bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Sensitivity and Interpretation of PCR and Serological COVID-19 Diagnostics for Patients Presenting to the Hospital
Authors: Miller Tyler E. , Garcia Beltran Wilfredo F. , Bard Adam Z. , Gogakos Tasos , Anahtar Melis N. , Astudillo Michael Gerino , Yang Diane , Thierauf Julia , Fisch Adam S. , Mahowald Grace K. , Fitzpatrick Megan J. , Nardi Valentina , Feldman Jared , Hauser Blake M. , Caradonna Timothy M. , Marble Hetal D. , Ritterhouse Lauren L. , Turbett Sara E. , Batten Julie , Georgantas Nicholas Zeke , Alter Galit , Schmidt Aaron G. , Harris Jason B. , Gelfand Jeffrey A. , Poznansky Mark C. , Bernstein Bradley E. , Louis David N. , Dighe Anand , Charles Richelle C. , Ryan Edward T. , Branda John A. , Pierce Virginia M. , Murali Mandakolathur R. , Iafrate A. John , Rosenberg Eric S. , Lennerz Jochen
Published: June 2020

Introduction

The diagnosis of COVID-19 requires integration of clinical and laboratory data. SARS-CoV-2 diagnostic assays play a central role in diagnosis and have fixed technical performance metrics. Interpretation becomes challenging because the clinical sensitivity changes as the virus clears and the immune response emerges. Our goal was to examine the clinical sensitivity of two most common SARS-CoV-2 diagnostic test modalities, polymerase chain reaction (PCR) and serology, over the disease course to provide insight into their clinical interpretation in patients presenting to the hospital.

Methods

A single-center, retrospective study. To derive clinical sensitivity of PCR, we identified 209 PCR-positive SARS-CoV-2 patients with multiple PCR test results (624 total PCR tests) and calculated daily sensitivity from date of symptom onset or first positive test. To calculate daily clinical sensitivity by serology, we utilized 157 PCR- positive patients with a total of 197 specimens tested by enzyme-linked immunosorbent assay for IgM, IgG, and IgA anti-SARS-CoV-2 antibodies.

Results

Clinical sensitivity of PCR decreased with days post symptom onset with >90% clinical sensitivity during the first 5 days after symptom onset, 70-71% from days 9-11, and 30% at day 21. In contrast, serological sensitivity increased with days post symptom onset with >50% of patients seropositive by at least one antibody isotype after day 7, >80% after day 12, and 100% by day 21.

Conclusion

PCR and serology are complimentary modalities that require time- dependent interpretation. Superimposition of sensitivities over time indicate that serology can function as a reliable diagnostic aid indicating recent or prior infection.
Sensitivity of RT-PCR testing of upper respiratory tract samples for SARS-CoV-2 in hospitalised patients: a retrospective cohort study
Authors: Williams Thomas C , Wastnedge Elizabeth , McAllister Gina , Bhatia Ramya , Cuschieri Kate , Kefala Kallirroi , Hamilton Fiona , Johannessen Ingólfur , Laurenson Ian F. , Shepherd Jill , Stewart Alistair , Waters Donald , Wise Helen , Templeton Kate E.
Published: June 2020

Objectives

To determine the sensitivity and specificity of RT-PCR testing of upper respiratory tract (URT) samples from hospitalised patients with COVID-19, compared to the gold standard of a clinical diagnosis.

Methods

All URT RT-PCR testing for SARS-CoV-2 in NHS Lothian, Scotland, United Kingdom between the 7th of February and 19th April 2020 (inclusive) was reviewed, and hospitalised patients were identified. All URT RT-PCR tests were analysed for each patient to determine the sequence of negative and positive results. For those who were tested twice or more but never received a positive result, case records were reviewed, and a clinical diagnosis of COVID-19 allocated based on clinical features, discharge diagnosis, and radiology and haematology results. For those who had negative URT RT-PCR tests but a clinical diagnosis of COVID-19, respiratory samples were retested using a multiplex respiratory panel, a second SARS-CoV-2 RT-PCR assay, and a human RNase P control.

Results

Compared to the gold standard of a clinical diagnosis of COVID-19, the sensitivity of an initial URT RT-PCR for COVID-19 was 82.2% (95% confidence interval 79.0-85.1%). Two consecutive URT RT-PCR tests increased sensitivity to 90.6% (CI 88.0-92.7%). A further 2.2% and 0.9% of patients who received a clinical diagnosis of COVID-19 were positive on a third and fourth test.

