Development of hybrid immunity during a period of high incidence of Omicron infections.

Seroprevalence and the proportion of people with neutralizing activity (functional immunity) against SARS-CoV-2 variants were high in early 2022. In this prospective, population- based, multi-region cohort study, we assessed the development of functional and hybrid immunity (induced by vaccination and infection) in the general population during this period of high incidence of infections with Omicron variants. We randomly selected and assessed individuals aged ≥16 years from the general population in southern (n = 739) and north-eastern (n = 964) Switzerland in March 2022. We assessed them again in June/July 2022, supplemented with a random sample from western (n = 850) Switzerland. We measured SARS-CoV-2 specific IgG antibodies and SARS-CoV-2 neutralizing antibodies against three variants (ancestral strain, Delta, Omicron). Seroprevalence remained stable from March 2022 (97.6%, n = 1894) to June/July 2022 (98.4%, n = 2553). In June/July, the percentage of individuals with neutralizing capacity against ancestral strain was 94.2%, against Delta 90.8% and against Omicron 84.9%, and 50.6% developed hybrid immunity. Individuals with hybrid immunity had highest median levels of anti-spike IgG antibodies titres [4518 World Health Organization units per millilitre (WHO U/mL)] compared with those with only vaccine- (4304 WHO U/mL) or infection- (269 WHO U/mL) induced immunity, and highest neutralization capacity against ancestral strain (hybrid: 99.8%, vaccinated: 98%, infected: 47.5%), Delta (hybrid: 99%, vaccinated: 92.2%, infected: 38.7%) and Omicron (hybrid: 96.4%, vaccinated: 79.5%, infected: 47.5%). This first study on functional and hybrid immunity in the Swiss general population after Omicron waves showed that SARS-CoV-2 has become endemic. The high levels of antibodies and neutralization support the emerging recommendations of some countries where booster vaccinations are still strongly recommended for vulnerable persons but less so for the general population

Prevalence of SARS-CoV-2 in Household Members and Other Close Contacts of COVID-19 Cases: A Serologic Study in Canton of Vaud, Switzerland.

Research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission within households and other close settings using serological testing is scarce. We invited coronavirus disease 2019 (COVID-19) cases diagnosed between February 27 and April 1, 2020, in Canton of Vaud, Switzerland, to participate, along with household members and other close contacts. Anti-SARS-CoV-2 immunoglobulin G antibodies were measured using a Luminex immunoassay. We estimated factors associated with serological status using generalized estimating equations. Overall, 219 cases, 302 household members, and 69 other close contacts participated between May 4 and June 27, 2020. More than half of household members (57.2%; 95% CI, 49.7%-64.3%) had developed a serologic response to SARS-CoV-2, while 19.0% (95% CI, 10.0%-33.2%) of other close contacts were seropositive. After adjusting for individual and household characteristics, infection risk was higher in household members aged ≥65 years than in younger adults (adjusted odds ratio [aOR], 3.63; 95% CI, 1.05-12.60) and in those not strictly adhering to simple hygiene rules like hand washing (aOR, 1.80; 95% CI, 1.02-3.17). The risk was lower when more than 5 people outside home were met during semiconfinement, compared with none (aOR, 0.35; 95% CI, 0.16-0.74). Individual risk of household members to be seropositive was lower in large households (22% less per each additional person). During semiconfinement, household members of a COVID-19 case were at very high risk of getting infected, 3 times more than close contacts outside home. This highlights the need to provide clear messages on protective measures applicable at home. For elderly couples, who were especially at risk, providing external support for daily basic activities is essential

The mating-specific Gα interacts with a kinesin-14 and regulates pheromone-induced nuclear migration in budding yeast

