bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular disease protein biomarkers are associated with kidney function: the Framingham Heart Study
Authors: Keshawarz Amena , Hwang Shih-Jen , Lee Gha Young , Yu Zhi , Yao Chen , Köttgen Anna , Levy Daniel
Published: January 2022

Background

Biomarkers common to chronic kidney disease (CKD) and cardiovascular disease (CVD) may reflect early impairments underlying both diseases.

Methods

We evaluated associations of 71 CVD-related plasma proteins measured in 2,873 Framingham Heart Study (FHS) Offspring cohort participants with cross-sectional continuous eGFR and with longitudinal change in eGFR from baseline to follow-up (ΔeGFR). We also evaluated the associations of the 71 CVD proteins with the following dichotomous secondary outcomes: prevalent CKD stage ≥3 (cross-sectional), new-onset CKD stage ≥3 (longitudinal), and rapid decline in eGFR (longitudinal). Proteins significantly associated with eGFR and ΔeGFR were subsequently validated in 3,951 FHS Third Generation cohort participants and were tested using Mendelian randomization (MR) analysis to infer putatively causal relations between plasma protein biomarkers and kidney function.

Results

In cross-sectional analysis, 37 protein biomarkers were significantly associated with eGFR at FDR<0.05 in the FHS Offspring cohort and 20 of these validated in the FHS Third Generation cohort at p<0.05/37. In longitudinal analysis, 27 protein biomarkers were significantly associated with ΔeGFR at FDR<0.05 and 12 of these were validated in the FHS Third Generation cohort at p<0.05/27. Additionally, 35 protein biomarkers were significantly associated with prevalent CKD, five were significantly associated with new-onset CKD, and 17 were significantly associated with rapid decline in eGFR. MR suggested putatively causal relations of melanoma cell adhesion molecule (MCAM; -0.011±0.003 mL/min/1.73m2, p=5.11E-5) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1; - 0.006±0.002 mL/min/1.73m2, p=0.0001) concentration with eGFR.

Discussion/Conclusions

Eight protein biomarkers were consistently associated with eGFR in cross-sectional and longitudinal analysis in both cohorts and may capture early kidney impairment; others were implicated in association and causal inference analyses. A subset of CVD protein biomarkers may contribute causally to the pathogenesis of kidney impairment and should be studied as targets for CKD treatment and early prevention.
Factors Associated with COVID-19 Testing among People who Inject Drugs: Missed Opportunities for Reaching those Most at Risk
Authors: Yeager Samantha , Abramovitz Daniela , Harvey-Vera Alicia , Vera Carlos F. , Algarin Angel B. , Smith Laramie R. , Rangel Gudelia , Artamonova Irina , Patterson Thomas L. , Bazzi Angela R. , Brugman Emma L. , Strathdee Steffanie A.
Published: January 2022

People who inject drugs (PWID) are vulnerable to SARS-CoV-2 infection. We examined correlates of COVID-19 testing among PWID in the U.S.-Mexico border region and described encounters with services or venues representing potential opportunities (i.e., ‘touchpoints’) where COVID-19 testing could have been offered. Between October, 2020 and September, 2021, participants aged ≥18 years from San Diego, California, USA and Tijuana, Baja California, Mexico who injected drugs within the last month completed surveys and SARS-CoV-2, HIV, and HCV serologic testing. Logistic regression was used to identify factors associated with COVID-19 testing prior to enrollment. Of 583 PWID, 30.5% previously had a COVID-19 test. Of 172 PWID who tested SARS-CoV-2 seropositive in our study (30.1%), 50.3% encountered at least one touchpoint within the prior six months where COVID-19 testing could have been offered. Factors independently associated with at least two fold higher odds of COVID-19 testing were living in San Diego (versus Tijuana), having recently been incarcerated or attending substance use disorder (SUD) treatment and having at least one chronic health condition. In addition, recent homelessness, having had at least one COVID-19 vaccine dose and having been tested for HIV or HCV since the pandemic began were independently associated with COVID-19 testing. We identified several factors independently associated with COVID-19 testing and multiple touchpoints where COVID-19 testing could be scaled up for PWID, such as SUD treatment programs and syringe service programs. Integrated health services are needed to improve access to rapid, free COVID-19 testing in this vulnerable population.
Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review
Authors: Santyr Brendan , Abbass Mohamad , Chalil Alan , Vivekanandan Amirti , Tindale Margaret , Boulis Nicholas M. , Lau Jonathan C.
Published: January 2022

Introduction

Craniofacial pain is a prevalent group of conditions and when refractory to conventional treatments poses a significant burden. The last decade has seen a renewed interest in the multimodal management of pain. Interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex have been available as a treatment option since the 1930s, yet evidence for efficacy remains limited.

Methods

We present a systematic review of the literature providing a historical perspective on interventions targeting the NC leading up to the present. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to enable comparison among studies due to historically variable reporting methods.

