bluuebunny/crossref_metadata_2025 huggingface dataset:
mRNA-1273 vaccination protects against SARS-CoV-2 elicited lung inflammation in non-human primates
Authors: Waickman Adam T. , Victor Kaitlin , Newell Krista , Li Tao , Friberg Heather , Foulds Kathy , Roederer Mario , Bolton Diane L. , Currier Jeffrey R. , Seder Robert
Published: December 2021

Vaccine-elicited SARS-CoV-2 antibody responses are an established correlate of protection against viral infection in humans and non-human primates. However, it is less clear that vaccine-induced immunity is able to limit infection-elicited inflammation in the lower respiratory tract. To assess this, we collected bronchoalveolar lavage fluid samples post-SARS-CoV-2 strain USA-WA1/2020 challenge from rhesus macaques vaccinated with mRNA-1273 in a dose-reduction study. Single-cell transcriptomic profiling revealed a broad cellular landscape 48 hours post-challenge with distinct inflammatory signatures that correlated with viral RNA burden in the lower respiratory tract. These inflammatory signatures included phagocyte-restricted expression of chemokines such asCXCL10(IP10) andCCL3(MIP-1A) and the broad expression of interferon-induced genes such asMX1, ISG15, andIFIT1. Induction of these inflammatory profiles was suppressed by prior mRNA-1273 vaccination in a dose-dependent manner, and negatively correlated with pre-challenge serum and lung antibody titers against SARS-CoV-2 spike. These observations were replicated and validated in a second independent macaque challenge study using the B.1.351/beta-variant of SARS-CoV-2. These data support a model wherein vaccine-elicited antibody responses restrict viral replication following SARS-CoV-2 exposure, including limiting viral dissemination to the lower respiratory tract and infection-mediated inflammation and pathogenesis.

One Sentence Summary

Single cell RNA sequencing analysis demonstrates that mRNA-1273 vaccination limits the development of lower respiratory tract inflammation in SARS-CoV-2 challenged rhesus macaques
SIR model for assessing the impact of the advent of Omicron and mitigating measures on infection pressure and hospitalization needs
Authors: van Wees Jan-Diederik , van der Kuip Martijn , Osinga Sander , Keijser Bart , van Westerloo David , Hanegraaf Maurice , Pluymaekers Maarten , Leeuwenburgh Olwijn , Brunner Logan , van Furth Marceline Tutu
Published: December 2021

Background

On 26 November 2021, the world health organization (WHO) designated the coronavirus SARS-CoV-2 B.1.1.529 a variant of concern, named Omicron (WHO, 2021a). As of December 16, Omicron has been detected in 89 countries (WHO, 2021b). The thread posed by Omicron is highly uncertain.

Methods and findings

For the analysis of the impact of Omicron on infection pressure and hospitalization needs we developed an open-source stochastic SIR (Susceptible-Infectious-Removed) fast-model for simulating the transmission in the transition stage from the prevailing variant (most often Delta) to Omicron. The model is capable to predict trajectories of infection pressure and hospitalization needs, considering (a) uncertainties for the (Omicron) parametrization, (b) pre-existing vaccination and/or partial immunity status of the population, and demographic specific aspects regarding reference hospitalization needs, (c) effects of mitigating measures including social distancing and accelerated vaccination (booster) campaigns.

Conclusions

The SIR model approach yields results in fair agreement with Omicron transmission characteristics observed in South Africa and prognosis results in Europe (UK and Netherlands). The equations underlying the SIR formulation allows to effectively explore the effect of Omicron parametrization on anticipated infection growth rates and hospitalization rates relative to the prevailing variant. The models are online available as open source on GitHub.

One Sentence Summary

fast-model for the impact of Omicron
Cooccurrence of N501Y, P681R and other key mutations in SARS-CoV-2 Spike
Authors: Lee Carol , Mangalaganesh Shruthi , Wilson Laurence O.W. , Kuiper Michael J. , Drew Trevor W. , Vasan Seshadri S.
Published: December 2021

