Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.

Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM). This retrograde breaching of the endothelium by neutrophils was governed by enhanced production of the chemokine CXCL1 from mast cells that localized at endothelial cell (EC) junctions. Increased EC expression of the atypical chemokine receptor 1 (ACKR1) supported this pro-inflammatory milieu in aged venules. Accumulation of CXCL1 caused desensitization of the chemokine receptor CXCR2 on neutrophils and loss of neutrophil directional motility within EC junctions. Fluorescent tracking revealed that in aged mice, neutrophils undergoing rTEM re-entered the circulation and disseminated to the lungs where they caused vascular leakage. Thus, neutrophils stemming from a local inflammatory site contribute to remote organ damage, with implication to the dysregulated systemic inflammation associated with aging.

Genetic insights into biological mechanisms governing human ovarian ageing.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C-H Functionalization of (Poly)fluoroarenes in Organic Synthesis.

The synthesis of organic compounds efficiently via fewer steps but in higher yields is desirable as this reduces energy and reagent use, waste production, and thus environmental impact as well as cost. The reactivity of C-H bonds ortho to fluorine substituents in (poly)fluoroarenes with metal centers is enhanced relative to meta and para positions. Thus, direct C-H functionalization of (poly)fluoroarenes without prefunctionalization is becoming a significant area of research in organic chemistry. Novel and selective methodologies to functionalize (poly)fluorinated arenes by taking advantage of the reactivity of C-H bonds ortho to C-F bonds are continuously being developed. This review summarizes the reasons for the enhanced reactivity and the consequent developments in the synthesis of valuable (poly)fluoroarene-containing organic compounds.

Analysis of the risk and pre-emptive control of viral outbreaks accounting for within-host dynamics: SARS-CoV-2 as a case study.

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multiscale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multiscale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

Identification and analysis of individuals who deviate from their genetically-predicted phenotype.

Findings from genome-wide association studies have facilitated the generation of genetic predictors for many common human phenotypes. Stratifying individuals misaligned to a genetic predictor based on common variants may be important for follow-up studies that aim to identify alternative causal factors. Using genome-wide imputed genetic data, we aimed to classify 158,951 unrelated individuals from the UK Biobank as either concordant or deviating from two well-measured phenotypes. We first applied our methods to standing height: our primary analysis classified 244 individuals (0.15%) as misaligned to their genetically predicted height. We show that these individuals are enriched for self-reporting being shorter or taller than average at age 10, diagnosed congenital malformations, and rare loss-of-function variants in genes previously catalogued as causal for growth disorders. Secondly, we apply our methods to LDL cholesterol (LDL-C). We classified 156 (0.12%) individuals as misaligned to their genetically predicted LDL-C and show that these individuals were enriched for both clinically actionable cardiovascular risk factors and rare genetic variants in genes previously shown to be involved in metabolic processes. Individuals whose LDL-C was higher than expected based on the genetic predictor were also at higher risk of developing coronary artery disease and type-two diabetes, even after adjustment for measured LDL-C, BMI and age, suggesting upward deviation from genetically predicted LDL-C is indicative of generally poor health. Our results remained broadly consistent when performing sensitivity analysis based on a variety of parametric and non-parametric methods to define individuals deviating from polygenic expectation. Our analyses demonstrate the potential importance of quantitatively identifying individuals for further follow-up based on deviation from genetic predictions.

Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.

Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)] = 1.06 (0.84, 1.35), MI [OR (95% CI) = 1.02 (0.79, 1.33)] or stroke [OR (95% CI) = 0.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN's role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00 g/dl increase in Hgb.

Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.

Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DDs) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes by using whole-exome-sequencing data from ∼200,000 individuals and rare copy-number variants overlapping known DD loci by using SNP-array data from ∼500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores, and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, had a higher BMI, and had significant socioeconomic disadvantages: they were less likely to be employed or be able to work and had a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within pediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong sub-clinical phenotypes in the general adult population.

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

When should lockdown be implemented? Devising cost-effective strategies for managing epidemics amid vaccine uncertainty.

