolated from marine alga collected in Weihai, PR China. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Dm15Trepresents a distinct line of the familyFlavobacteriaceae. Strain Dm15Thad the highest 16S rRNA gene sequence similarity to its closest phylogenetic neighbourArcticiflavibacter luteus(96.7 %) and 93.7–96.4 % sequence similarity to other phylogenetic neighbours (Bizionia paragorgiae,Winogradskyella thalassocola,Ichthyenterobacterium magnum,Psychroserpens burtonensisandArcticiflavibacter luteus) in the familyFlavobacteriaceae. The novel isolate was able to grow at 10–40 °C (optimum, 30–33 °C), pH 7.0–9.0 (optimum, pH 7.0–7.5) and with 0.5–6.0 % NaCl (optimum 2.0–3.0 %, w/v). It could grow at 40 °C, and degrade alginate and cellulose, which were different from the neighbour genera. The draft genome consisted of 3395 genes with a total length of 3 798 431 bp and 34.1mol% G+C content. Especially, there were some specific genes coding for cellulase and alginate lyase, which provided a basis for the above phenotypic characteristics. The strain's genome sequence showed 71.1–80.2 % average amino acid identity values and 71.8–77.7 % average nucleotide identity values compared to the type strains of related genera within the familyFlavobacteriaceae. It shared digital DNA–DNA hybridization identity of 19.8 and 20.9 % withI. magnumandA. luteus, respectively. The sole menaquinone was MK-6. The major fatty acids were iso-C15 : 0and iso-C15 : 1G. The polar lipids included six unidentified polar lipids, four unidentified aminolipids and phosphatidylethanolamine. Based on the results of phenotypic, chemotaxonomic and phylogenetic analyses, strain Dm15Trepresents a novel species of a new genus in the familyFlavobacteriaceae, phylumBacteroidetes, for which the nameFlavihalobacter algicolagen. nov., sp. nov. is proposed. The type strain is Dm15T(KCTC 42256T=CICC 23815T).
Vishniacozyma changhuana sp. nov., and Vishniacozyma taiwanica sp. nov., two novel yeast species isolated from mangrove forests in Taiwan
Authors: Chang Chin-Feng , Huang Sing-Yii , Lee Ching-Fu
Published: February 2021

Mangroves grow in the intertidal zone, which alternates between fresh water and sea water, with abundant bioresources. In mangrove habitats, yeasts play an important role in the decomposition of organic matter, and such nutrient cycling has high ecological importance. During a study of the diversity of yeast from Taiwan mangroves, seven strains of basidiomycetous yeasts were isolated and these yeasts represent two novel yeast species belonging to the genus Vishniacozyma. According to the sequences of the D1/D2 domain of large subunit (LSU) rRNA and the internal transcribed spacer (ITS) region, these seven strains could be clearly classified into two groups representing two individual, distinct species. Strains HM5L06, HM6L07, HM11L11 and BJ3S01, differed from their closest relative species Vishniacozyma phoenicis by 4–5 nt substitutions (no gaps) in the sequences of the D1/D2 domain of LSU rRNA and by 23 nt substitutions (10 gaps) in the ITS region. Strains HM6L11, HM7L02 and HM8L19, differed from their closest relative species Vishniacozyma penaeus by 7 nt substitutions (one gap) in the sequences of the D1/D2 domain of LSU rRNA and by 27 nt substitutions (12 gaps) in the ITS region. The scientific names of Vishniacozyma taiwanica sp. nov. and Vishniacozyma changhuana sp. nov. are proposed for these strains. The holotypes are Vishniacozyma taiwanica BCRC 23477T (ex-type HM5L06=CBS 16558; MycoBank number MB837428) and Vishniacozyma changhuana BCRC 23478T (ex-type HM6L11=CBS 16556; MycoBank number MB837429).
Identification of Somatic Structural Variants in Solid Tumors By Optical Genome Mapping
Authors: Goldrich David Y. , LaBarge Brandon , Chartrand Scott , Zhang Lijun , Sadowski Henry B. , Zhang Yang , Pham Khoa , Way Hannah , Lai Chi-Yu Jill , Chun Pang Andy Wing , Clifford Benjamin , Hastie Alex R. , Oldakowski Mark , Goldenberg David , Broach James R.
Published: February 2021

