Successful thoracoscopic enucleation of a calcifying fibrous tumor of the lower mediastinum in a young woman.

BACKGROUND: Calcifying fibrous tumor (CFT) arising from the pleura is a relatively rare benign lesion in young and middle-aged adults. We report a 31-year-old woman with pleural CFT who underwent successful complete thoracoscopic enucleation. CASE PRESENTATION: An asymptomatic woman presented with a mass in the right lower lung field that was incidentally detected on a chest X-ray during a routine medical checkup. Chest computed tomography showed a well-defined mass in the lower mediastinum, with a maximum diameter of approximately 5.5 cm. Esophagogastroduodenoscopy showed no abnormal findings in the esophagus. An endoscopic ultrasonography (EUS) revealed a well-defined tumor with no internal blood flow. EUS-fine needle aspiration failed to establish a definitive diagnosis. Therefore, thoracoscopic tumor enucleation was performed for diagnostic and therapeutic purposes. Based on the histopathological findings of the resected specimen, the presence of a tumor with a high fibrous component in a young woman, and the identification of granulomatous calcifications, a diagnosis of CFT was established. CONCLUSIONS: Complete thoracoscopic tumor enucleation was successfully performed for CFT arising from the pleura in a young adult woman.

A Case of Contained Rupture of the Common Iliac Artery with Idiopathic Retroperitoneal Fibrosis: Efficacy of Surgical Treatment and Immunosuppressive Therapy at 2-Year Follow-Up.

Rupture of inflammatory aortic aneurysm associated with retroperitoneal fibrosis (RF) is rare. We report a 62-year-old man with an inflammatory abdominal aortic aneurysm (IAAA) complicated with idiopathic RF, resulting in a contained rupture of the common iliac artery. The patient also presented with mild renal insufficiency due to urethral obstruction and left hydronephrosis. Surgical procedures including graft replacement and ureterolysis relieved the symptoms. Postoperative immunosuppressive treatment using corticosteroid and methotrexate successfully maintained clinical remission without signs of recurrence of RF and IAAA at the 2-year follow-up.

Machine Learning Approaches to TCR Repertoire Analysis.

Sparked by the development of genome sequencing technology, the quantity and quality of data handled in immunological research have been changing dramatically. Various data and database platforms are now driving the rapid progress of machine learning for immunological data analysis. Of various topics in immunology, T cell receptor repertoire analysis is one of the most important targets of machine learning for assessing the state and abnormalities of immune systems. In this paper, we review recent repertoire analysis methods based on machine learning and deep learning and discuss their prospects.

Evaluation of CRISPR Diversity in the Human Skin Microbiome for Personal Identification.

The highly personalized human skin microbiome may serve as a viable marker in personal identification. Amplicon sequencing resolution using 16S rRNA cannot identify bacterial communities sufficiently to discriminate between individuals. Thus, novel higher-resolution genetic markers are required for forensic purposes. The clustered regularly interspaced short palindromic repeats (CRISPRs) are prokaryotic genetic elements that can provide a history of infections encountered by the bacteria. The sequencing of CRISPR spacers may provide phylogenetic information with higher resolution than other markers. However, using spacer sequencing for discrimination of personal skin microbiome is difficult due to limited information on CRISPRs in human skin microbiomes. It remains unclear whether personal microbiome discrimination can be achieved using spacer diversity or which CRISPRs will be forensically relevant. We identified common CRISPRs in the human skin microbiome via metagenomic reconstruction and used amplicon sequencing for deep sequencing of spacers. We successfully reconstructed 24 putative CRISPR arrays using metagenomic data sets. A total of 1,223,462 reads from three CRISPR arrays revealed that spacers in the skin microbiome were highly personalized, and conserved repeats were commonly shared between individuals. These individual specificities observed using CRISPR typing were confirmed by comparing the CRISPR diversity to microbiome diversity assessed using 16S rRNA amplicon sequencing. CRISPR typing achieved 95.2% accuracy in personal classification, whereas 16S rRNA sequencing only achieved 52.6%. These results suggest that sequencing CRISPRs in the skin microbiome may be a more powerful approach for personal identification and ecological studies compared to conventional 16S rRNA sequencing.IMPORTANCE Microbial community diversity analysis can be utilized to characterize the personal microbiome that varies between individuals. CRISPR sequences, which reflect virome structure, in the human skin environment may be highly personalized similar to the structures of individual viromes. In this study, we identified 24 putative CRISPR arrays using a shotgun metagenome data set of the human skin microbiome. The findings of this study expand our understanding of the nature of CRISPRs by identifying novel CRISPR candidates. We developed a method to efficiently determine the diversity of three CRISPR arrays. Our analysis revealed that the CRISPR spacer diversity in the human skin microbiome is highly personalized compared with the microbiome diversity assessed by 16S rRNA sequencing, providing a new perspective on the study of the skin microbiome.

