bluuebunny/crossref_metadata_2025 huggingface dataset:
Unfolding Trade Effect in Two Margins of Informality. The Peruvian Case
Authors: Cisneros-Acevedo Camila
Published: September 2021

This paper studies the effect of an increase in import competition on informality along two margins. It considers the extensive margin, where workers are hired by unregistered employers, and the intensive margin, where even though jobs are carried out by registered firms, employees are off the books. Peru’s relentless informal employment and its unprecedented trade-driven growth provides an ideal case study. Using a rich household survey, this study finds that exposure to trade impacts on informality through two competing and contrasting mechanisms. On the one hand, extensive-informal employment declines as unregistered employers shrink or exit due to their low productivity. On the other hand, intensive-informal employment rises as registered employers reduce costs by hiring informal workers. Furthermore, results suggest that the intensive margin drives the overall effect. Hence, trade liberalization increases informality.
The Past and Future of the Right to Petition the European Parliament
Authors: Vogiatzis Nikos
Published: September 2021

This article critically evaluates the right to petition the European Parliament, a right which has not managed, to date, to constitute a credible alternative for citizens’ participation in the EU. It argues that there are two main reasons for the shortcomings of this right. First, before Maastricht, the Petitions’ Committee suffered the consequences of a broader decline of parliamentary petitions within and beyond Europe. Second, after Maastricht and Lisbon, the petition right was affected by the (partly complementary and partly divergent) rights to complain to the European Ombudsman and to sign or support a European citizens’ initiative. In addition, and possibly as a consequence of the above reasons, throughout its life, the petition right and the Committee on Petitions more generally have not benefited from significant resources, while their visibility has been very limited. A comparative examination of the three rights (petitions, European Ombudsman, citizens’ initiative) in terms of access, scope, user-friendliness and outcome is undertaken. Looking at the future of the petition right, in an era marked by the resurgence of online petitions, the article argues that the Petitions’ Committee should strategically focus on areas which are not covered by the two aforementioned rights, namely the national level and broader policy choices in the EU, in order to maximize its input and relevancy within the EU’s decision-making world.
Recovery Plan for Scots Pine Blister Rust Caused by Cronartium pini
Authors: Kim Mee-Sook , Hantula Jarkko , Kaitera Juha , Zambino Paul J. , Woodward Stephen , Richardson Bryce A. , Stewart Jane E. , Spaine Pauline , Shaw David C. , Takeuchi Yu , Klopfenstein Ned B.
Published: September 2021

Scots pine blister rust caused by Cronartium pini, which includes the fungal rust pathogen with either a heteroecious life cycle (previously known as Cronartium flaccidum) or an autoecious life cycle (formerly known as Peridermium pini or Endocronartium pini), is capable of infecting many Eurasian pines including Pinus sylvestris (Scots pine). The heteroecious form of C. pini completes its life cycle alternating between pines and various species of flowering plants (Angiospermae); the related autoecious form spreads directly from pine to pine. If the Scots pine blister rust pathogen possesses or gains the capacity to infect North American pines, the economic and ecological impacts could be significant. Scots pine is one of the most widely distributed conifers in the world, and it has become naturalized in the northeastern and midwestern United States. Scots pine blister rust is also called resin-top disease and top-dieback of pine. Symptoms in pine include stem swelling, branch flagging, excessive pitch flow, and top-kill, and, in the alternate hosts, leaf spotting. The rust pathogen is spread in nature by wind-borne spores, which require live hosts for infection. However, the rust pathogen can also be transported on infected plant materials that can be nonsymptomatic. Early infections of host plant infections by C. pini are difficult to detect and diagnose, but molecular techniques offer a potential approach for early detection and diagnosis. This recovery plan is intended to provide a brief summary of the disease, assess the status of critical recovery components, and identify disease management research, extension, and education needs.
Assessing Loss to Follow-up After Newborn Hearing Screening in the Neonatal Intensive Care Unit: Sociodemographic Factors That Affect Completion of Initial Audiological Evaluation
Authors: Cheung Anthony , Chen Tammy , Rivero Rachel , Hartman-Joshi Kristin , Cohen Michael B. , Levi Jessica R.
Published: September 2021

Objectives:

Neonatal intensive care unit (NICU) patients are at high risk for congenital hearing loss. Previous studies have found sociodemographic factors associated with loss to follow-up for newborn hearing screening, but none have specifically studied the NICU population. Our objective is to determine if demographics and socioeconomic status is associated with loss to follow-up in a newborn population with extended NICU stay.

Design:

A retrospective cohort study was conducted on 443 NICU infants with extended NICU stay utilizing data extracted from infant and maternal medical records at an urban safety-net hospital.