Genomic structural variants comprise a significant fraction of somatic mutations driving cancer onset and progression. However, such variants are not readily revealed by standard next generation sequencing. Optical genome mapping (OGM) surpasses short read sequencing in detecting large (>500bp) and complex structural variants (SVs) but requires isolation of ultra-high molecular weight DNA from the tissue of interest. We have successfully applied a protocol involving a paramagnetic nanobind disc to a wide range of solid tumors. Using as little as 6.5mg of input tumor tissue, we show successful extraction of high molecular weight genomic DNA that provides a high genomic map rate and effective coverage by optical mapping. We demonstrate the system’s utility at identifying somatic SVs affecting functional and cancer-related genes for each sample. Duplicate/triplicate analysis of select samples shows intra-sample reliability but also intra-sample heterogeneity. We also demonstrate that simply filtering SVs based on a GRCh38 human control database provides high positive and negative predictive values for true somatic variants. Our results indicate that the solid tissue DNA extraction protocol, OGM and SV analysis can be applied to a wide variety of solid tumors to capture SVs across the entire genome with functional importance in cancer prognosis and treatment.
Estimation of real-infection and immunity against SARS-CoV-2 in Indian populations
Authors: Singh Prajjval Pratap , Tamang Rakesh , Shukla Manoj , Pathak Abhishek , Srivastava Anshika , Gupta Pranav , Bhatt Alay , Shrivastava Abhishek K. , Upadhyay Sudhir K. , Singh Ashish , Maurya Sanjeev , Saxena Purnendu , Singh Vanya , Chaubey Akhilesh Kumar , Mishra Dinesh Kumar , Patel Yashvant , Pandey Rudra Kumar , Srivastava Ankit , Khanam Nargis , Das Debashruti , Bandopadhyay Audditiya , Chorol Urgyan , Pasupuleti Nagarjuna , Shrivastav Sachin Kumar , Prakash Satya , Mishra Astha , Dubey Pavan Kumar , Parihar Ajit , Basu Priyoneel , Sequeira Jaison J , Lavanya KC , Vijayalaxmi  , Vishnu Shreekara Bhat. K. , Ijinu Thadiyan Parambil , Aggarwal Dau Dayal , Prakash Anand , Yadav Kiran , Yadav Anupam , Upadhyay Vandana , Mukim Gunjan , Bhandari Ankan , Ghosh Ankita , Kumar Akash , Yadav Vijay Kumar , Nigam Kriti , Harshey Abhimanyu , Das Tanurup , Devadas Deepa , Mishra Surendra Pratap , Ashish  , Yadav Abhay Kumar , Singh Nitish Kumar , Kaur Manpreet , Kumar Sanjay , Srivastava Nikhil , Sharma Charu , Chowdhury Ritabrata , Jain Dharmendra , Kumar Abhai , Shukla Ritesh , Mishra Raghav Kumar , Singh Royana , Tripathi Yamini B , Mishra Vijay Nath , Mustak Mohammed S. , Rai Niraj , Rawat Sumit Kumar , Survajhala Prashanth , Singh Keshav K , Mallick Chandana Basu , Shrivastava Pankaj , Chaubey Gyaneshwer
Published: February 2021

Infection born by Coronavirus SARS-CoV-2 has swept the world within a time of a few months. It has created a devastating effect on humanity with social and economic depressions. Europe and America were the hardest hit continents. India has also lost several lives, making the country fourth most deadly worldwide. However, the infection and death rate per million and the case fatality ratio in India were substantially lower than many of the developed nations. Several factors have been proposed including the genetics. One of the important facts is that a large chunk of Indian population is asymptomatic to the SARS-CoV-2 infection. Thus, the real infection in India is much higher than the reported number of cases. Therefore, the majority of people are already immune in the country. To understand the dynamics of real infection as well as level of immunity against SARS-CoV-2, we have performed antibody testing (serosurveillance) in the urban region of fourteen Indian districts encompassing six states. In our survey, the seroprevalence frequency varied between 0.01-0.48, suggesting high variability of viral transmission among states. We also found out that the cases reported by the Government were several fold lower than the real infection. This discrepancy is majorly driven by a higher number of asymptomatic cases. Overall, we suggest that with the high level of immunity developed against SARS-CoV-2 in the majority of the districts, it is less likely to have a second wave in India.
A mathematical model to identify optimal combinations of drug targets for dupilumab poor responders in atopic dermatitis
Authors: Miyano Takuya , Irvine Alan D , Tanaka Reiko J
Published: February 2021

Background

Several biologics for atopic dermatitis (AD) have demonstrated good efficacy in clinical trials, but with a substantial proportion of patients being identified as poor responders. This study aims to understand the pathophysiological backgrounds of patient variability in drug response, especially for dupilumab, and to identify promising drug targets in dupilumab poor responders.

