bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Characterization of Aminopeptidase N 1 Gene of the Indian Malaria Vector Anopheles culicifacies (Diptera: Culicidae)
Authors: Jakhar Renu , Gakhar Surendra Kumar
Published: March 2021

Aminopeptidase N1 (APN) is one of the important enzymes involved in blood digestion and is up-regulated along with several other enzymes in response to bloodmeal ingestion. APN is a zinc metalloprotease that cleaves one amino acid residue at a time from the amino terminus of the protein. The APN1 gene of the Indian malaria vector Anopheles culicifacies Giles was cloned and characterized. The An. culicifacies APN1 (AcAPN1) gene has an Open Reading Frame of 3084 basepairs which encodes a putative protein of 1027 amino acids. The coding region of the gene shares 81% and 78% similarity to the APN1 genes found in An. stephensi (Diptera: Culicidae) and An. gambiae (Diptera: Culicidae), respectively. The organization of the APN1 gene was studied in available mosquito genomes and a three-dimensional structure of AcAPN1 modeled using homology structure modeling. The enzymatic active site was predicted to consist of HEYAH and GAMEN amino acid residues, and a comparison of the protein sequences among different genera revealed the conservation of zinc-binding residues. The expression pattern of AcAPN1 showed that the gene was expressed rapidly in response to the ingestion of the bloodmeal and therefore this gene may be used to exploit its promoter region as an antiparasite candidate molecule.
Does It Pay to Conduct Midrotation Competition Control and/or Fertilization? Results from Two Thinned Loblolly Pine Studies in the Coastal Plain of Georgia
Authors: Li Yanshu , Dickens E David , Sault Matthew , Siry Jacek P , Izlar Robert L , Clabo David C , Tyson William G
Published: March 2021

The effects of midrotation competition control and fertilization were studied in two loblolly pine stands in the Coastal Plain of Georgia. The use of fertilizer or herbicide alone did not enhance wood yields above the control, which negates the cost spent to conduct these practices. The combined treatment of fertilization and herbicide promoted higher average pine annual increment and greater proportion of sawtimber. Site limiting factors, most likely both competing woody vegetation and low nutrient status, largely determined the effectiveness and priority of midrotation treatments. The economic returns of the combined treatment varied considerably depending on stumpage prices, treatment costs, and magnitude and duration of the growth response. Sawtimber prices (absolute value and relative to pulpwood and chip-n-saw) play a critical role in the marginal returns of midrotation treatments. Continued depressed sawtimber prices will discourage private landowners from investing in midrotation vegetation control and fertilization.
Sustainability and complexity: Knowledge and authority in the digital humanities
Authors: Drucker Johanna
Published: March 2021

Concepts of sustainability touch every aspect of scholarly work and are particularly urgent in thinking about those practices that depend on digital technology. The costs of digital scholarship are frequently posed in terms of human labor and rights abuses, ecological and environmental damage, carbon footprints, waste of resources associated with obsolescence, and other issues that affect every stage of the lifecycle of production. But sustainability also needs to be understood as an epistemic concept embedded in complex systems, not merely as a set of problems to be solved through instrumental means applied to operational logistics. This article addresses mechanistic approaches to sustainability, while suggesting that the complexity of the concept of sustainability requires the humanistic methods and ethical principles to be engaged in decisions about future practices in pedagogy, research, and institutional sites.
Observational manifestations of ‘cosmological dinosaurs’ at redshifts z ∼ 20
Authors: Dubrovich V K , Eroshenko Yu N , Grachev S I
Published: March 2021

We consider a primordial black hole of very high mass, $10^9\!-\!10^{10}\, \mathrm{M}_\odot$, surrounded by the dark matter and bayonic halo at redshifts z ∼ 20 without any local sources of energy release. Such heavy and concentrated objects in the early Universe were previously called ‘cosmological dinosaurs’. Spectral distribution and spatial variation of the brightness in the 21-cm line of atomic hydrogen are calculated with the theory of radiation transfer. It is shown that a narrow and deep absorption arises in the form of the spherical shell around the primordial black hole at the certain radius. The parameters of this shell depend almost exclusively on the mass of the black hole. The angular diameter 18 arcsec of the absorption ring at z ∼ 20 is well within the current technical possibilities of the Square Kilometre Array type telescopes. But the observation of the ring width itself requires an order of magnitude better resolution.
How to empirically model star formation in dark matter haloes – I. Inferences about central galaxies from numerical simulations
Authors: Chen Yangyao , Mo H J , Li Cheng , Wang Kai
Published: March 2021

