bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Imaging of Plant Oxygen Levels
Authors: Weits Daan Adriaan 
Published: March 2021

Abstract
Oxygen is essential for multicellular aerobic life due to its central role in energy metabolism. The availability of oxygen can drop below the level to sustain oxidative phosphorylation when plants are flooded, posing a severe threat to survival. However, under non-stressful conditions, the internal oxygen concentration of most plant tissue is not in equilibrium with the environment, which is attributed to cellular respiration and diffusion constrains imposed by O2 barriers and bulky tissue. This is exemplified by the observations of steep oxygen gradients in roots, fruits, tubers, anthers and meristems. To adapt to a varying availability of oxygen, plants sense O2 via the conditional proteolysis of transcriptional regulators. This mechanism acts to switch oxidative metabolism to anaerobic fermentation, but it was also shown to play a role in plant development and pathogen defense. To investigate how dynamic and spatial distribution of O2 impacts on these processes, accurate mapping of its concentration in plants is essential. Physical oxygen sensors have been employed for decades to profile internal oxygen concentrations in plants, while genetically encoded oxygen biosensors have only recently started to see use. Driven by the critical role of hypoxia in human pathology and development, several novel oxygen-sensing devices have also been characterized in cell lines and animal model organisms. This review aims to provide an overview of available oxygen biosensors and to discuss their potential application to image oxygen levels in plants.
The protein kinase CPK28 phosphorylates ascorbate peroxidase and enhances thermotolerance in tomato
Authors: Hu Zhangjian , Li Jianxin , Ding Shuting , Cheng Fei , Li Xin , Jiang Yuping , Yu Jingquan , Foyer Christine H. , Shi Kai 
Published: March 2021

Abstract
High temperatures are a major threat to plant growth and development, leading to yield losses in crops. Calcium-dependent protein kinases (CPKs) act as critical components of Ca2+ sensing in plants that transduce rapid stress-induced responses to multiple environmental stimuli. However, the role of CPKs in plant thermotolerance and their mechanisms of action remain poorly understood. To address this issue, tomato (Solanum lycopersicum) cpk28 mutants were generated using a CRISPR-Cas9 gene-editing approach. The responses of mutant and wild-type plants to normal (25°C) and high temperatures (45°C) were documented. Thermotolerance was significantly decreased in the cpk28 mutants, which showed increased heat stress-induced accumulation of reactive oxygen species (ROS) and levels of protein oxidation, together with decreased activities of ascorbate peroxidase (APX) and other antioxidant enzymes. The redox status of ascorbate and glutathione were also modified. Using a yeast two-hybrid library screen and protein interaction assays, we provide evidence that CPK28 directly interacts with cytosolic APX2. Mutations in APX2 rendered plants more sensitive to high temperatures, whereas the addition of exogenous reduced ascorbate (AsA) rescued the thermotolerance phenotype of the cpk28 mutants. Moreover, protein phosphorylation analysis demonstrated that CPK28 phosphorylates the APX2 protein at Thr-59 and Thr-164. This process is suggested to be responsive to Ca2+ stimuli and may be required for CPK28-mediated thermotolerance. Taken together, these results demonstrate that CPK28 targets APX2, thus improving thermotolerance. This study suggests that CPK28 is an attractive target for the development of improved crop cultivars that are better adapted to heat stress in a changing climate.
Deformations Of Multivalued Harmonic Functions
Authors: Donaldson Simon 
Published: March 2021

Abstract
We consider harmonic sections of a bundle over the complement of a codimension 2 submanifold in a Riemannian manifold, which can be thought of as multivalued harmonic functions. We prove a result to the effect that these are stable under small deformations of the data. The proof is an application of a version of the Nash-Moser implicit function theorem.
Monopoly without a Monopolist: An Economic Analysis of the Bitcoin Payment System
Authors: Huberman Gur , Leshno Jacob D , Moallemi Ciamac 
Published: March 2021

