bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in the quality of cancer care as assessed through performance indicators during the first wave of the COVID-19 pandemic in 2020: a Scoping Review
Authors: Carvalho Ana Sofia , Fernandes Óscar Brito , de Lange Mats , Lingsma Hester , Klazinga Niek , Kringos Dionne
Published: February 2022

Objectives

Summarize performance indicators used in the literature to evaluate the impact of the COVID-19 pandemic on cancer care (January-June 2020), and to assess changes in the quality of care as assessed via selected indicators.

Methods

Scoping review. Indicators and their reported trends were collated following the cancer care pathway.

Results

Database searches retrieved 6277 articles, 838 articles met the inclusion criteria, and 135 articles were included after full-text screening, from which 917 indicators were retrieved. Indicators assessing the diagnostic process showed a decreasing trend: from 33 indicators reporting on screening, 30 (91%) signalled a decrease during the pandemic (n=30 indicators, 91%). A reduction was also observed in the number of diagnostic procedures (n=64, 58%) and in the diagnoses (n=130, 89%). The proportion of diagnoses in the emergency setting and waiting times showed an increasing trend (n=8, 89% and n=14, 56%, respectively). Nine indicators (64%) showed stability in cancer stages distribution. A decreasing trend in the proportion of earliest stage cancers was reported by 63% of indicators (n=9), and 70% (n=43) of indicators showed an increasing trend in the proportion of advanced-stage cancers. Indicators reflecting the treatment process signalled a reduction in the number of procedures: 79% (n=82) of indicators concerning surgeries, 72% (n=41) of indicators assessing trends in radiotherapy, and 93% (n=40) of indicators related to systemic therapies. Modifications in cancer treatment were frequently reported: 64% (n=195) of indicators revealed changes in treatment. Ten indicators (83%) signalled a decreasing number of hospital admissions.

Conclusion

Health systems struggled to ensure continuity of cancer care. As this pandemic keeps evolving, the trends reported over the first 6 months of 2020 provide an argument to monitor these changes closely. This information needs to be transparent, standardised, and timely, allowing to monitor quality and outcomes of care during crises and inform policy responses.
Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-methadone for Use in Cells, Organelles, and Biofluids
Authors: Muthusamy Anand K. , Kim Charlene H. , Virgil Scott C. , Knox Hailey J. , Marvin Jonathan S. , Nichols Aaron L. , Cohen Bruce N. , Dougherty Dennis A. , Looger Loren L. , Lester Henry A.
Published: February 2022

We report a reagentless, intensity-based S-methadone fluorescent sensor, iS-methadoneSnFR, consisting of a circularly permuted GFP inserted within the sequence of a mutated bacterial periplasmic binding protein (PBP). We evolved a previously reported nicotine-binding PBP to become a selective S-methadone-binding sensor, via three mutations in the PBP’s second shell and hinge regions. iS-methadoneSnFR displays the necessary sensitivity, kinetics, and selectivity – notably enantioselectivity against R-methadone – for biological applications. Robust iS-methadoneSnFR responses in human sweat and saliva and mouse serum enable diagnostic uses. Expression and imaging in mammalian cells demonstrate that S-methadone enters at least two organelles and undergoes acid trapping in the Golgi apparatus, where opioid receptors can signal. This work shows a straightforward strategy in adapting existing PBPs to serve real-time applications ranging from subcellular to personal pharmacokinetics.
IgG1 responses following SARS-CoV-2 infection are polyclonal and highly personalized, whereby each donor and each clone displays a distinct pattern of cross-reactivity against SARS-CoV-2 variants
Authors: van Rijswijck Danique M.H. , Bondt Albert , Hoek Max , van der Straten Karlijn , Caniels Tom G. , Poniman Meliawati , Eggink Dirk , Reusken Chantal , de Bree Godelieve J. , Sanders Rogier W. , van Gils Marit J. , Heck Albert J.R.
Published: February 2022

Using a recently introduced efficient mass spectrometry-based approach we monitored individual donors’ IgG1 clonal responses in molecular detail, examining SARS-CoV-2 spike-protein-specific IgG1 repertoires. We monitored the plasma clonal IgG1 profiles of 8 donors (4 male and 4 female) who had recently experienced an infection by either the wild type Wuhan Hu-1 virus or one of 3 VOCs (Alpha, Beta and Gamma). In these donors we charted the full plasma IgG1 repertoires as well as the IgG1 repertoires targeting the SARS-CoV-2 spike protein trimer as antigen. We observed that shortly after infection in between <0.1% to almost 10% of all IgG1 antibody molecules present in plasma did bind to the spike protein. Each donor displayed a unique plasma IgG1 repertoire, but also each donor displayed a unique and polyclonal antibody response against the SARS-CoV-2 spike-protein variants. Our analyses revealed that certain clones exhibit (alike) binding affinity towards all four tested spike-protein variants, whereas other clones displayed strong unique mutant-specific affinity. We conclude that each infected person generates a unique polyclonal response following infection, whereby some of these clones can bind multiple viral variants, whereas other clones do not display such cross-reactivity. In general, by assessing IgG1 repertoires following infection it becomes possible to identify and select fully matured human plasma antibodies that target specific antigens, and display either high specificity or cross-reactivity versus mutated versions of the antigen, which will aid in selecting antibodies that may be developed into biotherapeutics.
Using predictive validity to compare associations between brain damage and behavior
Authors: Magnotti John F. , Patterson Jaclyn S. , Schnur Tatiana T.
Published: February 2022