Analysis of circa 4.2 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences on ‘Global Initiative on Sharing All Influenza Data (GISAID)’ shows the spike mutations ‘N501Y’ (common to Alpha, Beta, Gamma, Omicron variants) and ‘P681R’ (central to Delta variant’s spread) have cooccurred 3,678 times between 17 October 2020 and 1 November 2021. In contrast, the N501Y+P681H combination is present in Alpha and Omicron variants and circa 1.1 million entries. Two-thirds of the 3,678 cooccurrences were in France, Turkey or US (East Coast), and the rest across 62 other countries. 55.5% and 4.6% of the cooccurrences were Alpha’s Q.4 and Gamma’s P.1.8 sub-lineages acquiring P681R; 10.7% and 3.8% were Delta’s B.1.617.2 lineage and AY.33 sub-lineage acquiring N501Y; remaining 10.2% were in other variants. Despite the selective advantages individually conferred by N501Y and P681R, the N501Y+P681R combination counterintuitively didn’t outcompete other variants in every instance. Although a relief to worldwide public health efforts, in vitro and in vivo studies are urgently required in the absence of a strong in silico explanation for this phenomenon. This study demonstrates a pipeline to analyse combinations of key mutations from public domain information in a systematic manner and provide early warnings of spread.
The SARS-CoV-2 nucleocapsid protein preferentially binds long and structured RNAs
Authors: Tai Christen E. , Tayeb-Fligelman Einav , Griner Sarah , Salwinski Lukasz , Bowler Jeannette T. , Abskharon Romany , Cheng Xinyi , Seidler Paul M. , Jiang Yi Xiao , Eisenberg David S. , Guo Feng
Published: December 2021

The SARS-CoV-2 nucleocapsid protein (NCAP) functions in viral RNA genome packaging, virion assembly, RNA synthesis and translation, and regulation of host immune response. RNA-binding is central to these processes. Little is known how NCAP selects its binding partners in the myriad of host and viral RNAs. To address this fundamental question, we employed electrophoresis mobility shift and competition assays to compare NCAP binding to RNAs that are of SARS-CoV-2 vs. non-SARS-CoV-2, long vs. short, and structured vs. unstructured. We found that although NCAP can bind all RNAs tested, it primarily binds structured RNAs, and their association suppresses strong interaction with single-stranded RNAs. NCAP prefers long RNAs, especially those containing multiple structures separated by single-stranded linkers that presumably offer conformational flexibility. Additionally, all three major regions of NCAP bind RNA, including the low complexity domain and dimerization domain that promote formation of NCAP oligomers, amyloid fibrils and liquid-liquid phase separation. Combining these observations, we propose that NCAP-NCAP interactions that mediate higher-order structures during packaging also drive recognition of the genomic RNA and call this mechanism recognition-by-packaging. This study provides a biochemical basis for understanding the complex NCAP-RNA interactions in the viral life cycle and a broad range of similar biological processes.

HIGHLIGHTS

NCAP primarily binds structured RNAs.

NCAP prefers multiple RNA structures separated by single-stranded linkers.

NCAP favors binding to long RNAs.
Identification of a novel proteomic Biomarker in Parkinson’s Disease: Discovery and Replication in Blood, brain and CSF
Authors: Winchester Laura , Lawton Michael , Barber Imelda , Ash Jessica , Liu Benjamine , Evetts Samuel , Hopkins-Jones Lucinda , Lewis Suppalak , Bresner Catherine , Vingill Siv , Malpartida Ana Belen , Williams Nigel , Gentlemen Steve , Wade-Martins Richard , Ryan Brent , Holgado-Nevado Alejo , Hu Michele , Ben-Shlomo Yoav , Grosset Donald , Lovestone Simon
Published: December 2021

Biomarkers to aid diagnosis and delineate progression of Parkinson’s Disease (PD) are vital for targeting treatment in the early phases of disease. Here, we aim to discover a multi-protein panel representative of PD and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers.

We used aptamer-based technology (SomaLogic®) to measure proteins in 1,599 serum samples, 85 CSF samples and 37 brain tissue samples collected from two observational longitudinal cohorts (Oxford Parkinson’s Disease Centre and Tracking Parkinson’s) and the PD Brain Bank, respectively. Random forest machine learning was performed to discover new proteins related to disease status and generate multi-protein expression signatures with potential novel biomarkers. Differential regulation analysis and pathway analysis was performed to identify functional and mechanistic disease associations.

The most consistent diagnostic classifier signature was tested across modalities (CSF AUC = 0.74, p-value = 0.0009; brain AUC = 0.75, p-value = 0.006; serum AUC = 0.66, p-value = 0.0002). In the validation dataset we showed that the same classifiers were significantly related to disease status (p-values < 0.001). Differential expression analysis and Weighted Gene Correlation Network Analysis (WGCNA) highlighted key proteins and pathways with known relationships to PD. Proteins from the complement and coagulation cascades suggest a disease relationship to immune response.

The combined analytical approaches in a relatively large number of samples, across tissue types, with replication and validation, provides mechanistic insights into the disease as well as nominating a protein signature classifier that deserves further biomarker evaluation.
Can individuals with suboptimal antibody responses to conventional antiviral vaccines acquire adequate antibodies from SARS-CoV-2 mRNA vaccination?
Authors: Ogura Wataru , Ohtsuka Kouki , Matsuura Sachiko , Okuyama Takahiro , Matsushima Satsuki , Ymasaki Satoko , Miyagi Hiroyuki , Sekiguchi Kumiko , Ohnishi Hiroaki , Watanabe Takashi
Published: December 2021

Objective

In Japan, healthcare workers (HCWs) are vaccinated against contagious viruses (measles, rubella, chickenpox, mumps, and hepatitis B) to prevent nosocomial infection; however, some do not produce sufficient antibodies (suboptimal responders). Whether suboptimal responders to live attenuated viruses or inactivated viruses vaccines can produce adequate antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines remains to be elucidated.

