bluuebunny/crossref_metadata_2025 huggingface dataset:
Nectar biosynthesis is conserved among floral and extrafloral nectaries
Authors: Chatt Elizabeth C , Mahalim Siti-Nabilla , Mohd-Fadzil Nur-Aziatull , Roy Rahul , Klinkenberg Peter M , Horner Harry T , Hampton Marshall , Carter Clay J , Nikolau Basil J
Published: January 2021

Nectar is a primary reward mediating plant–animal mutualisms to improve plant fitness and reproductive success. Four distinct trichomatic nectaries develop in cotton (Gossypium hirsutum), one floral and three extrafloral, and the nectars they secrete serve different purposes. Floral nectar attracts bees for promoting pollination, while extrafloral nectar attracts predatory insects as a means of indirect protection from herbivores. Cotton therefore provides an ideal system for contrasting mechanisms of nectar production and nectar composition between different nectary types. Here, we report the transcriptome and ultrastructure of the four cotton nectary types throughout development and compare these with the metabolomes of secreted nectars. Integration of these datasets supports specialization among nectary types to fulfill their ecological niche, while conserving parallel coordination of the merocrine-based and eccrine-based models of nectar biosynthesis. Nectary ultrastructures indicate an abundance of rough endoplasmic reticulum positioned parallel to the cell walls and a profusion of vesicles fusing to the plasma membranes, supporting the merocrine model of nectar biosynthesis. The eccrine-based model of nectar biosynthesis is supported by global transcriptomics data, which indicate a progression from starch biosynthesis to starch degradation and sucrose biosynthesis and secretion. Moreover, our nectary global transcriptomics data provide evidence for novel metabolic processes supporting de novo biosynthesis of amino acids secreted in trace quantities in nectars. Collectively, these data demonstrate the conservation of nectar-producing models among trichomatic and extrafloral nectaries.
A systemic whole-plant change in redox levels accompanies the rapid systemic response to wounding
Authors: Fichman Yosef , Mittler Ron
Published: January 2021

The wounding-induced reactive oxygen species (ROS) wave is accompanied by a systemic whole-plant redox response in Arabidopsis.
Patient and Provider Acceptability of a Patient Preauthorized Concealed Opioid Reduction
Authors: Bedford Theresa , Adediran Timileyin , Haycock Nathaniel R , Mullins C Daniel , Medeiros Michelle , Wright Thelma , Curatolo Michele , Hamlin Lynette , Colloca Luana
Published: January 2021

Objective

Limited research of how to best taper opioids brings about an ethical and clinical dilemma. Experiments using overt and concealed administration of opioids have demonstrated the benefits of a concealed reduction to eliminate negative expectations and prolong analgesic benefits. This may allow for opioid tapering without significant increases in pain. Based on this, we investigated patient and provider acceptance of a concealed opioid reduction for chronic pain.

Methods

We conducted a cross-sectional survey via REDcap with 74 patients, who are currently taking or have taken high dose opioids, and 49 providers using a validated questionnaire based on two hypothetical clinical trials comparing a patient preauthorized concealed opioid reduction vs standard tapering.

Results

We found that patients and providers have positive attitudes toward a concealed reduction of opioid dosages. More than 60% of providers and patients surveyed viewed the hypothetical clinical trial as helpful to reduce pain, side effects, and withdrawal symptoms. Sixty-one percent of patients and 77.6% of providers recognized that there would be differences in pain relief depending upon which group the hypothetical participants would be enrolled in.

Conclusions

Patients and providers appear to understand the benefits of a concealed opioid reduction. Our findings support future randomized controlled trials that compare concealed and overt opioid tapering in patients with chronic pain. More research is needed to understand the difference in attitudes between research and clinical practice and to test the acceptability of a concealed reduction following a participation in an active clinical trial.
Women Veterans’ Experiences with Integrated, Biopsychosocial Pain Care: A Qualitative Study
Authors: Nicosia Francesca M , Gibson Carolyn J , Purcell Natalie , Zamora Kara , Tighe Jennifer , Seal Karen H
Published: January 2021

Objectives

Biopsychosocial, integrated pain care models are increasingly implemented in the Veterans Health Administration to improve chronic pain care and reduce opioid-related risks, but little is known about how well these models address women veterans’ needs.

Design

Qualitative, interview-based study.