Quantitative analysis reveals reciprocal regulations underlying recovery dynamics of thymocytes and thymic environment in mice.

Thymic crosstalk, a set of reciprocal regulations between thymocytes and the thymic environment, is relevant for orchestrating appropriate thymocyte development as well as thymic recovery from various exogenous insults. In this work, interactions shaping thymic crosstalk and the resultant dynamics of thymocytes and thymic epithelial cells are inferred based on quantitative analysis and modeling of the recovery dynamics induced by irradiation. The analysis identifies regulatory interactions consistent with known molecular evidence and reveals their dynamic roles in the recovery process. Moreover, the analysis also predicts, and a subsequent experiment verifies, a previously unrecognized regulation of CD4+CD8+ double positive thymocytes which temporarily increases their proliferation rate upon the decrease in their population size. Our model establishes a pivotal step towards the dynamic understanding of thymic crosstalk as a regulatory network system.

Quantification of Inter-Sample Differences in T-Cell Receptor Repertoires Using Sequence-Based Information.

Inter-sample comparisons of T-cell receptor (TCR) repertoires are crucial for gaining a better understanding of the immunological states determined by different collections of T cells from different donor sites, cell types, and genetic and pathological backgrounds. For quantitative comparison, most previous studies utilized conventional methods in ecology, which focus on TCR sequences that overlap between pairwise samples. Some recent studies attempted another approach that is categorized into Poisson abundance models using the abundance distribution of observed TCR sequences. However, these methods ignore the details of the measured sequences and are consequently unable to identify sub-repertoires that might have important contributions to the observed inter-sample differences. Moreover, the sparsity of sequence data due to the huge diversity of repertoires hampers the performance of these methods, especially when few overlapping sequences exist. In this paper, we propose a new approach for REpertoire COmparison in Low Dimensions (RECOLD) based on TCR sequence information, which can estimate the low-dimensional structure by embedding the pairwise sequence dissimilarities in high-dimensional sequence space. The inter-sample differences between repertoires are then quantified by information-theoretic measures among the distributions of data estimated in the embedded space. Using datasets of mouse and human TCR repertoires, we demonstrate that RECOLD can accurately identify the inter-sample hierarchical structures, which have a good correspondence with our intuitive understanding about sample conditions. Moreover, for the dataset of transgenic mice that have strong restrictions on the diversity of their repertoires, our estimated inter-sample structure was consistent with the structure estimated by previous methods based on abundance or overlapping sequence information. For the dataset of human healthy donors and Sézary syndrome patients, our method also showed robust estimation performance even under the condition of high sparsity in TCR sequences, while previous studies failed to estimate the structure. In addition, we identified the sequences that contribute to the pairwise-sample differences between the repertoires with the different genetic backgrounds of mice. Such identification of the sequences contributing to variation in immune cell repertoires may provide substantial insight for the development of new immunotherapies and vaccines.

Detecting Causality by Combined Use of Multiple Methods: Climate and Brain Examples.

