bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of venous thromboembolism associated with tofacitinib in patients with rheumatoid arthritis: a population-based cohort study
Authors: Desai Rishi J , Pawar Ajinkya , Khosrow-Khavar Farzin , Weinblatt Michael E , Kim Seoyoung C
Published: March 2021

Objective

To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared with TNFis in patients with RA.

Methods

RA patients initiating tofacitinib or a TNFi without use of any biologic or tofacitinib any time prior were identified from IBM ‘MarketScan’ (2012–18), Medicare (parts A, B and D, 2012–17) or ‘Optum’ Clinformatics (2012–19) and followed until treatment discontinuation, treatment switch, insurance disenrollment or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% CIs after accounting for confounding through propensity score fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method.

Results

A total of 42 201, 25 078 and 20 374 RA patients were identified from MarketScan, Medicare and Optum, respectively, of whom 7.1, 7.1 and 9.7% were tofacitinib initiators. The crude incidence rates per 100 person-years (95% CI) were 0.42 (0.20–0.77) and 0.35 (0.29–0.42) in MarketScan, 1.18 (0.68–1.92) and 0.83 (0.71–0.97) in Medicare, and 0.19 (0.04–0.57) and 0.34 (0.26–0.44) in Optum for tofacitinib and TNFis, respectively. Propensity score-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFis in any database with a pooled HR (95% CI) of 1.13 (0.77–1.65).

Conclusion

Overall, VTE occurred infrequently (<1 per 100) in a total of 87 653 RA patients initiating tofacitinib or a TNFi. We observed no evidence for an increased risk of VTE for tofacitinib vs TNFis in RA patients.
On Defining and Finding Islands of Trees and Mitigating Large Island Bias
Authors: Silva Ana Serra , Wilkinson Mark
Published: March 2021

How best can we summarize sets of phylogenetic trees? Systematists have relied heavily on consensus methods, but if tree distributions can be partitioned into distinct subsets, it may be helpful to provide separate summaries of these rather than relying entirely upon a single consensus tree. How sets of trees can most helpfully be partitioned and represented leads to many open questions, but one natural partitioning is provided by the islands of trees found during tree searches. Islands that are of dissimilar size have been shown to yield majority-rule consensus trees dominated by the largest sets We illustrate this large island bias and approaches that mitigate its impact by revisiting a recent analysis of phylogenetic relationships of living and fossil amphibians. We introduce a revised definition of tree islands based on any tree-to-tree pairwise distance metric that usefully extends the notion to any set or multiset of trees, as might be produced by, for example, Bayesian or bootstrap methods, and that facilitates finding tree islands a posteriori. We extract islands from a tree distribution obtained in a Bayesian analysis of the amphibian data to investigate their impact in that context, and we compare the partitioning produced by tree islands with those resulting from some alternative approaches. Distinct subsets of trees, such as tree islands, should be of interest because of what they may reveal about evolution and/or our attempts to understand it, and are an important, sometimes overlooked, consideration when building and interpreting consensus trees. [Amphibia; Bayesian inference; consensus; parsimony; partitions; phylogeny; Chinlestegophis.]
Evaluation of nitrogen-delivery methods for stocker cattle grazing annual ryegrass
Authors: Gunter Phillip A , Mullenix Mary K , Burdette Lance C , Muntifering Russell B
Published: March 2021

A 2-yr grazing experiment was conducted to evaluate efficacy of nitrogen (N) fertilization, interseeded legumes, and protein supplementation for N delivery to stocker cattle grazing annual ryegrass (Lolium multiflorum). Each year, 90 steers (initial BW, 241 ± 13 kg) were assigned to the following N-delivery methods, with or without monensin fed in a free-choice mineral supplement as a 5 × 2 factorial arrangement of treatments: ryegrass fertilized with 112 kg N/ha (NFERT); ryegrass interseeded with crimson clover (CC, Trifolium incarnatum); ryegrass interseeded with arrowleaf clover (AC, Trifolium vesiculosum); ryegrass plus distillers dried grains with solubles (DDGS) supplemented at 0.65% BW daily; and ryegrass plus whole cottonseed (WCS) supplemented at 0.65% BW daily. Pastures within the interseeded-clover and protein-supplementation treatments were fertilized with 56 kg N/ha at time of establishment. Steers were weighed every 28 d, and forage mass (FM, kg DM/ha) was measured concurrently using the destructive harvest/disk meter double-sampling method. Each of 30 0.81-ha paddocks was stocked initially with 3 “tester” steers, and stocking density (steers/ha) was adjusted using “put-and-take steers” based on changes in FM and steer BW in order to maintain a uniform forage allowance (FA) of 1 kg DM/kg steer BW. Grazing was discontinued on May 11, 2016 in Yr 1 and May 10, 2017 in Yr 2 following 140 and 84 d of grazing, respectively. Data were analyzed as a completely randomized design with repeated measures for which pasture (n = 3) was the experimental unit. Ionophore inclusion did not affect (P > 0.10) any variable measured. Mean FM differed (P < 0.0001) between years and among N-delivery methods (P < 0.10), and mean FA differed (P = 0.005) among N-delivery methods. Steer ADG differed among N-delivery methods (P = 0.02) and between years (P < 0.001), whereas total gain/ha differed (P < 0.0008) among N-delivery methods, but not between years (P = 0.78). Stocking density differed among N-delivery methods (P = 0.02) and between years (P < 0.0001), and grazing-days/ha differed between years (P < 0.0001) and among N-delivery methods (P = 0.001). Results indicate that supplementation with a high-protein by-product feed for cattle grazing annual ryegrass maintained ADG, total gain/ha and grazing-days/ha compared with N-fertilized annual ryegrass, and increased ADG, total gain/ha, and grazing-days over interseeded legumes.
Sensitivity of Phytophthora capsici from Tennessee to Mefenoxam, Fluopicolide, Oxathiapiprolin, Dimethomorph, Mandipropamid, and Cyazofamid
Authors: Siegenthaler Timothy B. , Hansen Zachariah R.
Published: March 2021