Lesion-behavior mapping (LBM) provides a statistical map of the association between voxel-wise brain damage and individual differences in behavior. To understand whether two behaviors are mediated by damage to distinct regions, researchers often compare LBM weight outputs by either the Overlap method or the Correlation method. However, these methods lack statistical criteria to determine whether two LBM are distinctvs. the same and are disconnected from a major goal of LBMs: predicting behavior from brain damage. Without such criteria, researchers may draw conclusions from numeric differences between LBMs that are irrelevant to predicting behavior. We developed and validated a Predictive Validity Comparison method (PVC) that establishes a statistical criterion for comparing two LBMs using predictive accuracy: two LBMs are distinct if and only if they provide unique predictive power for the behaviors being assessed. We applied PVC to two lesion-behavior stroke data sets, demonstrating its utility for determining when behaviors arise from the samevs. different lesion patterns. Using region-of-interest based simulations derived from proportion damage from a large data set (n= 131), PVC accurately detected when behaviors were mediated by different regions (high sensitivity) vs. the same region (high specificity). Both the Overlap method and Correlation method performed poorly on the simulated data. By objectively determining whether two behavioral deficits can be explained by a singlevs. distinct patterns of brain damage, PVC provides a critical advance in establishing the brain bases of behavior. We have developed and released a GUI-driven web app to encourage widespread adoption.
Hypoconnectivity between anterior insula and amygdala in neonates with familial history of autism
Authors: Scheinost Dustin , Chang Joseph , Lacadie Cheryl , Brennan-Wydra Emma , Foster Rachel , Boxberger Alexandra , Macari Suzanne , Vernetti Angelina , Constable R. Todd , Ment Laura R. , Chawarska Katarzyna
Published: February 2022

Background

Altered resting state functional connectivity (FC) involving the anterior insula (aINS), a key node in the salience network, has been reported consistently in autism.

Method

Here we examined, for the first time, FC between the aINS and the whole brain in a sample of full-term, postmenstrual age (PMA) matched neonates (mean 44.0 weeks, SD=1.5) who due to family history have high likelihood (HL) for developing autism (n=12) and in controls (n=41) without family history of autism (low likelihood, LL). Behaviors associated with autism were evaluated between 12 and 18 months (M=17.3 months, SD=2.5) in a subsample (25/53) of participants using the First Year Inventory (FYI).

Results

Compared to LL controls, HL neonates showed hypoconnectivity between left aINS and left amygdala. Lower connectivity between the two nodes was associated with higher FYI risk scores in the social domain (r(25) = −.561, p=.003) and this association remained robust when maternal mental health factors were considered. Considering that a subsample of LL participants (n=14/41) underwent brain imaging during the fetal period at PMA 31 and 34 weeks, in an exploratory analysis, we evaluated prospectively development of the LaINS-Lamy connectivity and found that the two areas strongly coactivate throughout the third trimester of pregnancy.

Conclusions

The study identifies left lateralized anterior insula - amygdala connectivity as a potential target of further investigation into neural circuitry that enhances likelihood of future onset of social behaviors associated with autism during neonatal and potentially prenatal periods.
Social interaction and rate effects in models of musical synchronization
Authors: Bégel Valentin , Demos Alexander P. , Wang Michelle , Palmer Caroline
Published: February 2022

Important individual differences are observed in people’s abilities to synchronize their body movements with regular auditory rhythms. We investigate whether synchronizing with a regular auditory cue is affected by each person’s spontaneous production rate (SPR) and by hearing a partner’s synchronization in a social context. Musically trained and untrained participants synchronized their tapping with an auditory cue presented at different rates (their own SPR or their partner’s SPR) and in a Solo or Joint (turn-taking) condition. Linear and nonlinear oscillator models were fit to participants’ mean asynchronies (signed timing differences between the cued onsets and taps). In Joint turn-taking, participants’ synchrony was increased when the auditory signal was cued at the participant’s own SPR, compared with their partner’s SPR; in contrast, synchronization did not differ across rates in the Solo condition. Asynchronies in the Joint task became larger as the difference between partners’ spontaneous rates increased; the increased asynchronies were driven by the faster partner who did not slow down to match the rate of their slower partner. Nonlinear delay-coupled models (with time delay, coupling strength, and intrinsic frequency) outperformed linear models (intrinsic frequency only) in accounting for tappers’ synchronization adjustments. The nonlinear model’s coupling value increased for musically trained participants, relative to untrained participants. Overall, these findings suggest that both intrinsic differences in partners’ spontaneous rates and the social turn-taking context contribute to the range of synchrony in the general population. Delay-coupled models are capable of capturing the wide range of individual differences in auditory-motor synchronization.
Protection of Hamsters Challenged with SARS-CoV-2 after Two Doses of MVC-COV1901 Vaccine Followed by a Single Intranasal Booster with Nanoemulsion Adjuvanted S-2P Vaccine
Authors: Lin Yi-Jiun , Lin Meei-Yun , Chuang Ya-Shan , Liu Luke Tzu-Chi , Kuo Tsun-Yung , Chen Charles , Ganesan Shyamala , Fattom Ali , Bitko Vira , Lien Chia-En
Published: February 2022