Results

A review of the literature revealed 33 retrospective studies published over the last 80 years reporting on 827 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy; however, there has been an emergence of novel approaches such as endoscopic and spinal cord stimulation in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 87% of patients demonstrated improvement with treatment.

Conclusion

The literature surrounding NC intervention techniques is reviewed. Recent advancements and the wide range of craniofacial pain syndromes for which these interventions show potential efficacy is discussed. New and less invasive techniques continue to emerge as putative therapeutic options. However, prospective studies are lacking. Furthermore, the evidence supporting even well-established techniques remain of poor quality. Future work should be prospective, utilize standard outcome reporting, and address efficacy comparisons between intervention type and preoperative diagnosis.
Unraveling membrane properties at the organelle-level with LipidDyn
Authors: Scrima Simone , Tiberti Matteo , Campo Alessia , Corcelle-Termeau Elisabeth , Judith Delphine , Foged Mads Møller , Clemmensen Knut Kristoffer Bundgaard , Tooze Sharon , Jäättelä Marja , Maeda Kenji , Lambrughi Matteo , Papaleo Elena
Published: January 2022

Cellular membranes are formed from many different lipids in various amounts and proportions depending on the subcellular localization. The lipid composition of membranes is sensitive to changes in the cellular environment, and their alterations are linked to several diseases, including cancer. Lipids not only form lipid-lipid interactions but also interact with other biomolecules, including proteins, profoundly impacting each other.

Molecular dynamics (MD) simulations are a powerful tool to study the properties of cellular membranes and membrane-protein interactions on different timescales and at varying levels of resolution. Over the last few years, software and hardware for biomolecular simulations have been optimized to routinely run long simulations of large and complex biological systems. On the other hand, high-throughput techniques based on lipidomics provide accurate estimates of the composition of cellular membranes at the level of subcellular compartments. The community needs computational tools for lipidomics and simulation data effectively interacting to better understand how changes in lipid compositions impact membrane function and structure. Lipidomic data can be analyzed to design biologically relevant models of membranes for MD simulations. Similar applications easily result in a massive amount of simulation data where the bottleneck becomes the analysis of the data to understand how membrane properties and membrane-protein interactions are changing in the different conditions. In this context, we developed LipidDyn, an in silico pipeline to streamline the analyses of MD simulations of membranes of different compositions. Once the simulations are collected, LipidDyn provides average properties and time series for several membrane properties such as area per lipid, thickness, diffusion motions, the density of lipid bilayers, and lipid enrichment/depletion. The calculations exploit parallelization and the pipelines include graphical outputs in a publication-ready form. We applied LipidDyn to different case studies to illustrate its potential, including membranes from cellular compartments and transmembrane protein domains. LipidDyn is implemented in Python and relies on open-source libraries. LipidDyn is available free of charge under the GNU General Public License from https://github.com/ELELAB/LipidDyn.
SPITFIR(e): A supermaneuverable algorithm for restoring 2D-3D fluorescence images and videos, and background subtraction
Authors: Prigent Sylvain , Nguyen Hoai-Nam , Leconte Ludovic , Valades-Cruz Cesar Augusto , Hajj Bassam , Salamero Jean , Kervrann Charles
Published: January 2022

While fluorescent microscopy imaging has become the spearhead of modern biology as it is able to generate long-term videos depicting 4D nanoscale cell behaviors, it is still limited by the optical aberrations and the photon budget available in the specimen and to some extend to photo-toxicity. A direct consequence is the necessity to develop flexible and “off-road” algorithms in order to recover structural details and improve spatial resolution, which is critical when pushing the illumination to the low levels in order to limit photo-damages. Moreover, as the processing of very large temporal series of images considerably slows down the analysis, special attention must be paid to the feasibility and scalability of the developed restoration algorithms. To address these specifications, we present a very flexible method designed to restore 2D-3D+Time fluorescent images and subtract undesirable out-of-focus background. We assume that the images are sparse and piece-wise smooth, and are corrupted by mixed Poisson-Gaussian noise. To recover the unknown image, we consider a novel convex and non-quadratic regularizer Sparse Hessian Variation) defined as the mixed norms which gathers image intensity and spatial second-order derivatives. This resulting restoration algorithm named SPITFIR(e) (SParse fIT for Fluorescence Image Restoration) utilizes the primal-dual optimization principle for energy minimization and can be used to process large images acquired with varied fluorescence microscopy modalities. It is nearly parameter-free as the practitioner needs only to specify the amount of desired sparsity (weak, moderate, high). Experimental results in lattice light sheet, stimulated emission depletion, multifocus microscopy, spinning disk confocal, and wide-field microscopy demonstrate the generic ability of the SPITFIR(e) algorithm to efficiently reduce noise and blur, and to subtract undesirable fluorescent background, while avoiding the emergence of deconvolution artifacts.
RNA-mediated nucleosome depletion is required for elimination of transposon-derived DNA
Authors: Singh Aditi , Maurer-Alcalá Xyrus X. , Solberg Therese , Gisler Silvan , Ignarski Michael , Swart Estienne C. , Nowacki Mariusz
Published: January 2022