We use TNG and EAGLE hydrodynamic simulations to investigate the central galaxy–dark matter halo relations that are needed for a halo-based empirical model of star formation in galaxies. Using a linear dimension reduction algorithm and a model ensemble method, we find that for both star-forming and quenched galaxies, the star formation history (SFH) is tightly related to the halo mass assembly history (MAH). The quenching of a low-mass galaxy is mainly due to the infall-ejection process related to a nearby massive halo, while the quenching of a high-mass galaxy is closely related to the formation of a massive progenitor in its host halo. The classification of star-forming and quenched populations based solely on halo properties contains contamination produced by sample imbalance and overlapping distributions of the two populations. Guided by the results from hydrodynamic simulations, we build an empirical model to predict the SFH of central galaxies based on the MAH of their host haloes, and we model the star-forming and quenched populations separately. Our model is based on the idea of adopting star formation templates from hydrodynamic simulations to reduce model complexity. We use various tests to demonstrate that the model can recover SFHs of individual galaxies, and can statistically reproduce the galaxy bimodal distribution, stellar mass–halo mass and star formation rate–halo mass relations from low to high redshift, and assembly bias. Our study provides a framework of using hydrodynamic simulations to discover, and to motivate the use of, key ingredients to model galaxy formation using halo properties.
Genome Sequence Resource of Phytophthora vignae, the Causal Agent of Stem and Root Rot of Cowpea
Authors: Yang Chengdong , Lin Lianyu , Bao Jiandong , Wang Zhixin , Li Zhiting , Guo Hengyuan , Lv Lin , Yu Dan , Chen Qinghe
Published: March 2021

The causal agent of stem and root rot of cowpea, Phytophthora vignae, is a widely distributed species of the Phytophthora genus. Here, we generate a high-quality complete genome assembly of P. vignae PSY2020 (89.39 Mb, N50 2.99 Mb) from China, using Oxford Nanopore Technologies (ONT) sequencing. The genome assembly completeness as evaluated by benchmarking universal single-copy orthologs was 94.51% at the eukaryote level. We identified 42.54% as repeat sequences and a total of 20,536 protein-encoding genes, of which 15,184 genes could be annotated. And we also identified 924 candidate RXLR effectors in the genome assembly. The described genome sequence will provide a valuable resource for better understanding of pathogenicity mechanisms of P. vignae and help in uncovering phylogenetical classification of Phytophthora species.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2021.
Antifungal Activity and Possible Mode of Action of Ningnanmycin Against Tea Gray Blight Disease Pathogen Pseudopestalotiopsis camelliae-sinensis
Authors: Yang Rui , Jiang Shilong , Wen Xiaodong , Song Xingchen , Wang Xue , Li Dongxue , Yin Qiaoxiu , Wu Xian , Wang Delu , Chen Zhuo
Published: March 2021

Gray blight is a serious disease of tea (Camellia sinensis) for which there is currently no effective control or preventive measure apart from fungicides. Screening for effectiveness of a natural antimicrobial against this pathogen and identifying its mode of action could contribute to the management of this disease. Antifungal activity of the antimicrobial ningnanmycin (NNM) from Streptomyces noursei var. xichangensis against the pathogen causing gray blight disease, Pseudopestalotiopsis camelliae-sinensis strain GZHS-2017-010, was confirmed in vitro by the mycelial growth rate method. Optical microscopy, scanning electron microscopy, and transmission electron microscopy were used to observe morphological changes in hyphae of P. camelliae-sinensis treated with NNM. RNA sequencing, bioinformatics, and quantitative real-time PCR were used to identify genes in the hyphae that were differentially expressed in response to treatment with NNM. Thirty-eight genes from 16 pathways, known as targets of antifungal agents, were used to investigate gene expression in hyphae at the half-maximal effective concentration (EC50), EC30, and EC70 for 1, 7, or 14 h. The results indicated that NNM can inhibit the growth of hyphae in vitro, with an EC50 of 75.92 U/ml, inducing morphological changes in organelles, septa, and extracellular polysaccharides, targeting ribosomes to disturb translation in protein synthesis and influencing some biosynthetic functions of the hyphae.
Comparison of pulse wave analysis parameters by oscillometry in hypertensive diabetic and nondiabetic patients in a Brazilian outpatient care
Authors: Resende Luiz Antonio Pertili Rodrigues , Silva Marco Antonio Vieira , Resende José Augusto Mantovani , Resende Elisabete Aparecida Mantovani Rodrigues , Silva Valdo José Dias , Correia Dalmo
Published: March 2021

Introduction:

Pulse wave analysis is an emerging approach that analyzes parameters comprising strong predictors of cardiovascular (CV) events and all-cause mortality, especially in patients with high CV risk based on established risk factors. This study used the oscillometric method, provided by the Mobil-o-Graph (PWA-EMI GmbH, Stolberg, Germany) device, to compare data regarding the pulse wave analysis parameters in hypertensive nondiabetic and diabetic patients.

Material and methods:

In this cross-sectional study, 276 individuals were examined in the academic hypertension outpatient care unit of the Federal University of the Triângulo, in Mineiro, Brazil, from January to December 2016. The pulse wave analysis was performed by oscillometry, and its parameters were acquired from all patients.

Results:

Of the 276 patients, 99 were diabetic and 177 nondiabetic. The mean systolic and pulse central blood pressure were significantly higher in diabetic patients than in nondiabetic patients (P = .008 and.0003, respectively). The mean peripheral systolic blood pressure and pulse pressure were also significantly higher in the diabetic group (P = .001 and P < .0001, respectively). The average pulse wave velocity (PWV, m/s) was 9.4 ± 1.6 and 8.8 ± 1.6 in the diabetic and nondiabetic groups, respectively (P = .003).