Intramuscular vaccines have greatly reduced hospitalization and death due to severe COVID-19. However, most countries are experiencing a resurgence of infection driven predominantly by the Delta and Omicron variants of SARS-CoV-2. In response, booster dosing of COVID-19 vaccines has been implemented in many countries to address waning immunity and reduced protection against the variants. However, intramuscular boosting fails to elicit mucosal immunity and therefore does not solve the problem of persistent viral carriage and transmission, even in patients protected from severe disease. In this study, two doses of stabilized prefusion SARS-CoV-2 spike (S-2P)-based intramuscular vaccine adjuvanted with Alum/CpG1018, MVC-COV1901, were used as a primary vaccination series, followed by an intranasal booster vaccination with nanoemulsion (NE01)-adjuvanted S-2P vaccine in a hamster model to demonstrate immunogenicity and protection from viral challenge. Here we report that this vaccination regimen resulted not only in the induction of robust immunity and protection against weight loss and lung pathology following challenge with SARS-CoV-2, but also led to increased viral clearance from both upper and lower respiratory tracts. Our findings showed that intramuscular MVC-COV1901 vaccine followed by a booster with intranasal NE01-adjuvanted vaccine promotes protective immunity against both viral infection and disease, suggesting that this immunization protocol may offer a solution in addressing a significant, unmet medical need for both the COVID-19 and future pandemics.
IFNβ-1b treatment leads to changes in the B cell subset and cytokine secretion profile in patients with relapsing-remitting multiple sclerosis
Authors: Mielcarz Daniel W. , Bergeron Alan J. , DeLong John K. , Dias Alexandra , Smith Kathleen M. , Mack Karen L. , Kasper Lloyd H. , Channon Jacqueline Y.
Published: February 2022

In order to explore the effect of IFNβ-1b treatment on B cell phenotype and function in RRMS patients, blood was drawn from RRMS patients before treatment and again 2 and 6 months after every other day injections of IFNβ-1b. Cryopreserved peripheral blood mononuclear cells (PBMCs) were thawed and stained with panels of antibodies against B cell surface antigens and the intracellular cytokines, IL-10 and IL-6. At baseline, PBMCs from RRMS patients have increased frequencies of B1 cells and a decreased frequencies of memory B cells when compared with PBMCs from age- and gender-matched healthy controls. CpG-stimulated PBMCs from patients treated with IFNβ-1b show an increase in IL-10 production and a decrease in IL-6 production by naïve, memory and B1 cells compared with healthy controls. In addition, this treatment alters the composition of circulating B cell subsets, leading to an increase after six months in circulating naïve B cells and a decrease in both memory and B1 cells, both cell types of which are potentially pathogenic in RRMS. Patients were divided into two groups based on disease activity, no/low or moderate/high. A significantly higher frequency of B1 cells and higher expression of CD27 on these cells was seen at baseline in the moderate/high disease activity group to IFNβ-1b compared with patients in the no/low disease activity group. Although the number of subjects in this study was limited, these findings suggest that alterations in the B cell compartment may be a mechanism by which IFNβ-1b reduces disease activity.
Reassessment of persistent symptoms, self-reported COVID-19 infection and SARS-CoV-2 serology in the SAPRIS-SERO cohort: identifying possible sub-syndromes of Long Covid
Authors: Spiers Nicola
Published: February 2022

Background

Long Covid remains a relatively new phenomenon with emerging understanding. Estimated UK prevalence of Long Covid with three or more symptoms lasting for 12 weeks or more was 2.2% at the end of 2021. The population-based French SAPRIS-SERO cohort has novel information about the pattern of symptoms of Long Covid that has been obscured by controversy around the original paper.

Methods

Secondary analysis was used to describe and re-interpret the frequencies of persistent symptoms by IgG seropositivity and self-reported Long Covid in the published report of the SAPRIS-SERO survey. Participants in the cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, the Euroimmun enzyme-linked immunosorbent assay was used to detect anti-SARS-CoV-2 antibodies. Surveyed online between December 2020 and January 2021, participants self-reported previous COVID-19 infection and physical symptoms during the previous four weeks that were new since March 2020, and had persisted for at least eight weeks.