Small RNAs are known to mediate silencing of transposable elements and other genomic loci, increasing nucleosome density and preventing undesirable gene expression. Post-zygotic development of the Paramecium somatic genome requires elimination of thousands of transposon remnants (IESs) and transposable elements that are scattered throughout the germline genome (Garnier et al. 2004). The elimination process is guided by Piwi-associated small RNAs and leads to precise cleavage at IES boundaries (Bouhouche et al. 2011; Furrer et al. 2017). Previous research suggests that small RNAs induce heterochromatin formation within IESs, which, in turn, is required for DNA elimination (Liu et al. 2007). Here we show that IES recognition and precise excision is facilitated by recruitment of a homolog of a chromatin remodeler ISWI, which depletes target genomic regions of nucleosomes, making the chromatin accessible for DNA cleavage. ISWI knockdown in Paramecium leads to pronounced inhibition of DNA elimination. Furthermore, nucleosome profiling indicates that ISWI is required for IES elimination in nucleosome-dense genomic regions, while other IESs do not require small RNAs or ISWI for excision. ISWI silencing notably also reduces DNA elimination precision, resulting in aberrant excision at alternative IES boundaries. In summary, we demonstrate that chromatin remodeling that increases DNA accessibility together with small RNAs are necessary for efficient and precise DNA elimination in Paramecium.
Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome
Authors: Catron Mackenzie A. , Howe Rachel K. , Besing Gai-Linn K. , John Emily K. St. , Potesta Cobie Victoria , Gallagher Martin J. , Macdonald Robert L. , Zhou Chengwen
Published: January 2022

Sleep is the brain state when cortical activity decreases and memory consolidates. However, in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome, sleep is the preferential period when epileptic spike-wave discharges (SWDs) appear, with more severe epileptic symptoms in female patients than male patients, which influencing patient sleep quality and memory. Currently, seizure onset mechanisms during sleep period still remain unknown. Our previous work has shown that the sleep-like state-dependent synaptic potentiation mechanism can trigger epileptic SWDs(Zhang et al., 2021). In this study, using one heterozygous (het) knock-in (KI) transgenic mice (GABAA receptor γ2 subunit Gabrg2Q390X mutation) and an optogenetic method, we hypothesized that slow-wave oscillations (SWOs) themselves in vivo could trigger epileptic seizures. We found that epileptic SWDs in het Gabrg2+/Q390X KI mice exhibited preferential incidence during NREM sleep period, accompanied by motor immobility/ facial myoclonus/vibrissal twitching, with more frequent incidence in female het KI mice than male het KI mice. Optogenetic induced SWOs in vivo significantly increased epileptic seizure incidence in het Gabrg2+/Q390X KI mice with increased duration of NREM sleep or quiet-wakeful states. Furthermore, suppression of SWO-related homeostatic synaptic potentiation by 4- (diethylamino)-benzaldehyde (DEAB) injection (i.p.) greatly decreased seizure incidence in het KI mice, suggesting that SWOs did trigger seizure activity in het KI mice. In addition, EEG delta-frequency (0.1-4 Hz) power spectral density during NREM sleep was significantly larger in female het Gabrg2+/Q390X KI mice than male het Gabrg2+/Q390X KI mice, which likely contributes to the gender difference in seizure incidence during NREM sleep/quiet-wake as that in human patients.
Resting-State Network Analysis of Suicide Attempt History in the UK Biobank
Authors: Thompson Matthew F. , Ghahramanlou-Holloway Marjan , Murphy Mikela A. , Perera Kanchana U. , Benca-Bachman Chelsie , Palmer Rohan H. C. , Gray Joshua C.
Published: January 2022

Background

Prior research has identified altered brain structure and function in individuals at risk for self-directed violence thoughts and behaviors. However, these studies have largely utilized healthy controls and findings have been inconsistent. Thus, this study examined differences in resting-state functional network connectivity among individuals with lifetime suicide attempt(s) versus lifetime self-directed violence thoughts alone.

Methods

Using data from the UK Biobank, this study utilized a series of linear regressions to compare individuals with lifetime suicide attempt(s) (n= 566) versus lifetime self-directed violence thoughts alone (n= 3,447) on within- and between-network resting-state functional connectivity subnetworks.

Results

There were no significant between-group differences for between-network, within-network, or whole-brain functional connectivity after adjusting for age, sex, ethnicity, and body mass index and performing statistical corrections for multiple comparisons.