Conclusions

The sensitivity of a single RT-PCR test of an URT sample in hospitalised patients is 82.2%. Sensitivity increases to 90.6% when patients are tested twice. A proportion of cases with clinically defined COVID-19 never test positive on URT RT-PCR despite repeated testing.
SARS-CoV-2 RT-PCR profile in 298 Indian COVID-19 patients : a retrospective observational study
Authors: Bhattacharya Bisakh , Kumar Rohit , Meena Ved Prakash , Soneja Manish , Vig Saurabh , Rastogi Vandana , Bhatnagar Sushma , Mohan Anant , Wig Naveet
Published: June 2020

Background

Despite being in the 5th month of pandemic, knowledge with respect to viral dynamics, infectivity and RT-PCR positivity continues to evolve.

Aim

To analyse the SARS CoV-2 nucleic acid RT-PCR profiles in COVID-19 patients.

Design

It was a retrospective, observational study conducted at COVID facilities under AIIMS, New Delhi.

Methods

Patients admitted with laboratory confirmed COVID-19 were eligible for enrolment. Patients with incomplete details, or only single PCR tests were excluded. Data regarding demographic details, comorbidities, treatment received and results of SARS-CoV-2 RT-PCR performed on nasopharyngeal and oropharyngeal swabs, collected at different time points, was retrieved from the hospital records.

Results

298 patients were included, majority were males (75·8%) with mean age of 39·07 years (0·6-88 years). The mean duration from symptom onset to first positive RT-PCR was 4·7 days (SD 3·67), while that of symptom onset to last positive test was 17·83 days (SD 6·22). Proportions of positive RT-PCR tests were 100%, 49%, 24%, 8·7% and 20·6% in the 1st, 2nd, 3rd, 4th & >4 weeks of illness. 12 symptomatic patients had prolonged positive test results even after 3 weeks of symptom onset. Age >= 60 years was associated with prolonged RT-PCR positivity (statistically significant).

Conclusion

This study showed that the average period of PCR positivity is more than 2 weeks in COVID-19 patients; elderly patients have prolonged duration of RT-PCR positivity and requires further follow up.
Methadone and Suboxone® mentions on Twitter: Thematic and Sentiment Analysis
Authors: Chenworth M , Perrone J , Love JS , Graves R , Hogg-Bremer W , Sarker A
Published: June 2020

Background

Methadone and buprenorphine-naloxone (Suboxone®) have been discussed and compared extensively in the medical literature as effective treatments for opioid use disorder (OUD). While the evidence basis for the use of these medications is very favorable, less is known about the perceptions of these medications within the general public.

Objective

This study aimed to use social media, specifically Twitter, to assess the public perception of these medications, and to compare the discussion content between each medication based on theme, subtheme, and sentiment.

Methods

We conducted a mixed methods descriptive study analyzing individual microposts (“tweets”) that mentioned “methadone” or “suboxone”. We then categorized these tweets into themes and subthemes, as well as by sentiment and personal experience, and compared the information posted about these two medications, including in tweets that mentioned both medications.

Results

We analyzed 900 tweets, most of which related to access (13.8% for methadone; 12.9% for suboxone®), stigma (15.3%; 14.0%), and OUD treatment (11.5%; 5.4%). Only a small proportion of tweets (16.4% for suboxone® and 9.3% for methadone) expressed positive sentiments about the medications, with few tweets describing personal experiences. Tweets mentioning both medications primarily discussed MOUD in general, rather than comparing the two medications directly.

Conclusions

Twitter content about methadone and suboxone are similar, with the same major themes and similar sub-themes. Despite the proven effectiveness of these medications, there was little dialogue related to their benefits or efficacy in the treatment of opioid use disorder. Perceptions of these medications may contribute to their underutilization in combatting opioid use disorder.
The support needs of Australian primary health care nurses during the COVID-19 pandemic
Authors: Halcomb Elizabeth , Williams Anna , Ashley Christine , McInnes Susan , Stephen Catherine , Calma Kaara , James Sharon
Published: June 2020

Aim

To identify Australian primary healthcare nurses immediate support needs during the COVID-19 pandemic.

Background

COVID-19 has had widespread implications for primary healthcare nurses. Supporting these nurses’ capacity to deliver quality care ensures that ongoing health needs can be met.

Methods

Primary healthcare nurses were recruited to an online survey via social media and professional organisations in April 2020.

Results

Six-hundred and thirty-seven responses were included in analysis. Participants provided 1213 statements about perceived supports required to provide quality clinical care. From these, seven key categories emerged, namely; personal protective equipment, communication, funding, industrial issues, self-care, workplace factors and valuing nurses.

Conclusion

A number of key issues relating to personal health and safety, care quality, and job security need to be addressed to support primary healthcare nurses during the COVID-19 pandemic. Addressing these support issues can assist in retaining nurses and optimising the role of primary healthcare nurses during a pandemic.