Methods

In this prospective cohort study, SARS-CoV-2 anti-spike antibodies were measured 11 times, from before the first BNT162b2 vaccination to 5 months after the second vaccination. Antibody titers of suboptimal and normal responders were compared. SARS-CoV-2 neutralizing antibody activity was measured twice in suboptimal responders, 1 week to 1 month, and 5 months after the second vaccination.

Patients

This study included 50 HCWs who received two doses of mRNA BNT162b2 vaccine 3 weeks apart.

Results

After vaccination, the SARS-CoV-2 anti-spike antibody was detectable in the samples from suboptimal and normal responders at each timepoint. The median SARS-CoV-2 anti-spike antibody titer was higher in suboptimal responders than in normal responders 1 week after receiving the second dose of BNT162b2 vaccine (3721.0 vs. 2251.5, P=0.029). Suboptimal responders had SARS-CoV-2 neutralizing antibody activity 1 week to 1 month, and 5 months after the second vaccination, which exceeded the positive threshold 5 months after the second vaccination.

Conclusion

After BNT162b2 vaccination, suboptimal responders acquired adequate SARS-CoV-2 anti-spike and SARS-CoV-2 neutralizing antibodies to prevent SARS-CoV-2. These results suggest that vaccination with mRNA vaccine against SARS-CoV-2 should also be recommended for suboptimal responders to conventional vaccines.
SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron
Authors: Keeton Roanne , Tincho Marius B. , Ngomti Amkele , Baguma Richard , Benede Ntombi , Suzuki Akiko , Khan Khadija , Cele Sandile , Bernstein Mallory , Karim Farina , Madzorera Sharon V. , Moyo-Gwete Thandeka , Mennen Mathilda , Skelem Sango , Adriaanse Marguerite , Mutithu Daniel , Aremu Olukayode , Stek Cari , Bruyn Elsa du , Van Der Mescht Mieke A. , de Beer Zelda , de Villiers Talita R. , Bodenstein Annie , van den Berg Gretha , Mendes Adriano , Strydom Amy , Venter Marietjie , Grifoni Alba , Weiskopf Daniela , Sette Alessandro , Wilkinson Robert J. , Bekker Linda-Gail , Gray Glenda , Ueckermann Veronica , Rossouw Theresa , Boswell Michael T. , Bihman Jinal , Moore Penny L. , Sigal Alex , Ntusi Ntobeko A. B. , Burgers Wendy A. , Riou Catherine
Published: December 2021

The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations that contribute to escape from the neutralizing antibody responses, and reducing vaccine protection from infection. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, and in unvaccinated convalescent COVID-19 patients (n = 70). We found that 70-80% of the CD4 and CD8 T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to that of the Beta and Delta variants, despite Omicron harbouring considerably more mutations. Additionally, in Omicron-infected hospitalized patients (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those found in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). These results demonstrate that despite Omicron’s extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell response, induced by vaccination or natural infection, cross-recognises the variant. Well-preserved T cell immunity to Omicron is likely to contribute to protection from severe COVID-19, supporting early clinical observations from South Africa.
NATIONAL SCALE REAL-TIME SURVEILLANCE OF SARS-COV-2 VARIANTS DYNAMICS BY WASTEWATER MONITORING IN ISRAEL
Authors: Bar-Or Itay , Indenbaum Victoria , Weil Merav , Elul Michal , Levi Nofar , Aguvaev Irina , Cohen Zvi , Levy Virginia , Azar Roberto , Mannasse Batya , Shirazi Rachel , Bochris Efrat , Zuckerman Neta S. , Brown Alin Sela , Sofer Danit , Mor Orna , Mendelson Ella , Erster Oran
Published: December 2021

In this report, we describe a national-scale monitoring of the SARS-COV-2 (SC-2) variant dynamics in Israel, using multiple-time sampling of twelve wastewater treatment plants. We used a combination of inclusive and selective quantitative PCR assays that specifically identify variants A19 or B.1.1.7 and tested each sample for the presence and relative viral RNA load of each variant. We show that between December-2020 and March-2021, a complete shift in the SC-2 variant circulation was observed, where the B.1.1.7 replaced the A19 in all examined test points. We further show that the normalized viral load (NVL) values and the average new cases per week reached a peak in January 2021, and then decreased gradually in almost all test points, in parallel with the progression of the national vaccination campaign, during February-March 2021. This study demonstrates the importance of monitoring SC-2 variant dynamics on a national scale through wastewater sampling. It also provides a proof-of-concept methodology for continuous surveillance by using a combination of inclusive and selective PCR tests, which is far more amendable for high throughput monitoring compared with sequencing. This approach may be useful for real-time dynamics surveillance of current and future variants, such as the Omicron (BA.1) variant.