Conclusion:

The group of hypertensive diabetic patients had significantly higher central blood pressure, peripheral blood pressure, and PWV than the hypertensive nondiabetic patients. The patients with overlapping established CV risk factors presented values of the pulse wave analysis parameters consistent with higher central pressure and greater arterial stiffness.
Terbinafine Hydrochloride Combined With Itraconazole for Fungal Skin Diseases: A Randomized Controlled Trial
Authors: Zhang Dongxing , Liao Wanqing , Chen Canhua , Lai Hongtao , Liu Shi
Published: March 2021

Background:

Terbinafine and itraconazole are the common antifungal drugs in clinic. In vitro experiments proved that terbinafine combined with itraconazole achieves better antifungal effects. However, clinical study addressing this issue was still scarce.

Study Question:

Terbinafine combined with itraconazole achieves better therapeutic effects in fungal skin diseases.

Study Design:

Approximately 178 patients with fungal skin diseases from Meizhou People's Hospital, China, between October 2016 and October 2017 were admitted to this study. Patients were randomly distributed to 3 groups by randomly selecting random numbers and were treated with terbinafine, itraconazole, monotherapy, or combined therapy. Both patients and study investigators were unaware of grouping situations during experiments. Fifteen patients were excluded due to poor compliance, and 11 patients were excluded due to incomplete data. Finally, 152 patients were analyzed for this study.

Measures and Outcomes:

The therapeutic effects were evaluated by clinic symptom scores, mycology examination, the cure rate, and the cure time. Adverse events, relapse of disease, and patient's satisfaction level were recorded during follow-up.

Results:

In the terbinafine + itraconazole group, at 14 days after treatment, the symptom scores were significantly decreased, compared with the terbinafine or itraconazole group (P
1 < 0.05, P
2 < 0.05). At 28 days after treatment, the fungal infection of 37 patients was eradicated, which were significantly more than 26 patients in the terbinafine group and 19 patients in the itraconazole group (P
1 < 0.05, P
2 < 0.05). The terbinafine + itraconazole group also exhibited 100% cure rate of patients with fungal skin diseases, shorter cure time, and increased number of cured patients during the same treatment period, which was better than terbinafine or itraconazole monotherapy (P
1 < 0.05, P
2 < 0.05). In addition, no adverse events and no relapse of fungal disease were reported in the terbinafine + itraconazole group during follow-up. Ninety-eight percent patients were satisfied with the therapeutic effects of combined treatment.

Conclusions:

Compared with terbinafine or itraconazole monotherapy, terbinafine + itraconazole combined treatment achieves better therapeutic effects in fungal skin diseases.
A Review of Acute Respiratory Distress Syndrome Management and Treatment
Authors: Hasan Zubair
Published: March 2021

Background:

Acute respiratory distress syndrome (ARDS) was first described in 1967, but its definition has evolved considerably since then. ARDS is defined as the onset of hypoxemia, tachypnea, and loss of lung compliance due to some stimulus. In the United States, the incidence of ARDS has been growing because it is being increasingly recognized. The incidence of ARDS has also gone up recently due to the COVID-19 pandemic.

Areas of Uncertainty:

To date, there is no known one treatment for ARDS. Multiple studies have looked into various causes of ARDS, pathophysiology, and ventilation and management strategies. However, there is still considerable variability in the treatment and management of these patients from institution to institution.

Data Sources:

A literature search was conducted through PubMed and Google Scholar. Publications describing the epidemiology, diagnostic criteria, pathophysiology, and treatment were included in this review.

Results:

The definition of ARDS has evolved over the years. The most recent and agreed upon diagnostic criteria are based on the Berlin criteria for ARDS. Management of patients with ARDS includes low tidal volume ventilation, prone ventilation, paralysis in certain patient populations, and perhaps extracorporeal membrane oxygenation (ECMO). This also applies to patients with ARDS due to COVID-19.

Conclusions:

Patients with ARDS have a high mortality due to the incredibly complex disease process. Because of the complexity of ARDS, the management and treatment is equally as difficult. This article reviews some of the strategies used to date, including the role of ECMO, and includes some society recommendations. Further research must be done into which methods best guide lung ventilation in severe ARDS and patients on ECMO.
Interventional Pulmonology: Diagnostic and Therapeutic Advances in Bronchoscopy
Authors: Agrawal Abhinav
Published: March 2021

Background:

Interventional pulmonology is a rapidly evolving subspecialty of pulmonary medicine that offers advanced consultative and procedural services to patients with airway diseases, pleural diseases, as well as in the diagnosis and management of patients with thoracic malignancy.

Areas of Uncertainty:

The institution of lung cancer screening modalities as well as the search of additional minimally invasive diagnostic and treatment modalities for lung cancer and other chronic lung diseases has led to an increased focus on the field of interventional pulmonology. Rapid advancements in the field over the last 2 decades has led to development of various new minimally invasive bronchoscopic approaches and techniques for patients with cancer as well as for patients with chronic lung diseases.

Data Sources:

A review of literature was performed using PubMed database to identify all articles published up till October 2020 relevant to the field of interventional pulmonology and bronchoscopy. The reference list of each article was searched to look for additional articles, and all relevant articles were included in the article.