Phytophthora blight is a destructive disease caused by the oomycete Phytophthora capsici, which affects vegetable production throughout the state of Tennessee and worldwide. Fungicides are a primary control method used in managing Phytophthora blight, but in some cases the efficacy of these products has been reduced or lost in the field. In 2018 and 2019, the efficacy of six fungicides was tested in vitro on 184 P. capsici isolates collected in Tennessee using radial growth assays. The fungicides included in the study were mefenoxam, fluopicolide, oxathiapiprolin, dimethomorph, mandipropamid, and cyazofamid. Seven isolates were resistant to mefenoxam, 86 were resistant to fluopicolide, one was resistant to oxathiapiprolin, and 13 were resistant to cyazofamid. None were resistant to dimethomorph or mandipropamid. Of the 86 isolates resistant to fluopicolide, five were also resistant to mefenoxam. Resistance to fluopicolide and cyazofamid was widespread in Tennessee, and it was more localized for mefenoxam and oxathiapiprolin. The results of this study show that fungicide resistance is widespread in P. capsici in Tennessee, and the implications for Phytophthora blight management are discussed.
Wound Bed Preparation 2021
Authors: Sibbald R. Gary , Elliott James A. , Persaud-Jaimangal Reneeka , Goodman Laurie , Armstrong David G. , Harley Catherine , Coelho Sunita , Xi Nancy , Evans Robyn , Mayer Dieter O. , Zhao Xiu , Heil Jolene , Kotru Bharat , Delmore Barbara , LeBlanc Kimberly , Ayello Elizabeth A. , Smart Hiske , Tariq Gulnaz , Alavi Afsaneh , Somayaji Ranjani
Published: March 2021

Wound Bed Preparation is a paradigm to optimize chronic wound treatment. This holistic approach examines the treatment of the cause and patient-centered concerns to determine if a wound is healable, a maintenance wound, or nonhealable (palliative). For healable wounds (with adequate blood supply and a cause that can be corrected), moisture balance is indicated along with active debridement and control of local infection or abnormal inflammation. In maintenance and nonhealable wounds, the emphasis changes to patient comfort, relieving pain, controlling odor, preventing infection by decreasing bacteria on the wound surface, conservative debridement of slough, and moisture management including exudate control. In this fourth revision, the authors have reformulated the model into 10 statements. This article will focus on the literature in the last 5 years or new interpretations of older literature. This process is designed to facilitate knowledge translation in the clinical setting and improve patient outcomes at a lower cost to the healthcare system.

GENERAL PURPOSE

To present the 2021 update of the Wound Bed Preparation paradigm.

TARGET AUDIENCE

This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.

LEARNING OBJECTIVES/OUTCOMES

After participating in this educational activity, the participant will: 1. Apply wound assessment strategies. 2. Identify patient concerns about wound care. 3. Select management options for healable, nonhealable, and maintenance wounds.
Human Amnion Chorion Membrane Allografts in the Treatment of Chronic Diabetic Foot Ulcers: A Literature Review
Authors: Oropallo Alisha , Goodwin Ashley , Morrissey MaKenzie , Del Pin Christina , Rao Amit
Published: March 2021

OBJECTIVE

To discuss human amnion chorion (placental) membrane allograft (HACMA) use for the treatment of chronic diabetic foot ulcers (DFUs) and to evaluate the effectiveness, cost, and product waste of this therapy.

DATA SOURCES

PubMed, Cochrane, and OVID databases.

STUDY SELECTION

Twenty-four articles pertaining to HACMA and DFUs published from 2016 to 2020 were selected.

DATA EXTRACTION

The data collected included type of wound care product, study design, study size, baseline size of DFU, cost, product wastage, number of applications, and wound healing outcomes.

DATA SYNTHESIS

Human amnion chorion membrane allografts in the treatment of chronic DFUs have led to a reduction in healing time and increased the overall percentage of healing, making them more effective in treating DFUs compared with standard of care. These products are offered in multiple sizes with various shelf lives and methods of storage, making them accessible, easy to use, less wasteful, and lower in cost compared with other commercially available products. Promising evidence demonstrates that HACMAs are beneficial in treating complex, high-grade DFUs with exposed tendon or bone.