Synopsis

This study describes the continuous monitoring of the SARS CoV-2 variant B.1.1.7 circulation in wastewater in Israel using a positive/negative quantitative PCR assay.
Use of Baricitinib in Treatment of COVID-19: A Systematic Review
Authors: Sampath A , Banerjee A , Atal S , Jhaj R
Published: December 2021

Objectives

To assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19.

Methods

Systematic literature search was conducted in the WHO COVID-19 Coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1st 2019 and September 30th 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, and relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools.

Results

A total of 267 articles were found to be eligible after primary screening of title and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add on to standard therapy, either alone or in combination with other drugs, was found to have favourable outcomes in moderate to severe hospitalised patients with COVID-19. Furthermore, ongoing trials indicate that drug is being extensively studied across the world for its safety and efficacy in COVID-19.

Conclusion

Baricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia and further evidence may establish the drug as a standard treatment among such patients.
Phytoremediation of EMS InducedBrassica junceaHeavy Metal Hyperaccumulator Genotypes
Authors: Halder Shema , Anirban Apurba
Published: December 2021

Buriganga, an economically important river of Dhaka, Bangladesh, is highly polluted by different toxic heavy metals. In this study, phytoremediation of EMS induced Indian mustard (Brassica junceaL) genotypes against three pollutantsviz. lead (Pb), chromium (Cr) and cadmium (Cd) of Buriganga riverbank soil was assessed in field condition. Among 1-, 2- and 3% EMS induced genotypes, better seed germination rate, germination speed and plant survival rate were observed in 1% EMS induced genotype, BE21. The highest concentration of Pb, Cr and Cd were also obtained in the leaf of BE21 genotype and therefore was considered as a super-hyperaccumulator genotype. Concentration of Pb in the next generation of this genotype was approximately two-fold higher in the root (91.53±6.59 mg/kg dry weight, DW); three-fold higher in the shoot (33.31±1.01 mg/kg DW) and leaf (28.35±3.61 mg/kg DW), and more in the fruit (5.59±0.93 mg/kg DW) than the control. Concentration of Cr was approximately two-fold in the root (57.02±3.24 mg/kg DW), shoot (18.51±1.36 mg/kg DW) and leaf (14.98±2.01 mg/kg DW), and more in the fruit (6.15±1.92 mg/kg DW) of BE21 genotype compared to the control. Cd concentration was more in the root (1.96±0.92 mg/kg DW), leaf (0.52±0.32 mg/kg DW) and fruit (0.19±0.02 mg/kg DW) and less in the shoot (0.19±0.01 mg/kg DW) of BE21 genotype than the control. Root, shoot, leaf and fruit of BE21 altogether accumulated 98-, 73- and 87% Pb, Cr and Cd, respectively and can thus be utilized to remove heavy metals of Buriganga River. As like root, shoot and leaf, fruit also accumulated heavy metals; hence those plants which are used in phytoremediation should not be used as food or fodder. To the best of our knowledge, this is the first report of developing EMS induced hyperaccumulator genotype ofB. junceafor phytoremediation of Buriganga riverbank soil of Bangladesh.
Brain Morphometry and Chronic Inflammation in Bangladeshi Children Growing up in Extreme Poverty
Authors: Turesky Ted K. , Pirazzoli Laura , Shama Talat , Kakon Shahria Hafiz , Haque Rashidul , Islam Nazrul , Someshwar Amala , Gagoski Borjan , Petri William A. , Nelson Charles A. , Gaab Nadine
Published: December 2021