During an infectious disease outbreak, public health policy makers are tasked with strategically implementing interventions whilst balancing competing objectives. To provide a quantitative framework that can be used to guide these decisions, it is helpful to devise a clear and specific objective function that can be evaluated to determine the optimal outbreak response. In this study, we have developed a mathematical modelling framework representing outbreaks of a novel emerging pathogen for which non-pharmaceutical interventions (NPIs) are imposed or removed based on thresholds for hospital occupancy. These thresholds are set at different levels to define four unique strategies for disease control. We illustrate that the optimal intervention strategy is contingent on the choice of objective function. Specifically, the optimal strategy depends on the extent to which policy makers prioritise reducing health costs due to infection over the costs associated with maintaining interventions. Motivated by the scenario early in the COVID-19 pandemic, we incorporate the development of a vaccine into our modelling framework and demonstrate that a policy maker's belief about when a vaccine will become available in future, and its eventual coverage (and/or effectiveness), affects the optimal strategy to adopt early in the outbreak. Furthermore, we show how uncertainty in these quantities can be accounted for when deciding which interventions to introduce. This research highlights the benefits of policy makers being explicit about the precise objectives of introducing interventions.

Prioritising older individuals for COVID-19 booster vaccination leads to optimal public health outcomes in a range of socio-economic settings.

The rapid development of vaccines against SARS-CoV-2 altered the course of the COVID-19 pandemic. In most countries, vaccinations were initially targeted at high-risk populations, including older individuals and healthcare workers. Now, despite substantial infection- and vaccine-induced immunity in host populations worldwide, waning immunity and the emergence of novel variants continue to cause significant waves of infection and disease. Policy makers must determine how to deploy booster vaccinations, particularly when constraints in vaccine supply, delivery and cost mean that booster vaccines cannot be administered to everyone. A key question is therefore whether older individuals should again be prioritised for vaccination, or whether alternative strategies (e.g. offering booster vaccines to the individuals who have most contacts with others and therefore drive infection) can instead offer indirect protection to older individuals. Here, we use mathematical modelling to address this question, considering SARS-CoV-2 transmission in a range of countries with different socio-economic backgrounds. We show that the population structures of different countries can have a pronounced effect on the impact of booster vaccination, even when identical booster vaccination targeting strategies are adopted. However, under the assumed transmission model, prioritising older individuals for booster vaccination consistently leads to the most favourable public health outcomes in every setting considered. This remains true for a range of assumptions about booster vaccine supply and timing, and for different assumed policy objectives of booster vaccination.

The impact of Mendelian sleep and circadian genetic variants in a population setting.

Rare variants in ten genes have been reported to cause Mendelian sleep conditions characterised by extreme sleep duration or timing. These include familial natural short sleep (ADRB1, DEC2/BHLHE41, GRM1 and NPSR1), advanced sleep phase (PER2, PER3, CRY2, CSNK1D and TIMELESS) and delayed sleep phase (CRY1). The association of variants in these genes with extreme sleep conditions were usually based on clinically ascertained families, and their effects when identified in the population are unknown. We aimed to determine the effects of these variants on sleep traits in large population-based cohorts. We performed genetic association analysis of variants previously reported to be causal for Mendelian sleep and circadian conditions. Analyses were performed using 191,929 individuals with data on sleep and whole-exome or genome-sequence data from 4 population-based studies: UK Biobank, FINRISK, Health-2000-2001, and the Multi-Ethnic Study of Atherosclerosis (MESA). We identified sleep disorders from self-report, hospital and primary care data. We estimated sleep duration and timing measures from self-report and accelerometery data. We identified carriers for 10 out of 12 previously reported pathogenic variants for 8 of the 10 genes. They ranged in frequency from 1 individual with the variant in CSNK1D to 1,574 individuals with a reported variant in the PER3 gene in the UK Biobank. No carriers for variants reported in NPSR1 or PER2 were identified. We found no association between variants analyzed and extreme sleep or circadian phenotypes. Using sleep timing as a proxy measure for sleep phase, only PER3 and CRY1 variants demonstrated association with earlier and later sleep timing, respectively; however, the magnitude of effect was smaller than previously reported (sleep midpoint ~7 mins earlier and ~5 mins later, respectively). We also performed burden tests of protein truncating (PTVs) or rare missense variants for the 10 genes. Only PTVs in PER2 and PER3 were associated with a relevant trait (for example, 64 individuals with a PTV in PER2 had an odds ratio of 4.4 for being "definitely a morning person", P = 4x10-8; and had a 57-minute earlier midpoint sleep, P = 5x10-7). Our results indicate that previously reported variants for Mendelian sleep and circadian conditions are often not highly penetrant when ascertained incidentally from the general population.