Methods

We conducted model-based meta-analysis of recent clinical trials of AD biologics and developed a mathematical model that reproduces reported clinical efficacies for nine biological drugs (dupilumab, lebrikizumab, tralokinumab, secukinumab, fezakinumab, nemolizumab, tezepelumab, GBR 830, and recombinant interferon-gamma) by describing systems-level AD pathogenesis. Using this model, we simulated the clinical efficacy of hypothetical therapies on virtual patients.

Results

Our model reproduced reported time courses of %improved EASI and EASI-75 of the nine drugs. The global sensitivity analysis and model simulation indicated the baseline level of IL-13 could stratify dupilumab good responders. Model simulation on the efficacies of hypothetical therapies revealed that simultaneous inhibition of IL-13 and IL-22 was effective, whereas application of the nine biologic drugs was ineffective, for dupilumab poor responders (EASI-75 at 24 weeks: 21.6% vs. max. 1.9%).

Conclusion

Our model identified IL-13 as a potential predictive biomarker to stratify dupilumab good responders, and simultaneous inhibition of IL-13 and IL-22 as a promising drug therapy for dupilumab poor responders. This model will serve as a computational platform for model-informed drug development for precision medicine, as it allows evaluation of the effects of new potential drug targets and the mechanisms behind patient variability in drug response.
Patterns of COVID-19 pandemic dynamics following deployment of a broad national immunization program
Authors: Rossman Hagai , Shilo Smadar , Meir Tomer , Gorfine Malka , Shalit Uri , Segal Eran
Published: February 2021

Studies on the real-life impact of the BNT162b2 vaccine, recently authorized for the prevention of coronavirus disease 2019 (COVID-19), are urgently needed. Here, we analysed the temporal dynamics of the number of new COVID-19 cases and hospitalization in Israel following a rapid vaccination campaign initiated on December 20th, 2020. We conducted a retrospective descriptive analysis of data originating from the Israeli Ministry of Health (MOH) from March 2020 to February 2021. In order to distill the possible effect of the vaccinations from other factors, including a third lockdown imposed in Israel on January 2021, we compared the time-dependent changes in number of COVID-19 cases and hospitalizations between (1) individuals aged 60 years and older, eligible to receive the vaccine earlier, and younger age groups; (2) the latest lockdown (which was imposed in parallel to the vaccine rollout) versus the previous lockdown, imposed on September 2020; (3) early-vaccinated cities compared to late-vaccinated cities; and (4) early-vaccinated geographical statistical areas (GSAs) compared to late-vaccinated GSAs. In mid-January, the number of COVID-19 cases and hospitalization started to decline, with a larger and earlier decrease among older individuals, followed by younger age groups, by the order in which they were prioritized for vaccination. This fast and early decline in older individuals was more evident in early-vaccinated compared to late-vaccinated cities. Such a pattern was not observed in the previous lockdown. Our analysis demonstrates evidence for the real-life impact of a national vaccination campaign in Israel on the pandemic dynamics. We believe that our findings have major public health implications in the struggle against the COVID-19 pandemic, including the public ’s perception of the need for and benefit of nationwide vaccination campaigns. More studies aimed at assessing the effectiveness and impact of vaccination both on the individual and on the population level, with longer followup, are needed.
ACE: Explaining cluster from an adversarial perspective
Authors: Lu Yang Young , Yu Timothy C. , Bonora Giancarlo , Noble William Stafford
Published: February 2021

