bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity of endemic behaviour of Covid-19 under a multi-dose vaccination regime, to various biological parameters and control variables
Authors: Dagpunar John , Wu Chenchen 
Published: October 2022

AbstractFor an infectious disease such as Covid-19, we present a new four-stage vaccination model (un-vaccinated, dose 1+2, booster, repeated boosters), which examines the impact of vaccination coverage, vaccination rate, generation interval, control reproduction number, vaccine efficacies, and rates of waning immunity, upon the dynamics of infection. We derive a single equation that allows computation of equilibrium prevalence and incidence of infection, given knowledge about these parameter and variable values. Based upon a 20 compartment model, we develop a numerical simulation of the associated differential equations. The model is not a forecasting or even predictive one, given the uncertainty about several biological parameter values. Rather, it is intended to aid qualitative understanding of how equilibrium levels of infection may be impacted upon, by the parameters of the system. We examine one at a time sensitivity analysis around a base case scenario. The key finding which should be of interest to policy makers, is that while factors such as improved vaccine efficacy, increased vaccination rates, lower waning rates, and more stringent non-pharmaceutical interventions might be thought to improve equilibrium levels of infection, this might only be done to good effect, if vaccination coverage on a recurrent basis, is sufficiently high.
Midlife “Deaths of Despair” Trends in the US, Canada, and UK, 2001-2019: Is the US an Anomaly?
Authors: Dowd Jennifer Beam , Angus Colin , Zajacova Anna , Tilstra Andrea M. 
Published: October 2022

AbstractBackgroundOver the past decade, “deaths of despair” were strongly implicated in rising mid-life mortality in the US. Whether despair deaths and mid-life mortality trends are also changing in the peer countries such as the UK and Canada is not well known.MethodsWe compared all-cause and “despair” mortality trends at mid-life in the US, the UK (constituent nations England & Wales, Northern Ireland, and Scotland) and Canada from 2000-2019, using publicly available mortality data, stratified by three age groups (35-44, 45-54 and 55-64) and by sex. We examined trends in all-cause mortality and mortality by causes categorized as 1) suicides 2) alcohol-specific deaths 3) drug-related deaths. We employ several descriptive approaches to visually inspect age, period, and cohort trends in these causes of death.ResultsThe US and Scotland both saw large increases and high absolute levels of drug-related deaths. The rest of the UK and Canada saw relative increases but much lower absolute levels in by comparison. Alcohol-specific deaths showed less consistent trends that did not track other “despair” causes, with older groups in Scotland seeing steep declines over time. Suicide deaths trended slowly upward in most countries.ConclusionsIn the UK, Scotland has suffered increases in drug-related mortality comparable to the US, while Canada and other UK constituent nations did not see dramatic increases. Alcohol-specific and suicide mortality generally follow different patterns to drug-related deaths across countries and over time, questioning the utility of a cohesive “deaths of despair” narrative.
Proton Transfers to DNA in Native Electrospray Ionization Mass Spectrometry: A QM/MM Study
Authors: Paulikat Mirko , Aranda Juan , Ippoliti Emiliano , Orozco Modesto , Carloni Paolo 
Published: October 2022

ABSTRACTNative electrospray ionization - ion mobility mass spectrometry (N-ESI/IM-MS) is a powerful approach for low-resolution structural studies of DNAs in the free state and in complex with ligands. Solvent vaporization is coupled with proton transfers from ammonium ions to the DNA resulting in a reduction of the DNA charge. Here we provide insight on these processes by classical MD and QM/MM free energy calculations on the (GpCpGpApApGpC) heptamer, for which a wealth of experiments is available. Our multiscale simulations, consistent with experimental data, reveal a highly complex scenario: the proton either sits on one of the molecules or is fully delocalized on both, depending on the level of hydration of the analytes and on size of the droplets formed during the electrospray experiments. This work complements our previous study on theintramolecularproton transfer on the same heptamer occurring after the processes studied here, and, together, provide a first molecular view of proton transfer in N-ESI/IM-MS.TOC GRAPHICS
Elucidating the molecular programming of a nonlinear nonribosomal peptide synthetase responsible for fungal siderophore biosynthesis
Authors: Jenner Matthew , Hai Yang , Nguyen Hong H. , Passmore Munro , Skyrud Will , Kim Junyong , Garg Neil K. , Zhang Wenjun , Ogorzalek Loo Rachel R. , Tang Yi 
Published: October 2022

ABSTRACTSiderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) assembly lines remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin.In vitroreconstitution of purified SidC revealed its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovered several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.
TRIM 25 nuclear translocation is hampered by localization to influenza A virus non-structural protein 1 cytosolic aggregates
Authors: Weiß Anne , Haralampiev Ivan , Kummer Susann 
Published: October 2022

AbstractNon-structural protein 1 (NS1) of influenza A virus (IAV) is involved in multiple blocking processes of cellular antiviral action. One of these includes the binding of cytosolic tripartite motif-containing protein 25 (TRIM25) to impede nuclear translocation and, thus, counteracting the block of viral RNA elongation taking place inside the nucleus. In addition, TRIM25 is part of the RIG-I signaling pathway and is an important component regarding the activation of interferon-induced genes and triggering cellular antiviral responses. In this study, we focus on the spatial localization of TRIM25 with respect to cytosolic NS1 aggregates found in IAV infected cells. Besides strain specific characteristics, we confirmed co-localization of TRIM25 to NS1 cytosolic aggregates at 16 hours post infection for all investigated IAV strains based on image analysis on single cell level. Immunoprecipitation further confirmed the interaction between NS1 and TRIM25 when comparing wt IAV and recombinant IAV devoid of NS1 expression. Of note, we combined fluorescencein situhybridization targeting viral RNA with immunolabeling of TRIM25 suitable for nanoscopy and the diffraction limited detection of NS1 in one imaging approach. Our study reveals strain dependent differences in the block of IRF3 activation in respect to the accumulation of TRIM25 in cytosolic NS1 aggregates.
Absence of estrogen leads to defects in spermatogenesis and increased semen abnormalities in male rabbits
Authors: Dewaele Aurélie , Dujardin Emilie , André Marjolaine , Albina Audrey , Jammes Hélène , Giton Frank , Sellem Eli , Jolivet Geneviève , Pailhoux Eric , Pannetier Maëlle 
Published: October 2022

AbstractEstrogens are steroid hormones produced by the aromatization of androgens by the aromatase enzyme, encoded by theCYP19A1gene. Although generally referred to as “female sex hormones”, estrogen is also produced in the adult testes of many mammals, including humans. To better understand the function of estrogens in the male, we used the rabbit model which is an important biomedical model. First, the expression ofCYP19A1was localized, demonstrating that testicular estrogens are produced by meiotic germ cells inside the seminiferous tubules. Next, the cells expressing ESR1 and ESR2 were identified, showing that estrogens could exert their function on post-meiotic germ cells in the tubules and play a role during sperm maturation, since ESR1 and ESR2 were detected in thecaudaepididymis. Then, CRISPR/Cas9CYP19A1−/−genetically modified rabbits were analyzed.CYP19A1−/−males showed decreased fertility with lower sperm count associated with hypo-spermatogenesis and lower spermatid number. Germ/sperm cell DNA methylation was unchanged, while sperm parameters were affected asCYP19A1−/−males exhibited reduced sperm motility associated with increased flagellar defects. In conclusion, testicular estrogens could be involved in the spermatocyte-spermatid transition in the testis, and in the acquisition of sperm motility in the epididymis.
Maternal patterns of inheritance alter transcript expression in eggs
Authors: Harry Nathan D. , Zakas Christina 
Published: October 2022

ABSTRACTModifications to early development can lead to evolutionary diversification. The early stages of development are under maternal control, as mothers produce eggs loaded with nutrients, proteins and mRNAs that direct early embryogenesis. Maternally provided mRNAs are the only expressed genes in initial stages of development and are known to be tightly regulated. Differences in maternal mRNA provisioning could lead to phenotypic changes in embryogenesis and ultimately evolutionary changes in development. However, the extent to which variation in maternal mRNA provisioning impacts ontogeny or life-history is unknown. Here, we use a species with dimorphic development— where females make eggs and larvae of different sizes and life-history modes—to investigate the extent of variation in maternal mRNA provisioning to the egg. We examine the effect of gene expression differences on subsequent generations of egg provisioning and determine the regulatory architecture underlying mRNA provisioning differences. We find that there is significant variation in gene expression across eggs of different development modes, and that both parent-of-origin and allele-specific effects contribute to mRNA expression differences. We also find that offspring of intraspecific crosses differentially provision their eggs based on their parents’ cross direction. This effect of allelic expression based on parent-of-origin has not been previously demonstrated in reproductive traits like oogenesis.AUTHOR SUMMARYVariation in early developmental programs can provide the basis for evolutionary diversification. In the early embryo, cellular functions are carried out by proteins and transcripts contributed by the mother to the egg until the embryo’s own genome can take over. Since these maternal factors are responsible for setting up all of the subsequent development of the offspring, they tend to be tightly regulated. However, variation exists in the amount and types of transcripts mothers provide. Here we examine how the variation in maternal transcripts that occurs in eggs of the speciesStreblospio benedicti, leads to developmental differences.S. benedictioffspring follow one of two distinct developmental programs that originate with egg size differences. We find significant variation in maternally provided transcripts correlated with the two life-histories, and that some of this variation in egg transcripts is directly related to the developmental type of the mother’s own parents. This parental effect on how mothers provide transcripts to their eggs has not previously been described and indicates the possibility for an offspring’s grandparents to affect their early developmental program by modulating the transcripts their mother provides.
A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens
Authors: Schlegel Jan , Porebski Bartlomiej , Andronico Luca , Hanke Leo , Edwards Steven , Brismar Hjalmar , Murrell Benjamin , McInerney Gerald , Fernandez-Capetillo Oscar , Sezgin Erdinc 
Published: October 2022