Results

There was similarity of prevalence over the majority of symptoms in those self-reporting COVID-19 infection, regardless of blood test result. Persistent symptoms significantly associated with self-reported COVID-19 infection and common in both groups include respiratory tract symptoms and a group of symptoms that might be related to chronic fatigue, malaise or postural issues. Seropositivity for IgG antibodies did not predict symptoms independently of self-reported Long Covid, except for anosmia.

Conclusions

There may be three common sub-syndromes of Long Covid, one with persistent anosmia, another with other respiratory tract symptoms and a third, currently under researched, with symptoms relatable to chronic fatigue. Antibody tests are insufficient for case detection while Long Covid remains poorly understood.

Key Messages

IgG seropositivity is insufficient to identify potential cases of Long Covid

Persistent anosmia is very strongly associated with IgG seropositivity and may define a subsyndrome of Long Covid

Other potential subsyndromes are those with persistent respiratory symptoms and those with persistent symptoms relatable to fatigue, malaise or postural issues

The Long Covid research effort should be rebalanced towards understanding the fatigue/tiredness subsyndrome.
Impact of Omicron variant on the response to SARS-CoV-2 mRNA Vaccination in multiple myeloma
Authors: Storti Paola , Marchica Valentina , Vescovini Rosanna , Franceschi Valentina , Russo Luca , Raimondi Vincenzo , Toscani Denise , Garcia Jessica Burroughs , Costa Federica , Palma Benedetta Dalla , Soressi Naomi , Giaimo Mariateresa , Iannozzi Nicolas Thomas , Notarfranchi Laura , Sammarelli Gabriella , Donofrio Gaetano , Giuliani Nicola
Published: February 2022

Multiple myeloma (MM) patients may have a reduced response to vaccination due to immunodeficiency. The humoral and cellular response to SARS-CoV-2 mRNA full vaccination and booster dose as well as the impact of spike variants, including the emerging Omicron one, are still unclear and have been investigated in this study in a cohort of MM patients and those with pre-malignant monoclonal gammopathies.

Firstly, we have shown that MM patients with relapsed-refractory disease (MMR) had a reduced spike-specific antibody levels and neutralizing titers after SARS-CoV-2 mRNA full vaccination. Interestingly, all the analyzed variants, remarkably Omicron, had a significant negative impact on the neutralizing ability of the vaccine-induced antibodies in all patients with MM and in smoldering MM too. Moreover, lower spike-specific IL-2-producing CD4+ T cells and reduced cytotoxic spike-specific IFN-γ and TNF-α-producing-CD8+ T cells were found in MM patients as compared to MGUS.

Finally, we found that booster immunization improved SARS-CoV-2 spike humoral and cellular responses in newly diagnosed MM (MMD) patients and in most, but not all, MMR patients. After the booster dose, a significant increase of the neutralizing antibody titers against almost all the analyzed variants was achieved in MMD. On the other hand, in MMR patients, Omicron retain a negative impact on neutralizing ability, suggesting these patients need to be considered still at risk of Omicron SARS-CoV-2 infection with a clinically relevant disease.
Late-Ensemble of Convolutional Neural Networks with Test Time Augmentation for Chest XR COVID-19 Detection
Authors: Qayyum Abdul , Razzak Imran , Mazher Moona , Puig Domenec
Published: February 2022

COVID-19, a severe acute respiratory syndrome aggressively spread among global populations in just a few months. Since then, it has had four dominant variants (Alpha, Beta, Gamma and Delta) that are far more contagious than original. Accurate and timely diagnosis of COVID-19 is critical for analysis of damage to lungs, treatment, as well as quarantine management [7]. CT, MRI or X-rays image analysis using deep learning provide an efficient and accurate diagnosis of COVID-19 that could help to counter its outbreak. With the aim to provide efficient multi-class COVID-19 detection, recently, COVID-19 Detection challenge using X-ray is organized [12]. In this paper, the late-fusion of features is extracted from pre-trained various convolutional neural networks and fine-tuned these models using the challenge dataset. The DensNet201 with Adam optimizer and EffecientNet-B3 are fine-tuned on the challenge dataset and ensembles the features to get the final prediction. Besides, we also considered the test time augmentation technique after the late-ensembling approach to further improve the performance of our proposed solution. Evaluation on Chest XR COVID-19 showed that our model achieved overall accuracy is 95.67%. We made the code is publicly available1. The proposed approach was ranked 6th in Chest XR COVID-19 detection Challenge [1].
Longitudinal analysis of UK Biobank participants suggests age and APOE-dependent alterations of energy metabolism in development of dementia
Authors: Liu Jun , Amin Najaf , Sproviero William , Arnold Matthias , Batra Richa , Bonnechere Bruno , Chiou Yu-Jie , Fernandes Marco , Krumsiek Jan , Newby Danielle , Nho Kwangsik , Kim Jun Pyo , Saykin Andrew J , Shi Liu , Winchester Laura , Yang Yang , Nevado-Holgado Alejo J , Kastenmüller Gabi , Kaddurah-Daouk Rima F , van Duijn Cornelia M
Published: February 2022