Identifying causal relations from time series is the first step to understanding the behavior of complex systems. Although many methods have been proposed, few papers have applied multiple methods together to detect causal relations based on time series generated from coupled nonlinear systems with some unobserved parts. Here we propose the combined use of three methods and a majority vote to infer causality under such circumstances. Two of these methods are proposed here for the first time, and all of the three methods can be applied even if the underlying dynamics is nonlinear and there are hidden common causes. We test our methods with coupled logistic maps, coupled Rössler models, and coupled Lorenz models. In addition, we show from ice core data how the causal relations among the temperature, the CH4 level, and the CO2 level in the atmosphere changed in the last 800,000 years, a conclusion also supported by irregularly sampled data analysis. Moreover, these methods show how three regions of the brain interact with each other during the visually cued, two-choice arm reaching task. Especially, we demonstrate that this is due to bottom up influences at the beginning of the task, while there exist mutual influences between the posterior medial prefrontal cortex and the presupplementary motor area. Based on our results, we conclude that identifying causality with an appropriate ensemble of multiple methods ensures the validity of the obtained results more firmly.

Experimental and theoretical bases for mechanisms of antigen discrimination by T cells.

Interaction only within specific molecules is a requisite for accurate operations of a biochemical reaction in a cell where bulk of background molecules exist. While structural specificity is a well-established mechanism for specific interaction, biophysical and biochemical experiments indicate that the mechanism is not sufficient for accounting for the antigen discrimination by T cells. In addition, the antigen discrimination by T cells also accompanies three intriguing properties other than the specificity: sensitivity, speed, and concentration compensation. In this work, we review experimental and theoretical works on the antigen discrimination by focusing on these four properties and show future directions towards understanding of the fundamental principle for molecular discrimination.

Hydroxyl Radical-Mediated Novel Modification of Peptides: N-Terminal Cyclization through the Formation of α-Ketoamide.

The hydroxyl radical-mediated oxidation of peptides and proteins constitutes a large group of post-translational modifications that can result in structural and functional changes. These oxidations can lead to hydroxylation, sulfoxidation, or carbonylation of certain amino acid residues and cleavage of peptide bonds. In addition, hydroxyl radicals can convert the N-terminus of peptides to an α-ketoamide via abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. In the present study, we identified N-terminal cyclization as a novel modification mediated by a hydroxyl radical. The reaction of angiotensin (Ang) II (DRVYIHPF) and the hydroxyl radical generated by the Cu(II)/ascorbic acid (AA) system or UV/hydrogen peroxide system produced N-terminal cyclized-Ang II (Ang C) and pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The structure of Ang C was confirmed by mass spectrometry and comparison to an authentic standard. The subsequent incubation of isolated Ang P in the presence of Cu(II)/AA revealed that Ang P was the direct precursor of Ang C. The proposed mechanism involves the formation of a nitrogen-centered (aminyl) radical, which cyclizes to form a five-membered ring containing the alkoxy radical. The subsequent ß-scission reaction of the alkoxyl radical results in the cleavage of the terminal CH3CO group. The initial aminyl radical can be stabilized by chelation to the Cu(II) ions. The affinity of Ang C toward the Ang II type 1 receptor was significantly lower than that of Ang II or Ang P. Ang C was not further metabolized by aminopeptidase A, which converts Ang II to Ang III. Hydroxyl radical-mediated N-terminal cyclization was also observed in other Ang peptides containing N-terminal alanine, arginine, valine, and amyloid ß 1-11 (DAEFRHDSGYE).

Learning-stage-dependent plasticity of temporal coherence in the auditory cortex of rats.