AbstractSpeed is key during infectious disease outbreaks. It is essential, for example, to identify critical host binding factors to the pathogens as fast as possible. The complexity of host plasma membrane is often a limiting factor hindering fast and accurate determination of host binding factors as well as high-throughput screening for neutralizing antimicrobial drug targets. Here we describe a multi-parametric and high-throughput platform tackling this bottleneck and enabling fast screens for host binding factors as well as new antiviral drug targets. The sensitivity and robustness of our platform was validated by blocking SARS-CoV-2 spike particles with nanobodies and IgGs from human serum samples.TeaserA fast screening platform tackling host-pathogen interactions.
Single-cell phenotypic plasticity modulates social behaviour inDictyostelium discoideum
Authors: Forget Mathieu , Adiba Sandrine , De Monte Silvia 
Published: October 2022

AbstractInDictyosteliumchimeras, strains social behaviour is defined based on their relative representation in the spores – the reproductive cells resulting from development – referred to as spore bias. Some strains, called ‘cheaters’, display systematically positive spore bias in chimeras and are considered a threat to the evolutionary stability of multicellular organization. The selective advantage gained by cheaters is indeed predicted to undermine collective functions whenever social behaviours are genetically determined. However, genotypes are not the only determinant of spore bias, and the relative role of genetic and plastic phenotypic differences in strains evolutionary success is unclear.Here, we control phenotypic heterogeneity by harvesting cells in different growth phases, and study the effects of plastic variation on spore bias in chimeras composed of isogenic or genetically different populations. Spore bias is shown to depend both on growth phase and on population composition, and to be negatively correlated to the fraction of ‘loners’,i.e. cells that do not join aggregates. We examined several single-cell mechanical properties that are expected to affect aggregation efficiency, and found that variations in the fraction of slowly moving cells with growth phase may explain why earlier cultures appear to be underrepresented in the spores. The involvement of a go-or-grow mechanism during cell aggregation is also consistent with known variations of cell-cycle phase distribution during population growth. We confirm the expected ubiquity of growth-phase induced spore bias variation by showing that it is not negligible in genetic chimeras, and can even reverse the classification of a strain’s social behaviour. These results suggest that aggregation can provide an efficient ‘lottery’ system to harness the evolutionary spread of cheaters.
The heat shock protein LarA activates the Lon protease at the onset of proteotoxic stress
Authors: Omnus Deike J. , Fink Matthias J. , Kallazhi Aswathy , Zaragoza Maria Xandri , Jonas Kristina 
Published: October 2022

AbstractThe Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that LarA is regulated by Lon itself, which is critical to prevent toxic overactivation of Lon. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand at the onset of protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.
Allelic compatibility in plant immune receptors facilitates engineering of new effector recognition specificities
Authors: Bentham Adam R. , De la Concepcion Juan Carlos , Benjumea Javier Vega , Jones Sally , Mendel Melanie , Stubbs Jack , Stevenson Clare E. M. , Maidment Josephine H.R. , Youles Mark , Kourelis Jiorgos , Zdrzałek Rafał , Kamoun Sophien , Banfield Mark J. 
Published: October 2022