Incubation Period and Serial Interval of Mpox in 2022 Global Outbreak Compared with Historical Estimates.

Understanding changes in the transmission dynamics of mpox requires comparing recent estimates of key epidemiologic parameters with historical data. We derived historical estimates for the incubation period and serial interval for mpox and contrasted them with pooled estimates from the 2022 outbreak. Our findings show the pooled mean infection-to-onset incubation period was 8.1 days for the 2022 outbreak and 8.2 days historically, indicating the incubation periods remained relatively consistent over time, despite a shift in the major mode of transmission. However, we estimated the onset-to-onset serial interval at 8.7 days using 2022 data, compared with 14.2 days using historical data. Although the reason for this shortening of the serial interval is unclear, it may be because of increased public health interventions or a shift in the mode of transmission. Recognizing such temporal shifts is essential for informed response strategies, and public health measures remain crucial for controlling mpox and similar future outbreaks.

Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight.

BACKGROUND: Higher birthweight is associated with higher adult body mass index (BMI). Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favorable adiposity alleles on birthweight is unknown. AIM: We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favorable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. METHODS: We used published genome wide association study data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favorable adult adiposity or BMI. We combined summary data across single nucleotide polymorphisms (SNPs) with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. RESULTS: Fetal genetic predisposition to higher metabolically favorable adult adiposity and higher adult BMI were both associated with higher birthweight (3 g per effect allele (95% CI: 1-5) averaged over 14 SNPs; P = 0.002; 0.5 g per effect allele (95% CI: 0-1) averaged over 76 SNPs; P = 0.042, respectively). SNPs with greater effects on metabolically favorable adiposity tended to have greater effects on birthweight (R2 = 0.2912, P = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, P = 0.602). CONCLUSIONS: Fetal genetic predisposition to both higher adult metabolically favorable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favorable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Reconstitution of an N-AChR from Brugia malayi, an evolved change in acetylcholine receptor accessory protein requirements in filarial parasites.

Neurotransmission is an important target for anthelmintic drugs, where receptor characteristics and response can be examined through reconstitution ex vivo in Xenopus laevis oocytes. The homomeric ACR-16 nicotine sensitive acetylcholine receptors (N-AChRs) of several helminth species have been characterized in this way. Our efforts to reconstitute the N-AChR from the clade III filarial parasite, Brugia malayi using similar conditions, initially produced no detectable response. A robust response to acetylcholine is obtained from the closely related clade III parasite Ascaris suum, suggesting that specific changes have occurred between Ascaris and Brugia. N-AChRs from three species intermediate between A. suum and B. malayi were characterized to provide information on the cause. Maximal response to acetylcholine did not change abruptly, consistent with a discrete event, but rather decreased progressively from A. suum through Dracunculus medinensis, Gonglylonema pulchrum and Thelazia callipaeda. Receptor responses to the characteristic nicotine, and other agonists were generally similar. The decrease in maximal current did correlate with a delayed time to reach larger response. Together, this suggested that the failure to reconstitute the B. malayi N-AChR was one extreme of a progressive decrease and that an issue with synthesis of the receptor in oocytes was responsible. Addition of accessory proteins EMC-6, NRA-2 and NRA-4, in addition to RIC-3, produced a small, but measurable B. malayi N-AChR response. Pharmacological properties of a chimeric B. malayi N-AChR were equivalent to the other species, confirming the receptor response remains unchanged while its production is increasingly dependent on accessory proteins. One possibility is that loss of many subunits for acetylcholine receptors from the filarial nematode genome is linked to new subunit combinations that lead to such a dependence. This novel phylogenetic approach allowed the first characterization of a B. malayi AChR ex vivo and in doing so, provides a framework for the successful characterization of other receptors that have yet to be reconstituted.