CONCLUSIONS

Human amnion chorion membrane allografts are effective in treating chronic DFUs with a greater percentage of complete wound closure and a reduction in healing time versus standard of care.
Diverse Treatments for Deep Burn Wounds: A Case Report
Authors: Zhou Ling , Liu Chunmei , Luo Yimei , Xiang Fei , Song Huapei
Published: March 2021

Patients with extensive deep burns usually experience infections and organ dysfunction. Proactive and effective wound repair is key to treatment. If large wounds remain open, systemic infection and multiple organ dysfunction syndrome can occur, threatening the lives of patients. Current wound repair methods include skin grafts, flap repair, negative-pressure wound therapy, and cellular and/or tissue-based products. For deep, complex burn wounds, a single form of treatment is usually ineffective.

 This article reports a rare case of burn wound repair. The patient was burned by a charcoal flame on multiple parts of his body after carbon monoxide poisoning. Pneumothorax and acute renal failure occurred after the injury, accompanied by multiple osteonecroses of the trunk and lower limbs. A multidisciplinary team formulated an individualized treatment plan; the diverse treatments included closed chest drainage, continuous renal replacement therapy, infection control, analgesia, wound debridement, negative-pressure wound therapy, cellular and/or tissue-based products, autologous dermal scaffold graft, skin grafts, flap transposition, platelet-rich plasma, and rehabilitation, which ultimately saved the patient’s life and led to healing of all the wounds.
Pharmacogenetic testing
Authors: Fredrikson Karin M. , Fasolino Tracy
Published: March 2021

NPs commonly prescribe pharmaceutical therapies such as opiates, antidepressants, and/or other analgesics to improve the health and well-being of patients experiencing chronic pain. This article provides NPs with pharmacogenetic testing knowledge, such as readiness for clinical implementation, considerations for choosing a testing service, and testing costs for chronic pain management.
Posterior Quadratus Lumborum Block in Total Hip Arthroplasty: A Randomized Controlled Trial
Authors: Brixel Sophia Margareta , Biboulet Philippe , Swisser Fabien , Choquet Olivier , Aarab Yassir , Nguyen Helen , Bringuier Sophie , Capdevila Xavier
Published: March 2021

Background

Pain management is important for ensuring early mobilization after hip arthroplasty; however, the optimal components remain controversial. Recently, the quadratus lumborum block has been proposed as an analgesic option. The current study tested the hypothesis that the posterior quadratus lumborum block combined with multimodal analgesia decreases morphine consumption after hip arthroplasty.

Methods

This study was a prospective, randomized, double-blind, placebo-controlled trial. Before general anesthesia, 100 participating patients scheduled for elective total hip arthroplasty were randomly allocated to receive a 30-ml injection posterior to the quadratus lumborum muscle with either 0.33% ropivacaine (n = 50) or normal saline (n = 50). For all patients, multimodal analgesia included systematic administration of acetaminophen, ketoprofen, and a morphine intravenous patient-controlled analgesia. The primary outcome was total intravenous morphine consumption in the first 24 h. Secondary outcomes recorded intraoperative sufentanil consumption; morphine consumption in the postanesthesia care unit; pain scores at extubation and at 2, 6, 12, and 24 h; motor blockade; time to first standing and ambulation; hospital length of stay; and adverse events.

Results

There was no significant difference in the 24-h total morphine consumption (ropivacaine group, median [interquartile range], 13 [7 to 21] versus saline group, 16 [9 to 21] mg; median difference, −1.5; 95% CI, −5 to 2; P = 0.337). Pain scores were not different between the groups (β = −0.4; 95% CI, −0.9 to 0.2; P = 0.199). There was no statistical difference between the two groups in intraoperative sufentanil consumption, morphine consumption in the postanesthesia care unit, motor blockade, times to first standing (median difference, 0.83 h; 95% CI, −1.7 to 3.4; P = 0.690) and ambulation (median difference, −1.85 h; 95% CI, −4.5 to 0.8; P = 0.173), hospital length of stay, and adverse events.

Conclusions

After elective hip arthroplasty, neither morphine consumption nor pain scores were reduced by the addition of a posterior quadratus lumborum block to a multimodal analgesia regimen.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Compounded bioidentical hormone therapy: new recommendations from the 2020 National Academies of Sciences, Engineering, and Medicine
Authors: Stuenkel Cynthia A.
Published: March 2021

Bioidentical hormones have the exact same chemical and molecular structure as hormones that are produced in the human body. Bioidentical hormones are available as FDA-approved hormone formulations. Nonapproved custom-compounded preparations are marketed as bioidentical, but content is uncertain. The widespread use of compounded bioidentical hormone therapy despite the lack of evidence to support its safety and efficacy is concerning. This Practice Pearl highlights the 2020 recommendations from the National Academies of Sciences, Engineering, and Medicine regarding the use of compounded bioidentical hormones.
Depressive symptoms and type II diabetes mellitus among midlife women
Authors: Im Eun-Ok , Yi Jee-Seon , Chee Wonshik
Published: March 2021

Objectives:

A decision tree analysis helps determine the complex characteristics of the groups that are closely connected with specific outcomes. Using a decision tree analysis, the purpose of this secondary analysis was to examine the associations of type II diabetes mellitus (DM) to depressive symptoms among midlife women from four major racial/ethnic groups in the US. while identifying the complex characteristics of the women that were closely linked to depressive symptoms.