Abstract
Bitcoin provides its users with transaction-processing services which are similar to those of traditional payment systems. This article models the novel economic structure implied by Bitcoin’s innovative decentralized design, which allows the payment system to be reliably operated by unrelated parties called miners. We find that this decentralized design protects users from monopoly pricing. Competition among service providers within the platform and free entry imply no entity can profitably affect the level of fees paid by users. Instead, a market for transaction-processing determines the fees users pay to gain priority and avoid transaction-processing delays. The article (i) derives closed-form formulas of the fees and waiting times and studies their properties, (ii) compares pricing under the Bitcoin Payment System to that under a traditional payment system operated by a profit-maximizing firm, and (iii) suggests protocol design modifications to enhance the platform’s efficiency. The Appendix describes and explains the main attributes of Bitcoin and the underlying blockchain technology.
Summarizing current refractory disease definitions in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis: systematic review
Authors: Chaplin Hema , Carpenter Lewis , Raz Anni , Nikiphorou Elena , Lempp Heidi , Norton Sam 
Published: March 2021

AbstractObjectivesTo identify how refractory disease (or relevant terminology variations) in RA and polyarticular JIA (polyJIA) is defined and establish the key components of such definitions.MethodsSearches were undertaken of English-language articles within six medical databases, including manual searching, from January 1998 to March 2020 (PROSPERO: CRD42019127142). Articles were included if they incorporated a definition of refractory disease, or non-response, in RA/polyJIA, with clear components to the description. Qualitative content analysis was undertaken to describe refractory disease in RA/polyJIA and classify each component within each definition.ResultsOf 6251 studies screened, 646 met the inclusion criteria; 581 of these applied non-response criteria while 65 provided refractory disease definitions/descriptions. From the non-response studies, 39 different components included various disease activity measures, emphasizing persistent disease activity and symptoms, despite treatment with one or more biologic DMARD (bDMARD). From papers with clear definitions for refractory disease, 41 components were identified and categorized into three key themes: resistance to multiple drugs with different mechanisms of action, typically two or more bDMARDs; persistence of symptoms and disease activity; and other contributing factors. The most common term used was ‘refractory’ (80%), while only 16.9% reported explicitly how their definition was generated (e.g. clinical experience or statistical methods).ConclusionRefractory disease is defined as resistance to multiple drugs with different mechanisms of action by persistence of physical symptoms and high disease activity, including contributing factors. A clear unifying definition needs implementing, as the plethora of different definitions makes study comparisons and appropriate identification of patients difficult.
Depression and anxiety symptoms at TNF inhibitor initiation are associated with impaired treatment response in axial spondyloarthritis
Authors: Zhao Sizheng Steven , Jones Gareth T , Hughes David M , Moots Robert J , Goodson Nicola J 
Published: March 2021

Abstract

Objectives
Depression and anxiety are associated with more severe disease in cross-sectional studies of axial spondyloarthritis (axSpA). We examined the association between baseline symptoms of depression or anxiety and response to TNF inhibitors (TNFi) in axSpA.

Methods
Biologic naïve participants from a national axSpA register completed the Hospital Anxiety and Depression Scale (HADS) before initiating TNFi. Symptoms of anxiety and depression were each categorized as moderate–severe (≥11), mild (8–10) and ‘none’ (≤7), and compared against change in disease indices [BASDAI and AS Disease Activity Score (ASDAS)] over time and time to treatment discontinuation using marginal structural models. Inverse-probability weights balanced baseline age, gender, BMI, deprivation, education and baseline values of respective disease indices.

Results
Of the 742 participants (67% male, mean age 45 years), 176 (24%) had moderate–severe and 26% mild depression; 295 (40%) had moderate–severe and 23% mild anxiety. Baseline disease activity was higher in higher HADS symptom categories for both depression and anxiety. Participants with moderate–severe depression had significantly poorer response compared with those with ‘none’ throughout follow-up. At 6 months, the difference was approximately 2.2 BASDAI and 0.8 ASDAS units after balancing their baseline values. Equivalent comparisons for anxiety were 1.7 BASDAI and 0.7 ASDAS units. Treatment discontinuation was 1.59-fold higher (hazard ratio 95% CI: 1.12, 2.26) in participants with moderate–severe anxiety compared with ‘none’.