Setting

San Francisco VA Health Care System Integrated Pain Team (IPT), an interdisciplinary team that provides short-term, personalized chronic pain care emphasizing functional goals and active self-management.

Subjects

Women with chronic pain who completed ≥3 IPT sessions.

Methods

Semistructured phone interviews focused on overall experience with IPT, perceived effectiveness of IPT care, pain care preferences, and suggested changes for improving gender-sensitive pain care. We used a rapid approach to qualitative thematic analysis to analyze interviews.

Results

Fourteen women veterans (mean age 51 years; range 33–67 years) completed interviews. Interviews revealed several factors impacting women veterans’ experiences: 1) an overall preference for receiving both primary and IPT care in gender-specific settings, 2) varying levels of confidence that IPT could adequately address gender-specific pain issues, 3) barriers to participating in pain groups, and 4) barriers to IPT self-management recommendations due to caregiving responsibilities.

Conclusions

Women veterans reported varied experiences with IPT. Recommendations to improve gender-sensitive pain care include increased provider training; increased knowledge of and sensitivity to women’s health concerns; and improved accommodations for prior trauma, family and work obligations, and geographic barriers. To better meet the needs of women veterans with chronic pain, integrated pain care models must be informed by an understanding of gender-specific needs, challenges, and preferences.
Pain Management Evaluation in Maintenance Hemodialysis Patients
Authors: Dreiher Jacob , Fleishman Tatiana Talya , Shvartzman Pesach
Published: January 2021

Context

Pain is a common complaint in maintenance hemodialysis (MHD) patients, and it is often inadequately assessed and inappropriately treated.

Objectives

The study goal was to preliminarily evaluate pain management in MHD patients.

Methods

The study was a cross-sectional study conducted in 2013–2015. A sample of 277 MHD patients who reported pain within the last 24 hours from five hospital hemodialysis units in Israel were interviewed and evaluated. Study tools included the Brief Pain Inventory, the Pain Management Index (PMI), demographic and clinical characteristics. Pharmacy computerized data were reviewed to identify the type of analgesics used.

Results

Mean pain level was 7.2 ± 2.2 (median: 8). Pain level was mild in 17 (6.1%), moderate in 120 (43.3%) and severe in 140 (50.5%) of patients. Only 185 participants (66.8%) were treated with analgesics during the year prior to the interview. Of these, 99 (53.5%) received opioids. Using the PMI to preliminarily assess the appropriateness of the treatment, 214 (77.3%) of patients with pain in the last 24 hours were undertreated, and 52 patients (18.8%) were appropriately treated. In a multivariable analysis, factors associated with inappropriate treatment were severe pain intensity and a higher Functional Independent Measure (FIM). A lower FIM was associated with opioid use in a multivariable analysis.

Conclusions

According to the PMI, most dialysis patients were found to be inappropriately treated. About one third received opioids, but even among them, inappropriate treatment was common. Pain management in MHD patients needs to be improved.
Electronic Delivery of Pain Education for Chronic Overlapping Pain Conditions: A Prospective Cohort Study
Authors: McKernan Lindsey C , Crofford Leslie J , Kim Ahra , Vandekar Simon N , Reynolds William S , Hansen Kathryn A , Clauw Daniel J , Williams David A
Published: January 2021

Objective

To examine the impact of educational materials for chronic overlapping pain conditions (COPCs), the feasibility of delivering materials online, and to explore its impact on self-reported self-management applications at 3-month follow-up.

Design

Prospective cohort study

Setting

Online

Subjects

Individuals from a university-wide active research repository with ≥1 coded diagnostic COPC by ICD-9/10 in the medical record.

Methods

We determined the number of COPCs per participant as indicated by diagnostic codes in the medical record. Consenting participants completed self-report questionnaires and read educational materials. We assessed content awareness and knowledge pre- and post-exposure to education. Comprehension was assessed via embedded questions in reading materials in real time. Participants then completed assessments regarding concept retention, self-management engagement, and pain-related symptoms at 3-months.

Results

N = 216 individuals enrolled, with 181 (84%) completing both timepoints. Results indicated that participants understood materials. Knowledge and understanding of COPCs increased significantly after education and was retained at 3-months. Patient characteristics suggested the number of diagnosed COPCs was inversely related to age. Symptoms or self-management application did not change significantly over the 3-month period.