Therapeutic Advances:

Newer technologies are now available such navigation platforms to diagnose and possibly treat peripheral pulmonary nodules, endobronchial ultrasound in diagnosis of mediastinal and hilar adenopathy as well as cryobiopsy in the diagnosis of diffuse lung diseases. In addition, flexible and rigid bronchoscopy continues to provide new and expanding ability to manage patients with benign and malignant central airway obstruction. Interventions are also available for diseases such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, and emphysema that were traditionally treated with medical management alone.

Conclusions:

With continued high quality research and an increasing body of evidence, interventional bronchoscopy has enormous potential to provide both safe and effective options for patients with a variety of lung diseases.
Early estimates of SARS-CoV-2 B.1.1.7 variant emergence in a university setting
Authors: Johnson Kaitlyn E. , Woody Spencer , Lachmann Michael , Fox Spencer J. , Klima Jessica , Hines Terrance S. , Meyers Lauren Ancel
Published: March 2021

Recent identification of the highly transmissible novel SARS-CoV-2 variant in the United Kingdom (B.1.1.7) has raised concerns for renewed pandemic surges worldwide 1,2. B.1.1.7 was first identified in the US on December 29, 2020 and may become dominant by March 2021 3. However, the regional prevalence of B.1.1.7 is largely unknown because of limited molecular surveillance for SARS-CoV-2 4. Quantitative PCR data from a surveillance testing program on a large university campus with roughly 30,000 students provides local situational awareness at a pivotal moment in the COVID-19 pandemic.
Structural Analysis of Spike Protein Mutations in the SARS-CoV-2 P.3 Variant
Authors: Bascos Neil Andrew D. , Mirano-Bascos Denise , Saloma Cynthia P.
Published: March 2021

A SARS-CoV-2 lineage designated as P.3 with multiple signature mutations in the Spike protein region was recently reported with cases from the Central Visayas Region of the Philippines. Whole genome sequencing revealed that the 33 samples under this lineage all contain the E484K, N501Y, and P681H Spike mutations previously found in variants of concern (VOC) such as the B.1.351, the P.1 and B.1.1.7 variants first reported in South Africa, Brazil, and the United Kingdom, respectively. The possible implications of the mutations found in the Spike protein of P.3 were analyzed for their potential effects on structure, stability, and molecular surface character. The analysis suggests that these mutations could significantly impact the possible interactions of the Spike protein with the ACE2 receptor and neutralizing antibodies, and warrants further clinical investigation. Some of the mutations affecting the N and C terminal domains may have effects on Spike monomer and trimer stability. This report provides insights on relevant targets for the design of future diagnostics, therapeutics and vaccines against the evolving SARS-CoV-2 variants in the Philippines.
Protocol for disease-oriented Russian disc degeneration study (RuDDS) biobank facilitating functional omics studies of lumbar disc degeneration
Authors: Leonova Olga N. , Elgaeva Elizaveta E. , Golubeva Tatiana S. , Peleganchuk Alexey V. , Krutko Aleksandr V. , Aulchenko Yurii S. , Tsepilov Yakov A.
Published: March 2021

Introduction

Lumbar intervertebral disc degeneration (DD) disease is one of the main risk factors for low back pain. The social and economic importance of low back pain is very high: back pain is among the leading causes of absenteeism and the cost of treating back pain exceeds the cost of treatment of many other serious diseases (cancer, in particular); however, therapy does not always provide the desired result. Despite the variability of biological studies of lumbar DD, it is still not fully understood, partially due to the fact that there are only few studies using systematic and integrative approaches. Hence, more integrative omics studies are needed to link all pieces of knowledge together, build a complete picture of biology of lumbar DD and obtain a deeper understanding of the processes underlying this pathology.

Methods and analysis

This disease-oriented biobank to study lumbar disc degeneration will be recruited from two clinical centers. A total of 1100 participants with available lumbar MRI will be enrolled during the three-year period. General information about a patient, medical history, lumbar MRI parameters and biological material (whole blood and plasma) will be collected in the centers at baseline. Then, from those patients, who will undergo a spine surgery during the treatment, disc tissue samples will be gained. Eventually, postoperative clinical data will be collected from operated patients during the follow-up.

Ethics and dissemination

The study will be performed according to the Helsinki Declaration. The study protocol was approved by the Local Ethical Committee of NRITO (№034/20 dated 02 Oct 2020) and by the Local Ethical Committee of Priorov CITO (№1/21 dated 25 Feb 2021). Preliminary and final results will be presented in peer-reviewed journals, at national and international congresses.

Trial registration number

NCT04600544

ARTICLE SUMMARY

STRENGTHS AND LIMITATIONS OF THIS STUDY

Two-center and multiple-discipline study: the study includes two centers (Moscow in the European and Novosibirsk in the Asian part of Russia), with research teams specializing in following fields: (1) clinical aspects of lumbar disc degeneration disease, (2) biology and genetics of pain, (3) generation of omics data and (4) multi-omics data analysis

Collection of variable biological material: whole blood, plasma and, for part of the participants, intraoperative material of the lumbar disc (with different DD status) will be available for omics studies

Objective diagnosis: lumbar DD status is confirmed by MRI, not self-reported diagnosis

