Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure.

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure.

Learning from HIV-1 to predict the immunogenicity of T cell epitopes in SARS-CoV-2.

We describe a physics-based learning model for predicting the immunogenicity of cytotoxic T lymphocyte (CTL) epitopes derived from diverse pathogens including SARS-CoV-2. The model was trained and optimized on the relative immunodominance of CTL epitopes in human immunodeficiency virus infection. Its accuracy was tested against experimental data from patients with COVID-19.

Damage-induced chromatome dynamics link Ubiquitin ligase and proteasome recruitment to histone loss and efficient DNA repair.

Eukaryotic cells package their genomes around histone octamers. In response to DNA damage, checkpoint activation in yeast induces core histone degradation resulting in 20%-40% reduction in nucleosome occupancy. To gain insight into this process, we developed a new approach to analyze the chromatin-associated proteome comprehensively before and after damage.

Viral surface geometry shapes influenza and coronavirus spike evolution through antibody pressure.

The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the glycoprotein (spike). However, not all antigenic sites are targeted equally by antibodies, leading to complex immunodominance patterns. We used 3D computational models to estimate antibody pressure on the seasonal influenza H1N1 and SARS spikes.

Defining and Manipulating B Cell Immunodominance Hierarchies to Elicit Broadly Neutralizing Antibody Responses against Influenza Virus.

The antibody repertoire possesses near-limitless diversity, enabling the adaptive immune system to accommodate essentially any antigen. However, this diversity explores the antigenic space unequally, allowing some pathogens like influenza virus to impose complex immunodominance hierarchies that distract antibody responses away from key sites of virus vulnerability. We developed a computational model of affinity maturation to map the patterns of immunodominance that evolve upon immunization with natural and engineered displays of hemagglutinin (HA), the influenza vaccine antigen.

DNA Damage-Induced Nucleosome Depletion Enhances Homology Search Independently of Local Break Movement.

To determine whether double-strand break (DSB) mobility enhances the physical search for an ectopic template during homology-directed repair (HDR), we tested the effects of factors that control chromatin dynamics, including cohesin loading and kinetochore anchoring. The former but not the latter is altered in response to DSBs. Loss of the nonhistone high-mobility group protein Nhp6 reduces histone occupancy and increases chromatin movement, decompaction, and ectopic HDR.

Advances in Chromatin and Chromosome Research: Perspectives from Multiple Fields.

Nucleosomes package genomic DNA into chromatin. By regulating DNA access for transcription, replication, DNA repair, and epigenetic modification, chromatin forms the nexus of most nuclear processes. In addition, dynamic organization of chromatin underlies both regulation of gene expression and evolution of chromosomes into individualized sister objects, which can segregate cleanly to different daughter cells at anaphase.

Guided nuclear exploration increases CTCF target search efficiency.

The enormous size of mammalian genomes means that for a DNA-binding protein the number of nonspecific, off-target sites vastly exceeds the number of specific, cognate sites. How mammalian DNA-binding proteins overcome this challenge to efficiently locate their target sites is not known. Here, through live-cell single-molecule tracking, we show that CCCTC-binding factor, CTCF, is repeatedly trapped in small zones that likely correspond to CTCF clusters, in a manner that is largely dependent on an internal RNA-binding region (RBR).

The low spike density of HIV may have evolved because of the effects of T helper cell depletion on affinity maturation.

The spikes on virus surfaces bind receptors on host cells to propagate infection. High spike densities (SDs) can promote infection, but spikes are also targets of antibody-mediated immune responses. Thus, diverse evolutionary pressures can influence virus SDs.

A Population Dynamics Model for Clonal Diversity in a Germinal Center.

Germinal centers (GCs) are micro-domains where B cells mature to develop high affinity antibodies. Inside a GC, B cells compete for antigen and T cell help, and the successful ones continue to evolve. New experimental results suggest that, under identical conditions, a wide spectrum of clonal diversity is observed in different GCs, and high affinity B cells are not always the ones selected.

Visualization of Chromatin Decompaction and Break Site Extrusion as Predicted by Statistical Polymer Modeling of Single-Locus Trajectories.

Chromatin moves with subdiffusive and spatially constrained dynamics within the cell nucleus. Here, we use single-locus tracking by time-lapse fluorescence microscopy to uncover information regarding the forces that influence chromatin movement following the induction of a persistent DNA double-strand break (DSB). Using improved time-lapse imaging regimens, we monitor trajectories of tagged DNA loci at a high temporal resolution, which allows us to extract biophysical parameters through robust statistical analysis.

Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates.

Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating the recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated.

Structural Fluctuations of the Chromatin Fiber within Topologically Associating Domains.

Experiments based on chromosome conformation capture have shown that mammalian genomes are partitioned into topologically associating domains (TADs), within which the chromatin fiber preferentially interacts. TADs may provide three-dimensional scaffolds allowing genes to contact their appropriate distal regulatory DNA sequences (e.g.

Analysis of Single Locus Trajectories for Extracting In Vivo Chromatin Tethering Interactions.

Is it possible to extract tethering forces applied on chromatin from the statistics of a single locus trajectories imaged in vivo? Chromatin fragments interact with many partners such as the nuclear membrane, other chromosomes or nuclear bodies, but the resulting forces cannot be directly measured in vivo. However, they impact chromatin dynamics and should be reflected in particular in the motion of a single locus. We present here a method based on polymer models and statistics of single trajectories to extract the force characteristics and in particular when they are generated by the gradient of a quadratic potential well.

First-passage distributions in a collective model of anomalous diffusion with tunable exponent.

We consider a model system in which anomalous diffusion is generated by superposition of underlying linear modes with a broad range of relaxation times. In the language of Gaussian polymers, our model corresponds to Rouse (Fourier) modes whose friction coefficients scale as wave number to the power 2-z. A single (tagged) monomer then executes subdiffusion over a broad range of time scales, and its mean square displacement increases as t(alpha) with alpha = 1/z.