Conclusions

The educational materials facilitated teaching of key pain concepts in self-management programs, which translated easily into an electronic format. Education alone may not elicit self-management engagement or symptom reduction in this population; however, conclusions are limited by the study’s uncontrolled design. Education is likely an important and meaningful first step in comprehensive COPC self-management.
The 4-Element Movement System Model to Guide Physical Therapist Education, Practice, and Movement-Related Research
Authors: McClure Philip , Tevald Michael , Zarzycki Ryan , Kantak Shailesh , Malloy Philip , Day Kristin , Shah Kshamata , Miller Amy , Mangione Kathleen
Published: January 2021

The movement system has been adopted as the key identity for the physical therapy profession, and recognition of physical therapists’ primary expertise in managing movement dysfunction is an important achievement. However, existing movement system models seem inadequate for guiding education, practice, or research. Lack of a clear, broadly applicable model may hamper progress in physical therapists actually adopting this identity. We propose a model composed of 4 primary elements essential to all movement: motion, force, energy, and control. Although these elements overlap and interact, they can each be examined and tested with some degree of specificity. The proposed 4-element model incorporates specific guidance for visual, qualitative assessment of movement during functional tasks that can be used to develop hypotheses about movement dysfunction and serve as a precursor to more quantitative tests and measures. Human movement always occurs within an environmental context and is affected by personal factors, and these concepts are represented within the model. The proposed scheme is consistent with other widely used models within the profession, such as the International Classification of Functioning, Disability and Health and the Patient Management Model. We demonstrate with multiple examples how the model can be applied to a broad spectrum of patients across the lifespan with musculoskeletal, neurologic, and cardiopulmonary disorders.
Predictive value of anti-CarP and anti-PAD3 antibodies alone or in combination with RF and ACPA for the severity of rheumatoid arthritis
Authors: Lamacchia Celine , Courvoisier Delphine S , Jarlborg Matthias , Bas Sylvette , Roux-Lombard Pascale , Möller Burkhard , Ciurea Adrian , Finckh Axel , Bentow Chelsea , Martinez-Prat Laura , Mahler Michael , Gabay Cem , Nissen Michael J ,   the SCQM Rheumatologists
Published: January 2021

Objectives

The objective of this study was to analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with RF and ACPA, to identify patients at high risk of developing severe RA outcomes.

Methods

Patients within the Swiss Clinical Quality Management registry with a biobank sample were tested for RF, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally.

Results

Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and PsA (196)]. Anti-CarP and anti-PAD3 antibodies were, respectively, present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; P= 0.005) and significantly more radiographic damage (14.9 vs 8.8; P= 0.02) than anti-PAD3-negative patients. In the ACPA-negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3-positive patients (P= 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (P= 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (P= 0.02). There were no differences in RA outcome measures with regards to anti-CarP.

Conclusions

Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.
Association between current medication use and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative
Authors: Perry Thomas A , Wang Xia , Nevitt Michael , Abdelshaheed Christina , Arden Nigel , Hunter David J
Published: January 2021

Objective

Use of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA.

Methods

We used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren–Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW.

Results

Of 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = −0.042, 95% CI −0.08, −0.0004). No other associations were observed.

Conclusions

In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.
RNAi-mediated repression of dormancy-related genes results in evergrowing apple trees
Authors: Wu Rongmei , Cooney Janine , Tomes Sumathi , Rebstock Ria , Karunairetnam Sakuntala , Allan Andrew C , Macknight Richard C , Varkonyi-Gasic Erika
Published: January 2021