Over three hundred million children live in environments of extreme poverty, and the biological and psychosocial hazards endemic to these environments often expose these children to infection, disease, and inflammatory responses. Chronic inflammation in early childhood has been associated with diminished cognitive outcomes, and despite this established relationship, the mechanisms explaining how inflammation affects brain development are not well known. Importantly, the prevalence of chronic inflammation in areas of extreme poverty raises the possibility that it may serve as a mechanism explaining the known relationship between low socioeconomic status (SES) and altered brain development. To examine these potential pathways, seventy-nine children growing up in an extremely poor, urban area of Bangladesh underwent MRI scanning at six years of age. Structural brain images were submitted to Mindboggle software, a Docker-compliant and high-reproducibility tool for regional estimations of volume, surface area, cortical thickness, sulcal depth, and mean curvature. C-reactive protein was assayed at eight time points between infancy and five years of age and the frequency with which children had elevated concentrations of inflammatory marker represented the measure of chronic inflammation. Childhood SES was measured with maternal education and income-to-needs (i.e., monthly household income divided by the number of household members). Chronic inflammation predicted volume in bilateral basal ganglia structures and mediated the link between maternal education and bilateral putamen volumes. These findings suggest that chronic inflammation is associated with brain morphometry in the basal ganglia, predominantly the putamen, and further offers inflammation as a potential mechanism linking SES to brain development.
Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats
Authors: Takeda Tomoki , Yamano Shotaro , Goto Yuko , Hirai Shigeyuki , Furukawa Yusuke , Kikuchi Yoshinori , Misumi Kyohei , Suzuki Masaaki , Takanobu Kenji , Senoh Hideki , Saito Misae , Kondo Hitomi , Daghlian George , Hong Young Kwon , Yoshimatsu Yasuhiro , Hirashima Masanori , Kobashi Yoichiro , Okamoto Kenzo , Kishimoto Takumi , Umeda Yumi
Published: December 2021

Background

In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace.

Methods

Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 hour, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 hours/day for 2 days.

Results

CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages.

Conclusions

Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.
Structural development of amyloid precursors in insulin B chain and the inhibition effect by fibrinogen
Authors: Yamamoto Naoki , Inoue Rintaro , Makino Yoshiteru , Shibayama Naoya , Naito Akira , Sugiyama Masaaki , Chatani Eri
Published: December 2021

Amyloid fibrils are abnormal protein aggregates that relate to a large number of amyloidoses and neurodegenerative diseases. The oligomeric precursors, or prefibrillar intermediates, which emerge prior to the amyloid fibril formation, have been known to play a crucial role for the formation. Therefore, it is essential to elucidate the mechanisms of the structural development of the prefibrillar intermediates and ways to prevent its fibril formation. An insulin-derived peptide, insulin B chain, has been known for its stable accumulation of the prefibrillar intermediates. In this study, structural development of B chain prefibrillar intermediates was monitored by transmission electron microscopy and small-angle X-ray scattering combined with size exclusion chromatography and solid-state NMR spectroscopy to elucidate the stability and secondary structure. We further tracked its inhibition process by fibrinogen (Fg), which has been known to effectively prevent the amyloid fibril formation of B chain. We demonstrated that prefibrillar intermediates are wavy structures with low β-sheet content, growing in a multistep manner toward the nucleation for the amyloid fibril formation. In the presence of Fg, the formation of the prefibrillar intermediates slowed down by forming specific complexes. These observations suggest that the prefibrillar intermediates serve as reaction fields for the nucleation and its propagation for the amyloid fibril formation, whereas the inhibition of prefibrillar intermediate elongation by Fg is the significant factor to suppress the fibril formation. We propose that the obtained molecular picture could be a general inhibition mechanism of the amyloid fibril formation by the inhibitors.
OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways
Authors: Oikawa Daisuke , Gi Min , Kosako Hidetaka , Shimizu Kouhei , Takahashi Hirotaka , Shiota Masayuki , Hosomi Shuhei , Komakura Keidai , Wanibuchi Hideki , Tsuruta Daisuke , Sawasaki Tatsuya , Tokunaga Fuminori
Published: December 2021

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. InOtud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.
SARS-CoV-2 Omicron VOC Transmission in Danish Households
Authors: Lyngse Frederik Plesner , Mortensen Laust Hvas , Denwood Matthew J. , Christiansen Lasse Engbo , Møller Camilla Holten , Skov Robert Leo , Spiess Katja , Fomsgaard Anders , Lassaunière Maria Magdalena , Rasmussen Morten , Stegger Marc , Nielsen Claus , Sieber Raphael Niklaus , Cohen Arieh Sierra , Møller Frederik Trier , Overvad Maria , Mølbak Kåre , Krause Tyra Grove , Kirkeby Carsten Thure
Published: December 2021

1

The Omicron variant of concern (VOC) is a rapidly spreading variant of SARS-CoV-2 that is likely to overtake the previously dominant Delta VOC in many countries by the end of 2021.

We estimated the transmission dynamics following the spread of Omicron VOC within Danish households during December 2021. We used data from Danish registers to estimate the household secondary attack rate (SAR).

Among 11,937 households (2,225 with the Omicron VOC), we identified 6,397 secondary infections during a 1-7 day follow-up period. The SAR was 31% and 21% in households with the Omicron and Delta VOC, respectively. We found an increased transmission for unvaccinated individuals, and a reduced transmission for booster-vaccinated individuals, compared to fully vaccinated individuals. Comparing households infected with the Omicron to Delta VOC, we found an 1.17 (95%-CI: 0.99-1.38) times higher SAR for unvaccinated, 2.61 times (95%-CI: 2.34-2.90) higher for fully vaccinated and 3.66 (95%-CI: 2.65-5.05) times higher for booster-vaccinated individuals, demonstrating strong evidence of immune evasiveness of the Omicron VOC.