Conclusions
Symptoms of depression and anxiety at TNFi initiation are associated with poorer treatment outcomes. Targeted interventions to optimize mental health have potential to substantially improve treatment response and persistence.
HIV-2 diversity displays two clades within group A with distinct geographical distribution and evolution
Authors: Visseaux Benoit , Bertine Mélanie , Le Hingrat Quentin , Ferré Valentine , Charpentier Charlotte , Collin Fidéline , Damond Florence , Matheron Sophie , Hué Stéphane , Descamps Diane 
Published: March 2021

Abstract
Genetic diversity of HIV-2 groups A and B has not yet been fully described, especially in a few Western Africa countries such as Ivory-Coast or Mali. We collected 444 pol, 152 vif, 129 env, and 74 LTR sequences from patients of the French ANRS CO5 HIV-2 cohort completed by 221 pol, 18 vif, 377 env, and 63 LTR unique sequences from public databases. We performed phylogenetic reconstructions and revealed two distinct lineages within HIV-2 group A, herein called A1 and A2, presenting non-negligible genetic distances and distinct geographic distributions as A1 is related to coastal Western African countries and A2 to inland Western countries. Estimated early diversification times for groups A and B in human populations were 1940 [95% higher probability densitiy: 1935–53] and 1961 [1952–70]. A1 experienced an early diversification in 1942 [1937–58] with two distinct early epidemics in Guinea-Bissau or Senegal, raising the possibility of group A emergence in those countries from an initial introduction from Ivory-Coast to Senegal, two former French colonies. Changes in effective population sizes over time revealed that A1 exponentially grew concomitantly to Guinea-Bissau independence war, but both A2 and B lineages experienced a latter growth, starting during the 80s economic crisis. This large HIV-2 genetic analysis provides the existence of two distinct subtypes within group A and new data about HIV-2 early spreading patterns and recent epidemiologic evolution for which data are scarce outside Guinea-Bissau.
The CR9 element is a novel mechanical load‐responsive enhancer that regulates natriuretic peptide genes expression
Authors: Miyashita Yohei , Tsukamoto Osamu , Matsuoka Ken , Kamikubo Kenta , Kuramoto Yuki , Ying Fu Hai , Tsubota Tomoya , Hasuike Hirona , Takayama Toshio , Ito Hiroaki , Hitsumoto Tatsuro , Okamoto Chisato , Kioka Hidetaka , Oya Ryohei , Shinomiya Haruki , Hakui Hideyuki , Shintani Yasunori , Kato Hisakazu , Kitakaze Masafumi , Sakata Yasushi , Asano Yoshihiro , Takashima Seiji 
Published: March 2021

AbstractEnhancers regulate gene expressions in a tissue‐ and pathology‐specific manner by altering its activities. Plasma levels of atrial and brain natriuretic peptides, encoded by the Nppa and Nppb, respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative Nppb enhancer at 22‐kb upstream from the Nppb gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in Nppb expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and Nppb expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and Nppb expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and Nppa and Nppb expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell‐specific response to mechanical loads than the −520‐bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes.
Organ‐on‐chip of the cervical epithelial layer: A platform to study normal and pathological cellular remodeling of the cervix
Authors: Tantengco Ourlad Alzeus G. , Richardson Lauren S. , Medina Paul Mark B. , Han Arum , Menon Ramkumar 
Published: March 2021

AbstractDamage to the cervical epithelial layer due to infection and inflammation is associated with preterm birth. However, the individual and/or collective roles of cervical epithelial layers in maintaining cervical integrity remain unclear during infection/inflammation. To determine the intercellular interactions, we developed an organ‐on‐chip of the cervical epithelial layer (CE‐OOC) composed of two co‐culture chambers connected by microchannels, recapitulating the ectocervical and endocervical epithelial layers. Further, we tested the interactions between cells from each distinct region and their contributions in maintaining cervical integrity in response to LPS and TNFα stimulations. The co‐culture of ectocervical and endocervical cells facilitated cellular migration of both epithelial cells inside the microchannels. Compared to untreated controls, both LPS and TNFα increased apoptosis, necrosis, and senescence as well as increased pro‐inflammatory cytokine productions by cervical epithelial cells. In summary, the CE‐OOC established an in vitro model that can recapitulate the ectocervical and the endocervical epithelial regions of the cervix. The established CE‐OOC may become a powerful tool in obstetrics and gynecology research such as in studying cervical remodeling during pregnancy and parturition and the dynamics of cervical epithelial cells in benign and malignant pathology in the cervix.
Bladder and Bowel Dysfunction Network: Improving the Management of Pediatric Bladder and Bowel Dysfunction
Authors: Pokarowski Martha , Rickard Mandy , Kanani Ronik , Mistry Niraj , Saunders Megan , Rockman Rebecca , Sam Jonathan , Varghese Abby , Malach Jessica , Margolis Ivor , Roushdi Amani , Levin Leo , Singh Manbir , Lopes Roberto Iglesias , Farhat Walid A. , Koyle Martin A. , Dos Santos Joana 
Published: March 2021