DORMANCY-ASSOCIATED MADS-box (DAM) and SHORT VEGETATIVE PHASE (SVP) genes have been implicated in the regulation of winter dormancy in perennials. Ectopic expression of apple (Malus × domestica Borkh. ‘Royal Gala’) DAM and SVP genes delays budbreak and constrains lateral shoot outgrowth. In this study, we used RNA interference (RNAi) to simultaneously target all apple DAM and SVP genes in order to study their role and mode of action in the regulation of bud dormancy, budbreak and flowering. A synthetic construct carrying a hairpin fragment assembled from sequences specific to coding regions of three DAM and two SVP genes was used to generate transgenic lines. Reduced expression of DAM/SVP genes resulted in delayed leaf senescence and abscission in autumn, failure to enter bud dormancy in winter and continual growth of new leaves regardless of the season for over 3 years. Precocious flowering but normal flower morphology, fertility and fruit development were observed. The non-dormant phenotype was associated with modified phytohormone composition. The content of gibberellins (GAs) and jasmonates (JAs) was significantly increased in terminal buds of RNAi lines compared with wildtype plants, accompanied by elevated expression of the key GA biosynthesis pathway gene GIBBERELLIN 20 OXIDASE-2 (MdGA20ox-2) along with the FLOWERING LOCUS T gene MdFT2. The key mediator of plasmodesmatal closure, MdCALLOSE SYNTHASE 1 (MdCALS1), was repressed in RNAi lines. This study provides functional evidence for the role of DAM/SVP genes in vegetative phenology of apple and paves the way for production of low-chill varieties suitable for growth in warming climates.
High-Quality Genome Resource of the Pathogen of Botryosphaeria dothidea Causing Kiwifruit Soft Rot
Authors: Liang Kuan , Lan Jianbin , Wang Baoquan , Liu Yuanyuan , Lu Qi , Liu Pu
Published: January 2021

Kiwifruit soft rot caused by the fungal pathogen Botryosphaeria dothidea is a serious disease in kiwifruit-growing regions worldwide. In this study, we reported the high-quality genome sequence of the highly virulent B. dothidea strain PTZ1 using PacBio Sequel techniques. In total, 100.87 million clean reads with mean read length of 9,871 bp were obtained. De novo assembly resulted in 28 contigs with a total size of 44.45 Mb. The GC content of the genome was 54.59%. Furthermore, genes related to specific virulence of the strain were identified, including 259 fungal cytochrome P450s, 550 carbohydrate-active enzymes, 860 secretory proteins, and 1,182 pathogen–host interactions related proteins. The genome is a useful resource to serve as a reference to facilitate the analysis of B. dothidea isolates and comparative genomic studies of the necrotroph pathogens.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Multi-omics Comparison Reveals Landscape of Citrus limon and Citrus sinensis Response to ‘Candidatus Liberibacter asiaticus’
Authors: Chin Elizabeth L. , Ramsey John , Saha Surya , Mishchuk Darya , Chavez Juan , Howe Kevin , Zhong Xuefei , Flores-Gonzalez Mirella , Mitrovic Elizabeth , Polek MaryLou , Godfrey Kris , Mueller Lukas A. , Bruce James , Heck Michelle , Slupsky Carolyn M.
Published: January 2021

Comparison of the metabolic changes prior to symptom development upon infection with Candidatus Liberibacter asiaticus (CLas), the bacterium associated with citrus greening disease, between citrus hosts with different tolerances is lacking. The objective of this study was to compare the early response of Lisbon lemon (Citrus limon) and Washington navel orange (Citrus sinensis [L.] Osbeck), two citrus species commercially important to California, to CLas through graft inoculation. Here, we compare the transcriptome, proteome, and metabolome response, using RNA sequencing, liquid chromatography tandem mass spectrometry, and 1H nuclear magnetic resonance, respectively, from our two recently published studies examining the response of the lemon and navel oranges separately, and introduce new micronutrient data from inductively coupled plasma mass spectrometry analysis, focusing on lemons at 10 and 14 weeks postgrafting (wpg), and navels at 8 and 18 wpg, prior to symptom development. Several micronutrients accumulated in presymptomatic infected lemons compared with controls, whereas little change was observed in the navels. Photosynthesis proteins were substantially altered by CLas infection in navels, with fewer changes observed in lemons. The metabolome differed between control and infected navels throughout infection, although differences between control and infected lemons were identified only after symptom expression. Taken together, these findings highlight differences in response to CLas between two varieties with differing tolerances.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Stochastic resonance in deformable potential with time-delayed feedback
Authors: Wadop Ngouongo Y. J. , Djolieu Funaye M. , Djuidjé Kenmoé G. , Kofané T. C.
Published: January 2021

This paper reports the stochastic resonance (SR) phenomenon with memory effects for a Brownian particle in a potential whose shape is subjected to deformation. We model the deformation in the system by the Remoissenet–Peyrard potential and the memory effects by the time-delayed feedback. The question of the possible influence of time-delayed feedback on the occurrence of SR is then of our interest. We examine numerically the effect of feedback strength as well as time delay on SR phenomenon in terms of hysteresis loop area. It is found that time-delayed feedback has a significant effect on SR and can induce double resonances in the system. We show that the properties of SR are varying, depending on interdependence between feedback strength, time delay and shape parameter.