A common workflow in single-cell RNA-seq analysis is to project the data to a latent space, cluster the cells in that space, and identify sets of marker genes that explain the differences among the discovered clusters. A primary drawback to this three-step procedure is that each step is carried out independently, thereby neglecting the effects of the nonlinear embedding and inter-gene dependencies on the selection of marker genes. Here we propose an integrated deep learning framework, Adversarial Clustering Explanation (ACE), that bundles all three steps into a single work-flow. The method thus moves away from the notion of “marker genes” to instead identify a panel of explanatory genes. This panel may include genes that are not only enriched but also depleted relative to other cell types, as well as genes that exhibit differences between closely related cell types. Empirically, we demonstrate that ACE is able to identify gene panels that are both highly discriminative and nonredundant, and we demonstrate the applicability of ACE to an image recognition task.1
Development and evaluation of a new methodology for Soft Tissue Artifact compensation in the lower limb
Authors: Lahkar Bhrigu K. , Rohan Pierre-Yves , Assi Ayman , Pillet Helene , Bonnet Xavier , Thoreux Patricia , Skalli Wafa
Published: February 2021

Skin Marker (SM) based motion capture is the most widespread technique used for motion analysis. Yet, the accuracy is often hindered by Soft Tissue Artifact (STA). This is a major issue in clinical gait analysis where kinematic results are used for decision-making. It also has a considerable influence on the results of rigid body and Finite Element (FE) musculoskeletal models that rely on SM-based kinematics to estimate muscle, contact and ligament forces. Current techniques designed to compensate for STA, in particular multi-body optimization methods, assume anatomical simplifications to define joint constraints. These methods, however, cannot adapt to subjects’ bone morphology, particularly for patients with joint lesions, nor easily can account for subject- and location-dependent STA. In this perspective, we propose to develop a conceptual FE based model of the lower limb for STA compensation and evaluate it for 66 healthy subjects under level walking motor task.

Both hip and knee joint kinematics were analyzed, considering both rotational and translational joint motion. Results showed that STA caused underestimation of the hip joint kinematics (up to 2.2°) for all rotational DoF, and overestimation of knee joint kinematics (up to 12°) except in flexion/extension. Joint kinematics, in particular the knee joint, appeared to be sensitive to soft tissue stiffness parameters (rotational and translational mean difference up to 1.5° and 3.4 mm). Analysis of the results using alternative joint representations highlighted the versatility of the proposed modeling approach. This work paves the way for using personalized models to compensate for STA in healthy subjects and different activities.
Next-generation sequencing-based bulked segregant analysis without sequencing the parental genomes
Authors: Zhang Jianbo , Panthee Dilip R.
Published: February 2021

The genomic region(s) that controls a trait of interest can be rapidly identified using BSA-Seq, a technology in which next-generation se-quencing (NGS) is applied to bulked segregant analysis (BSA). We recently developed the significant structural variant method for BSA-Seq data analysis that exhibits higher detection power than standard BSA-Seq analysis methods. Our original algorithm was developed to analyze BSA-Seq data in which genome sequences of one parent served as the reference sequences in genotype calling, and thus required the availability of high-quality assembled parental genome sequences. Here we modified the original script to allow for the effective detection of the genomic region-trait associations using only bulk genome sequences. We analyzed a public BSA-Seq dataset using our modified method and the standard allele frequency and G-statistic methods with and without the aid of the parental genome sequences. Our results demonstrate that the genomic region(s) associated with the trait of interest could be reliably identified only via the significant structural variant method without using the parental genome sequences.

Significance Statement

BSA-Seq can be utilized to rapidly identify structural varianttrait associations, and our modified significant structural variant method allows the detection of such associations without sequencing the parental genomes, leading to further lower the sequencing cost and making BSA-Seq more accessible to the research community and more applicable to the species with a large genome.
Constructing smaller genome graphs via string compression
Authors: Qiu Yutong , Kingsford Carl
Published: February 2021

The size of a genome graph — the space required to store the nodes, their labels and edges — affects the efficiency of operations performed on it. For example, the time complexity to align a sequence to a graph without a graph index depends on the total number of characters in the node labels and the number of edges in the graph. The size of the graph also affects the size of the graph index that is used to speed up the alignment. This raises the need for approaches to construct space-efficient genome graphs.