Temporal coherence among neural populations may contribute importantly to signal encoding, specifically by providing an optimal tradeoff between encoding reliability and efficiency. Here, we considered the possibility that learning modulates the temporal coherence among neural populations in association with well-characterized map plasticity. We previously demonstrated that, in appetitive operant conditioning tasks, the tone-responsive area globally expanded during the early stage of learning, but shrank during the late stage. The present study further showed that phase locking of the first spike to band-specific oscillations of local field potentials (LFPs) significantly increased during the early stage of learning but decreased during the late stage, suggesting that neurons in A1 were more synchronously activated during early learning, whereas they were more asynchronously activated once learning was completed. Furthermore, LFP amplitudes increased during early learning but decreased during later learning. These results suggest that, compared to naïve encoding, early-stage encoding is more reliable but energy-consumptive, whereas late-stage encoding is more energetically efficient. Such a learning-stage-dependent encoding strategy may underlie learning-induced, non-monotonic map plasticity. Accumulating evidence indicates that the cholinergic system is likely to be a shared neural substrate of the processes for perceptual learning and attention, both of which modulate neural encoding in an adaptive manner. Thus, a better understanding of the links between map plasticity and modulation of temporal coherence will likely lead to a more integrated view of learning and attention.

N-terminal α-ketoamide peptides: formation and transamination.

We have previously reported that N-terminal α-ketoamide peptides can be formed through 4-oxo-2(E)-nonenal (ONE)-derived oxidative decarboxylation of aspartic acid (Asp), which converts angiotensin (Ang) II (DRVYIHPF) to pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The pyruvamide group significantly inhibits Ang P binding to the Ang II type 1 receptor, which mediates the major biological effects of Ang II. In the present study, we found that ONE can also introduce an α-ketoamide moiety at the N-terminus of peptides containing N-terminal residues other than Asp. Subsequent investigation of alternative biosynthetic pathways for N-terminal α-ketoamide peptides revealed that hydroxyl radical-mediated formation is a much more efficient route. The proposed mechanism involves initial abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. The resulting N-terminal α-ketoamide is then converted to the D- and L-amino acids by nonenzymatic transamination in the presence of pyridoxamine (PM). The formation of the epimeric N-terminus depended on the incubation time and the concentration of PM, and increased further upon the addition of Cu(II) ions. A conversion of approximately 60% after three days of incubation was observed for Ang P. We propose that the reaction intermediate contains a prochiral α-carbon and is stabilized by the chelate effect of Cu(II) ions. The ONE- and hydroxyl radical-derived formation of N-terminal α-ketoamide and its transamination in the presence of PM were also observed in amyloid ß 1-11 (DAEFRHDSGYE), where the N-terminal Asp was converted to epimeric alanine. This suggests that these N-terminal modifications could occur in vivo and modulate the biological functions of peptides and proteins.

Response variance in functional maps: neural darwinism revisited.

The mechanisms by which functional maps and map plasticity contribute to cortical computation remain controversial. Recent studies have revisited the theory of neural Darwinism to interpret the learning-induced map plasticity and neuronal heterogeneity observed in the cortex. Here, we hypothesize that the Darwinian principle provides a substrate to explain the relationship between neuron heterogeneity and cortical functional maps. We demonstrate in the rat auditory cortex that the degree of response variance is closely correlated with the size of its representational area. Further, we show that the response variance within a given population is altered through training. These results suggest that larger representational areas may help to accommodate heterogeneous populations of neurons. Thus, functional maps and map plasticity are likely to play essential roles in Darwinian computation, serving as effective, but not absolutely necessary, structures to generate diverse response properties within a neural population.

Successful treatment of sepsis caused by Staphylococcus lugdunensis in an adult with 22q11.2 deletion syndrome.

A 27-year-old woman visited our hospital because of high fever. She had been diagnosed as 22q11.2 deletion syndrome (22q11.2DS) due to her cardiac history (tetralogy of Fallot), thymic hypoplasia and 22q11.2 deletion. She had a normal CD4/CD8 ratio, a slightly decreased lymphocyte count and normal serum immunoglobulin levels. Blood cultures were positive for Staphylococcus lugdunensis (S. lugdunensis). Infection route of S. lugdunensis in this case was unclear. The patient was successfully treated with several intravenous antibiotics. Infection should be considered when managing patients with 22q.11.2DS. regardless of whether their immune system is impaired.