Implications for nursing management

Responding to the needs of primary healthcare nurses has the potential to facilitate their role in providing community based healthcare. This knowledge can guide the provision of support for primary healthcare nurses during the current pandemic, as well as informing planning for future health crises.
Can root-associated fungi mediate the impact of abiotic conditions on the growth of a High Arctic herb?
Authors: Wutkowska Magdalena , Ehrich Dorothee , Mundra Sunil , Vader Anna , Eidesen Pernille B.
Published: June 2020

Arctic plants are affected by many stressors. Root-associated fungi are thought to influence plant performance in stressful environmental conditions. However, the relationships are not transparent; do the number of fungal partners, their ecological functions and community composition mediate the impact of environmental conditions and/or influence host plant performance? To address these questions, we used a common arctic plant as a model system: Bistorta vivipara. Whole plants (including root system) were collected from nine locations in Spitsbergen (n=214). Morphometric features were measured as a proxy for performance and combined with metabarcoding datasets of their root-associated fungi (amplicon sequence variants, ASVs), edaphic and meteorological variables. Seven biological hypotheses regarding fungal influence on plant measures were tested using structural equation modelling. The best-fitting model revealed that local temperature affected plants both directly (negatively aboveground and positively below-ground) and indirectly - mediated by fungal richness and the ratio of symbio- and saprotrophic ASVs. Fungal community composition did not impact plant measurements and plant reproductive investment did not depend on any fungal parameters. The lack of impact of fungal community composition on plant performance suggests that the functional importance of fungi is more important than their identity. The influence of temperature on host plants is therefore complex and should be examined further.
An implant for long-term cervical vagus nerve stimulation in mice
Authors: Mughrabi Ibrahim T. , Hickman Jordan , Jayaprakash Naveen , Papadoyannis Eleni S. , Abbas Adam , Chang Yao-Chuan , Lee Sunhee , Datta-Chaudhuri Timir , Chang Eric H. , Zanos Theodoros P. , Froemke Robert C. , Welle Cristin , Al-Abed Yousef , Zanos Stavros
Published: June 2020

Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity, atherosclerosis and heart failure. Many of these diseases have well-established mouse models but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic approach remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for between-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or conscious mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing across animals. Overall, 60-90% of implants produced stimulus-evoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4- to 6-week-old implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provide a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.
Identification of Neuronal Polarity by Node-Based Machine Learning
Authors: Su Chen-Zhi , Chou Kuan-Ting , Huang Hsuan-Pei , Lo Chung-Chuan , Wang Daw-Wei
Published: June 2020

Identifying the directions of signal flows in neural networks is one of the most important stages for understanding the intricate information dynamics of a living brain. Using a dataset of 213 projection neurons distributed in different regions of aDrosophilabrain, we develop a powerful machine learning algorithm: node-based polarity identifier of neurons (NPIN). The proposed model is trained by nodal information only and includes both Soma Features(which contain spatial information from a given node to a soma)and Local Features(which contain morphological information of a given node). After including the spatial correlations between nodal polarities, our NPIN provided extremely high accuracy (>96.0%) for the classification of neuronal polarity, even for complex neurons with more than two dendrite/axon clusters. Finally, we further apply NPIN to classify the neuronal polarity of the blowfly, which has much less neuronal data available. Our results demonstrate that NPIN is a powerful tool to identify the neuronal polarity of insects and to map out the signal flows in the brain’s neural networks.

Availability of data and material

The FlyCircuit database(http://www.flycircuit.tw/)is provided by the National Center for High-Performance Computing.

Code availability

We provide an online version of NPIN to be used or tested by other research groups at the following address:https://npin-for-drosophila.herokuapp.com/
Body mass index, time of day, and genetics affect perivascular spaces in the white matter
Authors: Barisano Giuseppe , Sepehrband Farshid , Sheikh-Bahaei Nasim , Law Meng , Toga Arthur W.
Published: June 2020

The analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explorein vivotheir contributions to neurological disorders. To date the normal amount and distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31-14.49 cm3). We then identified body mass index, time of day, and genetics as new elements significantly affecting PVSin vivounder physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.
Unambiguous observation of vesicle fusion in the interior of a cone
Authors: Zhenpeng Ge
Published: June 2020

When a vesicle was put onto the inner surface of a cone, it would spontaneously move to the bottom of the cone. The mechanism was explained elsewhere. In this work, we showed that when we put two vesicles onto the inner surface of a cone, both of them would spontaneously climb to the bottom of the cone. What’s following is the unambiguous fusion of these two vesicles. The probability of fusion was greatly enhanced by the confined space and close contact between these two vesicles. Our result may shed new insights on the fusions of vesicles in complex environments in biological systems, especially in the axonal and nerve growth processes.
Preference for animate domain sounds in the fusiform gyrus of blind individuals is modulated by shape-action mapping
Authors: Bola Łukasz , Yang Huichao , Caramazza Alfonso , Bi Yanchao
Published: June 2020