Results:

Younger maternal age (adjusted odds ratio [OR] 0.95, confidence interval [CI] 0.91 to 0.99), higher gravidity (adjusted OR 1.39, CI 1.12 to 1.72), and former smoking status (adjusted OR 2.57, CI 1.07–6.18) were identified as independent predictors of loss to follow-up for NHS after conducting a multivariable logistic regression. Demographic and socioeconomic variables, such as sex, parity, birth weight, mode of birth, highest level of maternal education, maternal race/ethnicity, zip code metrics, and maternal language were not found to be associated with loss to follow-up.

Conclusions:

Maternal age, gravidity, and smoking status are risk factors for loss to follow-up for NHS in newborns with extended NICU stay, a group at high risk for hearing loss. Our findings demonstrate that socioeconomic and demographic factors for loss to follow-up in the extended-stay NICU population are distinct from the well-baby population. Further investigation of these patients will allow prioritization of limited resources to subgroups within the extended-stay NICU population at risk for loss to follow-up for newborn hearing screening.
Extracorporeal Life Support for Respiratory Failure in Patients With Electronic Cigarette or Vaping Product Use–Associated Lung Injury
Authors: Gupta Vikas S. , Hayes Don , Hsu Stephanie C. , Tonna Joseph E. , Rycus Peter T. , Bridges Brian C. , Diaban Fatima , Bosma Karen J. , Bhatt Jayesh M. , Sakla Nicole M. , Han Jason J. , Bermudez Christian A. , Manetta Frank , Garcia Elisa I. , Harting Matthew T.
Published: September 2021

OBJECTIVES:

Electronic cigarette or vaping product use–associated lung injury is a clinical entity that can lead to respiratory failure and death. Despite the severity of electronic cigarette or vaping product use–associated lung injury, the role of extracorporeal life support in its management remains unclear. Our objective was to describe the clinical characteristics and outcomes of patients with electronic cigarette or vaping product use–associated lung injury who received extracorporeal life support.

DESIGN:

We performed a retrospective review of records of electronic cigarette or vaping product use–associated lung injury patients who received extracorporeal life support. Standardized data were collected via direct contact with extracorporeal life support centers. Data regarding presentation, ventilatory management, extracorporeal life support details, and outcome were analyzed.

SETTING:

This was a multi-institutional, international case series with patients from 10 different institutions in three different countries.

PATIENTS:

Patients who met criteria for confirmed electronic cigarette or vaping product use–associated lung injury (based on previously reported diagnostic criteria) and were placed on extracorporeal life support were included. Patients were identified via literature review and by direct contact with extracorporeal life support centers.

MEASUREMENTS AND MAIN RESULTS:

Data were collected for 14 patients ranging from 16 to 45 years old. All had confirmed vape use within 3 months of presentation. Nicotine was the most commonly used vaping product. All patients had respiratory symptoms and radiographic evidence of bilateral pulmonary opacities. IV antibiotics and corticosteroids were universally initiated. Patients were intubated for 1.9 days (range, 0–6) prior to extracorporeal life support initiation. Poor oxygenation and ventilation were the most common indications for extracorporeal life support. Five patients showed evidence of ventricular dysfunction on echocardiography. Thirteen patients (93%) were placed on venovenous extracorporeal life support, and one patient required multiple rounds of extracorporeal life support. Total extracorporeal life support duration ranged from 2 to 37 days. Thirteen patients survived to hospital discharge; one patient died of septic shock.

CONCLUSIONS:

Electronic cigarette or vaping product use–associated lung injury can cause refractory respiratory failure and hypoxemia. These data suggest that venovenous extracorporeal life support can be an effective treatment option for profound, refractory respiratory failure secondary to electronic cigarette or vaping product use–associated lung injury.
Impact of Reverberation on Speech Perception and Sound Localization Accuracy in Cochlear Implant Users With Single-Sided Deafness
Authors: Körtje Monika , Eichenauer Anja , Stöver Timo , Baumann Uwe , Weissgerber Tobias
Published: September 2021

Objectives:

The aim of this study was to compare the impact of reverberation on sound localization accuracy and speech perception in noise between subjects with single-sided deafness using a cochlear implant (SSD-CI) and a normal-hearing control group.

Methods:

Nine SSD-CI subjects and 21 normal-hearing subjects participated in the study. In Experiment 1, the sound localization accuracy was measured with and without reverberation. In Experiment 2, speech reception thresholds were determined with four asymmetrically arranged noise sources in free-field and in reverberation. For the realization of reverberation, a room simulation system comprising of 128 loudspeakers was used.

Results:

No significant impact of reverberation was found on the sound localization accuracy of the SSD-CI subjects (free-field: 12.6°, reverberation: 11.9°), whereas the normal-hearing subjects performed significantly worse in reverberation (free-field: 1.8°, reverberation: 3.3°).

