Notes

Treatments for continual bronchopleural fistula along with recurrent empyema employing a latissimus dorsi myocutaneous flap: in a situation record and literature evaluate.
Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation. The viscoelastic chromatin network could impact their stability and may hold the key for understanding experimental observations that defy predictions of classical theories. However, quantitative studies on the role of the chromatin network in phase separation have remained challenging. Using a diploid human genome model parameterized with chromosome conformation capture (Hi-C) data, we study the thermodynamics and kinetics of nucleoli formation. Dynamical simulations predict the formation of multiple droplets for nucleolar particles that experience specific interactions with nucleolus-associated domains (NADs). Coarsening dynamics, surface tension, and coalescence kinetics of the simulated droplets are all in quantitative agreement with experimental measurements for nucleoli. Free energy calculations further support that a two-droplet state, often observed for nucleoli in somatic cells, is metastable and separated from the single-droplet state with an entropic barrier. Our study suggests that nucleoli-chromatin interactions facilitate droplets' nucleation but hinder their coarsening due to the coupled motion between droplets and the chromatin network as droplets coalesce, the chromatin network becomes increasingly constrained. Therefore, the chromatin network supports a nucleation and arrest mechanism to stabilize the multi-droplet state for nucleoli and possibly for other nuclear bodies.Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.To significantly increase the amount of exsolved particles, the complete phase reconstruction from simple perovskite to Ruddlesden-Popper (R-P) perovskite is greatly desirable. However, a comprehensive understanding of key parameters affecting the phase reconstruction to R-P perovskite is still unexplored. Herein, we propose the Gibbs free energy for oxygen vacancy formation in Pr0.5(Ba/Sr)0.5TO3-δ (T = Mn, Fe, Co, and Ni) as the important factor in determining the type of phase reconstruction. Furthermore, using in-situ temperature & environment-controlled X-ray diffraction measurements, we report the phase diagram and optimum 'x' range required for the complete phase reconstruction to R-P perovskite in Pr0.5Ba0.5-xSrxFeO3-δ system. Among the Pr0.5Ba0.5-xSrxFeO3-δ, (Pr0.5Ba0.2Sr0.3)2FeO4+δ - Fe metal demonstrates the smallest size of exsolved Fe metal particles when the phase reconstruction occurs under reducing condition. The exsolved nano-Fe metal particles exhibit high particle density and are well-distributed on the perovskite surface, showing great catalytic activity in fuel cell and syngas production.Network analysis methods can potentially quantify cancer aberrations in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. N6-methyladenosine The method is applied to high-grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs) and to rank key genes associated with prognosis. Copy number alterations (CNAs) from targeted and whole-exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein-protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier-Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan-Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups. The network curvature analysis stratified patients at high risk of mortality with p = 0.00047 in Kaplan-Meier analysis in HGSOC patients receiving ICI. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer. Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.Branching morphogenesis governs the formation of many organs such as lung, kidney, and the neurovascular system. Many studies have explored system-specific molecular and cellular regulatory mechanisms, as well as self-organizing rules underlying branching morphogenesis. However, in addition to local cues, branched tissue growth can also be influenced by global guidance. Here, we develop a theoretical framework for a stochastic self-organized branching process in the presence of external cues. Combining analytical theory with numerical simulations, we predict differential signatures of global vs. local regulatory mechanisms on the branching pattern, such as angle distributions, domain size, and space-filling efficiency. We find that branch alignment follows a generic scaling law determined by the strength of global guidance, while local interactions influence the tissue density but not its overall territory. Finally, using zebrafish innervation as a model system, we test these key features of the model experimentally. Our work thus provides quantitative predictions to disentangle the role of different types of cues in shaping branched structures across scales.Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals.Driving and controlling single-skyrmion motion promises skyrmion-based spintronic applications. Recently progress has been made in moving skyrmionic bubbles in thin-film heterostructures and low-temperature chiral skyrmions in the FeGe helimagnet by electric current. Here, we report the motion tracking and control of a single skyrmion at room temperature in the chiral-lattice magnet Co9Zn9Mn2 using nanosecond current pulses. We have directly observed that the skyrmion Hall motion reverses its direction upon the reversal of skyrmion topological number using Lorentz transmission electron microscopy. Systematic measurements of the single-skyrmion trace as a function of electric current reveal a dynamic transition from the static pinned state to the linear flow motion via a creep event, in agreement with the theoretical prediction. We have clarified the role of skyrmion pinning and evaluated the intrinsic skyrmion Hall angle and the skyrmion velocity in the course of the dynamic transition. Our results pave a way to skyrmion applications in spintronic devices.The development and progression of gastric cancer (GC) is greatly influenced by gastric microbiota and their metabolites. Here, we characterized the gastric microbiome and metabolome profiles of 37 GC tumor tissues and matched non-tumor tissues using 16s rRNA gene sequencing and ultrahigh performance liquid chromatography tandem mass spectrometry, respectively. Microbial diversity and richness were higher in GC tumor tissues than in non-tumor tissues. The abundance of Helicobacter was increased in non-tumor tissues, while the abundance of Lactobacillus, Streptococcus, Bacteroides, Prevotella, and 6 additional genera was increased in the tumor tissues. The untargeted metabolome analysis revealed 150 discriminative metabolites, among which the relative abundance of the amino acids, carbohydrates and carbohydrate conjugates, glycerophospholipids, and nucleosides was higher in tumor tissues compared to non-tumor tissues. The targeted metabolome analysis further demonstrated that the combination of 1-methylnicotinesis and progression.Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.Bacterial defenses against phage, which include CRISPR-mediated immunity and other mechanisms, can carry substantial growth rate costs and can be rapidly lost when pathogens are eliminated. How bacteria preserve their molecular defenses despite their costs, in the face of variable pathogen levels and inter-strain competition, remains a major unsolved problem in evolutionary biology. Here, we present a multilevel model that incorporates biophysics of molecular binding, host-pathogen population dynamics, and ecological dynamics across a large number of independent territories. Using techniques of game theory and non-linear dynamical systems, we show that by maintaining a non-zero failure rate of defenses, hosts sustain sufficient levels of pathogen within an ecology to select against loss of the defense. This resistance switching strategy is evolutionarily stable, and provides a powerful evolutionary mechanism that maintains host-pathogen interactions, selects against cheater strains that avoid the costs of immunity, and enables co-evolutionary dynamics in a wide range of systems.
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