In high-level visual shape areas in the human brain, preference for inanimate objects is observed regardless of stimulation modality (visual/auditory/tactile) and subjects’ visual experience (sighted/blind individuals), whereas preference for animate entities seems robust only in the visual modality. Here, we test a hypothesis explaining this effect: visual shape representations can be reliably activated through different sensory modalities when they are systematically related to action system representations. We studied fMRI activations in congenitally blind and sighted subjects listening to animal, object, and human sounds. We found that, in blind individuals, the typical anatomical location of the fusiform face area responds to human facial expression sounds, with a clear mapping between the facial motor action and the resulting face shape, but not to speech or animal sounds. Using face areas’ activation in the blind subjects we could distinguish between specific facial expressions used in the study, but not between specific speech sounds. We conclude that auditory stimulation can reliably activate visual representations of those stimuli – inanimate or animate - for which shape and action computations are transparently related. Our study suggests that visual experience is not necessary for the development of functional preference for face-related information in the fusiform gyrus.
fruitlesstunes functional flexibility of courtship circuitry during development
Authors: Chen Jie , Jin Sihui , Cao Jie , Peng Qionglin , Pan Yufeng
Published: June 2020

Drosophilamale courtship is controlled by the male-specific products of thefruitless (fruMgene and its expressing neuronal circuitry.fruMis considered a master gene that controls all aspects of male courtship. By temporally and spatially manipulatingfruMexpression, we found thatfruMis required during a critical developmental period for innate courtship towards females, and its function during adulthood is relatively trivial. By altering or eliminatingfruMexpression, we generated males that are innately heterosexual, homosexual, bisexual, or without innate courtship but could acquire such behavior in an experience-dependent manner. These findings show thatfruMis not absolutely necessary for courtship but is critical during development to build a sex circuitry with reduced flexibility and enhanced efficiency and provide a new view about howfruMtunes functional flexibility of a sex circuitry.
Distinct roles for RAB10 and RAB29 in pathogenic LRRK2-mediated endolysosomal trafficking alterations
Authors: Rivero-Ríos Pilar , Romo-Lozano Maria , Fernández Belén , Fdez Elena , Hilfiker Sabine
Published: June 2020

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson’s disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, whilst RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
Determination of COVID-19 parameters for an agent-based model: Easing or tightening control strategies
Authors: Najmi Ali , Safarighouzhdi Farshid , Miller Eric J. , MacIntyre Raina , Rashidi Taha H.
Published: June 2020

Different agent-based models have been developed to estimate the spread progression of coronavirus disease 2019 (COVID-19) and to evaluate different control strategies to control outbreak of the infectious disease. While there are several estimation methods for the disease-specific parameters of COVID-19, they have been used for aggregate level models such as SIR and not for agent-based models. We propose a mathematical structure to determine parameter values of agent-based models considering the mutual effects of parameters. Then, we assess the extent to which different control strategies can intervene the transmission of COVID-19. Accordingly, we consider scenarios of easing social distancing restrictions, opening businesses, speed of enforcing control strategies and quarantining family members of isolated cases on the disease progression. We find the social distancing compliance level in the Sydney greater metropolitan area to be around 85%. Then we elaborate on consequences of easing the compliance level in the disease suppression. We also show that tight social distancing levels should be considered when the restrictions on businesses and activity participations are easing.
Early and Midterm Outcomes of Transcatheter Aortic-Valve Replacement with Balloon-Expandable Versus Self-Expanding Valves: A Systematic Review and Meta-Analysis
Authors: Zhang Xin-Lin , Zhang Xiao-Wen , Wei Zhong-Hai , Kang Li-Na , Lan Rong-Fang , Chen Jian-Zhou , Xie Jun , Wang Lian , Xu Wei , Xu Biao
Published: June 2020

Background

The comparative performances of transcatheter aortic-valve replacement (TAVR) with balloon-expandable valves (BEV) and self-expanding valves (SEV) in severe aortic stenosis remain unclear.

Purpose

To compare the early (30-day) and midterm (1-year) mortality and cardiovascular outcomes of BEV with SEV.

Data Sources

PubMed, EMBASE, and the Cochrane Library from inception until February 13, 2020.

Study Selection

3 randomized controlled trials (RCTs) and 12 propensity-score matched (PSM) studies, with 37,958 patients.