Methods:

The data from two larger Internet survey studies were used for this analysis. The data from a total of 164 women (62 with type II diabetes and 102 without diabetes) were included. The data were collected using several instruments to measure background characteristics, health and menopausal status, and depressive symptoms (the Depression Index for Midlife Women). The data analysis was conducted using independent t tests, Mann-Whitney U tests, and decision tree analyses.

Results:

The total numbers and total severity scores of depressive symptoms were significantly higher in those with DM compared with those without DM (P < 0.05). There were significant differences in the total numbers and total severity scores of depressive symptoms by menopausal status and race/ethnicity (P < 0.05). DM was a significant factor that influenced the total severity scores of depressive symptoms among midlife women in peri- or postmenopausal stages who were born outside the US and among midlife women in their premenopausal stage (P < 0.05).

Conclusions:

This study indicated several combined characteristics of midlife women at high risk for depressive symptoms that could provide directions for future interventions.

Video Summary:
http://links.lww.com/MENO/A726.
Intraoperative Stromal Vascular Fraction Therapy Improves Histomorphometric and Vascular Outcomes in Irradiated Mandibular Fracture Repair
Authors: Urlaub Kevin M. , Ranganathan Kavitha , Lynn Jeremy V. , Luby Alexandra O. , Patrick Lauren N. , Nelson Noah S. , Donneys Alexis , Buchman Steven R.
Published: March 2021

Background:

Cell-based treatments have demonstrated the capacity to enhance reconstructive outcomes in recent decades but are hindered in clinical utility by regulatory hurdles surrounding cell culture. This investigation examines the ability of a noncultured stromal vascular fraction derived from lipoaspirate to enhance bone healing during fracture repair to further the development of translatable cell therapies that may improve outcomes in irradiated reconstruction.

Methods:

Isogenic male Lewis rats were divided into three groups: fracture, irradiated fracture, and irradiated fracture with stromal vascular fraction treatment. Irradiated groups received a fractioned dose of 35 Gy before mandibular osteotomy. Stromal vascular fraction was harvested from the inguinal fat of isogenic donors, centrifuged, and placed intraoperatively into the osteotomy site. All mandibles were evaluated for bony union and vascularity using micro–computed tomography before histologic analysis.

Results:

Union rates were significantly improved in the irradiated fracture with stromal vascular fraction treatment group (82 percent) compared to the irradiated fracture group (25 percent) and were not statistically different from the fracture group (100 percent). Stromal vascular fraction therapy significantly improved all metrics of bone vascularization compared to the irradiated fracture group and was not statistically different from fracture. Osteocyte proliferation and mature bone formation were significantly reduced in the irradiated fracture group. Bone cellularity and maturity were restored to nonirradiated levels in the irradiated fracture with stromal vascular fraction treatment group despite preoperative irradiation.

Conclusions:

Vascular and cellular depletion represent principal obstacles in the reconstruction of irradiated bone. This study demonstrates the efficacy of stromal vascular fraction therapy in remediating these damaging effects and provides a promising foundation for future studies aimed at developing noncultured, cell-based therapies for clinical implementation.
Rhabdothermincola sediminis gen. nov., sp. nov., a new actinobacterium isolated from hot spring sediment, and emended description of the family Iamiaceae
Authors: Liu Ze-Tao , Jiao Jian-Yu , Liu Lan , Li Meng-Meng , Ming Yu-Zhen , Song Jiang-Lin , Lv Ai-Ping , Xian Wen-Dong , Fang Bao-Zhu , Li Wen-Jun
Published: March 2021

One thermophilic bacterium, designated strain SYSU G02662T, was isolated from hot spring sediment sampled in Tibet, PR China. Polyphasic taxonomic analyses and whole-genome sequencing were used to determine the taxonomy position of the strain. Phylogenetic analysis using 16S rRNA gene sequences indicated that strain SYSU G02662Tshowed the highest sequence similarity toActinomarinicola tropicaSCSIO 58843T(95.1 %). The strain could be differentiated from other species of the familyIamiaceaeby its distinct phenotypic and genotypic characteristics. Cells of strain SYSU G02662Twere aerobic, Gram-staining-positive and short rodshaped. Growth occurred optimally at 45 °C and pH 7.0. In addition,meso-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan. The respiratory quinone was MK-9 (H8), while the major fatty acids (>10 %) were C16 : 0, C17 : 0, C18 : 0and iso-C16 : 0. The detected polar lipids included diphosphatidylglycerol, phosphatidylinositol mannoside and phosphatidylinositol. The G+C content of the genomic DNA was 70.5 % based on the draft genomic sequence. On the basis of phenotypic, genotypic and phylogenetic data, strain SYSU G02662Trepresents a novel species of a novel genus in the familyIamiaceae, for which the nameRhabdothermincola sediminisgen. nov., sp. nov. is proposed. The type strain of the proposed novel species is SYSU G02662T(=CGMCC 4.7688T=KCTC 49500T).
Adaptations of carbapenem resistant Acinetobacter baumannii (CRAB) in the hospital environment causing sustained outbreak
Authors: Sharma Swati , Das Arghya , Banerjee Tuhina , Barman Hiranmay , Yadav Ghanshyam , Kumar Ashok
Published: March 2021

Introduction. Carbapenem resistance in

Acinetobacter baumannii

(

A. baumannii

) is an emerging global threat.

