Defining Patient-Level Molecular Heterogeneity in Psoriasis Vulgaris Based on Single-Cell Transcriptomics

Identifying genetic variation underlying human diseases establishes targets for therapeutic development and helps tailor treatments to individual patients. Large-scale transcriptomic profiling has extended the study of such molecular heterogeneity between patients to somatic tissues. However, the lower resolution of bulk RNA profiling, especially in a complex, composite tissue such as the skin, has limited its success. Here we demonstrate approaches to interrogate patient-level molecular variance in a chronic skin inflammatory disease, psoriasis vulgaris, leveraging single-cell RNA-sequencing of CD45+ cells isolated from active lesions. Highly psoriasis-specific transcriptional abnormalities display greater than average inter-individual variance, nominating them as potential sources of clinical heterogeneity. We find that one of these chemokines, CXCL13, demonstrates significant correlation with severity of lesions within our patient series. Our analyses also establish that genes elevated in psoriatic skin-resident memory T cells are enriched for programs orchestrating chromatin and CDC42-dependent cytoskeleton remodeling, specific components of which are distinctly correlated with and against Th17 identity on a single-cell level. Collectively, these analyses describe systematic means to dissect cell type- and patient-level differences in cutaneous psoriasis using high-resolution transcriptional profiles of human inflammatory disease

Topical TWEAK Accelerates Healing of Experimental Burn Wounds in Mice

The interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) participates in inflammatory responses, fibrosis, and tissue remodeling, which are central in the repair processes of wounds. Fn14 is expressed in main skin cells including dermal fibroblasts. This study was designed to explore the therapeutic effect of TWEAK on experimental burn wounds and the relevant mechanism underlying such function. Third-degree burns were introduced in two BALB/c mouse strains. Recombinant TWEAK was administrated topically, followed by the evaluation of wound areas and histologic changes. Accordingly, the downstream cytokines, inflammatory cell infiltration, and extracellular matrix synthesis were examined in lesional tissue. Moreover, the differentiation markers were analyzed in cultured human dermal fibroblasts upon TWEAK stimulation. The results showed that topical TWEAK accelerated the healing of burn wounds in wild-type mice but not in Fn14-deficient mice. TWEAK strengthened inflammatory cell infiltration, and exaggerated the production of growth factor and extracellular matrix components in wound areas of wild-type mice. Moreover, TWEAK/Fn14 activation elevated the expression of myofibroblastic differentiation markers, including alpha-smooth muscle actin and palladin, in cultured dermal fibroblasts. Therefore, topical TWEAK exhibits therapeutic effect on experimental burn wounds through favoring regional inflammation, cytokine production, and extracellular matrix synthesis. TWEAK/Fn14 activation induces the myofibroblastic differentiation of dermal fibroblasts, partially contributing to the healing of burn wounds

Exact Hawking Radiation of Scalars, Fermions, and Bosons Using the Tunneling Method Without Back-Reaction

Hawking radiation is studied for arbitrary scalars, fermions, and spin-1 bosons, using a tunneling approach, to every order in $\hbar$ but ignoring back-reaction effects. It is shown that the additional quantum terms yield no new contribution to the Hawking temperature. Indeed, it is found that the limit of small $\hbar$ in the standard quantum WKB approximation is replaced by the near-horizon limit in the gravitational WKB approach.Comment: 8 pages, no figures. v3: Introduction updated. Version to appear in PL

Electron Tomography of Cryofixed, Isometrically Contracting Insect Flight Muscle Reveals Novel Actin-Myosin Interactions