Both subject groups experienced significantly deteriorated speech reception thresholds due to reverberation (p
SSD-CI = 0.008, p
NH < 0.001). Mean speech reception thresholds in the SSD-CI subjects were −9.7 dB SNR (free-field) and −4.2 dB SNR (reverberation) and a median individual decrease of 5.7 dB SNR in reverberation. Mean speech reception thresholds in the normal-hearing group were −14.0 dB SNR (free-field) and −10.3 dB SNR (reverberation).

Conclusion:

A strong deterioration of sound localization accuracy due to reverberation did not occur. However, although partial restoration of binaural hearing is assumed in SSD-CI users, the impact of reverberation on speech perception in noise is much stronger compared to normal-hearing.
Extracorporeal measurement of femoral nail length in the treatment of trochanteric hip fractures: the “box” technique
Authors: Garg Kartik , Herring Matthew J. , Marmor Meir
Published: September 2021

Intramedullary nails, long and short, are widely used for fixation of trochanteric femur fractures. In theory, long nails may be able to protect the entire length of the femur from a future periprosthetic fracture, providing that the nail spans the length of the entire femoral canal. The described technique for long nail insertion calls for the use of an intramedullary guidewire and depth gauge for premeasurement of the length of the canal, as well as the use of a reamer. However, compared with short nails, this technique may add cost, operating time, and blood loss. We describe a safe technique for long nail measurement that reliably spans the length of the femur while potentially reducing surgical cost, time, and blood loss. We also describe 21 cases in which the technique was applied.
Patient and Provider Perspectives on Glaucoma Treatment Adherence: A Delphi Study in Urban Alabama
Authors: Poleon Shervonne , Racette Lyne , Fifolt Matthew , Schoenberger-Godwin Yu-Mei , Abu Sampson Listowell , Twa Michael D.
Published: September 2021

SIGNIFICANCE

Patients with glaucoma and providers recognized perceived treatment efficacy, patient-provider relationship, psychological stress, instillation skill, good quality of life, and forgetfulness as key determinants of glaucoma adherence. This shared insight could help shape the development of clinical and behavioral interventions for addressing treatment barriers and improving adherence.

PURPOSE

Despite their impact on adherence in glaucoma, sociobehavioral factors may not be adequately explored during clinical consultations. We aimed to elicit consensus between patients and providers around key determinants of adherence and hypothesized that patients would place greater emphasis on sociobehavioral factors compared with providers.

METHODS

A two-round Delphi survey was used to assess treatment beliefs, barriers, facilitators, motivators, and needs among 18 patients with glaucoma and providers. In round 1, agreement with 46 statements was scored on a 5-point Likert scale (strongly disagree to strongly agree). Statements with which 80% or more of panelists agreed reached consensus and advanced to round 2, where participants were asked to prioritize them based on their importance to treatment.

RESULTS

There was consensus regarding the influence of perceived treatment efficacy, good provider relationship, good quality of life, psychological stress, glaucoma knowledge, instillation skill, and forgetfulness on glaucoma adherence. For statements that failed to reach consensus, the Bonferroni-corrected Mann-Whitney U test revealed that the greatest differences between patients and providers pertained to regimen complexity (provider median, 4 [interquartile range {IQR}, 1]; patient median, 1.5 [IQR, 1]; P = .002), instillation skill (providers, 4 [IQR, 0.5]; patients, 2 [IQR, 1]; P = .001), and low motivation (providers, 3 [IQR, 2.25]; patients, 1 [IQR, 0]; P = .003).

CONCLUSIONS

Although patients and providers prioritized sociobehavioral factors as key determinants of adherence, disagreement between these groups was observed in other areas. Continued juxtaposition of patient and provider perspectives could spotlight underexplored areas and guide the development of successful interventions for improving adherence.
Case Report: Multimodal Imaging of Acute Idiopathic Maculopathy in a Chinese Woman
Authors: Zhang Ke , Liu Jian , Jiang Deyong , Myers Frank L. , Zhou Liang
Published: September 2021

SIGNIFICANCE

Acute idiopathic maculopathy is a rare disease with the characteristics of sudden, severe, unilateral central vision loss after a flu-like illness. The prognosis is generally good, and poor vision usually results from complications such as choroidal neovascularization or subfoveal pigment degeneration. Multimodal imaging is helpful in the diagnosis and follow-up of this disease.

PURPOSE

We report a case of acute idiopathic maculopathy and present multimodal imaging results in the diagnosis of this condition.

CASE REPORT

A 37-year-old Chinese woman noted a central scotoma in her right eye a day after a prodrome of flu-like symptoms. Best-corrected visual acuity of the right eye was 20/40. Multimodal imaging was performed, and a diagnosis of acute idiopathic maculopathy was made. The variable clinical appearance of acute idiopathic maculopathy on autofluorescence, near-infrared reflectance, and optical coherence tomography (OCT) was shown. The patient's vision spontaneously recovered to 20/20 two weeks after the onset of the disease, but macular sensitivity, as measured by microperimetry, did not return to normal until 1 month. Retrobulbar injection of triamcinolone was done at 3 weeks to prevent retinal pigment epithelium hyperplasia and choroidal neovascularization. Written informed consent was obtained from the patient.