Sample size is limited compared to nationwide biobanks

Patients with severe lumbar DD status will be more prevalent in the biobank than these with mild or no lumbar DD compared to the general population
Uterine fluid transcriptome as potential non-invasive biomarker for predicting endometrial receptivity
Authors: He Aihua , Wu Hong , Zou Yangyun , Wan Cheng , Zhao Jing , Zhang Qiong , Liu Nenghui , Liu Donge , Li Yumei , Fu Jing , Li Hui , Huang Xi , Yang Tianli , Hu Chunxu , Hou Zhaojuan , Sun Yue , Dong Xin , Wu Jian , Lu Sijia , Li Yanping
Published: March 2021

Background

The synchrony between the embryo and the receptive endometrium is essential for successful implantation. Therefore, a reliable non-invasive ER prediction method is highly demanded. We aimed to establish a method that could be used to predict endometrium receptivity non-invasively and to evaluate its clinical application potential in patients undergoing IVF.

Methods

The non-invasive RNA-seq based endometrial receptivity test (nirsERT) was established by sequencing and analyzing the RNA of uterine fluid from 48 IVF patients with normal ER. Subsequently, 22 IVF patients were recruited and analyzed the correlation between the predicted results of nirsERT and pregnancy outcomes.

Results

87 marker genes and 3 hub genes were selected to establish the nirsERT. 10-fold cross-validation resulted in a mean accuracy of 93.0%. A small cohort retrospective observation showed that 77.8% (14/18) of IVF patients predicted with normal WOI had successful intrauterine pregnancies, while none of the 3 patients with displaced WOI had successful pregnancy.

Conclusions

nirsERT is potential for a non-invasive, accurate and same cycle testing for ER in reproductive clinic.

Funding

Funded by the National Natural Science Foundation of China (grant no. 8187061497) and the National Key Research and Developmental Program of China (grant no. 2018YFC1004800).

Clinical trial number

ChiCTR-DDD-17013375.
Performance and Operational Evaluation of the Access Bio CareStart Rapid Antigen Test in a High-throughput Drive-through Community Testing Site in Massachusetts
Authors: Pollock Nira R. , Tran Kristine , Jacobs Jesica R. , Cranston Amber E. , Smith Sita , O’Kane Claire Y. , Roady Tyler J. , Moran Anne , Scarry Alison , Carroll Melissa , Volinsky Leila , Perez Gloria , Patel Pinal , Gabriel Stacey , Lennon Niall J. , Madoff Lawrence C. , Brown Catherine , Smole Sandra C.
Published: March 2021

Background

To facilitate deployment of point-of-care testing for SARS-CoV-2, we evaluated the Access Bio CareStart COVID-19 Antigen test in a high-throughput, drive-through, free community testing site using anterior nasal (AN) swab RT-PCR for clinical testing.

Methods

Consenting symptomatic and asymptomatic children (≤18 years) and adults received dual AN swabs. CareStart testing was performed with temperature/humidity monitoring. All tests had two independent reads to assess inter-operator agreement. Patients with positive CareStart results were called and instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.

Results

Of 1603 participants, 1245 adults and 253 children had paired RT-PCR/CareStart results and complete symptom data. 83% of adults and 87% of children were asymptomatic. CareStart sensitivity/specificity were 84.8% (95% confidence interval [CI] 71.1-93.7)/97.2% (92.0-99.4) and 85.7% (42.1-99.6)/89.5% (66.9-98.7) in adults and children, respectively, within 5 days of symptoms. Sensitivity/specificity were 50.0% (41.0-59.0)/99.1% (98.3-99.6) in asymptomatic adults and 51.4% (34.4-68.1)/97.8% (94.5-99.4) in asymptomatic children. Sensitivity in all 234 RT-PCR-positive people was 96.3% with cycle threshold (Ct) ≤25, 79.6% with Ct ≤30, and 61.4% with Ct ≤35. All 21 false positive CareStart tests had faint but normal bands. Inter-operator agreement was 99.5%. Operational challenges included identification of faint test bands and inconsistent swab elution volumes.

Conclusions

CareStart had high sensitivity in people with Ct ≤25 and moderate sensitivity in symptomatic people overall. Specificity was unexpectedly lower in symptomatic versus asymptomatic people. Excellent inter-operator agreement was observed, but operational challenges indicate that operator training is warranted.
Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers – a Danish cohort study
Authors: Moustsen-Helms Ida Rask , Emborg Hanne-Dorthe , Nielsen Jens , Nielsen Katrine Finderup , Krause Tyra Grove , Mølbak Kåre , Møller Karina Lauenborg , Berthelsen Ann-Sofie Nicole , Valentiner-Branth Palle
Published: March 2021

Background

At the end of 2020, Denmark launched an immunization program against SARS-CoV-2. The Danish health authorities prioritized persons currently living in long-term care facilities (LTCF residents) and frontline healthcare workers (HCW) as the first receivers of vaccination. Here we present preliminary population based vaccine effectiveness (VE) estimates in these two target groups.

Methods

The study was designed as a retrospective registry- and population-based observational cohort study including all LTCF residents and all HWC. The outcome was a polymerase chain reaction confirmed SARS-CoV-2, and VE was estimated for different periods following first and second dose. We used Poisson and Cox regressions to estimate respectively crude and calendar time-adjusted VE for the BNT162b2 mRNA Covid-19 Vaccine from Pfizer/BioNTech with 95% confidence intervals (CI) for vaccinated versus unvaccinated.