Conclusions

Resting-state network measures may not differentiate between individuals with lifetime suicide attempt(s) and lifetime self-directed violence thoughts alone. Null findings diverge from results reported in smaller neuroimaging studies of suicide risk, but are consistent with null findings in other large-scale studies and meta-analyses. Strengths of the study include its large sample size and stringent control group. Future research on a wider array of imaging, genetic, and psychosocial risk factors can clarify relative contributions of individual and combined variables to suicide risk and inform scientific understanding of ideation-to-action framework.
Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in In Vitro, In Vivo and Ex Vivo Models of Pulmonary Fibrosis
Authors: Ahangari Farida , Becker Christine , Foster Daniel G. , Chioccioli Maurizio , Nelson Meghan , Beke Keriann , Wang Xing , Readhead Benjamin , Meador Carly , Correll Kelly , Lili Loukia , Roybal Helen M. , Rose Kadi-Ann , Ding Shuizi , Barnthaler Thomas , Briones Natalie , Deluliis Giuseppe , Schupp Jonas C. , Li Qin , Omote Norihito , Aschner Yael , Kopf Katrina W. , Magnusson Björn , Hicks Ryan , Backmark Anna , Cousens Leslie P. , Dudley Joel T. , Kaminski Naftali , Downey Gregory P.
Published: January 2022

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two FDA approved anti-fibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. We investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: (i) in vitro in normal human lung fibroblasts (NHLFs); (ii) in vivo in bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis; and (iii) ex vivo in precision cut lung slices from these mouse models. In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone.
Recurrent co-option and recombination of cytokine and three finger proteins in multiple reproductive tissues throughout salamander evolution
Authors: Wilburn Damien B. , Kunkel Christy L. , Feldhoff Richard C. , Feldhoff Pamela W. , Searle Brian C.
Published: January 2022

The proteomic composition of amphibian gametes is largely a molecular mystery, particularly for Urodeles (salamanders and newts) which have few genomic-scale resources. Lungless salamanders (family Plethodontidae) include approximately two thirds of all extant salamander species and are classic models of vertebrate mating behavior. As part of an extended, multi-stage courtship ritual, male plethodontid salamanders deliver rapidly evolving protein pheromones that modify female behavior and improve male reproductive success. Despite great interest in this set of pre-mating reproductive barriers, limited characterization of plethodontid gametes has prohibited investigation of post-mating pre-zygotic barriers such as sperm-egg recognition. In this study, we performed transcriptomic analyses of testis and ovary using long-read PacBio sequencing and proteomic analyses of sperm using mass spectrometry for two evolutionary divergent plethodontid species, Plethodon shermani and Desmognathus ocoee. In both species, many of the most abundant sperm proteins were paralogs of the courtship pheromones Plethodontid Receptivity Factor (PRF), Plethodontid Modulating Factor (PMF), and Sodefrin Precursor-like Factor (SPF). Sperm-specific paralogs of PMF and SPF are likely the most abundant secreted proteins in P. shermani and D. ocoee, respectively. In contrast, sperm PRF lacks a signal peptide and may be expressed in cytoplasm. PRF pheromone genes evolved independently multiple times through repeated gene duplication of sperm PRF genes and signal peptides recovered by recombination with PMF genes. Phylogenetic analysis of courtship pheromones and their sperm paralogs support that each protein family evolved for these two reproductive contexts at distinct evolutionary time points between 17 and 360 million years ago. As the first molecular characterization of salamander gametes, this study expands our knowledge of amphibian fertilization beyond frogs and provides novel insight into the evolutionary processes by which new, rapidly evolving reproductive proteins may evolve.
Towards transboundary networks of climate-smart marine reserves in the Southern California Bight
Authors: Arafeh-Dalmau Nur , Munguia-Vega Adrian , Micheli Fiorenza , Vilalta-Navas Ainoa , Villasenor-Derbez Juan Carlos , Précoma-de la Mora Magdalena , Schoeman David S. , Medellín-Ortíz Alfonso , Cavanaugh Kyle C. , Sosa-Nishizaki Oscar , Burnham Theresa L.U. , Knight Christopher J. , Woodson C. Brock , Abas Marina , Abadía-Cardoso Alicia , Aburto-Oropeza Octavio , Esgro Michael W. , Espinosa-Andrade Noemi , Beas-Luna Rodrigo , Cardenas Nirari , Carr Mark H. , Dale Katherine E. , Cisneros-Soberanis Frida , Flores-Morales Ana Laura , Fulton Stuart , García-Rodríguez Emiliano , Giron-Nava Alfredo , Gleason Mary G. , Green Alison L. , Hernández-Velasco Arturo , Ibarra-Macías Beatriz , Johnson Andrew F. , Lorda Julio , Malpica-Cruz Luis , Montaño-Moctezuma Gabriela , Olguín-Jacobson Carolina , Parés-Sierra Alejandro , Raimondi Peter T. , Ramírez-Ortiz Georgina , Ramirez-Valdez Arturo , Reyes-Bonilla Héctor , Saarman Emily , Saldaña-Ruiz Luz Erandi , Smith Alexandra , Soldatini Cecilia , Suárez Alvin , Torres-Moye Guillermo , Walther Mariana , Watson Elizabeth Burke , Worden Sara , Possingham Hugh P.
Published: January 2022