Gap statement. The adaptation strategies of

A. baumannii

for this emergence as a nosocomial pathogen has been less studied.

Aim. This prospective study analysed a sustained outbreak of carbapenem resistant

Acinetobacter baumannii

(CRAB) in the intensive care unit (ICU) with reference to antimicrobial resistance and virulence in the colonizing and pathogenic isolates under carbapenem stress.

Results. The CRAB isolates from initial and sustained outbreak were found harbouring multiple carbapenemase genes. These genes included bla
OXA-23
,bla
IMP, bla
VIM and bla
NDM. From NICU environment three phenotypically carbapenem susceptible isolates were found carrying bla
OXA-23,
bla
IMP, bla
VIM genes. Prior imipenem therapy was one of the risk factors (P=0.0016). The outbreak was polyclonal. Under imipenem stress, outbreak isolates showed no loss of carbapenemase genes against stress free conditions (23.7±1.33 days). Biofilm formation increased with imipenem concentration, with outbreak isolates producing highest biomass. While the pathogens showed a slow growth rate on imipenem exposure, the colonisers grew rapidly (P <0.0001).

Methods. Sustained outbreak of CRAB was identified in the ICU (July 2015 to December 2017). Risk factors for acquisition of CRAB was studied.

A. baumannii

isolates were also collected from the environments of ICU and neonatal ICU (NICU) and blood cultures of septic neonates. Isolates were characterized based on antimicrobial susceptibility, genetic profile, integrons carriage and clonality. Biofilm formation and growth kinetics were studied under varying carbapenem stress.

Conclusion. Intense carbapenem exposure in the ICU facilitates persistence of CRAB by several adaptations causing sustained outbreaks.
Accuracy and precision in super-resolution MRI: Enabling spherical tensor diffusion encoding at ultra-high b-values and high resolution
Authors: Vis Geraline , Nilsson Markus , Westin Carl-Fredrik , Szczepankiewicz Filip
Published: March 2021

Diffusion MRI (dMRI) is a useful probe of tissue microstructure but suffers from low signal-to-noise ratio (SNR) whenever high resolution and/or high diffusion encoding strengths are used. Low SNR leads not only to poor precision but also poor accuracy of the diffusion-weighted signal, as the rectified noise floor gives rise to a positive signal bias. Recently, super-resolution techniques have been proposed for signal acquisition at a low spatial resolution but high SNR, whereafter a higher spatial resolution is recovered by image reconstruction. In this work, we describe a super-resolution reconstruction framework for dMRI and investigate its performance with respect to signal accuracy and precision. Using strictly controlled phantom experiments, we show that the super-resolution approach improves accuracy by facilitating a more beneficial trade-off between spatial resolution and diffusion encoding strength before the noise floor affects the signal. Moreover, precision is shown to have a less straightforward dependency on acquisition, reconstruction, and intrinsic tissue parameters. Indeed, we find that a gain in precision from super-resolution reconstruction (SRR) is substantial only when some spatial resolution is sacrificed. We also demonstrated the value of SRR in the challenging combination of high resolution and spherical b-tensor encoding at ultrahigh b-values—a configuration that produces a unique contrast that emphasizes tissue in which diffusion is restricted in all directions. We conclude that SRR is most valuable in low-SNR conditions, where it can suppress rectified noise floor effects and recover signal with high accuracy. The in vivo application showcases a vastly superior image contrast when using SRR compared to conventional imaging, facilitating investigations of brain tissue that would otherwise have prohibitively low SNR, resolution or required non-conventional MRI hardware.
Antagonistic effects of chemical mixtures on the oxidative stress response are silenced by heat stress and reversed under dietary restriction
Authors: Arulalan Karthik Suresh , Huayta Javier , Stallrich Jonathan W. , San-Miguel Adriana
Published: March 2021

Chemical agents released into the environment can induce oxidative stress in organisms, which is detrimental for health. Although environmental exposures typically incorporate multiple chemicals, organismal studies on oxidative stress derived from chemical agents commonly study exposures to individual compounds. In this work, we explore how chemical mixtures drive the oxidative stress response under various conditions in the nematodeC. elegans, by quantitatively assessing levels ofgst-4expression. Our results indicate that naphthoquinone mixtures drive responses differently than individual components, and that altering environmental conditions, such as increased heat and reduced food availability, result in dramatically different oxidative stress responses mounted byC. elegans. When exposed to heat, the oxidative stress response is diminished. Notably, when exposed to limited food, the oxidative stress response specific to juglone is significantly heightened, while identified antagonistic interactions between some naphthoquinone components in mixtures are abolished. This implies that organismal responses to xenobiotics is confounded by environment and stressor interactions. Given the high number of variables under study, and their potential combinations, a simplex centroid design was used to capture such non-trivial response over the design space. This makes the case for the adoption of Design of Experiments approaches as they can greatly expand the experimental space probed in noisy biological readouts, and in combinatorial experiments. Our results also reveal gaps in our current knowledge of the organismal oxidative stress response, which can be addressed by employing sophisticated design of experiments approaches to identify significant interactions.
Closed-loop auditory stimulation method to modulate sleep slow waves and motor learning performance in rats
Authors: Moreira Carlos G. , Baumann Christian R. , Scandella Maurizio , Nemirovsky Sergio I. , Leach Sven , Huber Reto , Noain Daniela
Published: March 2021