BACKGROUND: Isometric muscle contraction, where force is generated without muscle shortening, is a molecular traffic jam in which the number of actin-attached motors is maximized and all states of motor action are trapped with consequently high heterogeneity. This heterogeneity is a major limitation to deciphering myosin conformational changes in situ. METHODOLOGY: We used multivariate data analysis to group repeat segments in electron tomograms of isometrically contracting insect flight muscle, mechanically monitored, rapidly frozen, freeze substituted, and thin sectioned. Improved resolution reveals the helical arrangement of F-actin subunits in the thin filament enabling an atomic model to be built into the thin filament density independent of the myosin. Actin-myosin attachments can now be assigned as weak or strong by their motor domain orientation relative to actin. Myosin attachments were quantified everywhere along the thin filament including troponin. Strong binding myosin attachments are found on only four F-actin subunits, the "target zone", situated exactly midway between successive troponin complexes. They show an axial lever arm range of 77°/12.9 nm. The lever arm azimuthal range of strong binding attachments has a highly skewed, 127° range compared with X-ray crystallographic structures. Two types of weak actin attachments are described. One type, found exclusively in the target zone, appears to represent pre-working-stroke intermediates. The other, which contacts tropomyosin rather than actin, is positioned M-ward of the target zone, i.e. the position toward which thin filaments slide during shortening. CONCLUSION: We present a model for the weak to strong transition in the myosin ATPase cycle that incorporates azimuthal movements of the motor domain on actin. Stress/strain in the S2 domain may explain azimuthal lever arm changes in the strong binding attachments. The results support previous conclusions that the weak attachments preceding force generation are very different from strong binding attachments

Structural Changes in Isometrically Contracting Insect Flight Muscle Trapped following a Mechanical Perturbation

The application of rapidly applied length steps to actively contracting muscle is a classic method for synchronizing the response of myosin cross-bridges so that the average response of the ensemble can be measured. Alternatively, electron tomography (ET) is a technique that can report the structure of the individual members of the ensemble. We probed the structure of active myosin motors (cross-bridges) by applying 0.5% changes in length (either a stretch or a release) within 2 ms to isometrically contracting insect flight muscle (IFM) fibers followed after 5–6 ms by rapid freezing against a liquid helium cooled copper mirror. ET of freeze-substituted fibers, embedded and thin-sectioned, provides 3-D cross-bridge images, sorted by multivariate data analysis into ∼40 classes, distinct in average structure, population size and lattice distribution. Individual actin subunits are resolved facilitating quasi-atomic modeling of each class average to determine its binding strength (weak or strong) to actin. ∼98% of strong-binding acto-myosin attachments present after a length perturbation are confined to “target zones” of only two actin subunits located exactly midway between successive troponin complexes along each long-pitch helical repeat of actin. Significant changes in the types, distribution and structure of actin-myosin attachments occurred in a manner consistent with the mechanical transients. Most dramatic is near disappearance, after either length perturbation, of a class of weak-binding cross-bridges, attached within the target zone, that are highly likely to be precursors of strong-binding cross-bridges. These weak-binding cross-bridges were originally observed in isometrically contracting IFM. Their disappearance following a quick stretch or release can be explained by a recent kinetic model for muscle contraction, as behaviour consistent with their identification as precursors of strong-binding cross-bridges. The results provide a detailed model for contraction in IFM that may be applicable to contraction in other types of muscle

Query-controllable Video Summarization

When video collections become huge, how to explore both within and across videos efficiently is challenging. Video summarization is one of the ways to tackle this issue. Traditional summarization approaches limit the effectiveness of video exploration because they only generate one fixed video summary for a given input video independent of the information need of the user. In this work, we introduce a method which takes a text-based query as input and generates a video summary corresponding to it. We do so by modeling video summarization as a supervised learning problem and propose an end-to-end deep learning based method for query-controllable video summarization to generate a query-dependent video summary. Our proposed method consists of a video summary controller, video summary generator, and video summary output module. To foster the research of query-controllable video summarization and conduct our experiments, we introduce a dataset that contains frame-based relevance score labels. Based on our experimental result, it shows that the text-based query helps control the video summary. It also shows the text-based query improves our model performance. Our code and dataset: https://github.com/Jhhuangkay/Query-controllable-Video-Summarization.Comment: This paper is accepted by ACM International Conference on Multimedia Retrieval (ICMR), 202