Climate-smart conservation addresses the vulnerability of biodiversity to climate change impacts but may require transboundary considerations. Here, we adapt and refine 16 biophysical guidelines for climate-smart marine reserves for the transboundary California Bight ecoregion. We link several climate-adaptation strategies (e.g., maintaining connectivity, representing climate refugia, and forecasting effectiveness of protection) by focusing on kelp forests and associated species. We quantify transboundary larval connectivity along ∼800 km of coast and find that the number of connections and the average density of larvae dispersing through the network under future climate scenarios could decrease by ∼50%, highlighting the need to protect critical steppingstone nodes. We also find that although focal species will generally recover with 30% protection, marine heatwaves could hinder subsequent recovery in the following 50 years, suggesting that protecting climate refugia and expanding the coverage of marine reserves is a priority. Together, these findings provide a first comprehensive framework for integrating climate resilience for networks of marine reserves and highlight the need for a coordinated approach in the California Bight ecoregion.
Herpes simplex virus 1 expressing GFP-tagged virion host shutoff (vhs) protein uncouples the activities of degradation and nuclear retention of the infected cell transcriptome
Authors: Wise Emma L , Samolej Jerzy , Elliott Gillian
Published: January 2022

Virion host shutoff (vhs) protein is an endoribonuclease encoded by herpes simplex virus 1 (HSV1). Vhs causes a number of changes to the infected cell environment that favour translation of late (L) virus proteins: cellular mRNAs are degraded, immediate-early (IE) and early (E) viral transcripts are sequestered in the nucleus with polyA binding protein (PABPC1), and dsRNA is degraded to help dampen the PKR-dependent stress response. To further our understanding of the cell biology of vhs, we constructed a virus expressing vhs tagged at its C-terminus with GFP. When first expressed, vhs-GFP localised to juxtanuclear clusters, and later it colocalised and interacted with its binding partner VP16, and was packaged into virions. Despite vhs-GFP maintaining activity when expressed in isolation, it failed to degrade mRNA or relocalise PABPC1 during infection, while viral transcript levels were similar to those seen for a vhs knockout virus. PKR phosphorylation was also enhanced in vhs-GFP infected cells, in line with a failure to degrade dsRNA. Nonetheless, mRNA FISH revealed that as in Wt but not Δvhs infection, IE and E, but not L transcripts were retained in the nucleus of vhs-GFP infected cells at late times. Moreover, a representative cellular transcript which is ordinarily highly susceptible to vhs degradation, was also retained in the nucleus. These results reveal that the vhs-induced nuclear retention of the infected cell transcriptome is dependent on vhs expression but not on its endoribonuclease activity, uncoupling these two functions of vhs.

Importance

Like many viruses, herpes simplex virus 1 (HSV1) expresses an endoribonuclease, the virion host shutoff (vhs) protein, which regulates the RNA environment of the infected cell and facilitates the classical cascade of virus protein translation. It does this by causing the degradation of some mRNA molecules and the nuclear retention of others. Here we describe a virus expressing vhs tagged at its C-terminus with green fluorescent protein (GFP) and show that the vhs-GFP fusion protein retains the physical properties of native vhs, but does not induce the degradation of mRNA. Nonetheless, vhs-GFP maintains the ability to trap the infected cell transcriptome in the nucleus, proving for the first time that mRNA degradation is not a prerequisite for vhs effects on the nuclear transcriptome. This virus has therefore uncoupled the nuclear retention and degradation activities of vhs, providing new understanding of vhs during infection.
Lineage replacement and evolution captured by three years of the United Kingdom Covid Infection Survey
Authors: Lythgoe Katrina , Golubchik Tanya , Hall Matthew , House Thomas , Cahuantzi Roberto , MacIntyre-Cockett George , Fryer Helen , Thomson Laura , Nurtay Anel , Ghafani Mahan , Buck David , Green Angie , Trebes Amy , Piazza Paolo , Lonie Lorne J , Studley Ruth , Rourke Emma , Smith Darren , Bashton Matthew , Nelson Andrew , Crown Matthew , McCann Clare , Young Gregory R , Santos Rui Andre Nunes dos , Richards Zack , Tariq Adnan ,   Wellcome Sanger Institute COVID-19 Surveillance Team,   COVID-19 Infection Survey Group,   The COVID-19 Genomics UK (COG-UK) Consortium, Fraser Christophe , Diamond Ian , Barrett Jeff , Walker Ann Sarah , Bonsall David
Published: January 2022

The Office for National Statistics COVID-19 Infection Survey (ONS-CIS) is the largest surveillance study of SARS-CoV-2 positivity in the community, and collected data on the United Kingdom (UK) epidemic from April 2020 until March 2023 before being paused. Here, we report on the epidemiological and evolutionary dynamics of SARS-CoV-2 determined by analysing the sequenced samples collected by the ONS-CIS during this period. We observed a series of sweeps or partial sweeps, with each sweeping lineage having a distinct growth advantage compared to their predecessors. The sweeps also generated an alternating pattern in which most samples had either S-gene target failure (SGTF) or non- SGTF over time. Evolution was characterised by steadily increasing divergence and diversity within lineages, but with step increases in divergence associated with each sweeping major lineage. This led to a faster overall rate of evolution when measured at the between-lineage level compared to within lineages, and fluctuating levels of diversity. These observations highlight the value of viral sequencing integrated into community surveillance studies to monitor the viral epidemiology and evolution of SARS-CoV-2, and potentially other pathogens, particularly in the current phase of the pandemic with routine RT-PCR testing now ended in the community.
Durability of protection post-primary COVID-19 vaccination in the US: matched case-control study
Authors: Zheutlin Amanda , Ott Miles , Sun Ran , Zemlianskaia Natalia , Rubel Meagan , Hayden Jennifer , Neri Breno , Kamath Tripthi , Khan Najat , Schneeweiss Sebastian , Sarsour Khaled
Published: January 2022