Data Extraction

2 reviewers independently extracted study data and rated study quality. Data Synthesis: Compared with SEV, BEV was associated with significantly lower mortality at 30 days (OR 0.77, 95% CI 0.71–0.83, P<0.00001, I2=0) and a trend toward lower mortality at 1 year (OR 0.88, 95% CI 0.78–1.00, P=0.05, I2=15.8%), mainly driven from PSM studies, but regardless of valve generations and SEV types. 30-day and 1-year cardiovascular mortality, 30-day incidences of moderate to severe paravavular leak, procedural contrast agent volume and procedure time were lower, but transvalvular pressure gradient was higher in BEV than SEV. 30-day incidences of permanent pacemaker implantation (PPI), acute kidney injury, stroke, major bleeding, major vascular complications and rehospitalization were not statistically different between BEV and SEV. Early-generation SEV was associated with a higher 30-day PPI risk than corresponding BEV comparators. PPI risk was lower in ACURATE neo but higher in Evolut R SEV, both compared with SAPIEN 3 BEV.

Limitations

Study-level but not patient-level data; residual confounders in PSM studies; study designs and patient characteristics were heterogeneous.

Conclusions

Compared with SEV, BEV might be associated with lower early and midterm mortality. Results from adequately powered RCTs with long-term follow-up are critically needed to confirm these findings.

Registration

PROSPERO (CRD42020172889).

Funding Source

National Natural Science Foundation of China (NO. 81600312).
Extracellular lipids ofCamelina sativa: Characterization of cutin and suberin reveals typical polyester monomers and novel functionalized dicarboxylic fatty acids
Authors: Razeq Fakhria M. , Kosma Dylan K. , França Débora , Rowland Owen , Molina Isabel
Published: June 2020

Camelina sativais relatively drought tolerant and requires less fertilizer than other oilseed crops. Various lipid- and phenolic-based extracellular barriers of plants help to protect them against biotic and abiotic stresses. These barriers, which consist of solvent-insoluble polymeric frameworks and solvent-extractable waxes, include the cuticle of aerial plant surfaces and suberized cell walls found, for example, in periderms and seed coat. Cutin, the polymeric matrix of the cuticle, and the aliphatic domain of suberin are fatty acid- and glycerol-based polyesters. These polyesters were investigated by base-catalyzed transesterification ofC. sativaaerial and underground delipidated tissues followed by gas chromatographic analysis of the released monomer mixtures. Seed coat and root suberin had similar compositions, with 18-hydroxyoctadecenoic and 1,18-octadecenedioic fatty acids being the dominant species. Root suberin presented a typical lamellar ultrastructure, but seed coats showed almost imperceptible, faint dark bands. Leaf and stem lipid polyesters were composed of fatty acids (FA), dicarboxylic acids (DCA), ω-hydroxy fatty acids (OHFA) and hydroxycinnamic acid derivatives (HCA). Dihydroxypalmitate (DHP) and caffeic acid were the major constituents of leaf cutin, whereas stem cutin presented similar molar proportions in several monomers across the four classes. Unlike the leaf cuticle, theC. sativastem cuticle presented lamellar structure by transmission electron microscopy. Flower cutin was dominated by DHP and did not contain aromatics. We found striking differences between the lipid polyester monomer compositions of aerial tissues ofC. sativaand that of its close relativesArabidopsis thalianaandBrassica napus.

Graphical Abstract

Camelina sativaleaf and stem cutin is dominated by 16:0 dihydroxy fatty acid and aromatics, with dicarboxylic fatty acids representing 20-30 % of the monomers. Suberin of root and seed coat is largely composed of 18:1 dicarboxylic and ω-hydroxy fatty acids.

Highlight bullet points

Camelina sativais an oil crop tolerant to biotic and abiotic stresses

Extracellular lipid polyesters may in part confer these attributes

Dihydroxypalmitate and caffeic acid were major components ofC. sativaleaf cutin

Flower cutin lacked aromatics and contained monomers not previously reported

Root and seed coat suberin was dominated by 18:1 ω-hydroxy and dicarboxylic fatty acids

C18 monounsaturated photo-oxidation products were found in leaf cutin and suberin
Trefoil factor 3 positively associates with IL-25 in patients with Chronic Rhinosinusitis
Authors: Ortiz-Carpena Jorge F. , Maina Ivy W. , Lin Cailu , Patel Neil N. , Triantafillou Vasiliki , Luu Neil N. , Kohanski Michael A. , Kuan Edward C. , Tong Charles C. L. , Bosso John V. , Adappa Nithin D. , Palmer James N. , Reed Danielle R. , Herbert De’Broski R. , Cohen Noam A.
Published: June 2020

Background

Trefoil factor family cytokines (TFF1-3) have documented reparative and immunoregulatory effects on mucosal epithelial cells that include: blocking apoptosis, directed cell migration, and regulation of pro-inflammatory cytokine production. TFF1 and TFF3 have been shown to undergo altered expression within sinonasal tissues of patients with various forms of chronic rhinosinusitis including those with or wthout polyp associated disease, but the cellular source(s) of TFF members in CRS remains unclear. To further explore the role of TFF3 in inflammatory sinonasal disease, we sought to determine its expression pattern in immune and non-immune cell types in CRS disease.