This article is part of the theme issue ‘Vibrational and stochastic resonance in driven nonlinear systems (part 1)’.
Study of vibrational resonance in nonlinear signal processing
Authors: Pan Yan , Duan Fabing , Chapeau-Blondeau François , Xu Liyan , Abbott Derek
Published: January 2021

Vibrational resonance (VR) intentionally applies high-frequency periodic vibrations to a nonlinear system, in order to obtain enhanced efficiency for a number of information processing tasks. Note that VR is analogous to stochastic resonance where enhanced processing is sought via purposeful addition of a random noise instead of deterministic high-frequency vibrations. Comparatively, due to its ease of implementation, VR provides a valuable approach for nonlinear signal processing, through detailed modalities that are still under investigation. In this paper, VR is investigated in arrays of nonlinear processing devices, where a range of high-frequency sinusoidal vibrations of the same amplitude at different frequencies are injected and shown capable of enhancing the efficiency for estimating unknown signal parameters or for detecting weak signals in noise. In addition, it is observed that high-frequency vibrations with differing frequencies can be considered, at the sampling times, as independent random variables. This property allows us here to develop a probabilistic analysis—much like in stochastic resonance—and to obtain a theoretical basis for the VR effect and its optimization for signal processing. These results provide additional insight for controlling the capabilities of VR for nonlinear signal processing.

This article is part of the theme issue ‘Vibrational and stochastic resonance in driven nonlinear systems (part 1)’.
Systematic analysis of nuclear localization of Autographa californica multiple nucleopolyhedrovirus proteins
Authors: He Lihong , Shao Wei , Li Jiang , Deng Fei , Wang Hualin , Hu Zhihong , Wang Manli
Published: January 2021

Baculoviruses are large DNA viruses that replicate within the nucleus of infected host cells. Therefore, many viral proteins must gain access to the nucleus for efficient viral genome replication, gene transcription and virion assembly. To date, the global protein localization pattern of baculoviral proteins is unknown. In this study, we systematically analysed the nuclear localization of 154 ORFs encoded by the prototypic baculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV), either during transient expression or with super-infection of the virus. By transient expression of vectors containingegfp-fused ORFs, we found that in the absence of virus infection, 25 viral proteins were localized in the nucleus. Most of these, which we called ‘auto-nuclear localization’ proteins, are related to virus replication, transcription or virion structure, and 20 of them contain predicted classical nuclear localization signal. Upon virus infection, 11 proteins, which originally localized in the cytoplasm or both cytoplasm and nucleus in the transfection assays, were completely translocated into the nucleus, suggesting that their nuclear import is facilitated by other viral or host proteins. Further co-transfection experiments identified that four of the 11 proteins, including P143, P33, AC73 and AC114, were imported into the nucleus with the assistance of the auto-nuclear localization proteins LEF-3 (for P143), TLP (for P33) and VP80 (for both AC73 and AC114). This study presents the first global nuclear localization profile of AcMNPV proteins and provides useful information for further elucidation of the mechanisms of baculovirus nuclear entry and gene functions.
Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death
Authors: Law Mary E. , Yaaghubi Elham , Ghilardi Amanda F. , Davis Bradley J. , Ferreira Renan B. , Koh Jin , Chen Sixue , DePeter Sadie F. , Schilson Christopher M. , Chiang Chi-Wu , Heldermon Coy D. , Nørgaard Peter , Castellano Ronald K. , Law Brian K.
Published: January 2021

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal and DDA-induced DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.
SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy
Authors: Lee Tzu-Han , Wu David , Guzy Robert , Schoettler Nathan , Adegunsoye Ayodeji , Mueller Jeffrey , Hussein Aliya , Sperling Anne , Mutlu Gökhan M. , Fang Yun
Published: January 2021

Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Krüppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.
Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites
Authors: Silva Lakmali M , Doyle Andrew D , Tran Collin L , Greenwell-Wild Teresa , Dutzan Nicolas , Lum Andrew G , Agler Cary S , Sibree Megan , Jani Priyam , Martin Daniel , Kram Vardit , Castellino Francis J , Flick Matthew J , Divaris Kimon , Bugge Thomas H , Moutsopoulos Niki M
Published: January 2021