Experimental models shows that bioenergetic homeostasis changes with increasing age based on apolipoprotein E (APOE) gene. However, such link with dementia remains unclear in population. We used H1-NMR metabolome in blood from 118,021 random-selected participants in UK Biobank (n=118,021 individuals), and identified 56 metabolites associated with the risk of dementia. In the participants without developing dementia during follow-up, 82% (46/56) metabolites are also associated with reaction time, and dementia shares metabolite signatures with total brain volume. We found that incident Alzheimer’s disease (AD) is associated with energy metabolism-related metabolites, i.e, β-hydroxybutyrate, acetone, and valine, whose concentrations in blood are influenced by age and APOE genotype. Valine shows a declined trajectories after a plateau at age around 60 years which is in parallel with body mass index. Moreover, we found associations of AD with valine and β-hydroxybutyrate in brain tissue are different as their associations in the periphery, which implies the key role of transports in regulating the energy metabolism of AD. Our study provides strong evidence in population level that the onset of AD in APOE4 carriers is regulated by the impaired energy balance in the brain.
Structural basis for receptor selectivity and inverse agonism in S1P5 receptors
Authors: Lyapina Elizaveta , Marin Egor , Gusach Anastasiia , Orekhov Philipp , Gerasimov Andrey , Luginina Aleksandra , Vakhrameev Daniil , Ergasheva Margarita , Kovaleva Margarita , Khusainov Georgii , Khorn Polina , Shevtsov Mikhail , Kovalev Kirill , Okhrimenko Ivan , Popov Petr , Hu Hao , Weierstall Uwe , Liu Wei , Cho Yunje , Gushchin Ivan , Rogachev Andrey , Bourenkov Gleb , Park Sehan , Park Gisu , Hyun Hyo Jung , Park Jaehyun , Gordeliy Valentin , Borshchevskiy Valentin , Mishin Alexey , Cherezov Vadim
Published: February 2022

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PR) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric subpocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, the new S1P5-inverse agonist structure sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR-family.
Thermal regime during parental sexual maturation, but not during offspring rearing, modulates DNA methylation in brook charr (Salvelinus fontinalis)
Authors: Venney Clare J , Wellband Kyle W , Normandeau Eric , Houle Carolyne , Garant Dany , Audet Céline , Bernatchez Louis
Published: February 2022

Epigenetic inheritance can result in plastic responses to changing environments being faithfully transmitted to offspring. However, it remains unclear how epigenetic mechanisms such as DNA methylation can contribute to multigenerational acclimation and adaptation to environmental stressors. Brook charr (Salvelinus fontinalis), an economically important salmonid, is highly sensitive to thermal stress, and is of conservation concern in the context of climate change. We studied the effects of temperature during parental sexual maturation and offspring rearing on whole-genome DNA methylation in brook charr juveniles (fry). Parents were split between warm and cold temperatures during sexual maturation, mated in controlled breeding designs, then offspring from each family were split between warm (8°C) and cold (5°C) rearing environments. We found 188 differentially methylated regions (DMRs) due to parental maturation temperature after controlling for family structure. In contrast, offspring rearing temperature had a negligible effect on offspring methylation. Stable intergenerational inheritance of DNA methylation and minimal plasticity in progeny could result in transmission of acclimatory epigenetic states to offspring, priming them for a warming environment. Our findings have implications pertaining to the role of intergenerational epigenetic inheritance in response to ongoing climate change.
Nicotinamide Riboside alleviates exercise intolerance in ANT1-deficient mice
Authors: Schaefer Patrick M. , Huang Jessica , Butic Arrienne , Perry Caroline E. , Yardeni Tal , Tan Wendy , Morrow Ryan , Baur Joseph A. , Wallace Douglas C.
Published: February 2022

Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. We have analyzed the exercise physiology of mice deficient in ANT1, demonstrating a peripheral limitation of skeletal muscle mitochondrial respiration. Upon exercise, lack of Nicotinamide adenine dinucleotide+ (NAD+) results in a substrate limitation and stalling of the TCA cycle and mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and improved the exercise capacity and mitochondrial respiration. Thus, increasing NAD+ levels with nicotinamide riboside can alleviate the exercise intolerance associated with ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in specific mitochondrial myopathies.
Distinct execution modes of a biochemical necroptosis model explain cell type-specific responses and variability to cell-death cues
Authors: Ildefonso Geena V. , Oliver-Metzig Marie , Hoffmann Alexander , Harris Leonard A. , Lopez Carlos F.
Published: February 2022