Slow waves and cognitive output have been modulated in humans by phase-targeted auditory stimulation. However, to advance its technical development and further our understanding, implementation of the method in animal models is indispensable. Here, we report the successful employment of slow waves’ phase-targeted closed-loop auditory stimulation (CLAS) in rats. To validate this new tool both conceptually and functionally, we tested the effects of up- and down-phase CLAS on proportions and spectral characteristics of sleep, and on learning performance in the single pellet-reaching task, respectively. Without affecting 24-h sleep-wake behavior, CLAS specifically altered delta (slow waves) and sigma (sleep spindles) power persistently over chronic periods of stimulation. Down-phase CLAS exerted a detrimental effect on overall engagement and success rate in the behavioral test, and overall CLAS-dependent spectral changes were positively correlated with learning performance. Altogether, our results provide proof-of-principle evidence that phase-targeted CLAS of slow waves in rodents is efficient, safe and stable over chronic experimental periods, enabling the use of this high-specificity tool for basic and preclinical translational sleep research.
Cross-Species Experiments Reveal Widespread Cochlear Neural Damage in Normal Hearing
Authors: Bharadwaj Hari M. , Hustedt-Mai Alexandra R. , Ginsberg Hannah M. , Dougherty Kelsey M. , Muthaiah Vijaya Prakash Krishnan , Hagedorn Anna , Simpson Jennifer M. , Heinz Michael G.
Published: March 2021

Animal models suggest that cochlear afferent nerve endings may be more vulnerable than sensory hair cells to damage from acoustic overexposure and aging, but that such damage cannot be detected in standard clinical audiometry. Co-ordinated experiments in at-risk humans and a chinchilla model using two distinct physiological assays suggest that cochlear neural damage exists even in populations without clinically recognized hearing loss.
RENET2: High-Performance Full-text Gene-Disease Relation Extraction with Iterative Training Data Expansion
Authors: Su Junhao , Wu Ye , Ting Hing-Fung , Lam Tak-Wah , Luo Ruibang
Published: March 2021

Background

Relation extraction is a fundamental task for extracting gene-disease associations from biomedical text. Existing tools have limited capacity, as they can extract gene-disease associations only from single sentences or abstract texts.

Results

In this work, we propose RENET2, a deep learning-based relation extraction method, which implements section filtering and ambiguous relations modeling to extract gene-disease associations from full-text articles. We designed a novel iterative training data expansion strategy to build an annotated full-text dataset to resolve the scarcity of labels on full-text articles. In our experiments, RENET2 achieved an F1-score of 72.13% for extracting gene-disease associations from an annotated full-text dataset, which was 27.22%, 30.30% and 29.24% higher than the best existing tools BeFree, DTMiner and BioBERT, respectively. We applied RENET2 to (1) ~1.89M full-text articles from PMC and found ~3.72M gene-disease associations; and (2) the LitCovid articles set and ranked the top 15 proteins associated with COVID-19, supported by recent articles.

Conclusion

RENET2 is an efficient and accurate method for full-text gene-disease association extraction. The source-code, manually curated abstract/full-text training data, and results of RENET2 are available athttps://github.com/sujunhao/RENET2.
Systematic review ofPlasmodium falciparumandPlasmodium vivaxpolyclonal infections: Impact of prevalence, study population characteristics, and laboratory procedures
Authors: Lopez Luis , Koepfli Cristian
Published: March 2021

Multiple infections of genetically distinct clones of the samePlasmodiumspecies are common in many malaria endemic settings. Mean multiplicity of infection (MOI) and the proportion of polyclonal infections are often reported as surrogate marker of transmission intensity, yet the relationship with traditional measures such as parasite prevalence is not well understood. We have searched Pubmed for articles onP. falciparumandP. vivaxmultiplicity, and compared the proportion of polyclonal infections and mean MOI to population prevalence. The impact of the genotyping method, number of genotyping markers, method for diagnosis (microscopy/RDT vs. PCR), presence of clinical symptoms, age, geographic region, and year of sample collection on multiplicity indices were assessed. ForP. falciparum, 153 studies met inclusion criteria, yielding 275 individual data points and 33526 genotyped individuals. The proportion of polyclonal infections ranged from 0-96%, and mean MOI from 1-6.1. ForP. vivax, 54 studies met inclusion criteria, yielding 115 data points and 13325 genotyped individuals. The proportion of polyclonal infections ranged from 0-100%, and mean MOI from 1-3.8. For both species, the proportion of polyclonal infections ranged from very low to close to 100% at low prevalence, while at high prevalence it was always high. Each percentage point increase in prevalence resulted in a 0.34% increase in the proportion of polyclonalP. falciparuminfections (P<0.001), and a 0.78% increase in the proportion of polyclonalP. vivaxinfections (P<0.001). In multivariable analysis, higher prevalence, typing multiple markers, diagnosis of infections by PCR, and sampling in Africa were found to result in a higher proportion ofP. falciparumpolyclonal infections. ForP. vivax, prevalence, year of study, typing multiple markers, and geographic region were significant predictors. In conclusion, polyclonal infections are frequently present in all settings, but the association between multiplicity and prevalence is weak.
Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits
Authors: Sey Nancy Y.A , Hu Benxia , Iskhakova Marina , Sun Huaigu , Shokrian Neda , Hutta Gabriella Ben , Marks Jesse , Quach Bryan C. , Johnson Eric O. , Hancock Dana B. , Akbarian Schahram , Won Hyejung
Published: March 2021