CONCLUSIONS

Our findings suggest that near-infrared reflectance corresponds to the change of the outer retina and retinal pigment epithelium on OCT and complements autofluorescence in the diagnosis and follow-up of acute idiopathic maculopathy. Fundus autofluorescence, near-infrared reflectance, and OCT are recommended as routine examinations in this disease.
Disinfection of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and Acinetobacter baumannii using Klaran WD array system
Authors: Mariita Richard M. , Randive Rajul V.
Published: September 2021

Hospital-associated infections (HAIs) are a major burden in healthcare systems. In this study, UVC LEDs emitting radiation from 260 to 270 nm were evaluated for effectiveness in reducing methicillin-resistant

Staphylococcus aureus

(MRSA), vancomycin-resistant

Enterococcus faecium

and

Acinetobacter baumannii

. The array has four WD LEDs, each with 70 mW placed at 7 cm from test organisms. With 11.76 mJ cm−2, the study obtained 99.99% reduction (log10 reduction factor of 4) against MRSA and VRE. For

A. baumannii

, 9 mJ cm−2 obtained 99.999% reduction (log10 reduction factor of 5). These results present scientific evidence on how effective UVC LEDs can be used in the fight against HAIs.
A natural variant in ANP32B impairs influenza virus replication in human cells
Authors: Staller Ecco , Sheppard Carol M. , Baillon Laury , Frise Rebecca , Peacock Thomas P. , Sancho-Shimizu Vanessa , Barclay Wendy S.
Published: September 2021

Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.
BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
Authors: Peron Angela , D’Arco Felice , Aldinger Kimberly A. , Smith-Hicks Constance , Zweier Christiane , Gradek Gyri A. , Bradbury Kimberley , Accogli Andrea , Andersen Erica F. , Au Ping Yee Billie , Battini Roberta , Beleford Daniah , Bird Lynne M. , Bouman Arjan , Bruel Ange-Line , Busk Øyvind Løvold , Campeau Philippe M. , Capra Valeria , Carlston Colleen , Carmichael Jenny , Chassevent Anna , Clayton-Smith Jill , Bamshad Michael J , Earl Dawn L. , Faivre Laurence , Philippe Christophe , Ferrerira Patrick , Graul-Neumann Luitgard , Green Mary J. , Haffner Darrah , Haldipur Parthiv , Hanna Suhair , Houge Gunnar , Hurst Jane , Kraus Cornelia , Kristiansen Birgit Elisabeth , Lespinasse James , Low Karen J. , Lynch Sally Ann , Maia Sofia , Mao Rong , Marcinkute Ruta , Melver Catherine , McDonald Kimberly , Montgomery Tara , Morleo Manuela , Motter Constance , Openshaw Amanda S. , Palumbos Janice Cox , Parikh Aditi Shah , Person Richard , Desai Megha , Piard Juliette , Pfundt Rolph , Scala Marcello , Serey-Gaut Margaux , Slavotinek Anne , Suri Mohnish , Turner Claire , Tvrdik Tatiana , Weiss Karin , Wentzensen Ingrid M. , Zollino Marcella ,   C4RCD Research Group,   Telethon Undiagnosed Disease Program (TUDP),   University of Washington Center for Mendelian Genomics (UW-CMG), de Vries Bert B.A. , Guillemot Francois , Dobyns William B. , Viskochil David , Dias Cristina
Published: September 2021

Purpose

Heterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.

Methods

We performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.

Results

Molecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.

Conclusions

We expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
COVID-19 convalescent plasma and randomized clinical trials: explaining conflicting outcomes and finding signals of efficacy
Authors: Focosi Daniele , Franchini Massimo , Pirofski Liise-anne , Burnouf Thierry , Paneth Nigel , Joyner Michael J. , Casadevall Arturo
Published: September 2021