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we document that the clotting factor fibrin is a critical regulator of neutrophil function at mucosal barriers. We demonstrate that fibrin engages neutrophils through the αMβ2integrin receptor and activates effector functions, including the production of reactive oxygen species and NET formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis. Indeed, the accumulation of fibrin due to Mendelian genetic defects in plasmin leads to severe oral mucosal immunopathology in mice and humans. Concordantly, genetic polymorphisms in the humanPLGgene, encoding plasminogen, are associated with common forms of the oral mucosal disease periodontitis. Our work uncovers fibrin as a critical regulator of neutrophil effector function within the mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in common mucosal disease.
Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes
Authors: Gutiérrez-González Matias , Fahad Ahmed S. , Ardito Matt , Nanaware Padma , Lu Liying , Normandin Erica , Madan Bharat , Tivin Jacob , Coates Emily , Henry Amy R. , Laboune Farida , Graham Barney S. , Douek Daniel C. , Ledgerwood Julie E. , Mascola John R. , Martin William D. , Stern Lawrence J. , De Groot Annie S. , DeKosky Brandon J.
Published: January 2021

Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody developmentin vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of class-switched sequences and serum proteomic data revealed that MHC-II epitope deletion is associated with antibody class switching and long-term secretion into serum. These data suggest that the MHC-II peptide epitope content of a BCR is an important determinant of antibody maturation that shapes the composition and durability of humoral immunity.

Highlights

Antibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors.

Antibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching.

MHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum.

MHC-II genotype provides a personalized selection pressure on human antibody development.
Optimal strategies for learning multi-ancestry polygenic scores vary across traits
Authors: Lehmann B.C.L. , Mackintosh M. , McVean G. , Holmes C.C.
Published: January 2021

Polygenic scores (PGSs) are individual-level measures that aggregate the genome-wide genetic predisposition to a given trait. As PGS have predominantly been developed using European-ancestry samples, trait prediction using such European ancestry-derived PGS is less accurate in non-European ancestry individuals. Although there has been recent progress in combining multiple PGS trained on distinct populations, the problem of how to maximize performance given a multiple-ancestry cohort is largely unexplored. Here, we investigate the effect of sample size and ancestry composition on PGS performance for fifteen traits in UK Biobank. For some traits, PGS estimated using a relatively small African-ancestry training set outperformed, on an African-ancestry test set, PGS estimated using a much larger European-ancestry only training set. We observe similar, but not identical, results when considering other minority-ancestry groups within UK Biobank. Our results emphasise the importance of targeted data collection from underrepresented groups in order to address existing disparities in PGS performance.
Pathological turret mutations in the cardiac sodium channel cause long-range pore disruption
Authors: Habib Zaki F , Kohli Manas , Salvage Samantha C , Rahman Taufiq , Huang Christopher L-H , Jackson Antony P
Published: January 2021

The voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Germline mutations that disrupt Nav1.5 activity predispose affected individuals to inherited cardiopathologies. Some of these Nav1.5 mutations alter amino acids in extracellular turret domains DII and DIII. Yet the mechanism is unclear. In the rat Nav1.5 structure determined by cryogenic electron microscopy, the wild-type residues corresponding to these mutants form a complex salt-bridge between the DII and DIII turret interface. Furthermore, adjacent aromatic residues form cation-π interactions with the complex salt-bridge. Here, we examine this region using site-directed mutagenesis, electrophysiology andin silicomodeling. We confirm functional roles for the salt-bridges and the aromatic residues. We show that their disruption perturbs the geometry of both the DEKA selectivity ring and the inner pore vestibule that are crucial for sodium ion permeability. Our findings provide insights into a class of pathological mutations occurring not only in Nav1.5 but also in other sodium channel isoforms too. Our work illustrates how the sodium channel structures now being reported can be used to formulate and guide novel functional hypotheses.
The sensitivity of ECG contamination to surgical implantation site in adaptive neurostimulation
Authors: Neumann Wolf-Julian , Sorkhabi Majid Memarian , Benjaber Moaad , Feldmann Lucia K. , Saryyeva Assel , Krauss Joachim K. , Contarino Maria Fiorella , Sieger Tomas , Jech Robert , Tinkhauser Gerd , Pollo Claudio , Palmisano Chiara , Isaias Ioannis U. , Cummins Daniel , Little Simon J. , Starr Philip A. , Kokkinos Vasileios , Gerd-Helge Schneider , Herrington Todd , Brown Peter , Richardson R. Mark , Kühn Andrea A. , Denison Timothy
Published: January 2021

Background

Brain sensing devices are approved today for Parkinson’s, essential tremor, and epilepsy therapies. Clinical decisions for implants are often influenced by the premise that patients will benefit from using sensing technology. However, artifacts, such as ECG contamination, can render such treatments unreliable. Therefore, clinicians need to understand how surgical decisions may affect artifact probability.