Our findings confirm that the rapid spread of the Omicron VOC primarily can be ascribed to the immune evasiveness rather than an inherent increase in the basic transmissibility.
Omicron infection of vaccinated individuals enhances neutralizing immunity against the Delta variant
Authors: Khan Khadija , Karim Farina , Cele Sandile , San James Emmanuel , Lustig Gila , Tegally Houriiyah , Rosenberg Yuval , Bernstein Mallory , Ganga Yashica , Jule Zesuliwe , Reedoy Kajal , Ngcobo Nokuthula , Mazibuko Matilda , Mthabela Ntombifuthi , Mhlane Zoey , Mbatha Nikiwe , Miya Yoliswa , Giandhari Jennifer , Ramphal Yajna , Naidoo Taryn , Manickchund Nithendra , Magula Nombulelo , Karim Salim S. Abdool , Gray Glenda , Hanekom Willem , Gottberg Anne von ,   COMMIT-KZN Team, Milo Ron , Gosnell Bernadett I. , Lessells Richard J. , Moore Penny L. , de Oliveira Tulio , Moosa Mahomed-Yunus S. , Sigal Alex
Published: December 2021

Omicron variant (B.1.1.529) infections are rapidly expanding worldwide, often in settings where the Delta variant (B.1.617.2) was dominant. We investigated whether neutralizing immunity elicited by Omicron infection would also neutralize the Delta variant and the role of prior vaccination. We enrolled 23 South African participants infected with Omicron a median of 5 days post-symptoms onset (study baseline) with a last follow-up sample taken a median of 23 days post-symptoms onset. Ten participants were breakthrough cases vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV2.S. In vaccinated participants, neutralization of Omicron increased from a geometric mean titer (GMT) FRNT50 of 28 to 378 (13.7-fold). Unvaccinated participants had similar Omicron neutralization at baseline but increased from 26 to only 113 (4.4-fold) at follow-up. Delta virus neutralization increased from 129 to 790, (6.1-fold) in vaccinated but only 18 to 46 (2.5-fold, not statistically significant) in unvaccinated participants. Therefore, in Omicron infected vaccinated individuals, Delta neutralization was 2.1-fold higher at follow-up relative to Omicron. In a separate group previously infected with Delta, neutralization of Delta was 22.5-fold higher than Omicron. Based on relative neutralization levels, Omicron re-infection would be expected to be more likely than Delta in Delta infected individuals, and in Omicron infected individuals who are vaccinated. This may give Omicron an advantage over Delta which may lead to decreasing Delta infections in regions with high infection frequencies and high vaccine coverage.
Prenatal immune stress induces a prolonged blunting of microglia activation that impacts striatal connectivity
Authors: Hayes Lindsay N. , An Kyongman , Carloni Elisa , Li Fangze , Vincent Elizabeth , Paranjpe Manish , Dölen Gül , Goff Loyal A. , Ramos Adriana , Kano Shin-ichi , Sawa Akira
Published: December 2021

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1–3. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood4,5. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development6–8. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naïve microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.
Revisiting rustrela virus – new cases of encephalitis and a solution to the capsid enigma
Authors: Pfaff Florian , Breithaupt Angele , Rubbenstroth Dennis , Nippert Sina , Baumbach Christina , Gerst Sascha , Langner Christoph , Wylezich Claudia , Ebinger Arnt , Höper Dirk , Ulrich Rainer G. , Beer Martin
Published: December 2021