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ∼26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.
No evidence for a special role of language in feature-based categorization
Authors: Benn Yael , Ivanova Anna A. , Clark Oliver , Mineroff Zachary , Seikus Chloe , Silva Jack Santos , Varley Rosemary , Fedorenko Evelina
Published: March 2021

The relationship between language and human thought is the subject of long-standing debate. One specific claim implicates language in feature-based categorization. According to this view, language resources facilitate object categorization based on a certain feature (e.g., color). Specifically, it is hypothesized that verbal labels help maintain focus on a relevant categorization criterion and reduce interference from irrelevant features. As a result, language impairment is expected to affect categorization of items grouped according to a single feature (low-dimensional categories, e.g., ‘Things that are yellow’), where many irrelevant features need to be inhibited, more than categorization of items that share many features (high-dimensional categories, e.g., ‘Animals’), where few irrelevant features need to be inhibited. In two behavioral studies with individuals with aphasia, we failed to find consistent support for the role of language in low-dimensional categorization. We also collected fMRI data from healthy adults and observed little activity in language-responsive brain regions during both low-dimensional and high-dimensional categorization. Combined, these results demonstrate that the language system is not implicated in object categorization. Our work adds to the growing evidence that, although language may assist in accessing task-relevant information (e.g., instructions), many cognitive tasks in adult brains proceed without recruiting the language system.
Optogenetic manipulation of YAP cellular localisation and function
Authors: Toh P. J. Y. , Lai J. K. H. , Hermann A. , Destaing O. , Sheetz M. P. , Sudol M. , Saunders T. E.
Published: March 2021

YAP, an effector of the Hippo signalling pathway, promotes organ growth and regeneration. Prolonged YAP activation results in uncontrolled proliferation and cancer. Therefore, exogenous regulation of YAP activity has potential translational applications. We present a versatile optogenetic construct (optoYAP) for manipulating YAP localisation, and consequently its activity and function. We attached a LOV2 domain that photocages a nuclear localisation signal (NLS) to the N-terminus of YAP. In 488 nm light, the LOV2 domain unfolds, exposing the NLS, which shuttles optoYAP into the nucleus. Nuclear import of optoYAP is reversible and tuneable by light intensity. In cell culture, activated optoYAP promotes YAP target gene expression, cell proliferation, and anchorage-independent growth. Similarly, we can utilise optoYAP in zebrafish embryos to modulate target genes. OptoYAP is functional in both cell culture andin vivo, providing a powerful tool to address basic research questions and therapeutic applications in regeneration and disease.
Intraflagellar transport trains can turn around without the ciliary tip complex
Authors: Nievergelt Adrian Pascal , Zykov Ilia , Diener Dennis , Buchholz Tim-Oliver , Delling Markus , Diez Stefan , Jug Florian , S̆tĕpánek Ludĕk , Pigino Gaia
Published: March 2021

Cilia and flagella are microtubule doublet based organelles found across the eukaryotic tree of life. Their very high aspect ratio and crowded interior are unfavourable to diffusive transport for their assembly and maintenance. Instead, a highly dynamic system of intraflagellar transport (IFT) trains moves rapidly up and down the cilium. However, the mechanism of how these trains turn around upon reaching the ciliary tip has remained elusive. It has been hypothesized that there exists a dedicated calcium-dependent protein-based machinery at the ciliary tip to mediate this conversion. In this work, we use physical and chemical methods to manipulate IFT in the cilia of the unicellular green algaChlamydomonas reinhardtiito show that no such stationary tip-machinery is required for IFT turnaround. Instead, we demonstrate that the conversion from anterograde to retrograde IFT trains is a calcium independent intrinsic ability of the IFT system.
Cell signaling pathways in human mutant PAX6 corneal cells: an in vitro model for aniridia-related keratopathy
Authors: Słoniecka Marta , Vicente André , Byström Berit , Domellöf Fátima Pedrosa
Published: March 2021

PURPOSE

To establish anin vitromodel of aniridia-related keratopathy (ARK) using CRISPR/Cas9 engineered human keratocytes with mutations in the PAX6 gene, and to study the Notch Homolog 1, Translocation-Associated (Notch1), sonic hedgehog (SHH), mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways in the PAX6 mutant keratocytes.

METHODS

Primary human keratocytes were isolated from healthy corneas. Keratocytes were transduced with Cas9 lentiviral particles in order to create cells stably expressing Cas9 nuclease. Lentiviral particles carrying PAX6 sgRNA were transduced into the Cas9 keratocytes creating mutants. Analysis of signaling pathways was assessed by RT-qPCR for gene expression and western blot for protein expression.