Background

Intrinsic durability of immune responses elicited by COVID-19 vaccines will drive vaccine effectiveness long-term across settings and may differ by vaccine type. We aimed here to determine durability of protection of three COVID-19 vaccines BNT162b2, mRNA-1273 and Ad26.COV2.S following primary vaccination against breakthrough infections, hospitalisations, and intensive care unit (ICU) admissions in the United States (US).

Methods

Using national claims and laboratory data covering 168 million lives, we conducted a matched case-control study with fully vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing outcomes in months two through six following primary vaccination were estimated relative to the first month after primary vaccination for each vaccine separately. Results compare each vaccine to itself and are not directly comparative. Odds ratios were translated into vaccine effectiveness (VE) using assumptions about event rates in an unvaccinated cohort.

Findings

Relative to its baseline, stable protection was observed for the single-shot Ad26.COV2.S against infections and severe disease. Relative to their baseline protection waned overtime against infections for BNT162b2 and mRNA-1273 and against hospitalisations for BNT162b2. No waning of baseline protection was observed at any time for ICU admissions for all three vaccines. Calculated baseline VE was consistent with the published literature.

Interpretation

While the starting protection level provided by the primary series may differ by vaccine type and mechanism of action, this study demonstrated by comparing each vaccine to its own baseline protection that the three vaccines in three separate populations may have different durability profiles. Further investigation is required to fully characterize the durability profile of the three vaccines. Moreover, as the COVID-19 pandemic continues, and as more countries and populations implement a standard of care consisting of three doses of the mRNA vaccines or two doses of Ad26.COV2.S, further investigation is critical to understand the level of protection and the durability of response over longer periods, novel variants and in response to homologous and heterologous boosting.
A Composite Ranking of Risk Factors for COVID-19 Time-To-Event Data from a Turkish Cohort
Authors: Ulgen Ayse , Cetin Sirin , Cetin Meryem , Sivgin Hakan , LI Wentian
Published: January 2022

Having a complete and reliable list of risk factors from routine laboratory blood test for COVID-19 disease severity and mortality is important for
patient care and hospital management. It is common to use meta-analysis to combine analysis results from different studies to make it more reproducible.
In this paper, we propose to run multiple analyses on the same set of data to produce a more robust list of risk factors. With our time-to-event survival data, the standard survival analysis were extended in three directions. The first is to extend from tests and corresponding p-values to machine learning and their prediction performance. The second is to extend from single-variable to multiple-variable analysis. The third is to expand from analyzing time-to-decease data with death as the event of interest to analyzing time-to-hospital-release data to treat early recovery as a meaningful event as well. Our extension of the type of analyses leads to ten ranking lists. We conclude that 20 out of 30 factors are deemed to be reliably associated to faster-death or faster-recovery. Considering correlation among factors and evidenced by stepwise variable selection in random survival forest, 10~15 factors seem to be able to achieve the optimal prognosis performance. Our final list of risk factors contain calcium, white blood cell and neutrophils count, urea and creatine, d-dimer, red cell distribution widths, age, ferritin, glucose,
lactate dehydrogenase, lymphocyte, basophils, anemia related factors (hemoglobin, hematocrit, mean corpuscular hemoglobin concentration), sodium, potassium, eosinophils, and aspartate aminotransferase.
Protection afforded by prior infection against SARS-CoV-2 reinfection with the Omicron variant
Authors: Altarawneh Heba , Chemaitelly Hiam , Tang Patrick , Hasan Mohammad R. , Qassim Suelen , Ayoub Houssein H. , AlMukdad Sawsan , Yassine Hadi M. , Benslimane Fatiha M. , Khatib Hebah A. Al , Coyle Peter , Kanaani Zaina Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul Rahim Hanan F. , Nasrallah Gheyath K. , Al Kuwari Mohamed Ghaith , Butt Adeel A. , Al Romaihi Hamad Eid , Al-Thani Mohamed H. , Khal Abdullatif Al , Bertollini Roberto , Abu-Raddad Laith J.
Published: January 2022

BACKGROUND

Natural SARS-CoV-2 infection elicits strong protection against reinfection with the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. However, the Omicron (B.1.1.529) variant harbors multiple mutations that can mediate immune evasion. We estimated effectiveness of prior infection in preventing reinfection (PES) with Omicron and other SARS-CoV-2 variants in Qatar.