Objectives

Investigate neural signal contamination with ECG activity in sensing enabled neurostimulation systems, and in particular clinical choices such as implant location that impact signal fidelity.

Methods

Electric field modelling and empirical signals from 85 patients were used to investigate the relationship between implant location and ECG contamination.a

Results

The impact on neural recordings depends on the difference between ECG signal and noise floor of the electrophysiological recording. Empirically, we demonstrate that severe ECG contamination was more than 3.2x higher in left-sided subclavicular implants (48.3%), when compared to right-sided implants (15.3%). Cranial implants did not show ECG contamination.

Conclusions

Given the relative frequency of corrupted neural signals, we conclude that implant location will impact the ability of brain sensing devices to be used for “closed-loop” algorithms. Clinical adjustments such as implant location can significantly affect signal integrity and need consideration.

Highlights

Chronic embedded brain sensing promises algorithm-based neurostimulation

Algorithms for closed-loop stimulation can be impaired by artifacts

The relationship of implant location to cardiac dipole has relevant impact on neural signal fidelity; simple models can provide guidance on the sensitivity

ECG artifacts are present in up to 50% of neural signals from left subclavicular DBS systems

Implanting DBS in a right subclavicular location significantly reduces frequency of ECG artifacts

Cranial-mounted implants are relatively immune to artifacts
Optimizing viral genome subsampling by genetic diversity and temporal distribution (TARDiS) for Phylogenetics
Authors: Marini Simone , Mavian Carla , Riva Alberto , Salemi Marco , Magalis Brittany Rife
Published: January 2021

TARDiS for Philogenetics is a novel tool for optimal genetic sub-sampling. It optimizes both genetic diversity and temporal distribution through a genetic algorithm. TARDiS, along with example data sets and a user manual, is available at https://github.com/smarini/tardis-phylogenetics
Rbec: a tool for analysis of amplicon sequencing data from synthetic microbial communities
Authors: Zhang Pengfan , Spaepen Stjin , Bai Yang , Hacquard Stephane , Garrido-Oter Ruben
Published: January 2021

Synthetic microbial communities (SynComs) constitute an emerging and powerful tool in biological, biomedical, and biotechnological research. Despite recent advances in algorithms for the analysis of culture-independent amplicon sequencing data from microbial communities, there is a lack of tools specifically designed for analysing SynCom data, where reference sequences for each strain are available. Here we present Rbec, a tool designed for the analysis of SynCom data that accurately corrects PCR and sequencing errors in amplicon sequences and identifies intra-strain polymorphic variation. Extensive evaluation using mock bacterial and fungal communities show that our tool outperforms current methods for samples of varying complexity, diversity, and sequencing depth. Furthermore, Rbec also allows accurate detection of contaminants in SynCom experiments.

Availability and implementation

Rbec is freely available as an open-source multi-platform R package. Release versions can be obtained via Bioconductor. The developer version is maintained and can be downloaded at:https://github.com/PengfanZhang/Rbec.

Contact

garridoo@mpipz.mpg.de
Investigating the impact of reference assembly choice on genomic analyses in a cattle breed
Authors: Lloret-Villas Audald , Bhati Meenu , Kadri Naveen Kumar , Fries Ruedi , Pausch Hubert
Published: January 2021

Background

Reference-guided read alignment and variant genotyping are prone to reference allele bias, particularly for samples that are greatly divergent from the reference genome. A Hereford-based assembly is the widely accepted bovine reference genome. Haplotype-resolved genomes that exceed the current bovine reference genome in quality and continuity have been assembled for different breeds of cattle. Using whole genome sequencing data of 161 Brown Swiss cattle, we compared the accuracy of read mapping and sequence variant genotyping as well as downstream genomic analyses between the bovine reference genome (ARS-UCD1.2) and a highly continuous Angus-based assembly (UOA_Angus_1).