A new method to analyse mosaics based on Symmetry Group theory applied to Islamic Geometric Patterns

[EN] This article presents a new method for analysing mosaics based on the mathematical principles of Symmetry Groups. This method has been developed to get the understanding present in patterns by extracting the objects that form them, their lattice, and the Wallpaper Group. The main novelty of this method resides in the creation of a higher level of knowledge based on objects, which makes it possible to classify the objects, to extract their main features (Point Group, principal axes, etc.), and the relationships between them. In order to validate the method, several tests were carried out on a set of Islamic Geometric Patterns from different sources, for which the Wallpaper Group has been successfully obtained in 85% of the cases. This method can be applied to any kind of pattern that presents a Wallpaper Group. Possible applications of this computational method include pattern classification, cataloguing of ceramic coatings, creating databases of decorative patterns, creating pattern designs, pattern comparison between different cultures, tile cataloguing, and so on.The authors wish to thank the Patronato de la Alhambra y Generalife (Granada, Spain) and the Patronato del Real Alcázar de Sevilla (Seville, Spain) for their valuable collaboration in this research work.Albert Gil, FE.; Gomis Martí, JM.; Blasco, J.; Valiente González, JM.; Aleixos Borrás, MN. (2015). A new method to analyse mosaics based on Symmetry Group theory applied to Islamic Geometric Patterns. Computer Vision and Image Understanding. 130:54-70. doi:10.1016/j.cviu.2014.09.002S547013

Quantum corrections and black hole spectroscopy

In the work \cite{BRM,RBE}, black hole spectroscopy has been successfully reproduced in the tunneling picture. As a result, the derived entropy spectrum of black hole in different gravity (including Einstein's gravity, Einstein-Gauss-Bonnet gravity and Ho\v{r}ava-Lifshitz gravity) are all evenly spaced, sharing the same forms as $S_n=n$, where physical process is only confined in the semiclassical framework. However, the real physical picture should go beyond the semiclassical approximation. In this case, the physical quantities would undergo higher-order quantum corrections, whose effect on different gravity shares in different forms. Motivated by these facts, in this paper we aim to observe how quantum corrections affect black hole spectroscopy in different gravity. The result shows that, in the presence of higher-order quantum corrections, black hole spectroscopy in different gravity still shares the same form as $S_n=n$, further confirming the entropy quantum is universal in the sense that it is not only independent of black hole parameters, but also independent of higher-order quantum corrections. This is a desiring result for the forthcoming quantum gravity theory.Comment: 14 pages, no figure, use JHEP3.cls. to be published in JHE

Back reaction, emission spectrum and entropy spectroscopy

Recently, an interesting work, which reformulates the tunneling framework to directly produce the Hawking emission spectrum and entropy spectroscopy in the tunneling picture, has been received a broad attention. However, during the emission process, most related observations have not incorporated the effects of back reaction on the background spacetime, whose derivations are therefore not the desiring results for the real physical process. With this point as a central motivation, in this paper we suitably adapt the \emph{reformulated} tunneling framework so that it can well accommodate the effects of back reaction to produce the Hawking emission spectrum and entropy spectroscopy. Consequently, we interestingly find that, when back reaction is considered, the Parikh-Wilczek's outstanding observations that, an isolated radiating black hole has an unitary-evolving emission spectrum that is \emph{not} precisely thermal, but is related to the change of the Bekenstein-Hawking entropy, can also be reproduced in the reformulated tunneling framework, meanwhile the entropy spectrum has the same form as that without inclusion of back reaction, which demonstrates the entropy quantum is \emph{independent} of the effects of back reaction. As our final analysis, we concentrate on the issues of the black hole information, but \emph{unfortunately} find that, even including the effects of back reaction and higher-order quantum corrections, such tunneling formalism can still not provide a mechanism for preserving the black hole information.Comment: 16 pages, no figure, use JHEP3.cls. to be published in JHE