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCT) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. Reasons for CCP success and failure may be hidden in study details, which are usually difficult to explain to physicians and the public but provide fertile ground for designing next-generation studies. We analyzed variables associated with efficacy such as clinical settings, disease severity, CCP SARS-CoV-2 antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance and time for collection, and criteria for efficacy. Focusing only on the results from the 30 available RCTs we noted that these were more likely to show signals of efficacy, including reductions in mortality, if the plasma neutralizing titer was ≥ 160 and the time to randomization was ≤ 9 days, consistent with passive antibody therapy efficacy requiring dosing with sufficient antibody. The fact that most studies revealed signals of efficacy despite variability in CCP and its use suggest likely therapeutic effects that become apparent despite the data noise. Despite the recent WHO guidelines discouraging CCP usage, the Omicron variant of concern is reminding us the superiority of polyclonal antibody therapies over monoclonal antibodies, and CCP from vaccinated convalescents is likely to be evaluated soon
Antibody kinetics to SARS-CoV-2 at 13.5 months, by disease severity
Authors: Violán Concepción , Torán Pere , Quirant Bibiana , Lamonja-Vicente Noemi , Carrasco-Ribelles Lucía A. , Chacón Carla , Manresa-Dominguez Josep Maria , Ramos-Roure Francesc , Roso-Llorach Albert , Pujol Aleix , Ouchi Dan , Monteagudo Mónica , Montero Pilar , Garcia-Sierra Rosa , Arméstar Fernando , Dacosta-Aguayo Rosalia , Doladé Maria , Prat Nuria , Bonet Josep Maria , Clotet Bonaventura , Blanco Ignacio , Prado Julia G , Martínez Cáceres Eva María ,   for the ProHEpiC-19 Investigators
Published: September 2021

Background

Understanding humoral responses and seroprevalence in SARS-CoV-2 infection is essential for guiding vaccination strategies in both infected and uninfected individuals.

Methods

We determine the kinetics of IgM against the nucleocapsid (N) and IgG against the spike (S) and N proteins of SARS-CoV-2 in a cohort of 860 health professionals (healthy and infected) in northern Barcelona. We model the kinetics of IgG and IgM at nine time points over 13.5 months from infection, using non-linear mixed models by sex and clinical disease severity.

Results

Of the 781 participants who were followed up, 478 (61.2%) became infected with SARS-CoV-2. Significant differences were found for the three antibodies by disease severity and sex. At day 270 after diagnosis, median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease, while IgG(N, S) levels remained positive to days 360 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay whose rate depended on disease severity. IgG(S) levels increased at day 15 and remained relatively constant over time.

Conclusions

We describe kinetic models of IgM(N) and IgG(N, S) SARS-CoV-2 antibodies at 13.5 months from infection and disease spectrum. Our analyses delineate differences in the kinetics of IgM and IgG over a year and differences in the levels of IgM and IgG as early as 15 days from symptoms onset in severe cases. These results can inform public health policies around vaccination criteria.

Funded by the regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478)
Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2
Authors: Kaaijk Patricia , Pimentel Verónica Olivo , Emmelot Maarten E. , Poelen Martien , Cevirgel Alper , Schepp Rutger M. , den Hartog Gerco , Reukers Daphne F.M. , Beckers Lisa , van Beek Josine , van Els Cécile A.C.M. , Meijer Adam , Rots Nynke Y. , de Wit Jelle
Published: September 2021

Background

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory.

Methods

To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19.

Results

Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-γ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-γ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals.

Conclusions

Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.
The Morbidity Costs of Air Pollution through the Lens of Health Spending in China
Authors: Zhang Xin , Zhang Xun , Chen Xi , Liu Yuehua , Zhao Xintong
Published: September 2021

This study offers one of the first causal evidence on the morbidity costs of fine particulates (PM2.5) for all age cohorts in a developing country, using individual-level healthcare spending data from the basic medical insurance program in Wuhan, China. Our instrumental variable (IV) approach uses thermal inversion to address potential endogeneity in PM2.5 concentrations and shows that PM2.5 imposes a significant impact on medical expenditures. The IV estimate suggests that a 10 μg/m3 reduction in monthly average PM2.5 leads to a 2.79% decrease in the value of health spending and a 0.70% decline in the number of transactions in pharmacies and health facilities. The effect is more salient for males, children, and older adults. Moreover, our estimates provide a lower bound of people’s willingness-to-pay, which amounts to CNY 51.85 (or USD 8.38) per capita per year for a 10 μg/m3 reduction in PM2.5.

JEL Codes

Q51, Q53, I11, I31

Conflict of interest

The authors declare that they have no conflict of interest.
An almost nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, as an odorant for the grass puffer
Authors: Noguchi Yoshihisa , Suzuki Takehisa , Matsutani Keigo , Sakakibara Ryo , Nakahigashi Ryota , Adachi Masaatsu , Nishikawa Toshio , Abe Hideki
Published: September 2021