Introduction:
Lower urinary tract symptoms with constipation characterize bladder and bowel dysfunction (BBD). Due to high referral volumes to hospital pediatric urology clinics and time-consuming appointments, wait times are prolonged. Initial management consists of behavioral modification strategies that could be accomplished by community pediatricians. We aimed to create a network of community pediatricians trained in BBD (BBDN) management and assess its impact on care.

Methods:
We distributed a survey to pediatricians, and those interested attended training consisting of lectures and clinical shadowing. Patients referred to a hospital pediatric urology clinic were triaged to the BBDN and completed the dysfunctional voiding symptom score and satisfaction surveys at baseline and follow-up. The Bristol stool chart was used to assess constipation. Results were compared between BBDN and hospital clinic patients.

Results:
Surveyed pediatricians (n = 100) most commonly managed BBD with PEG3350 and dietary changes and were less likely to recommend bladder retraining strategies. Baseline characteristics were similar in BBDN (n = 100) and hospital clinic patients (n = 23). Both groups had similar improvements in dysfunctional voiding symptom score from baseline to follow-up (10.1 ± 4.2 to 5.6 ± 3.3, P = 0.01, versus 10.1 ± 4.2 to 7.8 ± 4.5, P = 0.02). BBDN patients waited less time for their follow-up visit with 56 (28–70) days versus 94.5 (85–109) days for hospital clinic patients (P < 0.001). Both groups demonstrated high familial satisfaction.

Conclusions:
Community pediatricians may require more knowledge of management strategies for BBD. Our pilot study demonstrates that implementing a BBDN is feasible, results in shorter wait times, and similar improvement in symptoms and patient satisfaction than a hospital pediatric urology clinic.
A Patient Navigator Intervention Supporting Timely Transfer Care of Adolescent and Young Adults of Hispanic Descents Attending an Urban Primary Care Pediatrics Clinic
Authors: Allende-Richter Sophie , Glidden Patricia , Maloyan Mariam , Khoury Zana , Ramirez Melanie , O’Hare Kitty 
Published: March 2021

Introduction:
While comprehensive health care transition is associated with better health outcomes, navigating health care transition can be difficult for adolescents and young adults (AYAs), especially those with fewer resources. Our practice serves low-income patients from birth to their 26th birthday; many are medically and socially complex and experience several obstacles to navigate care. As a result, most have not initiated a transfer to adult medicine by age 25. This quality-improvement initiative was designed to implement a structured intervention that supports the planned transfer of care to adult primary care.

Methods:
Informed by our baseline data on all patients eligible to transfer care, we designed a patient outreach workflow centered on a patient navigator (PN) intervention. We used a Plan-Do-Study-Act format to optimize our process and run charts to evaluate our intervention.

Results:
Over 3 years, our PN reached out to 96% of patients (n = 226) eligible to transfer care and offered transfer assistance in person or in writing. Among those surveyed, 92% (n = 93) reported awareness of our practice transition policy, and 83% (n = 64) rated their confidence to transfer care at 3 or higher on a 5-point scale.

Conclusions:
AYAs are aware of our practice transition policy, yet they welcome in-person transfer assistance. This intervention seems to improve their confidence to transfer care. However, despite PN outreach efforts, many remain empaneled in our practice and thus lack the self-care skills necessary to complete the transfer independently. Future transition interventions should address AYA’s self-management skills toward transition readiness.
Hydrogenophaga aromaticivorans sp. nov., isolated from a para-xylene-degrading enrichment culture, capable of degrading benzene, meta- and para-xylene
Authors: Banerjee Sinchan , Táncsics András , Tóth Erika , Révész Fruzsina , Bóka Károly , Kriszt Balázs 
Published: March 2021