We point out similarities in the string encoding approaches of genome graphs and the external pointer macro (EPM) compression model. Supported by these similarities, we present a pair of linear-time algorithms that transform between genome graphs and EPM-compressed forms. We show that the algorithms result in an upper bound on the size of the genome graph constructed based on an optimal EPM compression. In addition to the transformation, we show that equivalent choices made by EPM compression algorithms may result in different sizes of genome graphs. To further optimize the size of the genome graph, we purpose the source assignment problem that optimizes over the equivalent choices during compression and introduce an ILP formulation that solves that problem optimally. As a proof-of-concept, we introduce RLZ-Graph, a genome graph constructed based on the relative Lempel-Ziv EPM compression algorithm. We show that using RLZ-Graph, across all human chromosomes, we are able to reduce the disk space to store a genome graph on average by 40.7% compared to colored de Bruijn graphs constructed by Bifrost under the default settings.

The RLZ-Graph software is available athttps://github.com/Kingsford-Group/rlzgraph
CCG•CGG interruptions in high penetrance SCA8 families increase RAN translation and protein toxicity
Authors: Perez Barbara A. , Shorrock Hannah K. , Banez-Coronel Monica , Laboissonniere Lauren A. , Reid Tammy , Ikeda Yoshio , Reddy Kaalak , Gomez Christopher M. , Bird Thomas , Ashizawa Tetsuo , Schut Lawrence J. , Brusco Alfredo , Berglund J. Andrew , Hasholt Lis F. , Nielsen Jorgen E. , Subramony S.H. , Ranum Laura P.W.
Published: February 2021

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8 we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (N=77). We show that repeat expansion mutations from individuals with two or more affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability and steady state levels of SCA8 RAN polyAla and polySer proteins. Additionally, the CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame increase the toxicity of the resulting proteins. In summary, CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
An algal symbiont (Breviolum psygmophilum) responds more strongly to chronic high temperatures than its facultatively symbiotic coral host (Astrangia poculata)
Authors: Chan Andrea N. , González-Guerrero Luis A. , Iglesias-Prieto Roberto , Burmester Elizabeth M. , Rotjan Randi D. , Finnerty John R. , Baums Iliana B.
Published: February 2021

Scleractinian corals form the foundation of coral reefs by secreting skeletons of calcium carbonate. Their intracellular algal symbionts (Symbiodiniaceae) translocate a large proportion of photosynthate to the coral host, which is required to maintain high rates of calcification. Global warming is causing dissociation of coral host and algal symbiont, visibly presented as coral bleaching. Despite decades of study, the precise mechanisms of coral bleaching remain unknown. Separating the thermal stress response of the coral from the algal symbiont is key to understanding bleaching in tropical corals. The facultatively symbiotic northern star coral,Astrangia poculata, naturally occurs as both symbiotic and aposymbiotic (lacking algal symbionts) polyps – sometimes on the same coral colony. Thus, it is possible to separate the heat stress response of the coral host alone from the coral in symbiosis with its symbiontBreviolum psygmophilum. Using replicate symbiotic and aposymbiotic ramets ofA. poculata, we conducted a chronic heat stress experiment to increase our understanding of the cellular mechanisms resulting in coral bleaching. Sustained high temperature stress resulted in photosynthetic dysfunction inB. psygmophilum, including a decline in maximum photosynthesis rate, maximum photochemical efficiency, and the absorbance peak of chlorophylla. Interestingly, the metabolic rates of symbiotic and aposymbiotic corals were differentially impacted. RNAseq analysis revealed more differentially expressed genes between heat-stressed and control aposymbiotic colonies than heat-stressed and control symbiotic colonies. Notably, aposymbiotic colonies increased the expression of inflammation-associated genes such as nitric oxide synthases. Unexpectedly, the largest transcriptional response was observed between heat-stressed and controlB. psygmophilum, including genes involved in photosynthesis, response to oxidative stress, and meiosis. Thus, it appears that the algal symbiont suppresses the immune response of the host, potentially increasing the vulnerability of the host to pathogens. TheA. poculata-B. psygmophilumsymbiosis provides a tractable model system for investigating thermal stress and immune challenge in scleractinian corals.
Exosomes from COVID-19 patients carry tenascin-C and fibrinogen-β in triggering inflammatory signals in distant organ cells
Authors: Sur Subhayan , Khatun Mousumi , Steele Robert , Isbell T. Scott , Ray Ranjit , Ray Ratna B.
Published: February 2021