Toxic puffers contain the potent neurotoxin, tetrodotoxin (TTX). Although TTX is considered to serve as a defense substance, previous behavioral studies have demonstrated that TTX acts as an attractive pheromone for some toxic puffers. To elucidate the physiological mechanism of putative pheromonal action of TTX, we examined whether grass puffers Takifugu alboplumbeus can detect TTX. Electroolfactogram (EOG) results suggest that the olfactory epithelium (OE) of grass puffers responded to a type of TTX analog (5,6,11-trideoxyTTX), although it did not respond to TTX. We also examined the attractive action of 5,6,11-trideoxyTTX on grass puffers by recording their swimming behavior under dark conditions. Grass puffers preferred to stay on the side of the aquarium where 5,6,11-trideoxyTTX was administered, and their swimming speed decreased. Additionally, odorant-induced labeling of olfactory sensory neurons by immunohistochemistry against neural activity marker (phosphorylated extracellular signal regulated kinase; pERK) revealed that labeled olfactory sensory neurons were localized in the region surrounding “islets” where there was considered as nonsensory epithelium. 5,6,11-trideoxyTTX has been known to accumulate in grass puffers, but its toxicity is much lower (almost nontoxic) than TTX. Our results suggest that toxic puffers may positively use this TTX analog, which has been present in their body with TTX but whose function was unknown, as an odorant for chemical communication or effective TTX accumulation.
Fragment-based ab initio phasing of peptidic nanocrystals by MicroED
Authors: Richards Logan S. , Flores Maria D. , Millán Claudia , Glynn Calina , Zee Chih-Te , Sawaya Michael R. , Gallagher-Jones Marcus , Borges Rafael J. , Usón Isabel , Rodriguez Jose A.
Published: September 2021

Microcrystal electron diffraction (MicroED) is transforming the visualization of molecules from nanocrystals, rendering their three-dimensional atomic structures from previously unamenable samples. Peptidic structures determined by MicroED include naturally occurring peptides, synthetic protein fragments and peptide-based natural products. However, as a diffraction method, MicroED is beholden to the phase problem, and its de novo determination of structures remains a challenge. ARCIMBOLDO, an automated, fragment-based approach to structure determination. It eliminates the need for atomic resolution, instead enforcing stereochemical constraints through libraries of small model fragments, and discerning congruent motifs in solution space to ensure validation. This approach expands the reach of MicroED to presently inaccessible peptidic structures including segments of human amyloids, and yeast and mammalian prions, and portends a more general phasing solution while limiting model bias for a wider set of chemical structures.
Amelioration of L-DOPA-induced dyskinesia with vitamin D3in Parkinsonian mice model
Authors: Bayo-Olugbami Adedamola Aminat , Nafiu Abdulrazaq Bidemi , Amin Abdulbasit , Ogundele Olalekan Michael , Lee Charles C. , Owoyele Bamidele Victor
Published: September 2021

L-DOPA Induced Dyskinesia (LID) is associated with prolonged L-DOPA therapy. Vitamin-D receptor modulation improves motor-cognitive deficit in experimental LID Parkinsonism. Therefore, in this study, we investigated the mechanism underlying the anti-dyskinetic potential of Vitamin D3 (VD3). Dyskinesia was induced by chronic L-DOPA administration in 6-OHDA lesioned male C57BL6 mice. The experimental groups (Dyskinesia, Dyskinesia/VD3, and Dyskinesia/Amantadine) and controls were challenged with L-DOPA to determine the abnormal involuntary movements (AIMs) score during 14 days of VD3(30 mg/kg) or Amantadine (40 mg/kg) treatment. Global behavioral Axial, Limb & Orolingual (ALO) AIMs were scored for 1 min at every 20 mins interval, over a duration of 100 mins on days 1,3,7,11 and 14 of treatment. Thereafter, brain samples were collected and processed for immunoblotting to assess striatal expression of tyrosine hydroxylase (TH), monoamine oxidase (MAO), cathecol-o-methyl transferase (COMT), dopamine decarboxylase (DDC), CD11b, BAX, P47phox, and IL-1β. VD3significantly attenuated ALO AIMs only on days 11 & 14, with maximal reduction of 32.7% compared with dyskinetic mice but had no effect on days 1, 3 & 7, while amantadine decreased AIMs all through days 1 to 14 with maximal reduction of 64.5%. TH and MAO-B expression were not significantly different across the groups. DDC was significantly suppressed in dyskinetic micevscontrol (p<0.001) but remained unchanged in VD3micevsdyskinetic mice. COMT was upregulated in the dyskinetic groupvscontrol (p<0.01) and attenuated in VD3mice (p<0.05) compared to the dyskinetic group. Interestingly, VD3inhibited significantly (p<0.01) oxidative stress (p47phox), apoptosis (BAX), inflammation (IL-1β), and microglial activation (CD11b) in dyskinetic mice. Overall, we find that the anti-dyskinetic effects of VD3is associated with modulation of striatal oxidative stress, microglial responses, inflammation, and apoptotic signaling.