Rustrela virus (RusV, species Rubivirus strelense) is a recently discovered relative of rubella virus (RuV) that has been detected in cases of encephalitis across a wide spectrum of mammals, including placental and marsupial animals. Here we diagnosed two additional cases of fatal RusV-associated meningoencephalitis in a South American coati (Nasua nasua) and a Eurasian otter (Lutra lutra) that were detected in a zoological garden with history of prior RusV infections. Both animals showed abnormal movement or unusual behaviour and their brains tested positive for RusV using specific RT-qPCR and RNA in situ hybridization. As previous sequencing of RusV proved to be very challenging, we employed a sophisticated target-specific capture enrichment with specifically designed RNA baits to generate complete RusV genome sequences from both detected encephalitic animals and apparently healthy wild yellow-necked field mice (Apodemus flavicollis). Furthermore, the technique was used to revise three previously published RusV genomes from two encephalitic animals and a wild yellow-necked field mouse. Virus-to-host sequence ratio and thereby sequence coverage improved markedly using the enrichment method as compared to standard procedures. When comparing the newly generated RusV sequences to the previously published RusV genomes, we identified a previously undetected stretch of 309 nucleotides predicted to represent the intergenic region and the sequence encoding the N-terminus of the capsid protein. This indicated that the original RusV sequence was likely incomplete due to misassembly of the genome at a region with an exceptionally high G+C content of >80 mol%, which could not be resolved even by enormous sequencing efforts with standard methods. The updated capsid protein amino acid sequence now resembles those of RuV and ruhugu virus in size and harbours a predicted RNA binding domain that was not encoded in the original RusV genome version. The new sequence data indicate that RusV has the largest overall genome (9,631 nucleotides), intergenic region (290 nucleotides) and capsid protein-encoding sequence (331 codons) within the genus Rubivirus.
Denitrification in foraminifera has ancient origin and is complemented by associated bacteria
Authors: Woehle Christian , Roy Alexandra-Sophie , Glock Nicolaas , Michels Jan , Wein Tanita , Weissenbach Julia , Romero Dennis , Hiebenthal Claas , Gorb Stanislav N. , Schönfeld Joachim , Dagan Tal
Published: December 2021

Benthic foraminifera are unicellular eukaryotes that inhabit sediments of aquatic environments. Several foraminifera of the order Rotaliida are known to store and use nitrate for denitrification, a unique energy metabolism among eukaryotes. The rotaliid Globobulimina spp. has been shown to encode an incomplete denitrification pathway of bacterial origin. However, the prevalence of denitrification genes in foraminifera remains unknown and the missing denitrification pathway components are elusive. Analysing transcriptomes and metagenomes of ten foraminiferal species from the Peruvian oxygen minimum zone, we show that denitrification genes are highly conserved in foraminifera. We infer of the last common ancestor of denitrifying foraminifera, which enables us to predict the ability to denitrify for additional foraminiferal species. Additionally, an examination of the foraminiferal microbiota reveals evidence for a stable interaction with Desulfobacteracea, which harbour genes that complement the foraminiferal denitrification pathway. Our results provide evidence that foraminiferal denitrification is complemented by the foraminifera-associated microbiome. The interaction of foraminifera with their resident bacteria is at the basis of foraminiferal adaptation to anaerobic environments that manifested in ecological success within oxygen depleted habitats.

Significance Statement

A substantial component of the global nitrogen cycle is the production of biologically inaccessible dinitrogen attributed to anaerobic denitrification by prokaryotes. Recent evidence identified a eukaryote – foraminifera – as new key players in this ‘loss’ of bioavailable nitrogen. The evolution of denitrification in eukaryotes constitutes a rare event and the genetic mechanisms of the denitrification pathway in foraminifera are just starting to be elucidated. We present large-scale sequencing analyses of ten denitrifying foraminiferal species, which reveals the high conservation of the foraminiferal denitrification pathway. We further find evidence for a complementation of denitrification by the foraminiferal microbiome. Together, these findings provide novel insights on the early evolution of a previously overlooked component in the marine nitrogen cycle.
Properties and computational consequences of fast dendritic spikes during natural behavior
Authors: Destexhe Alain , Mehta Mayank
Published: December 2021

Dendritic membrane potential was recently measured for the first time in drug-free, naturally behaving rats over several days. These showed that neuronal dendrites generate a lot of sodium spikes, up to ten times as many as the somatic spikes. These key experimental findings are reviewed here, along with a discussion of computational models, and computational consequences of such intense spike traffic in dendrites. We overview the experimental techniques that enabled these measurements as well as a variety of models, ranging from conceptual models to detailed biophysical models. The biophysical models suggest that the intense dendritic spiking activity can arise from the biophysical properties of the dendritic voltage-dependent and synaptic ion channels, and delineate some computational consequences of fast dendritic spike activity. One remarkable aspect is that in the model, with fast dendritic spikes, the efficacy of synaptic strength in terms of driving the somatic activity is much less dependent on the position of the synapse in dendrites. This property suggests that fast dendritic spikes is a way to confer to neurons the possibility to grow complex dendritic trees with little computational loss for the distal most synapses, and thus form very complex networks with high density of connections, such as typically in the human brain. Another important consequence is that dendritically localized spikes can allow simultaneous but different computations on different dendritic branches, thereby greatly increasing the computational capacity and complexity of neuronal networks.
Estimation of the biosorption potential of certain representatives of the genus Bacillus in interaction with lead cation in vitro
Authors: Sizentsov A.N. , Galaktionova L.V. , Davydova O.K. , Nikiyan A.N. , Sizentsov Ya.A.
Published: December 2021