SARS-CoV-2 infection causes cytokine storm and overshoot immunity in humans; however, it remains to be determined whether genetic material of SARS-CoV-2 and/or virus induced soluble mediators from lung epithelial cells as natural host are carried out by macrophages or other vehicles at distant organs causing tissue damage. We speculated that exosomes as extracellular vesicles are secreted from SARS-CoV-2 infected cells may transport messages to other cells of distant organs leading to pathogenic consequences. For this, we took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and SARS-CoV-2 infected patients. Our results revealed that tenascin-C (TNC) and fibrinogen-β (FGB) are highly abundant in exosomes from SARS-CoV-2 infected patient’s plasma as compared to that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via NF-κB pathway, we examined the status of TNF-α, IL-6 and CCL5 expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase when compared with that from healthy subjects. Together, our results demonstrated that soluble mediators, like TNC and FGB, are transported through plasma exosomes in SARS-CoV-2 infected patients and trigger pro-inflammatory cytokine expression in cells of distant organs in COVID-19 patients.

Importance

Exosomes play an important role in intercellular communication by inducing physiological changes in recipient cells by transferring bioactive proteins. Little is known about exosomes from SARS-CoV-2 infected cells and their role in pathogenesis. Here, we have carefully examined and analyzed this aspect of SARS-CoV-2 infection. Our results uncovered the potential mechanisms by which SARS-CoV-2 communicates with other cells of distant organs and promotes pathogenesis. We expect to detect whether other factors are modulated in the presence of COVID-19 exosomes. Our exosomes related proteomic experiments prioritize after initial verification to further examine their role in SARS-CoV-2 associated other pathogenic mechanisms to target for therapeutic modalities.
SLC4A2 Anion Exchanger Promotes Tumor Cell Malignancy via Enhancing H+Leak across Golgi Membranes
Authors: Khosrowabadi Elham , Rivinoja Antti , Risteli Maija , Tuomisto Anne , Salo Tuula , Mäkinen Markus J , Kellokumpu Sakari
Published: February 2021

Proper functioning of each secretory and endocytic compartment relies on its unique pH micro-environment that is known to be dictated by the rates of V-ATPase-mediated H+pumping and its leakage back to the cytoplasm via an elusive “H+leak” pathway. Here, we show that this proton leak across Golgi membranes involves AE2a (SLC4A2a)-mediated bicarbonate-chloride exchange, as it is strictly dependent on both bicarbonate import (in exchange of chloride export) and the AE2a expression level in the cells. Imported bicarbonate anions and luminal protons then facilitate a common buffering reaction that yields carbon dioxide and water before their egress back to the cytoplasm via diffusion or water channels. The high surface-volume ratio of flattened Golgi cisternae helps this process, as their shape is optimal for water and gas exchange. Interestingly, this pathway is often upregulated in cancers and established cancer cell lines, and responsible for their markedly elevated Golgi resting pH and attenuated glycosylation potential. Accordingly, AE2 knockdown in SW-48 colorectal cancer cells was able to restore these two phenomena, and at the same time, to reverse cells’ invasive and anchorage-independent growth phenotype. These findings suggest that a malignant cell can be returned to a benign state by normalizing its Golgi resting pH.
Human monoclonal antibodies against Staphylococcus aureus surface antigens recognize in vitro biofilm and in vivo implant infections
Authors: de Vor Lisanne , van Dijk Bruce , van Kessel Kok P.M. , Kavanaugh Jeffrey S. , de Haas Carla J.C. , Aerts Piet C. , Viveen Marco C. , Boel Edwin C.H. , Fluit Ad C. , Kwiecinski Jakub M. , Krijger Gerard C. , Ramakers Ruud M. , Beekman Freek J. , Dadachova Ekaterina , Lam Marnix G.E.H. , Vogely H. Charles , van der Wal Bart C.H. , van Strijp Jos A.G. , Horswill Alexander R. , Weinans Harrie , Rooijakkers Suzan H.M.
Published: February 2021

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and/or treatment of biofilm-related infections. Here we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. In a mouse model, we show that mAb 4497 (recognizing wall teichoic acid (WTA)) specifically localizes to biofilm-infected implants. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo. This is an important first step to develop mAbs for imaging or treating S. aureus biofilms.
Broca area homologue’s asymmetry reflects gestural communication lateralisation in monkeys (Papio anubis)
Authors: Becker Yannick , Claidière Nicolas , Margiotoudi Konstantina , Marie Damien , Roth Muriel , Nazarian Bruno , Anton Jean-Luc , Coulon Olivier , Meguerditchian Adrien
Published: February 2021

Manual gestures and speech recruit a common neural network, involving Broca’s area in the left hemisphere. Such speech-gesture integration gave rise to theories on the critical role of manual gesturing in the origin of language.