RESULTS

Human keratocytes stably expressing Cas9 nuclease were created. Keratocytes carrying PAX6 gene mutation were successfully generated. PAX6 mutant keratocytes showed modified expression patterns of extracellular matrix components such as collagens and fibrotic markers. Analysis of the Notch1, SHH, mTOR, and Wnt/β-catenin signaling pathways in the PAX6 mutant keratocytes revealed altered gene and protein expression of the key players involved in these pathways.

CONCLUSIONS

A properly functioning PAX6 gene in keratocytes is crucial for the regulation of signaling pathways important for cell fate determination, proliferation, and inflammation. Pax6 mutation in thein vitrosettings leads to changes in these pathways which resemble those found in corneas of patients with ARK.
Cell-Tak coating may cause mis-normalization of Seahorse metabolic flux data
Authors: Sima Michal , Martinkova Stanislava , Kafkova Anezka , Pala Jan , Trnka Jan
Published: March 2021

Metabolic flux investigations of cells and tissue samples are a rapidly advancing tool in diverse research areas. Reliable methods of data normalization are crucial for an adequate interpretation of results and to avoid a misinterpretation of experiments and incorrect conclusions. The most common methods for metabolic flux data normalization are to cell number, DNA and protein. Data normalization may be affected by a variety of factors, such as density, healthy state, adherence efficiency, or proportional seeding of cells.

The mussel-derived adhesive Cell-Tak is often used to immobilize poorly adherent cells. Here we demonstrate that this coating may strongly affect the fluorescent detection of DNA leading to an incorrect and highly variable normalization of metabolic flux data. Protein assays are much less affected and cell counting can virtually completely remove the effect of the coating. Cell-Tak coating also affects cell shape in a cell line-specific manner and may change cellular metabolism.

Based on these observations we recommend cell counting as a gold standard normalization method for Seahorse metabolic flux measurements with protein content as a reasonable alternative.
Drosophilaantimicrobial peptides and lysozymes regulate gut microbiota composition and abundance
Authors: Marra A. , Hanson M.A. , Kondo S. , Erkosar B. , Lemaitre B.
Published: March 2021

The gut microbiota affects the physiology and metabolism of animals and its alteration can lead to diseases such as gut dysplasia or metabolic disorders. Several reports have shown that the immune system plays an important role in shaping both bacterial community composition and abundance inDrosophila, and that immune deficit, especially during aging, negatively affects microbiota richness and diversity. However, there has been little study at the effector level to demonstrate how immune pathways regulate the microbiota. A key set ofDrosophilaimmune effectors are the antimicrobial peptides (AMPs), which confer defense upon systemic infection. AMPs and lysozymes, a group of digestive enzymes with antimicrobial properties, are expressed in the gut and are good candidates for microbiota regulation. Here, we take advantage of the model organismDrosophila melanogasterto investigate the role of AMPs and lysozymes in regulation of gut microbiota structure and diversity.

Using flies lacking AMPs and newly generated lysozyme mutants, we colonized gnotobiotic flies with a defined set of commensal bacteria and analyzed changes in microbiota composition and abundance in vertical transmission and aging contexts through 16S rRNA gene amplicon sequencing. Our study shows that AMPs and, to a lesser extent, lysozymes are necessary to regulate the total and relative abundance of bacteria in the gut microbiota. We also decouple the direct function of AMPs from the IMD signaling pathway that regulates AMPs but also many other processes, more narrowly defining the role of these effectors in the microbial dysbiosis observed in IMD-deficient flies upon aging.

Importance

This study advances current knowledge in the field of host-microbe interactions by demonstrating that the two families of immune effectors, antimicrobial peptides and lysozymes, actively regulate the gut microbiota composition and abundance. Consequences of the loss of these antimicrobial peptides and lysozymes are exacerbated during aging, and their loss contributes to increased microbiota abundance and shifted composition in old flies. This work shows that immune effectors, typically associated with resistance to pathogenic infections, also help shape the beneficial gut community, consistent with the idea that host-symbiont interactions use the same ‘language’ typically associated with pathogenesis.
Observation of microstructure evolution during inertia friction welding using in-situ synchrotron X-ray diffraction
Authors: Rowson Matthew , Bennett Chris J. , Azeem Mohammed A. , Magdysyuk Oxana , Rouse James , Lye Ryan , Davies Joshua , Bray Simon , Lee Peter D.
Published: March 2021

The widespread use and development of inertia friction welding is currently restricted by an incomplete understanding of the deformation mechanisms and microstructure evolution during the process. Understanding phase transformations and lattice strains during inertia friction welding is essential for the development of robust numerical models capable of determining optimized process parameters and reducing the requirement for costly experimental trials. A unique compact rig has been designed and used in-situ with a high-speed synchrotron X-ray diffraction instrument to investigate the microstructure evolution during inertia friction welding of a high-carbon steel (BS1407). At the contact interface, the transformation from ferrite to austenite was captured in great detail, allowing for analysis of the phase fractions during the process. Measurement of the thermal response of the weld reveals that the transformation to austenite occurs 230 °C below the equilibrium start temperature of 725 °C. It is concluded that the localization of large strains around the contact interface produced as the specimens deform assists this non-equilibrium phase transformation.