Results

A total of 39,040 LTCF residents (median age at first dose; 84 years, Interquartile range (IQR): 77-90) and 331,039 HCW (median age at first dose; 47 years, IQR: 36-57) were included. Among LTCF residents, 95.2% and 86.0% received first and second dose from 27 December 2020 until 18 February 2021, for HWC the proportion was 27.8% and 24.4%. During a median follow-up of 53 days, there were 488 and 5,663 confirmed SARS-CoV-2 cases in the unvaccinated groups, whereas there were 57 and 52 in LTCF residents and HCW within the first 7 days after the second dose and 27 and 10 cases beyond seven days of second dose. No protective effect was observed for LTCF residents after first dose. In HCW, VE was 17% (95% CI; 4-28) in the > 14 days after first dose (before second dose). Furthermore, the VE in LTCF residents at day 0-7 of second dose was 52% (95% CI; 27-69) and 46% (95% CI; 28-59) in HCW. Beyond seven days of second dose, VE increased to 64% (95% CI; 14-84) and 90% (95% CI; 82-95) in the two groups, respectively.

Conclusion

The results were promising regarding the VE both within and beyond seven days of second vaccination with the BNT162b2 mRNA Covid-19 Vaccine currently used in many countries to help mitigate the global SARS-CoV-2 pandemic.

Impact of the research

So far, observational studies of the real-word effectiveness of the mRNA Vaccine BNT162b2 has been limited to the period after the administration of the first dose. This is the first report to date to present vaccine effectiveness (VE) estimates after the second BNT162b2 mRNA Covid-19 Vaccine. We estimated a VE of 52% and 46% in LTCF residents and HCW within seven days, which increased to 64% and 90% in the two groups respectively beyond seven days of immunization. These findings supports maintaining a two-dose schedule of the BNT162b2 mRNA Covid-19 Vaccine.
Transmission of SARS-CoV-2 by children to contacts in schools and households: a prospective cohort and environmental sampling study in London
Authors: Cordery Rebecca , Reeves Lucy , Zhou Jie , Rowan Aileen , Watber Patricia , Rosadas Carolina , Crone Michael , Storch Marko , Freemont Paul , Mosscrop Lucy , Cowley Alice , Zelent Gina , Bisset Kate , Blond Holly Le , Regmi Sadie , Buckingham Christian , Junaideen Ramlah , Abdulla Nadia , Eliahoo Joseph , Mindlin Miranda , Lamagni Theresa , Barclay Wendy , Taylor Graham P. , Sriskandan Shiranee
Published: March 2021

Background

Assessing transmission of SARS-CoV-2 by children in schools is of critical importance to inform public health action. We assessed frequency of acquisition of SARS-CoV-2 by contacts of children with COVID-19 in schools and households, as well as the amount of virus shed into the air and onto fomites in both settings.

Methods

Cases of COVID-19 in children in London schools were identified via notification. Weekly sampling for 3-4 weeks and PCR testing for SARS-CoV-2 of immediate classroom contacts (the “bubble”), non-bubble school contacts, and household contacts was undertaken supported by genome sequencing, along with surface and air sampling in the school and home environment.

Results

Within schools, secondary transmission was not detected in 28 individual bubble contacts, representing 10 distinct bubble classes. Across 8 non-bubble classes, 3/62 pupils tested positive– all three were asymptomatic and tested positive in one setting on the same day, unrelated to the original index case. In contrast, the secondary attack rate in naïve household contacts was 14.3% (5/35) rising to 19.1% (9/47) when considering all household contacts. Environmental contamination with SARS-CoV-2 was rare in schools, regardless of school type; fomite SARS-CoV-2 RNA was identified in 4/189 (2.1%) samples in bubble classrooms, 2/127 (1.6%) samples in non-bubble classrooms, and 5/130 (3.8%) samples in washrooms. This contrasted with fomites in households, where SARS-CoV-2 RNA was identified in 60/248 (24.2%) bedroom samples, 66/241 (27.4%) communal room samples, and 21/188 (11.2%) bathroom samples. Air sampling identified SARS-CoV-2 RNA in just 1/68 (1.5%) of school air samples, compared with 21/85 (24.7%) of air samples taken in homes.

The low levels of environmental contamination in schools are consistent with low transmission frequency and adequate levels of cleaning and ventilation in schools during the period of study. Secondary transmission in schools was rare. The high frequency of secondary transmission in households associated with evident viral shedding throughout the home suggests a need to improve advice to households with infection in children in order to prevent onward community spread by sibling and adult contacts. The data highlight that transmission from children is very likely to occur when precautions are reduced.
Localization of muscarinic acetylcholine receptor dependent rhythm generating modules in theDrosophilalarval locomotor network
Authors: Jonaitis Julius , MacLeod James , Pulver Stefan R.
Published: March 2021