Within this evolutionary framework, research on gestural communication in our closer primate relatives has received renewed attention for investigating its potential language-like features.

Here, using in-vivo anatomical MRI in 50 baboons, we found that communicative gesturing is related to Broca homologue’s marker in monkeys, namely the ventral portion of the Inferior Arcuate sulcus (IA sulcus). In fact, both direction and degree of gestural communication’s handedness – but not handedness for object manipulation - are associated and correlated with contralateral depth asymmetry at this exactIA sulcusportion. In other words, baboons that prefer to communicate with their right hand have a deeper left-than-rightIA sulcus, than those preferring to communicate with their left hand and vice versa. Interestingly, in contrast to handedness for object manipulation, gestural communication’s lateralisation is not associated to theCentral sulcusdepth asymmetry, suggesting a double dissociation of handedness’ types between manipulative action and gestural communication.

It is thus not excluded that this specific gestural lateralisation signature within the baboons’ frontal cortex might reflect a phylogenetical continuity with language-related Broca lateralisation in humans.
A linguistic representation in the visual system underlies successful lipreading
Authors: Nidiffer Aaron R , Cao Cody Zhewei , O’Sullivan Aisling , Lalor Edmund C
Published: February 2021

There is considerable debate over how visual speech is processed in the absence of sound and whether neural activity supporting lipreading occurs in visual brain areas. Surprisingly, much of this ambiguity stems from a lack of behaviorally grounded neurophysiological findings. To address this, we conducted an experiment in which human observers rehearsed audiovisual speech for the purpose of lipreading silent versions during testing. Using a combination of computational modeling, electroencephalography, and simultaneously recorded behavior, we show that the visual system produces its own specialized representation of speech that is 1) well-described by categorical linguistic units (“visemes”) 2) dissociable from lip movements, and 3) predictive of lipreading ability. These findings contradict a long-held view that visual speech processing co-opts auditory cortex after early visual processing stages. Consistent with hierarchical accounts of visual and audiovisual speech perception, our findings show that visual cortex performs at least a basic level of linguistic processing.
Mutation bias implicates RNA editing in a wide range of mammalian RNA viruses
Authors: Simmonds Peter , Ansari M. Azim
Published: February 2021

The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, potentially driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in the more genetically diverse datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 32 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (includingPicornaviridae, Flaviviridae, Matonaviridae, CaliciviridaeandCoronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x–7.5x). C->U transitions showed a favoured 5’ U upstream context consistent with previous analyses of APOBEC-mediated RNA targeting. Amongst several genomic compositional and structural parameters, the presence of genome scale RNA secondary structure (GORS) was associated with C->U/U->C transition asymmetries (p< 0.001), potentially reflecting the documented structure dependence of APOBEC-mediated RNA editing. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, consistent with extensive homoplasy documented in SARS-CoV-2. Excess C->U substitutions accounted for 15-20% of standing sequence variability of HCV and other RNA viruses; RNA editing may therefore represent a potent driver of RNA virus sequence diversification and longer term evolution.

Author Summary

The rapid evolution of RNA viruses is thought to arise from high mutation frequencies during replication and the rapid accumulation of genetic changes over time in response to its changing environments. This study describes an additional potent factor that contributes to the evolution of RNA infecting mammals, the deliberate mutation of the viral genome by host antiviral pathways active within the cell when it becomes infected. This so called “genome editing” by one or more APOBEC enzymes leads to characteristic C->U mutations that damage the virus’s ability to replicate. While this pathway is well characterised as an antiviral defence against HIV and other retroviruses, this study provides evidence for its activity against a wide range of human and veterinary viruses, including HCV and foot and mouth disease virus. APOBEC-driven mutations accounted for 15-20% of standing sequence variability of RNA virus groups, representing a potent driver of RNA virus sequence diversification.