Results

Read mapping accuracy did not differ notably between the ARS-UCD1.2 and UOA_Angus_1 assemblies. We discovered 22,744,517 and 22,559,675 high-quality variants from ARS-UCD1.2 and UOA_Angus_1, respectively. The concordance between sequence- and array-called genotypes was high and the number of variants deviating from Hardy-Weinberg proportions was low at segregating sites for both assemblies. More artefactual INDELs were genotyped from UOA_Angus_1 than ARS-UCD1.2 alignments. Using the composite likelihood ratio test, we detected 40 and 33 signatures of selection from ARS-UCD1.2 and UOA_Angus_1, respectively, but the overlap between both assemblies was low. Using the 161 sequenced Brown Swiss cattle as a reference panel, we imputed sequence variant genotypes into a mapping cohort of 30,499 cattle that had microarray-derived genotypes. The accuracy of imputation (Beagle R2) was very high (0.87) for both assemblies. Genome-wide association studies between imputed sequence variant genotypes and six dairy traits as well as stature produced almost identical results from both assemblies.

Conclusions

The ARS-UCD1.2 and UOA_Angus_1 assemblies are suitable for reference-guided genome analyses in Brown Swiss cattle. Although differences in read mapping and genotyping accuracy between both assemblies are negligible, the choice of the reference genome has a large impact on detecting signatures of selection using the composite likelihood ratio test. We developed a workflow that can be adapted and reused to compare the impact of reference genomes on genome analyses in various breeds, populations and species.
Patient-specific network connectivity combined with a next generation neural mass model to test clinical hypothesis of seizure propagation
Authors: Gerster Moritz , Taher Halgurd , Škoch Antonín , Hlinka Jaroslav , Guye Maxime , Bartolomei Fabrice , Jirsa Viktor , Zakharova Anna , Olmi Simona
Published: January 2021

Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population.

In this study we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine the mathematical modelling with structural information from non-invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values.

We demonstrate, along the example of diffusion-weighted magnetic resonance imaging (MRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e. the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.
Traumatic Brain Injury Impairs Systemic Vascular Function Through Altered Lipid Metabolism and Disruption of Inward-Rectifier Potassium (Kir2.1) Channels
Authors: Sackheim Adrian M. , Villalba Nuria , Sancho Maria , Harraz Osama F. , Bonev Adrian D. , D’Alessandro Angelo , Nemkov Travis , Nelson Mark T. , Freeman Kalev
Published: January 2021

BACKGROUND AND PURPOSE

Trauma can lead to widespread vascular endothelial dysfunction, but the underlying mechanisms remain largely unknown. Strong inward-rectifier potassium channels (Kir2.1) play a critical role in the dynamic regulation of regional perfusion and blood flow. Kir2.1 channel activity is modulated by phosphatidylinositol 4,5-bisphosphate (PIP2), a minor membrane phospholipid that is degraded by phospholipase A2(PLA2) in conditions of oxidative stress or severe inflammation. We hypothesized that PLA2–induced depletion of PIP2impairs Kir2.1 channel function.

METHODS

A fluid percussion injury model of traumatic brain injury (TBI) in rats was used to study mesenteric resistance arteries 24 hours after injury. Patch-clamp electrophysiology in freshly isolated endothelial and smooth muscle cells was performed to monitor Kir2.1 conductance, and the functional responses of intact arteries were assessed using pressure myography. We analyzed circulating PLA2, hydrogen peroxide (H2O2), and metabolites to identify alterations in signaling pathways associated with PIP2in TBI.

RESULTS

Electrophysiology analysis of endothelial and smooth muscle cells revealed a significant reduction of Ba2+-sensitive Kir2.1 currents after TBI. Additionally, dilations to elevated extracellular potassium and BaCl2- or ML 133-induced constrictions in pressurized arteries were significantly decreased following TBI, consistent with an impairment of Kir2.1 channel function. The addition of a PIP2analog to the patch pipette successfully rescued endothelial Kir2.1 currents after TBI. Both H2O2and PLA2activity were increased after injury. Metabolomics analysis demonstrated altered lipid metabolism signaling pathways, including increased arachidonic acid, and fatty acid mobilization after TBI.

CONCLUSIONS

Our findings support a model in which increased H2O2-induced PLA2activity after trauma hydrolyzes endothelial PIP2, resulting in impaired Kir2.1 channel function.