A benzene, para- and meta-xylene-degrading Gram-stain-negative, aerobic, yellow-pigmented bacterium, designated as D2P1T, was isolated from a para-xylene-degrading enrichment culture. Phylogenetic analyses based on 16S rRNA genes showed that D2P1T shares a distinct phyletic lineage within the genus

Hydrogenophaga

and shows highest 16S rRNA gene sequence similarity to

Hydrogenophaga taeniospiralis

NBRC 102512T (99.2 %) and

Hydrogenophaga palleronii

NBRC 102513T (98.3 %). The draft genome sequence of D2P1T is 5.63 Mb long and the genomic DNA G+C content is 65.5 %. Orthologous average nucleotide identity (OrthoANI) and digital DNA–DNA hybridization (dDDH) analyses confirmed low genomic relatedness to its closest relatives (OrthoANI <86 %; dDDH <30 %). D2P1T contains ubiquinone 8 (Q-8) as the only respiratory quinone and phospholipid, phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol as major polar lipids. The main whole-cell fatty acids of D2P1T are summed feature 3 (C16 : 1
ω7c/C16 : 1
ω6c), C16 : 0 and summed feature 8 (C18 : 1
ω7c/C18 : 1
ω6c). The polyphasic taxonomic results indicated that strain D2P1T represents a novel species of the genus

Hydrogenophaga

, for which the name Hydrogenophaga aromaticivorans sp. nov. is proposed. The type strain is D2P1T (=LMG 31780T=NCAIM B 02655T).
Population-based estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) prevalence and characteristics: A cross-sectional study
Authors: Hirschtick Jana L. , Titus Andrea R. , Slocum Elizabeth , Power Laura E. , Hirschtick Robert E. , Elliott Michael R. , McKane Patricia , Fleischer Nancy L. 
Published: March 2021

AbstractImportanceEmerging evidence suggests many people have persistent symptoms after acute COVID-19 illness.ObjectiveTo estimate the prevalence and correlates of persistent COVID-19 symptoms 30 and 60 days post onset using a population-based sample.Design & SettingThe Michigan COVID-19 Recovery Surveillance Study is a population-based cross-sectional survey of a probability sample of adults with confirmed COVID-19 in the Michigan Disease Surveillance System (MDSS). Respondents completed a survey online or via telephone in English, Spanish, or Arabic between June - December 2020.ParticipantsLiving non-institutionalized adults (aged 18+) in MDSS with COVID-19 onset through mid-April 2020 were eligible for selection (n=28,000). Among 2,000 adults selected, 629 completed the survey. We excluded 79 cases during data collection due to ineligibility, 6 asymptomatic cases, 7 proxy reports, and 24 cases missing outcome data, resulting in a sample size of 593. The sample was predominantly female (56.1%), aged 45 and older (68.2%), and Non-Hispanic White (46.3%) or Black (34.8%).ExposuresDemographic (age, sex, race/ethnicity, and annual household income) and clinical factors (smoking status, body mass index, diagnosed comorbidities, and illness severity).Main outcomes and MeasuresWe defined post-acute sequelae of SARS-CoV-2 infection (PASC) as persistent symptoms 30+ days (30-day COVID-19) or 60+ days (60-day COVID-19) post COVID-19 onset.Results30- and 60-day COVID-19 were highly prevalent (52.5% and 35.0%), even among respondents reporting mild symptoms (29.2% and 24.5%) and non-hospitalized respondents (43.7% and 26.9%, respectively). Low income was statistically significantly associated with 30-day COVID-19 in adjusted models. Respondents reporting very severe (vs. mild) symptoms had 2.25 times higher prevalence of 30-day COVID-19 (Adjusted Prevalence Ratio [aPR] 2.25, 95% CI 1.46-3.46) and 1.71 times higher prevalence of 60-day COVID-19 (aPR 1.71, 95% 1.02-2.88). Hospitalized (vs. non-hospitalized) respondents had about 40% higher prevalence of both 30-day (aPR 1.37, 95% CI 1.12-1.69) and 60-day COVID-19 (aPR 1.40, 95% CI 1.02-1.93).Conclusions and RelevancePASC is highly prevalent among cases with severe initial symptoms, and, to a lesser extent, cases with mild and moderate symptoms.