Impact statement

There are evidences showing that VD3supplementation improves motor disorders, including Parkinson’s disease. We hypothesized that VD3could improve LID, an abnormal involuntary movement that results from prolonged L-DOPA therapy in the management of PD. We have demonstrated the novel anti-dyskinetic effect of VD3and associated mechanistic factors in a mouse model of L-DOPA Induced Dyskinesia (LID), which identifies promising targets for dyskinesia therapy.
Remote immune processes revealed by immune-derived circulating cell-free DNA
Authors: Fox-Fisher Ilana , Piyanzin Sheina , Ochana Bracha-Lea , Klochendler Agnes , Magenheim Judith , Peretz Ayelet , Loyfer Netanel , Moss Joshua , Cohen Daniel , Drori Yaron , Friedman Nehemya , Mandelboim Michal , Rothenberg Marc E. , Caldwell Julie M. , Rochman Mark , Jamshidi Arash , Cann Gordon , Lavi David , Kaplan Tommy , Glaser Benjamin , Shemer Ruth , Dor Yuval
Published: September 2021

Blood cell counts often fail to report on immune processes occurring in remote tissues. Here we use immune cell type-specific methylation patterns in circulating cell-free DNA (cfDNA) for studying human immune cell dynamics. We characterized cfDNA released from specific immune cell types in healthy individuals (N=242), cross sectionally and longitudinally. Immune cfDNA levels had no individual steady state as opposed to blood cell counts, suggesting that cfDNA concentration reflects adjustment of cell survival to maintain homeostatic cell numbers. We also observed selective elevation of immune-derived cfDNA upon perturbations of immune homeostasis. Following influenza vaccination (N=92), B-cell-derived cfDNA levels increased prior to elevated B-cell counts and predicted efficacy of antibody production. Patients with Eosinophilic Esophagitis (N=21) and B-cell lymphoma (N=27) showed selective elevation of eosinophil and B-cell cfDNA respectively, which were undetectable by cell counts in blood. Immune-derived cfDNA provides a novel biomarker for monitoring immune responses to physiological and pathological processes that are not accessible using conventional methods.
Neurons expressing mu opioid receptors of the habenula promote negative affect in a projection-specific manner
Authors: Bailly Julie , Allain Florence , Tirel Chloé , Petit Florence , Darcq Emmanuel , Kieffer Brigitte
Published: September 2021

BACKGROUND

The mu opioid receptor (MOR) is central to hedonic balance, and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, and notably the medial habenula (MHb) where the receptor is highly dense, however this was not investigated. Our prior data suggest that the inhibitory activity of MOR in the MHb limits aversive states. Here we therefore tested the hypothesis that neurons expressing MOR in the MHb (MHb-MOR neurons) promote negative affective states.

METHODS

UsingOprm1-Cre knock-in mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of MHb-MOR neuron stimulation in approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze and marble burying) and despair-like behavior (tail suspension).

RESULTS

Opto-stimulation of MHb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus (IPN), MHb-MOR neurons project to the dorsal raphe nucleus (DRN), uncovering a yet unreported connection of MHb to a main mood center. Opto-stimulation of MHb-MOR/IPN neurons triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of MHb-MOR/DRN neurons increased levels of anxiety with no effect on other behaviors, revealing two dissociable pathways controlling negative affect.

CONCLUSIONS

This study demonstrates aversive activity of MHb neurons that respond to MOR opioids. We propose that inhibition of these neurons by endogenous or exogenous opioids relieves negative affect via two distinct MHb microcircuits, contributing to despair-like behavior (MHb-MOR/IPN) and anxiety (MHb-MOR/DRN). This mechanism has implications for hedonic homeostasis and addiction.
Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival
Authors: Kubinyecz Oana , Santos Fatima , Drage Deborah , Reik Wolf , Eckersley-Maslin Melanie A
Published: September 2021

Zygotic Genome Activation (ZGA) represents the initiation of transcription following fertilisation. Despite its importance in shifting developmental control from primarily maternal stores in the oocyte to the embryo proper, we know little of the molecular events that initiate ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells (ESCs) have revealed Developmental Pluripotency Associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, while fertile, Dppa2/4 maternal knockout mice had reduced litter sizes, indicating decreased offspring survival. Immunofluorescence and transcriptome analyses of 2-cell embryos revealed while ZGA took place there were subtle defects in embryos lacking maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together our results show that while Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.
Common micro- and macroscale principles of connectivity in the human brain
Authors: Scholtens Lianne H. , Pijnenburg Rory , de Lange Siemon C. , Huitinga Inge , van den Heuvel Martijn P. ,   Netherlands Brain Bank (NBB)
Published: September 2021