As a budding yeast cell elongates toward its mating partner, cytoplasmic microtubules connect the nucleus to the cell cortex at the growth tip. The Kar3 kinesin-like motor protein is then thought to stimulate plus-end depolymerization of these microtubules, thus drawing the nucleus closer to the site where cell fusion and karyogamy will occur. Here, we show that pheromone stimulates a microtubule-independent interaction between Kar3 and the mating-specific Gα protein Gpa1 and that Gpa1 affects both microtubule orientation and cortical contact. The membrane localization of Gpa1 was found to polarize early in the mating response, at about the same time that the microtubules begin to attach to the incipient growth site. In the absence of Gpa1, microtubules lose contact with the cortex upon shrinking and Kar3 is improperly localized, suggesting that Gpa1 is a cortical anchor for Kar3. We infer that Gpa1 serves as a positional determinant for Kar3-bound microtubule plus ends during mating. © 2009 by The American Society for Cell Biology

Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals

Braveheart, a Long Noncoding RNA Required for Cardiovascular Lineage Commitment

Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development.Damon Runyon Cancer Research Foundation (DRG 2032-09)Damon Runyon Cancer Research Foundation (DFS 04-12)European Molecular Biology Organization (Long-term Fellowship)National Heart, Lung, and Blood Institute. Bench to Bassinet Program (U01HL098179)National Heart, Lung, and Blood Institute. Bench to Bassinet Program (U01HL098188)Smith Family FoundationPew Charitable Trusts. Program in the Biomedical Science

Genomic mapping of phosphorothioates reveals partial modification of short consensus sequences

Bacterial phosphorothioate (PT) DNA modifications are incorporated by Dnd proteins A-E and often function with DndF-H as a restriction-modification (R-M) system, as in Escherichia coli B7A. However, bacteria such as Vibrio cyclitrophicus FF75 lack dndF-H, which points to other PT functions. Here we report two novel, orthogonal technologies to map PTs across the genomes of B7A and FF75 with >90% agreement: single molecule, real-time sequencing and deep sequencing of iodine-induced cleavage at PT (ICDS). In B7A, we detect PT on both strands of G[subscript ps]AAC/G[subscript ps]TTC motifs, but with only 12% of 40,701 possible sites modified. In contrast, PT in FF75 occurs as a single-strand modification at C[subscript ps]CA, again with only 14% of 160,541 sites modified. Single-molecule analysis indicates that modification could be partial at any particular genomic site even with active restriction by DndF-H, with direct interaction of modification proteins with GAAC/GTTC sites demonstrated with oligonucleotides. These results point to highly unusual target selection by PT-modification proteins and rule out known R-M mechanisms.National Natural Science Foundation (China)Ministry of Science and Technology of the People's Republic of China (973 and 863 Programs)Shanghai Municipal Council of Science and Technology. Shanghai Pujiang ProgramNational Science Foundation (U.S.) (CHE-1019990)National Institute of Environmental Health Sciences (ES002109)Singapore. National Research Foundation (Singapore-MIT Alliance for Research and Technology

Estimation of genetic parameters for feed efficiency traits using random regression models in dairy cattle.

Feed efficiency has become an increasingly important research topic in recent years. As feed costs rise and the environmental impacts of agriculture become more apparent, improving the efficiency with which dairy cows convert feed to milk is increasingly important. However, feed intake is expensive to measure accurately on large populations, making the inclusion of this trait in breeding programs difficult. Understanding how the genetic parameters of feed efficiency and traits related to feed efficiency vary throughout the lactation period is valuable to gain understanding into the genetic nature of feed efficiency. This study used 121,226 dry matter intake (DMI) records, 120,500 energy corrected milk (ECM) records, and 98,975 metabolic body weight (MBW) records, collected on 7,440 first lactation Holstein cows from 6 countries (Canada, Denmark, Germany, Spain, Switzerland, and United States of America), from January 2003 to February 2022. Genetic parameters were estimated using a multiple-trait random regression model with a fourth order Legendre polynomial for all traits. Weekly phenotypes for DMI were re-parameterized using linear regressions of DMI on ECM and MBW, creating a measure of feed efficiency that was genetically corrected for ECM and MBW, referred to as genomic residual feed intake (gRFI). Heritability (SE) estimates varied from 0.15 (0.03) to 0.29 (0.02) for DMI, 0.24 (0.01) to 0.29 (0.03) for ECM, 0.55 (0.03) to 0.83 (0.05) for MBW, and 0.12 (0.03) to 0.22 (0.06) for gRFI. In general, heritability estimates were lower in the first stage of lactation compared with the later stages of lactation. Additive genetic correlations between weeks of lactation varied, with stronger correlations between weeks of lactation that were close together. The results of this study contribute to a better understanding of the change in genetic parameters across the first lactation, providing insight into potential selection strategies to include feed efficiency in breeding programs