Methods

Polyp and inferior turbinate tissues were isolated from patients undergoing surgical resection for treatment of CRS. Tissue homogenates and single cell suspensions were subjected to enzyme linked immunosorbent assay (ELISA) and single-cell RNA sequencing. Air liquid interface cultures of sinonasal epithelia were subjected to immunofluorescence (IF) microscopy. Interleukin 25, TFF2 and TFF3 protein levels were compared to sinonasal outcome test scores (SNOT-22) to determine whether levels associated with post-operative outcomes.

Results

TFF3 was broadly expressed in goblet cells, ciliated cells, Tuft cells and T lymphocytes. TFF3 protein levels positively associated with IL-25 in CRSwNP patients. Lastly, TFF3 protein levels positively associated with clinical improvement post-surgery.

Conclusions

TFF3 is broadly expressed within multiple epithelial and immune cell lineages in patients with CRSwNP. Protein levels of TFF3 correlate with IL-25 and clinical signs of disease, however TFF3 levels associate with clinical improvement following surgical intervention indicating a potential beneficial role for this reparative cytokine in CRS patients.
Salient Safety Conditioning Improves Novel Discrimination Learning
Authors: Nahmoud I. , Ganay Vasquez J. , Cho H. , Dennis-Tiwary T. , Likhtik E.
Published: June 2020

Generalized fear is one purported mechanism of anxiety that is a target of clinical and basic research. Impaired fear discrimination has been primarily examined from the perspective of increased fear learning, rather than how learning about non-threatening stimuli affects fear discrimination. To address this question, we tested how three Safety Conditioning protocols with varied levels of salience allocated to the safety cue compared to classic Fear Conditioning in their impact on subsequent innate anxiety, and differential fear learning of new aversive and neutral cues. Using a high anxiety strain of mice (129SvEv, Taconic), we show that Fear Conditioned animals show little exploration of the anxiogenic center of an open field 24 hours later, and poor discrimination during new differential conditioning 7 days later. Three groups of mice underwent Safety Conditioning, (i) the safety tone was unpaired with a shock, (ii) the safety tone was unpaired with the shock and co-terminated with a house light signaling the end of the safety period, and (iii) the safety tone was unpaired with the shock and its beginning co-occurred with a house light, signaling the start of a safety period. Mice from all Safety Conditioning groups showed higher levels of open field exploration than the Fear Conditioned mice 24 hours after training. Furthermore, Safety Conditioned animals showed improved discrimination learning of a novel non-threat, with the Salient Beginning safety conditioned group performing best. These findings indicate that high anxiety animals benefit from salient safety training to improve exploration and discrimination of new non-threating stimuli.

Highlights

Safety training using salient cues improves safety learning in high anxiety mice

Salient Safety training improves novel fear discrimination learning

Safety training improves exploration in a novel anxiogenic environment
Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling
Authors: Konopelski Snavely Sara E. , Susman Michael W. , Kunz Ryan C. , Tan Jia , Srinivasan Srisathya , Cohen Michael D. , Okada Kyoko , Lamb Helen , Choi Shannon S. , Karuna Edith P. , Scales Michael K. , Gygi Steven P. , Greenberg Michael E. , Ho Hsin-Yi Henry
Published: June 2020

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development, but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a β-catenin-independent, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, CK1, and GSK3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain, which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a new Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.
The germline mutational process in rhesus macaque and its implications for phylogenetic dating
Authors: Bergeron Lucie A. , Besenbacher Søren , Bakker Jaco , Zheng Jiao , Li Panyi , Pacheco George , Sinding Mikkel-Holger S. , Kamilari Maria , Gilbert M. Thomas P. , Schierup Mikkel H. , Zhang Guojie
Published: June 2020

Understanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ca. 76X per individual, and estimated an average rate of 0.77 × 10−8de novomutations per site per generation (95 % CI: 0.69 × 10−8- 0.85 × 10−8). By phasing 50 % of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed an average of 81 % of thede novomutations, with a trend of an increasing male contribution for older fathers. About 3.5 % ofde novomutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated based on the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecidae/Hominoidea molecular divergence dated at 52 Mya using our new estimate of the yearly mutation rate.
Daytime light enhances the amplitude of circadian output in a diurnal mammal
Authors: Bano-Otalora Beatriz , Martial Franck , Harding Court , Bechtold David A. , Allen Annette E. , Brown Timothy M. , Belle Mino D. C. , Lucas Robert J.
Published: June 2020