The brain requires efficient information transfer between neurons and between large-scale brain regions. Brain connectivity follows predictable organizational principles: at the cellular level, larger supragranular pyramidal neurons have larger dendritic trees, more synapses, more complex branching and perform more complex neuronal computations; at the macro-scale, region-to-region connections are suggested to display a diverse architecture with highly connected hub-areas facilitating complex information integration and computation. Here, we explore the hypothesis that the branching structure of large-scale region-to-region connectivity follows similar organizational principles as known for the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across ten cortical areas in five human donor brains (1M/4F). Dendritic complexity was quantified as the number of branch points, tree length, spine count, spine density and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct ‘white matter trees’ of cortico-cortical wiring. Examining the complexity of the resulting white matter trees using the same measures as for dendritic trees shows multimodal association areas to have larger, more complexly branched white matter trees than primary areas (all p<0.0001) and regional macroscale complexity to run in parallel with microscale measures, in terms of number of inputs (r=0.677, p=0.032), branch points (r=0.790, p=0.006), total tree length (r=0.664, p=0.036) and branching complexity (r=0.724, p=0.018). Our findings support the integrative theory that brain connectivity is structured following similar ‘principles of connectivity’ at the neuronal and macroscale level, and provide a framework to study connectivity changes in brain conditions at multiple levels of brain organization.
Drought restricted sucrose transport from outer cottonseed coat to fiber and further inhibited cellulose synthesis during cotton fiber thickening
Authors: Zhu Honghai , Hu Wei , Li Yuxia , Zou Jie , He Jiaqi , Wang Youhua , Meng Yali , Chen Binglin , Zhao Wenqing , Wang Shanshan , Zhou Zhiguo
Published: September 2021

The formation of cotton fiber strength largely relies on continuous and steady sucrose supply to cellulose synthesis and is greatly impaired by drought. However, the effects of drought on sucrose import into fiber and its involvement in cellulose biosynthesis within fiber remain unclear. To end this, moisture deficiency experiments were conducted using two Gossypium hirsutum cultivars of Dexiamian 1 (drought-tolerant) and Yuzaomian 9110 (drought-sensitive). Fiber strength was significantly decreased under drought. The results of 13C isotope labeling indicated that drought notably reduced sucrose efflux from cottonseed coat to fiber, and this was caused by down-regulation of sucrose transporter genes (GhSWEET10 and GhSWEET15) in the outer cottonseed coat, finally leading to decreased sucrose accumulation in fiber. Further, under drought, the balance of sucrose allocation within fiber was disrupted by increasing the flow of sucrose into β-1,3-glucan synthesis and lignin synthesis but hindering that into cellulose synthesis in both cultivars. Additionally, glycolysis and starch synthesis were specifically enhanced by drought in Yuzaomian 9110, which further reduced the flow of sucrose into cellulose synthesis. Under drought, the cellulose deposition was decreased due to promoted cellulose degrading process in Dexiamian 1 and stunted cellulose synthesis in Yuzaomian 9110. Consequently, reduced cellulose content was measured in drought-stressed fibers for both cultivars. In summary, the inhibited cellulose accumulation caused by drought was mainly due to reduced sucrose translocation from the outer cottonseed coat to fiber, and less sucrose partitioned to cellulose synthesis pathway under the condition of intensified competition for sucrose by different metabolic pathways within fiber, finally degrading the fiber strength.

Highlight

This article revealed the path of sucrose flow from cottonseed coat to cotton fiber and sucrose competition patterns within cotton fiber under drought and their relationships with fiber strength loss.
Structural basis for mismatch surveillance by CRISPR/Cas9
Authors: Bravo Jack P. K. , Liu Mu-Sen , McCool Ryan S. , Jung Kyungseok , Johnson Kenneth A. , Taylor David W.
Published: September 2021

The widespread use of CRISPR/Cas9 as a programmable genome editing tool has been hindered by off-target DNA cleavage (Cong et al., 2013; Doudna, 2020; Fu et al., 2013; Jinek et al., 2013). While analysis of such off-target editing events have enabled the development of Cas9 variants with greater discrimination against mismatches (Chen et al., 2017; Kleinstiver et al., 2016; Slaymaker et al., 2016), the underlying molecular mechanisms by which Cas9 rejects or accepts mismatches are poorly understood (Kim et al., 2019; Liu et al., 2020; Slaymaker and Gaudelli, 2021). Here, we used kinetic analysis to guide cryo-EM structure determination of Cas9 at different stages of mismatch surveillance. We observe a distinct, previously undescribed linear conformation of the duplex formed between the guide RNA (gRNA) and DNA target strand (TS), that occurs in the presence of PAM-distal mismatches, preventing Cas9 activation. The canonical kinked gRNA:TS duplex is a prerequisite for Cas9 activation, acting as a structural scaffold to facilitate Cas9 conformational rearrangements necessary for DNA cleavage. We observe that highly tolerated PAM-distal mismatches achieve this kinked conformation through stabilization of a distorted duplex conformation via a flexible loop in the RuvC domain. Our results provide molecular insights into the underlying structural mechanisms that may facilitate off-target cleavage by Cas9 and provides a molecular blueprint for the design of next-generation high fidelity Cas9 variants that selectively reduce off-target DNA cleavage while retaining efficient cleavage of on-target DNA.