Protein Pattern Formation

Protein pattern formation is essential for the spatial organization of many intracellular processes like cell division, flagellum positioning, and chemotaxis. A prominent example of intracellular patterns are the oscillatory pole-to-pole oscillations of Min proteins in \textit{E. coli} whose biological function is to ensure precise cell division. Cell polarization, a prerequisite for processes such as stem cell differentiation and cell polarity in yeast, is also mediated by a diffusion-reaction process. More generally, these functional modules of cells serve as model systems for self-organization, one of the core principles of life. Under which conditions spatio-temporal patterns emerge, and how these patterns are regulated by biochemical and geometrical factors are major aspects of current research. Here we review recent theoretical and experimental advances in the field of intracellular pattern formation, focusing on general design principles and fundamental physical mechanisms.Comment: 17 pages, 14 figures, review articl

Multisite Phosphorylation of the Guanine Nucleotide Exchange Factor Cdc24 during Yeast Cell Polarization

BACKGROUND:Cell polarization is essential for processes such as cell migration and asymmetric cell division. A common regulator of cell polarization in most eukaryotic cells is the conserved Rho GTPase, Cdc42. In budding yeast, Cdc42 is activated by a single guanine nucleotide exchange factor, Cdc24. The mechanistic details of Cdc24 activation at the onset of yeast cell polarization are unclear. Previous studies have suggested an important role for phosphorylation of Cdc24, which may regulate activity or function of the protein, representing a key step in the symmetry breaking process. METHODOLOGY/PRINCIPAL FINDINGS:Here, we directly ask whether multisite phosphorylation of Cdc24 plays a role in its regulation. We identify through mass spectrometry analysis over thirty putative in vivo phosphorylation sites. We first focus on sites matching consensus sequences for cyclin-dependent and p21-activated kinases, two kinase families that have been previously shown to phosphorylate Cdc24. Through site-directed mutagenesis, yeast genetics, and light and fluorescence microscopy, we show that nonphosphorylatable mutations of these consensus sites do not lead to any detectable consequences on growth rate, morphology, kinetics of polarization, or localization of the mutant protein. We do, however, observe a change in the mobility shift of mutant Cdc24 proteins on SDS-PAGE, suggesting that we have indeed perturbed its phosphorylation. Finally, we show that mutation of all identified phosphorylation sites does not cause observable defects in growth rate or morphology. CONCLUSIONS/SIGNIFICANCE:We conclude that lack of phosphorylation on Cdc24 has no overt functional consequences in budding yeast. Yeast cell polarization may be more tightly regulated by inactivation of Cdc42 by GTPase activating proteins or by alternative methods of Cdc24 regulation, such as conformational changes or oligomerization

Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients

The CTLA-4 protein is expressed in activated T cells and plays an essential role in the immune response through its regulatory effect on T cell activation. Polymorphisms of the CTLA-4 gene have been correlated with autoimmune, neoplastic and infectious illnesses. This work aimed to verify possible associations between single nucleotide polymorphisms (SNPs) in CTLA-4, -318C/T in the promoter and +49A/G in exon 1 and paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. For this purpose, 66 chronic form PCM patients and 76 healthy controls had their allele, genotype and haplotype frequencies determined. The genetic admixture structure of the patients and controls was evaluated to eliminate ancestral bias. The comparison of frequencies indicated no significant differences between patients and controls that could link the SNPs to PCM. Groups were admixture matched with no difference observed in population ancestry inference, indicating that the absence of association between CTLA-4 polymorphisms and PCM could not be attributed to ancestral bias. This study showed that there was no association between the CTLA-4 SNPs -318 and +49 and the resistance or susceptibility to PCM