Mechanisms of rhythm generation have been extensively studied in motor systems that control locomotion over terrain in limbed animals; however, much less is known about rhythm generation in soft-bodied terrestrial animals. Here we explored how muscarinic acetylcholine receptor (mAChR) dependent rhythm generating networks are distributed in the central nervous system (CNS) of soft-bodiedDrosophilalarvae. We measured fictive motor patterns in isolated CNS preparations using a combination of Ca2+imaging and electrophysiology while manipulating mAChR signalling pharmacologically. Bath application of the mAChR agonist oxotremorine potentiated rhythm generation in distal regions of the isolated CNS, whereas application of the mAChR antagonist scopolamine suppressed rhythm generation in these regions. Oxotremorine raised baseline Ca2+levels and potentiated rhythmic activity in isolated posterior abdominal CNS segments as well as isolated anterior brain and thoracic regions, but did not induce rhythmic activity in isolated anterior abdominal segments. Bath application of scopolamine to reduced preparations lowered baseline Ca2+levels and abolished rhythmic activity. These results suggest the presence of a bimodal gradient of rhythmogenicity in the larval CNS, with mAChR dependent rhythm generating networks in distal regions separated by medial segments with severely reduced rhythmogenic abilities. This work furthers our understanding of motor control in soft-bodied locomotion and provides a foundation for study of rhythm generating networks in an emerging genetically tractable locomotor system.
Integrative multi-omics profiling reveals cAMP-independent mechanisms regulating hyphal morphogenesis inCandida albicans
Authors: Min Kyunghun , Jannace Thomas F. , Si Haoyu , Veeramah Krishna R. , Haley John D. , Konopka James B.
Published: March 2021

Microbial pathogens grow in a wide range of different morphologies that provide distinct advantages for virulence. In the fungal pathogenCandida albicans, adenylyl cyclase (Cyr1) is thought to be a master regulator of the switch to invasive hyphal morphogenesis and biofilm formation. However, faster growingcyr1Δ/Δ pseudorevertant (PR) mutants were identified that form hyphae in the absence of cAMP. Isolation of additional PR mutants revealed that their improved growth was due to loss of one copy ofBCY1, the negative regulatory subunit of protein kinase (A) from the left arm of chromosome 2. Furthermore, hyphal morphogenesis was improved in some of PR mutants by multigenic haploinsufficiency resulting from loss of large regions of the left arm of chromosome 2, including global transcriptional regulators. Interestingly, hyphal-associated genes were also induced in a manner that was independent of cAMP. This indicates that basal protein kinase A activity is an important prerequisite to induce hyphae, but activation of the cAMP pathway is not needed. Instead, phosphoproteomic analysis indicated that the Cdc28 cyclin-dependent kinase and the casein kinase 1 family member Yck2 play key roles in promoting polarized growth. In addition, integrating transcriptomic and proteomic data reveals hyphal stimuli induce increased production of key transcription factors that contribute to polarized morphogenesis.

AUTHOR SUMMARY

The human fungal pathogenCandida albicansswitches between budding and filamentous hyphal morphologies to gain advantages for virulence and survival in the host. Although adenylyl cyclase has been thought to be a master regulator that controls this switch, we identifiedC. albicanspseudorevertant mutants that grow better and form hyphae in the absence of adenylyl cyclase and cAMP. The mutant cells were also able to induce hyphal-associated genes in the absence of cAMP that are needed for virulence. Integrating information from different omics approaches identified cAMP-independent mechanisms that promote hyphal growth. This includes phosphoproteomic studies that revealed key roles for the Cdc28 cyclin-dependent kinase and casein kinase 1 in promoting hyphal growth. In addition, integrating transcriptomic and proteomic data revealed that post-transcriptional mechanisms regulate the levels of a set of key transcription factors that are important for hyphal induction, suggesting a novel form of translational regulation. These studies better define the pathways that stimulateC. albicansto switch from budding to hyphal growth, which is important for invasion into tissues, escape from the immune system, and biofilm formation.
immuneML: an ecosystem for machine learning analysis of adaptive immune receptor repertoires
Authors: Pavlović Milena , Scheffer Lonneke , Motwani Keshav , Kanduri Chakravarthi , Kompova Radmila , Vazov Nikolay , Waagan Knut , Bernal Fabian L. M. , Costa Alexandre Almeida , Corrie Brian , Akbar Rahmad , Al Hajj Ghadi S. , Balaban Gabriel , Brusko Todd M. , Chernigovskaya Maria , Christley Scott , Cowell Lindsay G. , Frank Robert , Grytten Ivar , Gundersen Sveinung , Haff Ingrid Hobæk , Hochreiter Sepp , Hovig Eivind , Hsieh Ping-Han , Klambauer Günter , Kuijjer Marieke L. , Lund-Andersen Christin , Martini Antonio , Minotto Thomas , Pensar Johan , Rand Knut , Riccardi Enrico , Robert Philippe A. , Rocha Artur , Slabodkin Andrei , Snapkov Igor , Sollid Ludvig M. , Titov Dmytro , Weber Cédric R. , Widrich Michael , Yaari Gur , Greiff Victor , Sandve Geir Kjetil
Published: March 2021