Necroptosis is a form of regulated cell death that has been associated with degenerative disorders, autoimmune processes, inflammatory diseases, and cancer. To better understand the biochemical mechanisms of necroptosis cell death regulation, we constructed a detailed biochemical model of tumor necrosis factor (TNF)-induced necroptosis based on known molecular interactions. Intracellular protein levels, used as model inputs, were quantified using label-free mass spectrometry, and the model was calibrated using Bayesian parameter inference to experimental protein time course data from a well-established necroptosis-executing cell line. The calibrated model accurately reproduced the dynamics of phosphorylated mixed lineage kinase domain-like protein (pMLKL), an established necroptosis reporter. A dynamical systems analysis identified four distinct modes of necroptosis signal execution, which can be distinguished based on rate constant values and the roles of the deubiquitinating enzymes A20 and CYLD in the regulation of RIP1 ubiquitination. In one case, A20 and CYLD both contribute to RIP1 deubiquitination, in another RIP1 deubiquitination is driven exclusively by CYLD, and in two modes either A20 or CYLD acts as the driver with the other enzyme, counterintuitively, inhibiting necroptosis. We also performed sensitivity analyses of initial protein concentrations and rate constants and identified potential targets for modulating necroptosis sensitivity among the biochemical events involved in RIP1 ubiquitination regulation and the decision between complex II degradation and necrosome formation. We conclude by associating numerous contrasting and, in some cases, counterintuitive experimental results reported in the literature with one or more of the model-predicted modes of necroptosis execution. Overall, we demonstrate that a consensus pathway model of TNF-induced necroptosis can provide insights into unresolved controversies regarding the molecular mechanisms driving necroptosis execution for various cell types and experimental conditions.
Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)
Authors: Abbas Qussai , Kusakin Alexey , Sharrouf Kinda , Jyakhwo Susan , Komissarov Aleksey S
Published: February 2022

Aided by extensive protein mutations, the SARS-CoV-2 Omicron (B.1.1.529) variant overtook the previously dominant Delta variant and rapidly spread around the world. It was shown to exhibit significant resistance to current vaccines and evasion from neutralizing antibodies. It is therefore critical to investigate the Omicron mutations’ trajectories. In this study, a literature search of published articles and SARS-CoV-2 databases was conducted, We explored the full list of mutations in Omicron BA.1, BA.1.1, BA.2, and BA.3 lineages. We described in detail the prevalence and occurrence of the mutations across variants, and how Omicron differs from them. We used GISAID as our primary data source, which provides open-access to genomics data of the SARS-CoV-2 virus, in addition to epidemiological and geographical data. We examined how these mutations interact with each other, their co-occurrence and clustering. Our study offers for the first time a comprehensive description of all mutations with a focus on non-spike mutations and demonstrated that mutations in regions other than the Spike (S) genes are worth investigating further. Our research established that the Omicron variant has retained some mutations reported in other SARS-CoV-2 variants, yet many of its mutations are extremely rare in other variants and unique to Omicron. Some of these mutations have been linked to the transmissibility and immune escape of the virus, and indicate a significant shift in SARS-CoV-2 evolution. The most likely theories for the evolution of the Omicron variant were also discussed.
Cryo-EM structure of the Rhodobaca bogoriensis RC-LH1-PufX dimeric complex at 2.9 Å
Authors: Semchonok Dmitry A. , Siponen Marina I. , Tüting Christian , Charras Quentin , Kyrilis Fotis L. , Hamdi Farzad , Sadian Yashar , Jungas Colette , Kastritis Panagiotis L.
Published: February 2022

The reaction centre-light harvesting 1 (RC-LH1) complex is essential for converting light into proton motive force in photosynthetic bacteria. RC-LH1 is a monomer in most purple bacteria, but in Rhodobacter species, it is a dimer. Its assembly depends on an accessory polypeptide (PufX) and, ultimately, on photosynthetic growth. To date, knowledge on the RC-LH1-PufX structure, where the dimer has two incomplete ‘C’-shaped antenna rings surrounding an RC, is mainly limited to the model organism Rhodobacter sphaeroides. Here we present a cryo-electron microscopy structure at 2.9 Å from Rhodobaca bogorensis strain LBB1. RCs are surrounded by 30 antennas and incorporate protein Y and PufX. RCs are stably connected by PufX, which self-interacts, electrostatically attracts cytochrome c2 (cyt c2) and forms extensive networks with co-factors. This structure underlines coordinated energy transfer in a combinatorial manner, providing a basis to describe bacterial photosynthesis within a dimeric photosynthetic apparatus.
A structural dynamic explanation for observed escape of SARS-CoV-2 BA.2 variant mutation S371L/F
Authors: Miller Nathaniel L. , Clark Thomas , Raman Rahul , Sasisekharan Ram
Published: February 2022