METHODS

PES was estimated using the test-negative, case-control study design, employing a methodology that was recently investigated and validated for derivation of robust estimates for PES. Cases (PCR-positive persons with a variant infection) and controls (PCR-negative persons) were exact-matched by sex, 10-year age group, nationality, and calendar time of PCR test, to control for known differences in the risk of exposure to SARS-CoV-2 infection in Qatar.

RESULTS

PES against symptomatic reinfection was estimated at 90.2% (95% CI: 60.2-97.6) for Alpha, 84.8% (95% CI: 74.5-91.0) for Beta, 92.0% (95% CI: 87.9-94.7) for Delta, and 56.0% (95% CI: 50.6-60.9) for Omicron. Only 1 Alpha, 2 Beta, 0 Delta, and 2 Omicron reinfections progressed to severe COVID-19. None progressed to critical or fatal COVID-19. PES against hospitalization or death due to reinfection was estimated at 69.4% (95% CI: −143.6-96.2) for Alpha, 88.0% (95% CI: 50.7-97.1) for Beta, 100% (95% CI: 43.3-99.8) for Delta, and 87.8% (95% CI: 47.5-97.1) for Omicron.

CONCLUSIONS

Protection afforded by prior infection in preventing symptomatic reinfection with Alpha, Beta, or Delta is robust, at about 90%. While such protection against reinfection with Omicron is lower, it is still considerable at nearly 60%. Prior-infection protection against hospitalization or death at reinfection appears robust, regardless of variant.
Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and November 2021
Authors: Kuodi Paul , Gorelik Yanay , Zayyad Hiba , Wertheim Ofir , Wiegler Karine Beiruti , Jabal Kamal Abu , Dror Amiel A. , Nazzal Saleh , Glikman Daniel , Edelstein Michael
Published: January 2022

Background

Long COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID-19 is not well understood. We determined whether vaccination was associated with the incidence of reporting long-term symptoms post-SARS-CoV-2 infection

Methods

We invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-November 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected in terms of self-reported symptoms post-acute infection.

Results

We included 951 infected and 2437 uninfected individuals. Of the infected, 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, those who received two doses less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Those who received two doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection.

Conclusions

Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.
In vitrocharacterization of the full-length human dynein-1 cargo adaptor BicD2
Authors: Fagiewicz Robert , Crucifix Corinne , Klos Torben , Deville Célia , Kieffer Bruno , Nominé Yves , Busselez Johan , Rossolillo Paola , Schmidt Helgo
Published: January 2022

Cargo adaptors are crucial in coupling motor proteins with their respective cargos and regulatory proteins. BicD2 is a prominent example within the cargo adaptor family. BicD2 is able to recruit the microtubule motor dynein to RNA, viral particles and nuclei. The BicD2-mediated interaction between the nucleus and dynein is implicated in mitosis, interkinetic nuclear migration (INM) in radial glial progenitor cells, and neuron precursor migration during embryonic neocortex development.In vitrostudies involving full-length cargo adaptors are difficult to perform due to the hydrophobic character, low-expression levels, and intrinsic flexibility of cargo adaptors. Here we report the recombinant production of full-length human BicD2 and confirm its biochemical activity by interaction studies with RanBP2. We also describe pH-dependent conformational changes of BicD2 using cryoEM, template-free structure predictions, and biophysical tools. Our results will help define the biochemical parameters for thein vitroreconstitution of higher order BicD2 protein complexes.
Presence of sodium taurocholate co-transporting polypeptide and Hepatitis B replication marker on placenta: Another home for the virus
Authors: Garg Garima , MN Meenu , Patel Kajal , Purwar Shashank , Mukhopadhyay Sramana , Mishra Nitu , Gupta Sudheer , Rawat Sumit Kumar , Khosla Ritu , Singh Jitendra , Nema Shashwati , Biswas Debasis , Singh Anirudh K , Vyas Ashish Kumar
Published: January 2022

Background

The role of sodium taurocholate co-transporting polypeptide (NTCP), in facilitating the binding of Hepatitis B virus (HBV) on surface of hepatocytes is well documented. Expression of NTCP in extra hepatic cells may make these cells susceptible to HBV infection and support cellular proliferation akin to hepatocytes. Placental replication of HBV is not well explored. In this study we have assessed the expression of NTCP and HBV replication markers (HBeAg, HBcAg, and HBV DNA) in placental cells, to investigate if these cells act as host for HBV.

Methods

Fourty one HBsAg+ve pregnant women along with 10 healthy controls were enrolled after obtaining informed consent. The HBV DNA in placenta was detected by qPCR using primers for X and core ORF. Expression of NTCP in placenta was analyzed by qRT-PCR and further investigated by immunohistochemistry (IHC) along with HBV replication biomarkers, HBeAg, and HBcAg.