A Remote Consult Retinal Artery Occlusion Diagnostic Protocol.

PURPOSE: To report a novel protocol for diagnosis of retinal artery occlusions at the point of care using OCT and a remote consult model. DESIGN: Retrospective case series and evaluation of a diagnostic test or technology. PARTICIPANTS: Adult patients who presented with painless monocular vision loss and were diagnosed with a nonarteritic retinal artery occlusion. METHODS: OCT machines were placed in the stroke center or emergency department at 3 hospitals within our health system. Patients who presented with painless monocular vision loss were evaluated by the stroke neurology service and an OCT was acquired. The images were interpreted remotely by the retina service. An in-house ophthalmology consult was not required to make the final treatment decision. Eligible patients were treated with intra-arterial tissue plasminogen activator (IA-tPA). Patients were followed by ophthalmology during their admission when an in-house consultation service was available or otherwise evaluated immediately after discharge. MAIN OUTCOME MEASURES: Visual acuity (VA) before and after treatment with IA-tPA; time from last known well (LKW) to treatment; and time from presentation to treatment. RESULTS: In the first 18 months since the protocol went live, 59 patients were evaluated. Twenty-five patients (42%) had a confirmed retinal artery occlusion based on OCT and follow-up examination. Ten patients were eligible for treatment, and 9 patients received treatment with IA-tPA. There was a statistically significant improvement in mean VA from logarithm of the minimum angle of resolution (logMAR) 2.14 to logMAR 0.7 within 24 hours after treatment (P = 0.0001) and logMAR 1.04 after 4 weeks (P = 0.01). Clinically significant improvement was noted in 66% of patients within 24 hours and maintained through 1 month in 56% of all treated patients. The mean time to treatment from LKW was 543 minutes and from presentation at the stroke center was 146 minutes. CONCLUSIONS: We report the successful implementation of a remote consult protocol using point-of-care automated OCT. This novel paradigm demonstrates the potential utility of remote consult services for the diagnosis of time-sensitive ophthalmic emergencies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2.

The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2-3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.

How a general vulnerability for psychopathology during adolescence manifests in young adults' daily lives.

BACKGROUND: There is widespread interest in the general factor of psychopathology or 'p factor', which has been proposed to reflect vulnerability to psychopathology. We examined to what extent this 'vulnerability' is associated with dysregulations in affect and behavior that occur in daily life. As such we hoped to provide an account of how this vulnerability may be maintained. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2,772) collected at ages 11, 14, 16, 19, and 22 years to fit a bifactor model with a general psychopathology factor, alongside internalizing, externalizing (EXT), attention-deficit/hyperactivity, and autism spectrum problem domains. Following the fifth TRAILS assessment, a subsample of participants (n = 133, age = 22.6, 43% women) with heightened risk for psychopathology completed a 6-month daily diary protocol with one assessment each day. Using a dynamic structural equation approach, we examined to what extent mean intensity, variability, inertia, and within-day co-occurrence of EXT, anxious-tense, and depressed-withdrawn affects and behaviors were associated with general factor scores. RESULTS: Unexpectedly, higher general factor scores were not associated with higher mean intensity of any of the three types of daily negative affects and behaviors, but were associated with higher variability and less carryover (inertia) EXT affects and behaviors. CONCLUSIONS: We showed that individual differences in general factor scores do not manifest as differences in average levels of daily affects and behaviors, but instead were related to a type of EXT reactivity to the environment. Future research is necessary to investigate whether reactive irritable moods may be involved in or signal vulnerability sustained psychopathology.

The FES Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis.

BACKGROUND: Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis. METHODS AND RESULTS: Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet. CONCLUSIONS: We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.