The SARS-CoV-2 Omicron sub-variants BA.1 and BA.2 have become the dominant variants worldwide due to enhanced transmissibility and immune evasion. In response to the rise of BA.1 and BA.2, two recent studies by Liu et al. and Iketani et al. provide a detailed analysis of loss of therapeutic antibody potency through evaluation of escape by pseudotyped viruses harboring BA.1 and BA.2 receptor binding domain (RBD) point mutations. Surprisingly, Liu et al. and Iketani et al. observed a profoundly broad escape effect for the individual mutations S371L and S371F. This result cannot be explained by known escape mechanisms of the SARS-CoV-2 RBD, and conflicts with existing computational and experimental escape measurements for S371 mutations performed on monomeric RBD. Through an examination of these conflicting datasets and a structural analysis of the antibodies assayed by Liu et al. and Iketani et al., we propose a mechanism to explain S371L/F escape according to a perturbation of spike trimer conformational dynamics that has not yet been described for any SARS-CoV-2 escape mutation. The proposed mechanism is relevant to Omicron and future variant surveillance as well as therapeutic antibody design.
Vision-related convergent gene losses revealSERPINE3’s unknown role in the eye
Authors: Indrischek Henrike , Hammer Juliane , Machate Anja , Hecker Nikolai , Kirilenko Bogdan M. , Roscito Juliana G. , Hans Stefan , Norden Caren , Brand Michael , Hiller Michael
Published: February 2022

Despite decades of research, knowledge about the genes that are important for development and function of the mammalian eye and are involved in human eye disorders remains incomplete. During mammalian evolution, mammals that naturally exhibit poor vision or regressive eye phenotypes have independently lost many eye-related genes. This provides an opportunity to predict novel eye-related genes based on specific evolutionary gene loss signatures. Building on these observations, we performed a genome-wide screen across 49 mammals for functionally uncharacterized genes that are preferentially lost in species exhibiting lower visual acuity values. The screen uncovered several genes, includingSERPINE3, a putative serine proteinase inhibitor. A detailed investigation of 381 additional mammals revealed thatSERPINE3is independently lost in 18 lineages that typically do not primarily rely on vision, predicting a vision-related function for this gene. To test this, we show thatSERPINE3has the highest expression in eyes of zebrafish and mouse. In the zebrafish retina,serpine3is expressed in Mueller glia cells, a cell type essential for survival and maintenance of the retina. A CRISPR-mediated knockout ofserpine3in zebrafish resulted in alterations in eye shape and defects in retinal layering. Furthermore, two human polymorphisms that are in linkage withSERPINE3are associated with eye-related traits. Together, these results suggest thatSERPINE3has a role in vertebrate eyes. More generally, by integrating comparative genomics with experiments in model organisms, we show that screens for specific phenotype-associated gene signatures can predict functions of uncharacterized genes.
Conservation and evolution of the sporulation gene set in diverse members of the Firmicutes
Authors: Galperin Michael Y. , Yutin Natalya , Wolf Yuri I. , Alvarez Roberto Vera , Koonin Eugene V.
Published: February 2022

The current classification of the phylum Firmicutes (new name,Bacillota) features eight distinct classes, six of which include known spore-forming bacteria. InBacillus subtilis, sporulation involves up to 500 genes, many of which do not have orthologs in other bacilli and/or clostridia. Previous studies identified about 60 sporulation genes ofB. subtilisthat were shared by all spore-forming members of the Firmicutes. These genes are referred to as the sporulation core or signature although many of these are found also in genomes of non-spore-formers. Using an expanded set of 180 firmicute genomes from 160 genera, including 76 spore-forming species, we investigated the conservation of the sporulation genes, in particular, seeking to identify lineages that lack some of the genes from the conserved sporulation core. The results of this analysis confirmed that many small acid-soluble spore proteins (SASPs), spore coat proteins, and germination proteins, which were previously characterized in bacilli, are missing in spore-forming members ofClostridiaand other classes of Firmicutes. A particularly dramatic loss of sporulation genes was observed in the spore-forming members of the familiesPlanococcaceaeandErysipelotrichaceae. Fifteen species from diverse lineages were found to carryskin(sigK-interrupting) elements of different sizes that all encoded SpoIVCA-like recombinases but did not share any other genes. Phylogenetic trees built from concatenated alignments of sporulation proteins and ribosomal proteins showed similar topology, indicating an early origin and subsequent vertical inheritance of the sporulation genes.

IMPORTANCE

Many members of the phylum Firmicutes (Bacillota) are capable of producing endospores, which enhance the survival of important Gram-positive pathogens that cause such diseases as anthrax, botulism, colitis, gas gangrene, and tetanus. We show that the core set of sporulation genes, defined previously through genome comparisons of several bacilli and clostridia, is conserved in a wide variety of spore-formers from several distinct lineages of Firmicutes. We also detect widespread loss of sporulation genes in many organisms, particularly within familiesPlanococcaceaeandErysipelotrichaceae.Members of these families, such asLysinobacillus sphaericusandClostridium innocuum, could be excellent model organisms for studying sporulation mechanisms, such as engulfment, formation of the spore coat, and spore germination.
Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation
Authors: Merour Emeric , Hmidan Hatem , Marie Corentine , Helou Pierre-Henri , Lu Haiyang , Potel Antoine , Hure Jean-Baptiste , Clavairoly Adrien , Shih Yi Ping , Goudarzi Salman , Dussaud Sebastien , Ravassard Philippe , Hafizi Sassan , Lo Su Hao , Hassan Bassem A. , Parras Carlos
Published: February 2022