Adaptive immune receptor repertoires (AIRR) are key targets for biomedical research as they record past and ongoing adaptive immune responses. The capacity of machine learning (ML) to identify complex discriminative sequence patterns renders it an ideal approach for AIRR-based diagnostic and therapeutic discovery. To date, widespread adoption of AIRR ML has been inhibited by a lack of reproducibility, transparency, and interoperability. immuneML (immuneml.uio.no) addresses these concerns by implementing each step of the AIRR ML process in an extensible, open-source software ecosystem that is based on fully specified and shareable workflows. To facilitate widespread user adoption, immuneML is available as a command-line tool and through an intuitive Galaxy web interface, and extensive documentation of workflows is provided. We demonstrate the broad applicability of immuneML by (i) reproducing a large-scale study on immune state prediction, (ii) developing, integrating, and applying a novel method for antigen specificity prediction, and (iii) showcasing streamlined interpretability-focused benchmarking of AIRR ML.
Using summary statistics to evaluate the genetic architecture of multiplicative combinations of initially analyzed phenotypes with a flexible choice of covariates
Authors: Wolf Jack , Westra Jason , Tintle Nathan
Published: March 2021

While the promise of electronic medical record and biobank data is large, major questions remain about patient privacy, computational hurdles, and data access. One promising area of recent development is pre-computing non-individually identifiable summary statistics to be made publicly available for exploration and downstream analysis. In this manuscript we demonstrate how to utilize pre-computed linear association statistics between individual genetic variants and phenotypes to infer genetic relationships between products of phenotypes (e.g., ratios; logical combinations of binary phenotypes using ‘and’ and ‘or’) with customized covariate choices. We propose a method to approximate covariate adjusted linear models for products and logical combinations of phenotypes using only pre-computed summary statistics. We evaluate our method’s accuracy through several simulation studies and an application modeling various fatty acid ratios using data from the Framingham Heart Study. These studies show consistent ability to recapitulate analysis results performed on individual level data including maintenance of the Type I error rate, power, and effect size estimates. An implementation of this proposed method is available in the publicly available R package pcsstools.
A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice
Authors: Fowler Alexandra , Sampson Maureen , Remaley Alan T. , Chackerian Bryce
Published: March 2021

Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is potential alternative to other ANGPTL3-inhibiting therapies.

Highlights

ANGPTL3 and ANGPTL4 are mediators of lipoprotein metabolism that inhibit lipoprotein lipase (LPL) activity.

Vaccination using virus-like particles (VLPs) targeting ANGPTL3 and ANGPTL4 elicits high-titer IgG antibody responses.

Immunization with ANGPTL3 VLPs lowers steady-state plasma triglycerides and enhances LPL activity.
Sialic acid-Dependent Binding and Viral Entry of SARS-CoV-2
Authors: Nguyen Linh , McCord Kelli A. , Bui Duong T. , Bouwman Kim M. , Kitova Elena N. , Kumawat Dhanraj , Daskhan Gour C. , Tomris Ilhan , Han Ling , Chopra Pradeep , Yang Tzu-Jing , Willows Steven D. , Mason Andrew L. , Lowary Todd L. , West Lori J. , Hsu Shang-Te Danny , Tompkins S. Mark , Boons Geert-Jan , de Vries Robert P. , Macauley Matthew S. , Klassen John S.
Published: March 2021

Emerging evidence suggests that host glycans influence infection by SARS-CoV-2. Here, we reveal that the receptor-binding domain (RBD) of the spike (S)-protein on SARS-CoV-2 recognizes oligosaccharides containing sialic acid (SA), with preference for the oligosaccharide of monosialylated gangliosides. Gangliosides embedded within an artificial membrane also bind the RBD. The monomeric affinities (Kd= 100-200 μM) of gangliosides for the RBD are similar to heparan sulfate, another negatively charged glycan ligand of the RBD proposed as a viral coreceptor. RBD binding and infection of SARS-CoV-2 pseudotyped lentivirus to ACE2-expressing cells is decreased upon depleting cell surface SA level using three approaches: sialyltransferase inhibition, genetic knock-out of SA biosynthesis, or neuraminidase treatment. These effects on RBD binding and pseudotyped viral entry are recapitulated with pharmacological or genetic disruption of glycolipid biosynthesis. Together, these results suggest that sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2.
Multiphasic value biases in fast-paced decisions
Authors: Corbett Elaine A. , Martinez-Rodriguez L. Alexandra , Judd Cian , O’Connell Redmond G. , Kelly Simon P.
Published: March 2021

Perceptual decisions are biased toward higher-value options when overall gains can be improved. When stimuli demand immediate reactions, the neurophysiological decision process dynamically evolves through distinct phases of growing anticipation, detection and discrimination, but how value biases are exerted through these phases remains unknown. Here, by parsing motor preparation dynamics in human electrophysiology, we uncovered a multiphasic pattern of countervailing biases operating in speeded decisions. Anticipatory preparation of higher-value actions began earlier, conferring a “starting point”-advantage at stimulus onset, but the delayed preparation of lower-value actions was steeper, conferring a value-opposed buildup rate bias. This, in turn, was countered by a transient deflection toward the higher value action evoked by stimulus detection. A neurally-constrained process model featuring anticipatory urgency, biased detection, and accumulation of growing stimulus-discriminating evidence, successfully captured both behavior and motor preparation dynamics. Thus, an intricate interplay of distinct biasing mechanisms serves to prioritise time-constrained perceptual decisions.