SummaryEngineering expanded effector recognition in plant immune receptors is a promising prospect for generating new disease resistant crop varieties. However, modification of plant NLR receptors has proven challenging due to the lack of understanding of their context as part of complex immune systems. Here, we demonstrate a new avenue for NLR-mediated engineering that exploits the allelic diversity in the Pik NLR pair to allow for the generation of receptors with expanded recognition specificities, which would otherwise result in constitutive cell death. This work lays the foundation for the incorporation of new effector recognition motifs into the Pik system and advances the development of designer NLRs that can be tailored to specific secreted pathogen signatures.AbstractEngineering the plant immune system offers genetic solutions to mitigate crop diseases caused by diverse agriculturally significant pathogens and pests. Modification of intracellular plant immune receptors of the nucleotide-binding leucine rich repeat (NLRs) superfamily for expanded recognition of pathogen virulence proteins (effectors) is a promising approach for engineering novel disease resistance. However, engineering can cause NLR autoactivation, resulting in constitutive defence responses that are deleterious to the plant. This may be due to plant NLRs associating in highly complex signalling networks that co-evolve together, and changes through breeding or genetic modification can generate incompatible combinations, resulting in autoimmune phenotypes. We have previously shown how alleles of the rice NLR pair Pik have differentially co-evolved, and how sensor/helper mismatching between non-co-evolved alleles triggers constitutive activation and cell death (De la Concepcion et al., 2021b). Here, we dissect incompatibility determinants in the Pik pair and found that HMA domains integrated in Pik-1 not only evolved to bind pathogen effectors but also likely co-evolved with other NLR domains to maintain immune homeostasis. This explains why changes in integrated domains can lead to autoactivation. We then used this knowledge to facilitate engineering of new effector recognition specificities overcoming initial autoimmune penalties. We show that by mismatching alleles of the rice sensor and helper NLRs Pik-1 and Pik-2, we can enable the integration of synthetic HMA domains with novel and enhanced recognition of an effector from the rice blast fungus. Taken together, our results reveal a new strategy for engineering NLRs, which has the potential to allow an expanded set of integrations and therefore new disease resistance specificities in plants.
E3-specific degrader discovery by dynamic tracing of substrate receptor abundance
Authors: Hanzl Alexander , Barone Eleonora , Bauer Sophie , Yue Hong , Nowak Radosław P. , Hahn Elisa , Pankevich Eugenia V. , Koren Anna , Kubicek Stefan , Fischer Eric S. , Winter Georg E. 
Published: October 2022

AbstractTargeted protein degradation (TPD) is a new pharmacology based on small-molecule degraders that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase. Of the approximately 600 E3s encoded in the human genome, only around two percent can be co-opted with degraders. This underrepresentation is caused by a paucity of discovery approaches to identify degraders for defined E3s. This hampers a rational expansion of the druggable proteome, and stymies critical advancements in the field, such as tissue- and cell-specific degradation. Here, we focus on dynamic NEDD8 conjugation, a posttranslational, regulatory circuit that controls the activity of 250 cullin RING E3 ligases (CRLs). Leveraging this regulatory layer enabled us to develop a scalable assay to identify compounds that alter the interactome of an E3 of interest by tracing their abundance after pharmacologically induced auto-degradation. Initial validation studies are performed for CRBN and VHL, but proteomics studies indicate broad applicability for many CRLs. Among amenable ligases, we select CRLDCAF15for a proof-of-concept screen, leading to the identification of a novel DCAF15-dependent molecular glue degrader inducing the degradation of RBM23 and RBM39. Together, this strategy empowers the scalable identification of degraders specific to a ligase of interest.
Financial toxicity among cancer patients, survivors, and their families in the United Kingdom: a scoping review
Authors: Ngan Tran Thu , Tien Tran Hoang , Donnelly Michael , O’Neill Ciaran 
Published: October 2022

AbstractBackgroundThe aim of this scoping review was to identify key research gaps and priorities in order to advance policy and practice for people living with cancer in the UK.MethodsThe review adhered to PRISMA guidelines for scoping review. We searched MEDLINE, EMBASE, Scopus, Web of Science, and Google Scholar on July 16, 2022. There were no restrictions in terms of study design and publication time; grey literature was included. The key words, ‘financial’ or ‘economic’, were combined with each of the following words ‘hardship/stress/burden/distress/strain/toxicity/catastrophe/consequence/impact.’Results29/629 studies/reports published during 1982-2022 were eligible to be included in the review. No study conducted a comprehensive inquiry and reported all aspects of FT or used a validated measure of FT. The most three commonly reported outcomes related to financial hardship were financial well-being (24/29), benefit/welfare (17/29), and mental health status (16/29).ConclusionsIt is evident that FT is experienced by UK cancer patients/survivors and that the issue is under-researched. There is an urgent need for further research including rigorous studies which contribute to a comprehensive understanding about the nature and extent of FT, disparities in experience, the impacts of FT on outcomes, and potential solutions to alleviate FT and related problems.