Results

HBsAg positive subjects were divided in two groups on the basis of viral load [High Viral Load (HVL) Group; viral load ≥ 2000IU/ml, Low Viral Load (LVL) Group; viral load <2000IU/ml] according to INASL guidelines 2018. HBV infected females showed increased expression of NTCP in trophoblasts of placenta compared to control group (HVL 3.69±0.13 Vs Control 1.74±0.15, p=0.0117). Furthermore, significant difference in NTCP expression was also observed between HVL and LVL group (HVL 3.69±0.13 Vs LVL 1.98±0.17, p=0.022) and positively correlated with the maternal HBV DNA load. Membranous and/or cytoplasmic immunostaining of NTCP, and cytoplasmic staining of HBeAg and HBcAg in trophoblasts along with presence of HBV DNA indicated that trophoblasts are not only susceptible to HBV infection but may also be a site for viral replication.

Conclusions

This is the pioneer study, which demonstrates expression of NTCP on placenta which may facilitate the entry of HBV. Furthermore, the study establishes the presence of HBeAg in placenta of patients without circulating HBeAg, indicating these cells may act as replication host/reservoir. This pioneering finding hints at the possibility of exploring the potential of NTCP blocking strategies in preventing vertical transmission of HBV.
Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24
Authors: Cong Zhaotong , Zhou Qingtong , Li Yang , Chen Li-Nan , Zhang Zi-Chen , Liang Anyi , Liu Qing , Wu Xiaoyan , Dai Antao , Xia Tian , Wu Wei , Zhang Yan , Yang Dehua , Wang Ming-Wei
Published: January 2022

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of them are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric non-peptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryo-electron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3 and 7, one arm of both compounds inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8-D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts showing an interaction feature substantially similar to a previously known small molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by non-peptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine tuning of pharmacological efficacy in the development of future small molecule therapeutics targeting GLP-1R.

Significance

GLP-1R agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric non-peptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryo-electron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a previously unknown binding pocket located deeper in the transmembrane domain for non-peptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target.
Nucleoplasmic Lamin C Rapidly Accumulates at Sites of Nuclear Envelope Rupture with BAF and cGAS
Authors: Kono Yohei , Adam Stephen A. , Reddy Karen L. , Zheng Yixian , Medalia Ohad , Goldman Robert D. , Kimura Hiroshi , Shimi Takeshi
Published: January 2022

In mammalian cell nuclei, the nuclear lamina (NL) underlies the nuclear envelope (NE) to maintain nuclear structure. The nuclear lamins, the major structural components of the NL, are involved in the protection against NE rupture induced by mechanical stress. However, the specific role of the lamins in repair of NE ruptures has not been fully determined. Our analyses using immunofluorescence and live-cell imaging revealed that lamin C but not the other lamin isoforms rapidly accumulated at sites of NE rupture induced by laser microirradiation in mouse embryonic fibroblasts. The immunoglobulin-like fold domain and the NLS were required for the recruitment from the nucleoplasm to the rupture sites with the Barrier-to-autointegration factor (BAF). The accumulation of nuclear BAF and cytoplasmic cyclic GMP-AMP synthase (cGAS) at the rupture sites was in part dependent on lamin A/C. These results suggest that nucleoplasmic lamin C, BAF and cGAS concertedly accumulate at sites of NE rupture for repair.

Kono et al. show the rapid recruitment of nucleoplasmic lamin C to sites of nuclear envelope rupture with Barrier-to-autointegration factor. Lamin A/C is also involved in nuclear DNA sensing with cytoplasmic cGAS at the ruptured sites.
Identification and molecular characterization of novel viruses in Ugandan cattle
Authors: Balinandi Stephen , Hayer Juliette , Cholleti Harindranath , Wille Michelle , Lutwama Julius J. , Malmberg Maja , Mugisha Lawrence
Published: January 2022

The risk for the emergence of novel viral zoonotic diseases in animals and humans in Uganda is high given its geographical location with high biodiversity. We aimed to identify and characterize viruses in 175 blood samples from cattle selected in Uganda using molecular approaches. We identified 8 viral species belonging to 4 families (Flaviviridae, Peribunyaviridae, Reoviridae and Rhabdoviridae) and 6 genera (Hepacivirus, Pestivirus, Orthobunyavirus, Coltivirus, Dinovernavirus and Ephemerovirus). Four viruses were novel and tetantively named as Zikole virus (Family: Flaviviridae), Zeboroti virus (Family: Reoviridae), Zebtine virus (Family: Rhabdoviridae) and Kokolu virus (Family: Rhabdoviridae). In addition, Bovine hepacivirus, Obodhiang virus, Aedes pseudoscutellaris reovirus and Schmallenberg virus were identified for the first time in Ugandan cattle. We report a broad range of viruses including novel ones in the blood of cattle likely as reservoir hosts for emergence of novel viruses with serious public health implications.

Highlights

Pan PCR and High Throughput Sequencing Approaches reveal novel viruses in the blood of cattle.

Identified 8 viral species belonging to 4 families: Flaviviridae, Peribunyaviridae, Reoviridae and Rhabdoviridae

60% of the identified viruses were found in the Ankole cattle breed