Mammalian circadian rhythms are orchestrated by a master pacemaker in the hypothalamic suprachiasmatic nuclei (SCN), which receives information about the 24 h light:dark cycle from the retina. The accepted function of this light signal is to reset circadian phase in order to ensure appropriate synchronisation with the celestial day. Here, we ask whether light also impacts another key property of the circadian oscillation, its amplitude. To this end, we measured rhythms in behavioural activity and body temperature, and SCN electrophysiological activity in the diurnal murid rodentRhabdomys pumiliofollowing stable entrainment to 12:12 light:dark cycles at 4 different daytime intensities (ranging from 12.77 to 14.80 log melanopsin effective photons/cm2/s).Rhabdomysshowed strongly diurnal activity and body temperature rhythms in all conditions, but measures of rhythm robustness were positively correlated with daytime irradiance under both entrainment and subsequent free run. Whole-cell and extracellular recordings of electrophysiological activity inex vivoSCN revealed substantial differences in electrophysiological activity between dim and bright light conditions. At lower daytime irradiance, daytime peaks in SCN spontaneous firing rate and membrane depolarisation were substantially depressed, leading to an overall marked reduction in the amplitude of circadian rhythms in spontaneous activity. Our data reveal a previously unappreciated impact of daytime light intensity on SCN physiology and the amplitude of circadian rhythms, and highlight the potential importance of daytime light exposure for circadian health.
Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus
Authors: Wang Nan , Han Shengli , Liu Rui , Meng Liesu , He Huaizhen , Zhang Yongjing , Wang Cheng , Lv Yanni , Wang Jue , Li Xiaowei , Ding Yuanyuan , Fu Jia , Hou Yajing , Lu Wen , Ma Weina , Zhan Yingzhuan , Dai Bingling , Zhang Jie , Pan Xiaoyan , Hu Shiling , Gao Jiapan , Jia Qianqian , Zhang Liyang , Ge Shuai , Wang Saisai , Liang Peida , Hu Tian , Lu Jiayu , Wang Xiangjun , Zhou Huaxin , Ta Wenjing , Wang Yuejin , Lu Shemin , He Langchong
Published: June 2020

Background

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating. The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial.

Purpose

The objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection.

Methods

In our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2hcells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2hcells.

Results

Results showed that HCQ is slightly more toxic to ACE2hcells than CQ. Both CQ and HCQ could bind to ACE2 withKD=(7.31±0.62)e−7M and (4.82±0.87)e−7M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2hcells.

Conclusions

CQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.
Epipelic biofilms respond early to the impacts of urbanization in lowland streams
Authors: Cochero Joaquín , Nicolosi Gelis María Mercedes
Published: June 2020

Multiple structural and functional endpoints of stream biofilms are employed by water quality monitoring programs to detect both direct and indirect environmental impacts. Since multiple co-occurring stressors influence biofilm development, active biomonitoring (translocation experiments) could provide a useful monitoring tool that reflects the overall water quality of the urbanized sites. The aim of this research was to study the short-term responses of epipelic biofilms caused by their translocation to more polluted reaches in lowland urban streams. Fluvial sediment was translocated in three streams that run through urban areas following an urbanization gradient. The epipelic biofilms in the sediment were sampled to identify any fast occurring changes in their algal and bacterial biomasses, in their respiration and oxygen consumption. The results show that structural changes in the biofilm, such as an increased bacterial density and chlorophyll-a concentration, were measurable after two days of exposure to sites with impaired water quality. These immediate changes in the structure of the biofilm indicate that they are sensitive endpoints that can be employed in fast and inexpensive biomonitoring programs in urbanized streams.
Maternal RND3/RhoE deficiency impairs placental mitochondrial function in preeclampsia by modulating the PPARγ-UCP2 cascade
Authors: Huang Liping , Ma Yanlin , Chen Lu , Chang Jiang , Zhong Mei , Wang Zhijian , Sun Ying , Chen Xia , Sun Fei , Xiao Lu , Chen Jianing , Lai Yingjun , Yan Chuming , Yue Xiaojing
Published: June 2020

Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury, and proton leakage from the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor γ (PPARγ) and promotes the PPARγ-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPARγ rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPARγ-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in PE pathogenesis.
Thalamocortical excitability adjustments guide human perception under uncertainty
Authors: Kosciessa Julian Q. , Lindenberger Ulman , Garrett Douglas D.
Published: June 2020