The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves largescale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-β1, a key mediator of survival at this transient stage. Constitutive Tns3 loss-of-function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of Tns3 in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a two-fold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-β1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation.
Adenosine A2A Receptor (A2AR) agonists improve survival in K28-hACE2 mice following SARS CoV-2 infection
Authors: Mann Barbara J. , Chhabra Preeti , Ma Mingyang , Brovero Savannah G. , Jones Marieke K. , Linden Joel , Brayman Kenneth L.
Published: February 2022

Effective and available therapies for the treatment of COVID-19 disease are limited. Apadenoson is a highly potent selective anti-inflammatory adenosine A2A receptor (A2AR) agonist and potential treatment option for COVID-19 patients. Apadenoson, when administered after infection with SARS CoV-2, was found to decrease weight loss, improve clinical symptoms, reduce levels of a several proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and promote increased survival in K18hACE2 transgenic mice. Of note, administering apadenoson after, but not prior to Covid-19 infection, caused a rapid decrease in lung viral burden. The work presented provides the foundation for further examination of these drugs as a therapy option for COVID-19.

Apadenoson therapy improves COVID-19 outcome
DLK-dependent biphasic reactivation of herpes simplex virus latency established in the absence of antivirals
Authors: Dochnal Sara , Merchant Husain Y. , Schinlever Austin R. , Babnis Aleksandra , Depledge Daniel P. , Wilson Angus C. , Cliffe Anna R.
Published: February 2022

Understanding the molecular mechanism of herpes simplex virus type 1 (HSV-1) latent infection and reactivation in neurons requires the use of model systems. However, establishing a quiescent infection in cultured neurons is problematic as infectious virus released from any productively infected neuron can superinfect the cultures. Here, we describe a new reporter virus, HSV-1 Stayput-GFP, that is defective for cell-to-cell spread and can be used to model latency and reactivation at the single neuron level. Importantly, quiescent infection of neurons with Stayput-GFP can be established without the use of a viral DNA replication inhibitor. The establishment of a quiescent state requires a longer time frame than previous models of HSV latency using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate, and the use of multiple reactivation triggers is required. Using this system, we demonstrate that an initial Phase I wave of lytic gene expression occurs independently of histone demethylase activity and viral DNA replication but is dependent on the neuronal cell stress protein, DLK. Progression into the later, Phase II wave of reactivation, characterized by detectable late viral protein synthesis and a requirement for histone demethylase activity, is also observed with the Stayput-GFP model system. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and occur when latent infections are established in the absence of a viral DNA replication inhibitor.

Importance

Herpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivationin vitrois invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novelin vitromodel system using a cell-to-cell spread defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infectionin vitro. Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK, but independent of histone demethylase activity and viral DNA replication. Our data therefore demonstrate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.
Natural Variation Meets Synthetic Biology: Promiscuous Trichome Expressed Acyltransferases from Nicotiana acuminata
Authors: Schenck Craig A. , Anthony Thilani M. , Jacobs MacKenzie , Jones A. Daniel , Last Robert L.
Published: February 2022

Acylsugars are defensive, trichome-synthesized sugar esters produced in plants across the Solanaceae (nightshade) family. Although assembled from simple metabolites and synthesized by a relatively short core biosynthetic pathway, tremendous within- and across-species acylsugar structural variation is documented across the family. To advance our understanding of the diversity and the synthesis of acylsugars within the Nicotiana genus, trichome extracts were profiled across the genus coupled with transcriptomics-guided enzyme discovery and in vivo and in vitro analysis. Differences in the types of sugar cores, numbers of acylations, and acyl chain structures contributed to over 300 unique annotated acylsugars throughout Nicotiana. Placement of acyl chain length into a phylogenetic context revealed that an unsaturated acyl chain type was detected in a few closely-related species. A comparative transcriptomics approach identified trichome-enriched Nicotiana acuminata acylsugar biosynthetic candidate enzymes. > 25 acylsugar variants could be produced in a single enzyme assay with four acylsugar acyltransferases (NacASAT1-4) together with structurally diverse acyl-CoAs and sucrose. Liquid chromatography coupled with mass spectrometry screening of in vitro products revealed the ability of these enzymes to make acylsugars not present in Nicotiana plant extracts. In vitro acylsugar production also provided insights into acyltransferase acyl donor promiscuity and acyl acceptor specificity as well as regiospecificity of some ASATs. This study suggests that promiscuous Nicotiana acyltransferases can be used as synthetic biology tools to produce novel and potentially useful metabolites.

ONE SENTENCE SUMMARY

Analysis of Nicotiana glandular trichome metabolites and BAHD acyltransferases revealed diverse sucrose and glucose based acylesters.