The article presents data on the physicochemical and metabolically dependent mechanisms of detoxification by microorganisms of heavy metals that enter the environment during anthropogenic pollution. The taxonomic and physiological-biochemical diversity of microorganisms capable of neutralizing toxicants has been demonstrated. In the experimental part of the study, the combination of the methods used made it possible to fully assess the degree of toxicity and the effect of lead cations on the growth of bacteria of the genus Bacillus in a model experiment. Thus, the use of atomic absorption spectrophotometry and atomic force microscopy gave an idea of the level of biosorption of a given xenobiotic element from a substrate with localization of inactive forms of lead. The data obtained indicate the presence of an inhibitory effect of Pb(NO3)2 and Pb(CH3COO)2 in concentrations from 1 mM to 0.063 mM about the test organisms under study. The presence of cations with a nutrient substrate gives a false-positive idea of the degree of influence of lead on the growth of the studied microorganisms, since an increase in optical density in test samples is due to high sorption characteristics and, as a consequence, is characterized by an increase in relative optical density. An assessment of the detoxification mechanisms, which is expressed by active bioaccumulation of lead on the surface elements of the microbial cell up to 65% at the point of entering the stationary growth phase, indicates the promising use of representatives of this group of microorganisms as microbial bioremediation and correctors of excess content of this element in the body or ecosystem as a whole.
Revealing the secrets beneath grapevine and Plasmopara viticola early communication: a picture of host and pathogen proteomes
Authors: Figueiredo Joana , Santos Rita B. , Guerra-Guimarães Leonor , Leclercq Céline C. , Renaut Jenny , Sousa Lisete , Figueiredo Andreia
Published: December 2021

Plant apoplast is the first hub of plant-pathogen communication where pathogen effectors are recognized by plant defensive proteins and cell receptors and several signal transduction pathways are activated. As a result of this first contact, the host triggers a defence response that involves the modulation of several extra and intracellular proteins. In grapevine-pathogen interactions, little is known about the communication between cells and apoplast. Also, the role of apoplastic proteins in response to pathogens still remains a blackbox. In this study we focused on the first 6 hours after Plasmopara viticola inoculation to evaluate grapevine proteome modulation in the apoplastic fluid (APF) and whole leaf tissue. Plasmopara viticola proteome was also assessed enabling a deeper understanding of plant and pathogen communication. Our results showed that oomycete recognition, plant cell wall modifications, ROS signalling and disruption of oomycete structures are triggered in Regent after P. viticola inoculation. Our results highlight a strict relation between the apoplastic pathways modulated and the proteins identified in the whole leaf proteome. On the other hand, P. viticola proteins related to growth/morphogenesis and virulence mechanisms were the most predominant. This pioneer study highlights the early dynamics of extra and intracellular communication in grapevine defence activation that leads to the successful establishment of an incompatible interaction.
Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern
Authors: Vangeel Laura , Chiu Winston , De Jonghe Steven , Maes Piet , Slechten Bram , Raymenants Joren , André Emmanuel , Leyssen Pieter , Neyts Johan , Jochmans Dirk
Published: December 2021

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.
Structural basis for potent antibody neutralization of SARS-CoV-2 variants including B.1.1.529
Authors: Zhou Tongqing , Wang Lingshu , Misasi John , Pegu Amarendra , Zhang Yi , Harris Darcy R. , Olia Adam S. , Talana Chloe Adrienna , Yang Eun Sung , Chen Man , Choe Misook , Shi Wei , Teng I-Ting , Creanga Adrian , Jenkins Claudia , Leung Kwanyee , Liu Tracy , Stancofski Erik-Stephane D. , Stephens Tyler , Zhang Baoshan , Tsybovsky Yaroslav , Graham Barney S. , Mascola John R. , Sullivan Nancy J. , Kwong Peter D.
Published: December 2021

With B.1.1.529 SARS-CoV-2 variant’s rapid spread and substantially increased resistance to neutralization by vaccinee and convalescent sera, monoclonal antibodies with potent neutralization are eagerly sought. To provide insight into effective neutralization, we determined cryo-EM structures and evaluated potent receptor-binding domain (RBD) antibodies for their ability to bind and neutralize this new variant. B.1.1.529 RBD mutations altered 16% of the RBD surface, clustering on a ridge of this domain proximal to the ACE2-binding surface and reducing binding of most antibodies. Significant inhibitory activity was retained, however, by select monoclonal antibodies including A19-58.1, B1-182.1, COV2-2196, S2E12, A19-46.1, S309 and LY-CoV1404, which accommodated these changes and neutralized B.1.1.529 with IC50s between 5.1-281 ng/ml, and we identified combinations of antibodies with potent synergistic neutralization. Structure-function analyses delineated the impact of resistance mutations and revealed structural mechanisms for maintenance of potent neutralization against emerging variants.

Summary Sentence

We show potent B.1.1.529 neutralization by select antibodies and use EM structures to reveal how potency can be retained.