Adaptive human behavior builds on prior knowledge about stimulus relevance. Some environments cue such knowledge more than others. To behave adaptively, observers need to flexibly adjust sensory processing to the degree of contextual uncertainty. We hypothesize that the neural basis for these perceptual adjustments consists in the ability of the cortical network to switch back and forth between a rhythmic state that serves selective processing, and a state of elevated asynchronous neural activity that boosts sensitivity. To test this hypothesis, we recorded non-invasive EEG and fMRI BOLD dynamics while 47 healthy young adults performed a parametric visual attention task with varying numbers of relevant stimulus features. Drift-diffusion modeling of response behavior and electrophysiological signatures revealed that greater contextual uncertainty lowered the rate of evidence accumulation while increasing thalamocortical engagement, with concomitant increments in cortical excitability and pupil dilation. As predicted, uncertainty-related processing adjustments were expressed as switches between a state of phase-dependent excitability modulation in the alpha band and a state of increased irregularity of brain dynamics. We conclude that humans dynamically adjust sensory excitability according to the processing fidelity afforded by an upcoming choice, and that neuromodulatory processes involving the thalamus play a key role in adjusting excitability in the human brain.

Highlights

With increasing contextual uncertainty, human cortical networks shift from a state of phase-dependent excitability modulation in the alpha band into a state of elevated excitatory tone and asynchronous neural activity

Evidence based on joint modeling of behavior, EEG, and BOLD suggests that neuromodulatory processes involving the thalamus regulate these shifts

Theoretical and empirical considerations suggest contributions of both frequency-specific and aperiodic neural dynamics to human behavior
Cholinergic relay from punishment- to reward-encoding dopamine neurons signals punishment withdrawal as reward inDrosophila
Authors: McCurdy Li Yan , Sareen Preeti , Davoudian Pasha A. , Nitabach Michael N.
Published: June 2020

Animals form and update learned associations between otherwise neutral cues and aversive outcomes to predict and avoid danger in changing environments. When a cue later occurs without punishment, this unexpected withdrawal of aversive outcome is encoded as reward, via activation of reward-encoding dopaminergic neurons. Using real-timein vivofunctional imaging, optogenetics, behavioral analysis, and electron-microscopy, we identify the neural mechanism through whichDrosophilareward-encoding dopaminergic neurons are activated when an olfactory cue is unexpectedly no longer paired with electric shock punishment. Reduced activation of punishment-encoding dopaminergic neurons relieves depression of synaptic inputs to cholinergic neurons, which in turn synaptically increase odor responses of reward-encoding dopaminergic neurons to decrease odor avoidance. These studies reveal for the first time how an indirect excitatory cholinergic synaptic relay from punishment- to reward-encoding dopaminergic neurons encodes the absence of a negative as a positive, revealing a general circuit motif for unlearning aversive memories that could be present in mammals.
Regulators of TNFα Mediated Insulin Resistance Elucidated by Quantitative Proteomics
Authors: Mohallem Rodrigo , Aryal Uma K.
Published: June 2020

Obesity is a growing epidemic worldwide and is a major risk factor for several chronic diseases, including diabetes, kidney disease, heart disease, and cancer. Obesity often leads to type 2 diabetes mellitus (T2DM, via the increased production of proinflammatory cytokines such as tumor necrosis factor-α (TNFα). Our study combines different proteomic techniques to investigate the changes in the global proteome, secretome and phosphoproteome of adipocytes under chronic inflammation condition, as well as fundamental cross-talks between different cellular pathways regulated by chronic TNFα exposure. Our results show that many key regulator proteins of the canonical and non-canonical NF-κB pathways, such as Nfkb2, and its downstream effectors, including Csf-1 and Lgals3bp, directly involved in leukocyte migration and invasion, were significantly upregulated at the intra and extracellular levels, culminating in the progression of inflammation. Our data provides evidence of several key proteins that play a role in the development of insulin resistance.
High-throughput binding affinity measurements for mutations spanning a transcription factor-DNA interface reveal affinity and specificity determinants
Authors: Aditham Arjun K. , Markin Craig J. , Mokhtari Daniel A. , DelRosso Nicole V. , Fordyce Polly M.
Published: June 2020

Transcription factors (TFs) bind regulatory DNA to control gene expression, and mutations to either TFs or DNA can alter binding affinities to rewire regulatory networks and drive phenotypic variation. While studies have profiled energetic effects of DNA mutations extensively, we lack similar information for TF variants. Here, we present STAMMP (Simultaneous Transcription Factor Affinity Measurements via Microfluidic Protein Arrays), a high-throughput microfluidic platform enabling quantitative characterization of hundreds of TF variants simultaneously. Measured affinities for ∼210 mutants of a model yeast TF (Pho4) interacting with 9 oligonucleotides (>1,800Kds) reveal that many combinations of mutations to poorly conserved TF residues and nucleotides flanking the core binding site alter but preserve physiological binding, providing a mechanism for mutations incisandtransto rewire networks without insurmountable evolutionary penalties. Moreover, biochemical double-mutant cycles across the TF-DNA interface reveal molecular mechanisms driving recognition, linking sequence to function.